Inverse Association of Dietary Fat with Development of Ischemic Stroke in Men

JAMA : the Journal of the American Medical Association. Dec 24-31, 1997  |  Pubmed ID: 9417007

A few ecological and cohort studies in Asian populations suggest an inverse association of the intake of both fat and saturated fat with risk of stroke. However, data among western populations are scant.

[Growth and Metabolism of Calcium in Rats Chronically Poisoned with Aluminium Hydroxide]

Acta Physiologica, Pharmacologica Et Therapeutica Latinoamericana : órgano De La Asociación Latinoamericana De Ciencias Fisiológicas Y [de] La Asociación Latinoamericana De Farmacología. 1998  |  Pubmed ID: 9504191

The effects of aluminum on growth have been studied in rats chronically poisoned with aluminum hydroxide (80 mg/kg b.w.-i.p.-three times a week, during 6 months) and in control rats, between 3 and 26 weeks of age. The growth data was evaluated according to Parks 'theory of feeding an growth. At the end of the poisoning period, the calcium metabolism was studied through a balance of calcium and the determination of bone Ca++ accretion and resorption rates with the aid of 45Ca++. The parathyroid glands function was studied using an indirect method. Treated rats showed a significant decrease in asymptotic weights and in the initial efficiency of food conversion into biomass regarding controls. No differences were observed in food intake between both group. Aluminum affected neither the peak growth rate nor the time necessary to attain maturity. The calcium balance in treated rats was significantly less than in the control group. This was accompanied by a significant increase in the calcium excreted by faces, caused perhaps by a less intestinal absorption. An important amount of aluminum on the surface of the trabecular bone and a reduction in the skeletal Ca++ mass, was observed in all treated rats. Nevertheless there are no differences in the latter when expressed for 100 g of body weight. The rate of skeletal Ca++ accretion was found to be significantly decreased in treated group with respect to controls, without any changes in the bone Ca resorption rate. The reduction in bone turnover revealed by the decrease of Vo+/Vo- was accompanied by less recovery velocity of calcemia in the aluminum treated group, being indirectly related to the parathyroid gland response to calcium depletion. In the model that we studied the decreased bone turnover could have been caused by deposits of aluminum in bone; however there could exist associated factors such as dysfunction in the secretion of PTH, or less affinity between its receptors at the bone level.

Acoustic Echoplanar Scanner Noise and Pure Tone Hearing Thresholds: the Effects of Sequence Repetition Times and Acoustic Noise Rates

Journal of Computer Assisted Tomography. May-Jun, 1998  |  Pubmed ID: 9606392

Our goal was to determine the effects of acoustic echoplanar scanner noise on pure tone hearing thresholds in normal volunteers and to determine the influence of echoplanar sequence repetition time on threshold effects.

Health Status and Practices of Urban Caribbean Latinos with Diabetes Mellitus

Ethnicity & Disease. 1998  |  Pubmed ID: 9681282

Although Caribbean Latinos are more likely than non-Hispanic whites to develop diabetes, their health status has been poorly characterized. Information on diabetes management, metabolic control, dietary habits, and diabetes knowledge was gathered from a group of urban Caribbean Latinos with diabetes in order to characterize the nutritional behaviors, diabetes attitudes, health perceptions, and metabolic control of this high risk group. Interviews and medical record reviews were conducted among seventy low-income urban Caribbean Latinos with type 2 diabetes mellitus. Patients attending outpatient clinics were interviewed by bilingual interviewers. Medical records were reviewed to ascertain prevalence of diabetes-related complications, medications, and metabolic parameters. Participants were primarily Spanish-speaking and of Puerto Rican origin. Eighty-one percent were unemployed, and only 27% had completed high school or higher educational levels. Average hemoglobin A1c was 10.6%. Among those with hypertension and hyperlipidemia, many were not receiving treatment. Participants' estimation of their own degree of metabolic control was poor, as was their understanding of desirable blood glucose and weight goals. A second evening meal was common. Diets were higher in fat and sugar content than currently recommended. More effective treatment strategies for both patients and providers are needed to improve glycemic control and cardiovascular risk factors among indigent urban Caribbean Latinos. Essential features of such strategies for patient programs include culturally appropriate dietary counseling and low literacy materials to better communicate glycemic and weight goals and dietary guidelines. Provider education is needed regarding established guidelines and cultural influences on diabetes-related practices.

Buena Alimentacion, Buena Salud: a Preventive Nutrition Intervention in Caribbean Latinos with Type 2 Diabetes

American Journal of Health Promotion : AJHP. Nov-Dec, 1998  |  Pubmed ID: 10346658

A culturally sensitive 3-month intervention was provided to 18 Caribbean Latino men and women with non-insulin-dependent (type 2) diabetes mellitus. Compared to the randomly assigned control group, the intervention group showed statistically significant decreases in total calories, fat calories, percent of calories from fat, saturated fat calories, and percent of calories from saturated fat The intervention group showed increases in calories from carbohydrates and in the percent of calories from fiber.

[Preventive Nutritional Services for the Elderly]

Zeitschrift Für Gerontologie Und Geriatrie. Jul, 1999  |  Pubmed ID: 10441808

Population aging is a global. These demographic transitions have brought about dramatic changes in the world's health needs and status. Chronic diseases of aging account for nearly half of population morbidity and mortality in the developing regions of the world 85% of deaths and disability in developed regions. Chronic diseases in the elderly is, in over 60%, associated with malnutrition. Malnutrition is one of the few preventable risk factors for chronic diseases. Carefully planned population-based nutrition interventions can lower risk malnutrition and thus for chronic diseases and as well as for their adverse outcomes. Nutrition interventions can also be used to reach particularly vulnerable segments of the population, such as extremely frail elders, to reduce the prevalence of nutrient deficiencies. Clearly, the prevention of nutrition-related problems in the population, including older persons, has important global health implications.

Neurogenetics of the Cerebellar System

Journal of Child Neurology. Sep, 1999  |  Pubmed ID: 10488902

The development of the cerebellum occurs in four basic steps. During the first epoch, genes that mark the cerebellar territory are expressed in a restricted pattern along the anterioposterior axis of the embryo. In the second, an embryonic region termed the rhombic lip generates precursors of the granule cell population of the cerebellar cortex, and the lateral pontine nucleus and olivary nucleus of the brain stem. In the third period, the program of neurogenesis of the granule neuron gives rise to the formation of the fundamental layers of the cerebellum and to the pattern of foliation. Concomitantly, programs of gene expression define the principal neuronal classes, the granule cell and Purkinje cell, that will establish the cerebellar circuitry in the postnatal period. Understanding the molecular mechanisms underlying these steps of development is likely to yield important insights into malformations such as Joubert syndrome.

Vestibular Compensation in Guinea Pigs Given Intravenous Lidocaine After Unilateral Labyrinthectomy

Otolaryngology--head and Neck Surgery : Official Journal of American Academy of Otolaryngology-Head and Neck Surgery. Jan, 1999  |  Pubmed ID: 9914543

Intravenous lidocaine has been reported to alleviate vertigo in Meniere's disease and suggested as a possible antivertigo agent after unilateral labyrinthectomy in a study of cats. To further evaluate the effects of intravenous lidocaine on the acute phase of postural compensation, we subjected 13 pigmented guinea pigs to unilateral labyrinthectomy. Seven received intravenous lidocaine (4 mg/kg) immediately after labyrinthectomy. The other six served as controls and received an equivalent-volume injection of normal saline solution. Total body curvature, trunk curvature, yaw head tilt, and roll head tilt were measured at frequent intervals for up to 30 hours after surgery. Both groups had immediate difficulties with posturing that gradually improved. The lidocaine group tended to exhibit delayed postural compensation, but this was only statistically significant for roll head tilt. These results do not show improvement in postural compensation from unilateral labyrinthectomy after the administration of intravenous lidocaine. A species-specific effect on the vestibular pathways is suggested, and we conclude that further evaluation of lidocaine and the vestibular system is warranted.

Aluminum Toxicity. Hematological Effects

Toxicology Letters. Jan, 2000  |  Pubmed ID: 10643868

Sequential effects of intoxication with aluminum hydroxide (Al) (80 mg/Kg body weight, i.p., three times a week), were studied on rats from weaning and up to 28 weeks. The study was carried out on hematological and iron metabolism-related parameters on peripheral blood, at the end of the 1st, 2nd, 3rd, 4th, 5th and 6th months of exposure. As it was described that hematotoxic effects of Al are mainly seen together with high levels of uremia, renal function was measured at the same periods. The animals treated developed a microcytosis and was accompanied by a decrease in mean corpuscular hemoglobin (MCH). Significantly lower red blood cell counts (RBC million/microl) were found in rats treated during the 1st month. These values matched those obtained for control rats during the 2nd month. From the 3rd month onwards, a significant increase was observed as compared to control groups, and the following values were obtained by the 6th month: (T) 10.0 +/- 0.3 versus (C) 8.7 +/- 0.2 (million/microl). Both MCH and mean corpuscular volume (MCV) were found to be significantly lower in groups treated from the 2nd month. At the end of the 6th month the following values were found: MCH (T) 13.3 +/- 0.1 versus (C) 16.9 +/- 0.3 (pg); MCV (T) 42.1 +/- 0.7 versus (C) 51.8 +/- 0.9 (fl). Al was found responsible for lower serum iron concentration levels and in the percentage of transferrin saturation. Thus, although microcytic anemia constitutes an evidence of chronic aluminum exposure, prolonged exposure could lead to a recovery of hematocrit and hemoglobin concentration values with an increase in red cell number. Nevertheless, both microcytosis and the decrease of MCH would persist. These modifications took place without changes being observed in the renal function during the observation period.

The Mouse Dreher Gene Lmx1a Controls Formation of the Roof Plate in the Vertebrate CNS

Nature. Feb, 2000  |  Pubmed ID: 10693804

In the vertebrate central nervous system (CNS), a cascade of signals that originates in the ectoderm adjacent to the neural tube is propagated by the roof plate to dorsalize the neural tube. Here we report that the phenotype of the spontaneous neurological mutant mouse dreher (dr) results from a failure of the roof plate to develop. Dorsalization of the neural tube is consequently affected: dorsal interneurons in the spinal cord and granule neurons in the cerebellar cortex are lost, and the dorsal vertebral neural arches fail to form. Positional cloning of dreher indicates that the LIM homeodomain protein, Lmx1a, is affected in three different alleles of dreher. Lmx1a is expressed in the roof plate along the neuraxis during development of the CNS. Thus, Lmx1a is required for development of the roof plate and, in turn, for specification of dorsal cell fates in the CNS and developing vertebrae.

Femoral Artery Ischemia During Spinal Scoliosis Surgery Detected by Posterior Tibial Nerve Somatosensory-evoked Potential Monitoring

Spine. Jun, 2000  |  Pubmed ID: 10828931

A case report of unilateral leg ischemia caused by femoral artery compression detected using posterior tibial nerve somatosensory-evoked potentials during spinal scoliosis instrumentation surgery.

The Debate Between Sedation and Anaesthesia for Children Undergoing MRI

Archives of Disease in Childhood. Sep, 2000  |  Pubmed ID: 10991759

Integrity and Research: Introducing the Concept of Dual Blindness. How Blind Are Double-blind Clinical Trials in Alternative Medicine?

Journal of Alternative and Complementary Medicine (New York, N.Y.). Dec, 2000  |  Pubmed ID: 11152053

Double-blind methodology is used in clinical studies to control for potential external or nonspecific influences such as belief and expectation, as well as to maintain as much objectivity as possible on the part of the researchers. Despite not being feasible in all medical disciplines, as in the case of some modalities of complementary and alternative medicine, there are numerous studies that spuriously claim its use. Distinctions and standards therefore need to be set to avoid misleading information. We propose a new term in research methodology, dual-blind, to describe a methodological alternative in which the caregiver is not blind but the patient and an external evaluator/investigator are. The term double-blind should be used strictly to describe a methodology in which both the patient and the caregiver are blind. Making the distinction between these two terms will result in more reliable reports of clinical trials and will support integrity in research.

An Educational Implementation of a Cancer Pain Algorithm for Ambulatory Care

Pain Management Nursing : Official Journal of the American Society of Pain Management Nurses. Dec, 2000  |  Pubmed ID: 11709865

Algorithms are proposed as a means of operationalizing guidelines or standards for cancer pain management. Professional education is used as the means to translate knowledge into practice. Outcomes measurement is the gold standard for validating improvement. This study used an educational intervention to transfer knowledge on implementing a previously tested algorithm for cancer pain management into community outpatient oncology clinics and, subsequently, measuring patient outcomes. Physicians and nurses from 9 Puget Sound clinics were randomized by institution blocks to either "training" or "no training." Role model physician/nurse teams were the core faculty for a day-long seminar. Written reference materials and documentation tools were provided to the trained physician/nurse teams. A total of 105 patients of trained and untrained providers were accrued and assessed over 4 months. Patients of trained providers had a significant reduction in usual pain over the 4 months of data collection compared with patients of untrained providers (t = 2.0; p = .05). Improvements were modest in the prescription of opioid analgesics and dramatic in the prescription of co-analgesics for neuropathic pain. There was a clear deterioration in the impact of the training over time. The most significant effect occurred within the first 140 days after the intervention and was followed by a gradual return to baseline practice. In conclusion, algorithmic interventions can be successfully transferred into community practice, but further work must be performed to develop methods for securing retention of knowledge and maintaining improved outcomes.

Relationship of Dietary Fat to Age-related Maculopathy in the Third National Health and Nutrition Examination Survey

Archives of Ophthalmology. Dec, 2001  |  Pubmed ID: 11735796

To evaluate the associations between dietary fat and age-related maculopathy (ARM) in persons 40 years or older who participated in the Third National Health and Nutrition Examination Survey.

Nutritional Risk in an Urban Homebound Older Population. The Nutrition and Healthy Aging Project

The Journal of Nutrition, Health & Aging. 2001  |  Pubmed ID: 11753494

To establish the prevalence of nutritional problems and their related socio-demographic and health-related risk factors in the homebound elderly population.

Lutein and Zeaxanthin in the Diet and Serum and Their Relation to Age-related Maculopathy in the Third National Health and Nutrition Examination Survey

American Journal of Epidemiology. Mar, 2001  |  Pubmed ID: 11226974

Relations of the carotenoids lutein and zeaxanthin in the diet and serum to photographic evidence of early and late age-related maculopathy (ARM) among persons over age 40 years (n = 8,222) were examined. Inverse relations of these carotenoids in the diet or serum to any form of ARM were not observed overall. There was a direct relation of dietary levels to one type of early ARM (soft drusen). However, relations differed by age and race. In the youngest age groups who were at risk for developing early (ages 40-59 years) or late (ages 60-79 years) ARM, higher levels of lutein and zeaxanthin in the diet were related to lower odds for pigmentary abnormalities, one sign of early ARM (odds ratio among persons in high vs. low quintiles = 0.1, 95 percent confidence interval: 0.1, 0.3) and of late ARM (odds ratio = 0.1, 95 percent confidence interval: 0.0, 0.9) after adjustment for age, gender, alcohol use, hypertension, smoking, and body mass index. Relations of these carotenoids to ARM may be influenced by age and race and require further evaluation in separate populations and in prospective studies.

Many Parallel Losses of InfA from Chloroplast DNA During Angiosperm Evolution with Multiple Independent Transfers to the Nucleus

The Plant Cell. Mar, 2001  |  Pubmed ID: 11251102

We used DNA sequencing and gel blot surveys to assess the integrity of the chloroplast gene infA, which codes for translation initiation factor 1, in >300 diverse angiosperms. Whereas most angiosperms appear to contain an intact chloroplast infA gene, the gene has repeatedly become defunct in approximately 24 separate lineages of angiosperms, including almost all rosid species. In four species in which chloroplast infA is defunct, transferred and expressed copies of the gene were found in the nucleus, complete with putative chloroplast transit peptide sequences. The transit peptide sequences of the nuclear infA genes from soybean and Arabidopsis were shown to be functional by their ability to target green fluorescent protein to chloroplasts in vivo. Phylogenetic analysis of infA sequences and assessment of transit peptide homology indicate that the four nuclear infA genes are probably derived from four independent gene transfers from chloroplast to nuclear DNA during angiosperm evolution. Considering this and the many separate losses of infA from chloroplast DNA, the gene has probably been transferred many more times, making infA by far the most mobile chloroplast gene known in plants.

Validation of a Dietary Pattern Approach for Evaluating Nutritional Risk: the Framingham Nutrition Studies

Journal of the American Dietetic Association. Feb, 2001  |  Pubmed ID: 11271691

To validate the use of cluster analysis for characterizing population dietary patterns.

The Crystal Structure of the MJ0796 ATP-binding Cassette. Implications for the Structural Consequences of ATP Hydrolysis in the Active Site of an ABC Transporter

The Journal of Biological Chemistry. Aug, 2001  |  Pubmed ID: 11402022

The crystal structure of the MJ0796 ATP-binding cassette, a member of the o228/LolD transporter family, has been determined at 2.7-A resolution with MgADP bound at its active site. Comparing this structure with that of the ATP-bound form of the HisP ATP-binding cassette (Hung, L. W., Wang, I. X., Nikaido, K., Liu, P. Q., Ames, G. F., and Kim, S. H. (1998) Nature 396, 703-707) shows a 5-A withdrawal of a phylogenetically invariant glutamine residue from contact with the gamma-phosphate of ATP in the active site. This glutamine is located in a protein segment that links the rigid F(1)-type ATP-binding core of the enzyme to an ABC transporter-specific alpha-helical subdomain that moves substantially away from the active site in the MgADP-bound structure of MJ0796 compared with the ATP-bound structure of HisP. A similar conformational effect is observed in the MgADP-bound structure of MJ1267 (Karpowich, N., et al. (2001) Structure, in press), establishing the withdrawal of the glutamine and the coupled outward rotation of the alpha-helical subdomain as consistent consequences of gamma-phosphate release from the active site of the transporter. Considering this subdomain movement in the context of a leading model for the physiological dimer of cassettes present in ABC transporters indicates that it produces a modest mechanical change that is likely to play a role in facilitating nucleotide exchange out of the ATPase active site. Finally, it is noteworthy that one of the intersubunit packing interactions in the MJ0796 crystal involves antiparallel beta-type hydrogen bonding interactions between the outermost beta-strands in the two core beta-sheets, leading to their fusion into a single extended beta-sheet, a type of structural interaction that has been proposed to play a role in mediating the aggregation of beta-sheet-containing proteins.

Nutritional Research Within the Framingham Heart Study

The Journal of Nutrition, Health & Aging. 2001  |  Pubmed ID: 11458282

Fifty years of research at the Framingham Heart Study have made important contributions to the diagnosis and treatment of cardiovascular disease (CVD). Within the scope of this prospective population-based cohort study, research investigations from the Framingham Nutrition Studies have developed and advanced nutritional epidemiologic methods, many of which are highlighted here. Ongoing nutrition research explores relationship between diet, nutritional status, and the development of chronic diseases, including CVD. This paper summarizes key findings from decades of nutrition research within the Framingham Heart Study. Cross-sectional and longitudinal investigations are described, including recent research on dietary patterns and coronary heart disease risk among women. Implications for the development of national nutrition policy, population-based dietary guidance for chronic disease prevention, and nutrition-related health promotion campaigns for CVD risk reduction are discussed.

Crystal Structures of the MJ1267 ATP Binding Cassette Reveal an Induced-fit Effect at the ATPase Active Site of an ABC Transporter

Structure (London, England : 1993). Jul, 2001  |  Pubmed ID: 11470432

ATP binding cassette (ABC) transporters are ubiquitously distributed transmembrane solute pumps that play a causative role in numerous diseases. Previous structures have defined the fold of the ABC and established the flexibility of its alpha-helical subdomain. But the nature of the mechanical changes that occur at each step of the chemical ATPase cycle have not been defined.

The Elderly Nutrition Program: an Effective National Framework for Preventive Nutrition Interventions

Journal of the American Dietetic Association. Feb, 2002  |  Pubmed ID: 11846117

To guide national policy, Congress mandated the 1992 research evaluation of the Elderly Nutrition Program (ENP), the nation's oldest framework for providing community- and home-based preventive nutrition and health-related services to older persons. This article summarizes key findings on the program's influence on nutritional health, the targeting and costs of its nutrition services, and the study's policy implications.

The Body of Evidence to Support a Protective Role for Lutein and Zeaxanthin in Delaying Chronic Disease. Overview

The Journal of Nutrition. Mar, 2002  |  Pubmed ID: 11880585

Recent evidence introduces the possibility that lutein and zeaxanthin may protect against the development of the two common eye diseases of aging, cataract and macular degeneration. This potential and the lack of other effective means to slow the progression of macular degeneration have fueled high public interest in the health benefits of lutein and zeaxanthin and the proliferation of supplements containing them on pharmacy shelves. An understanding of the biologic consequences of limiting or supplementing with these carotenoids is only beginning to emerge. Some epidemiologic evidence supports a role in eye disease and, to a lesser extent, cancer and cardiovascular disease. However, the overall body of evidence is insufficient to conclude that increasing levels of lutein and zeaxanthin, specifically, will confer an important health benefit. Future advances in scientific research are required to gain a better understanding of the biologic mechanisms of their possible role in preventing disease. Additional research is also required to understand the effect of their consumption, independent of other nutrients in fruits and vegetables, on human health. The newly advanced ability to measure levels of lutein and zeaxanthin in the retina in vivo creates a unique opportunity to contribute some of this needed evidence.

Cooperative, ATP-dependent Association of the Nucleotide Binding Cassettes During the Catalytic Cycle of ATP-binding Cassette Transporters

The Journal of Biological Chemistry. Jun, 2002  |  Pubmed ID: 11964392

ATP-binding cassette (ABC) transporters harvest the energy present in cellular ATP to drive the translocation of a structurally diverse set of solutes across the membrane barriers of eubacteria, archaebacteria, and eukaryotes. The positively cooperative ATPase activity (Hill coefficient, 1.7) of a model soluble cassette of known structure, MJ0796, from Methanococcus jannaschii indicates that at least two binding sites participate in the catalytic reaction. Mutation of the catalytic base in MJ0796, E171Q, produced a cassette that can bind but not efficiently hydrolyze ATP. The equivalent mutation (E179Q) in a homologous cassette, MJ1267, had an identical effect. Both mutant cassettes formed dimers in the presence of ATP but not ADP, indicating that the energy of ATP binding is first coupled to the transport cycle through a domain association reaction. The non-hydrolyzable nucleotides adenosine 5'-(beta,gamma-imino)triphosphate and adenosine 5'-3-O-(thio)triphosphate were poor analogues of ATP in terms of their ability to promote dimerization. Moreover, inclusion of MgCl2, substitution of KCl for NaCl, or alterations in the polarity of the side chain at the catalytic base all weakened the ATP-dependent dimer, suggesting that electrostatic interactions are critical for the association reaction. Thus, upon hydrolysis of bound ATP and the release of product, both electrostatic and conformational changes drive the cassettes apart, providing a second opportunity to couple free energy changes to the transport reaction.

The Internal Validity of a Dietary Pattern Analysis. The Framingham Nutrition Studies

Journal of Epidemiology and Community Health. May, 2002  |  Pubmed ID: 11964437

To examine the internal validity of a dietary pattern analysis and its ability to discriminate clusters of people with similar dietary patterns using independently assessed nutrient intakes and heart disease risk factors.

Conformational Remodeling of Proteasomal Substrates by PA700, the 19 S Regulatory Complex of the 26 S Proteasome

The Journal of Biological Chemistry. Jul, 2002  |  Pubmed ID: 12011044

PA700, the 19 S regulatory complex of the 26 S proteasome, plays a central role in the recognition and efficient degradation of misfolded proteins. PA700 promotes degradation by recruiting proteasomal substrates utilizing polyubiquitin chains and chaperone-like binding activities and by opening the access to the core of the 20 S proteasome to promote degradation. Here we provide evidence that PA700 in addition to binding misfolded protein substrates also acts to remodel their conformation prior to proteolysis. Scrambled RNase A (scRNase A), a misfolded protein, only slowly refolds spontaneously into an active form because of the rate-limiting unfolding of misfolded disulfide isomers. Notably, PA700 accelerates the rate of reactivation of scRNase A, consistent with its ability to increase the exposure of these disulfide bonds to the solvent. In this regard, PA700 also exposes otherwise buried sites to digestion by exogenous chymotrypsin in a polyubiquitinated enzymatically active substrate, pentaubiquitinated dihydrofolate reductase, Ub(5)DHFR. The dihydrofolate reductase ligand methotrexate counters the ability of PA700 to promote digestion by chymotrypsin. Together, these results indicate that in addition to increasing substrate affinity and opening the access channel to the catalytic sites, PA700 activates proteasomal degradation by remodeling the conformation of protein substrates.

Long PDE4 CAMP Specific Phosphodiesterases Are Activated by Protein Kinase A-mediated Phosphorylation of a Single Serine Residue in Upstream Conserved Region 1 (UCR1)

British Journal of Pharmacology. Jun, 2002  |  Pubmed ID: 12023945

1. Challenge of COS1 cells with the adenylyl cyclase activator forskolin led to the activation of recombinant PDE4A8, PDE4B1, PDE4C2 and PDE4D5 cAMP-specific phosphodiesterase long isoforms. 2. Forskolin challenge did not activate mutant long PDE4 isoforms where the serine target residue (STR) within the protein kinase A (PKA) consensus phosphorylation site in Upstream Conserved Region 1 (UCR1) was mutated to alanine. 3. The PKA inhibitor, H89, ablated forskolin activation of wild-type long PDE4 isoforms. 4. Activated PKA caused the in vitro phosphorylation of recombinant wild-type long PDE4 isoforms, but not those where the STR was mutated to alanine. 5. An antiserum specific for the phosphorylated form of the STR detected a single immunoreactive band for recombinant long PDE4 isoforms expressed in COS1 cells challenged with forskolin. This was not evident in forskolin-challenged cells treated with H89. Neither was it evident in forskolin-challenged cells expressing long isoforms where the STR had been mutated to alanine. 6. In transfected COS cells challenged with forskolin, only the phosphorylated PDE4D3 long form showed a decrease in mobility in Western blotting analysis. This decreased mobility of PDE4D3 was ablated upon mutation of either of the two serine targets for PKA phosphorylation in this isoform, namely Ser54 in UCR1 and Ser13 in the isoform-specific N-terminal region. 7. Activation by forskolin challenge did not markedly alter the sensitivity of PDE4A8, PDE4B1, PDE4C2 and PDE4D5 to inhibition by rolipram. 8. Long PDE4 isoforms from all four sub-families can be phosphorylated by protein kinase A (PKA). This leads to an increase in their activity and may thus contribute to cellular desensitization processes in cells where these isoforms are selectively expressed.

ATP Binding to the Motor Domain from an ABC Transporter Drives Formation of a Nucleotide Sandwich Dimer

Molecular Cell. Jul, 2002  |  Pubmed ID: 12150914

It has been proposed that the reaction cycle of ATP binding cassette (ABC) transporters is driven by dimerization of their ABC motor domains upon binding ATP at their mutual interface. However, no such ATP sandwich complex has been observed for an ABC from an ABC transporter. In this paper, we report the crystal structure of a stable dimer formed by the E171Q mutant of the MJ0796 ABC, which is hydrolytically inactive due to mutation of the catalytic base. The structure shows a symmetrical dimer in which two ATP molecules are each sandwiched between the Walker A motif in one subunit and the LSGGQ signature motif in the other subunit. These results establish the stereochemical basis of the power stroke of ABC transporter pumps.

Dietary Patterns and the Odds of Carotid Atherosclerosis in Women: the Framingham Nutrition Studies

Preventive Medicine. Dec, 2002  |  Pubmed ID: 12460521

We prospectively examined the relationship between dietary patterns, assessed using cluster analysis and a food frequency questionnaire, and the presence of carotid artery stenosis, a subclinical marker of atherosclerotic disease.

Dietary Patterns Predict the Development of Overweight in Women: The Framingham Nutrition Studies

Journal of the American Dietetic Association. Sep, 2002  |  Pubmed ID: 12792620

To investigate relationships between dietary patterns and the development of overweight.

Reciprocal Fusion Transcripts of Two Novel Zn-finger Genes in a Female with Absence of the Corpus Callosum, Ocular Colobomas and a Balanced Translocation Between Chromosomes 2p24 and 9q32

European Journal of Human Genetics : EJHG. Jul, 2003  |  Pubmed ID: 12825074

We have identified a female patient with a complex phenotype that includes complete agenesis of the corpus callosum, bilateral periventricular nodular heterotopia, and bilateral chorioretinal and iris colobomas. Karyotype analysis revealed an apparently balanced, reciprocal, de novo chromosome translocation t(2;9)(p24;q32). Physical mapping of the translocation breakpoint by fluorescence in situ hybridization and PCR analysis led to the identification of two novel, ubiquitously expressed, Zn-finger-encoding transcripts that are disrupted in this patient. Unexpectedly, the rearrangement produced in-frame reciprocal fusion transcripts, making genotype-phenotype correlation difficult.

Relations of Serum Ascorbic Acid and Alpha-tocopherol to Diabetic Retinopathy in the Third National Health and Nutrition Examination Survey

American Journal of Epidemiology. Aug, 2003  |  Pubmed ID: 12882944

The protective relation of ascorbic acid and alpha-tocopherol to the development of diabetic retinopathy has not been thoroughly evaluated in epidemiologic studies. The association of prevalent diabetic retinopathy with serum ascorbic acid and alpha-tocopherol was studied among participants with type 2 diabetes (>or=40 years) (n = 998) in the Third National Health and Nutrition Examination Survey (1988-1994); 20% of the sample (n = 199) had prevalent retinopathy. The overall odds ratio for retinopathy among participants in quartile 4 compared with quartile 1 for serum ascorbic acid was 1.3 (95% confidence interval: 0.8, 2.3), with a p for trend = 0.60 after adjustment for the confounders of smoking, race, waist/hip ratio, hypertension, and duration of diabetes. The overall odds ratio for retinopathy among participants in quartile 4 compared with quartile 1 for serum alpha-tocopherol was 2.7 (95% confidence interval: 1.6, 4.6), with a p for trend = 0.14 after adjustment for confounders. After removal of supplement users of vitamin C (n = 307) or vitamin E (n = 298), the odds ratio changed direction or was attenuated: adjusted odds ratios for retinopathy among participants in quartile 4 compared with quartile 1 for serum ascorbic acid and alpha-tocopherol = 0.7 (95% confidence interval: 0.3, 1.4) and 1.6 (95% confidence interval: 0.9, 2.9), respectively. In summary, no significant associations were observed between serum levels of major dietary antioxidants and retinopathy. Recent use of supplements for treatment of complications of diabetes may explain the direct associations.

Effect of Chronic Accumulation of Aluminum on Renal Function, Cortical Renal Oxidative Stress and Cortical Renal Organic Anion Transport in Rats

Archives of Toxicology. Nov, 2003  |  Pubmed ID: 12928767

The aim of the present work was to study the nephrotoxicity of aluminum lactate administered for 3 months (0.57 mg/100 g bodyweight aluminum, i.p., three times per week) to male Wistar rats. Renal function was studied after 6 weeks of treatment (urine was obtained from rats in metabolic cages) and at the end of the treatment using clearance techniques. Another group of rats was used as kidneys donors at the end of treatment. The renal cortex was separated and homogenized to determine glutathione (GSH) level, glutathione S-transferase (GST) activity and lipid peroxidation (LPO) level. Renal cortex slices were also used to study the p-aminohippuric acid (PAH) accumulation during steady-state conditions and the kinetics of uptake process. Clearance results, at the end of the treatment, indicated that renal functions in treated-rats were not different from those measured in control rats, although the renal concentration parameters differ when they were measured in treated rats after 24 h of food and water deprivation. Balances of water and sodium were also modified at both 1.5 and 3 months of treatment. The activity of alkaline phosphatase (AP) relative to inulin excreted in urine was significantly impaired: controls 2.2+/-0.6 IUI/mg, Al-treated 5.1+/-0.5 IU/mg, P<0.05. These data indicated that proximal tubular cells were loosing apical brush border membranes. Data obtained in cortex homogenates indicated that both GSH and GST activity were significantly decreased, and a significant increase of LPO was noted simultaneously in Al-treated rats. Renal accumulation of PAH, estimated as slice-to-medium ratio, decreased significantly in the Al-treated rats: control rats 3.06+/-0.02 ( n=12), Al-treated rats 2.26+/-0.04 ( n=12), P<0.0001. The maximal rate of uptake was also diminished in treated rats, while the apparent affinity remained unchanged. All these results indicate that aluminum accumulation in renal tissue affects cellular metabolism, promotes oxidative stress and induces alterations in renal tubular PAH transport, together with an impairment in sodium and water balance only detected under conditions of water deprivation, without other evident changes in glomerular filtration rate or other global functions measured by clearance techniques at least at this time of chronic toxicity.

Abdominal Complications and Sequelae After Breast Reconstruction with Pedicled TRAM Flap: is There Still an Indication for Pedicled TRAM in the Year 2003?

Plastic and Reconstructive Surgery. Sep, 2003  |  Pubmed ID: 12973225

Development and Malformations of the Cerebellum in Mice

Molecular Genetics and Metabolism. Sep-Oct, 2003  |  Pubmed ID: 14567957

The cerebellum is the primary motor coordination center of the CNS and is also involved in cognitive processing and sensory discrimination. Multiple cerebellar malformations have been described in humans, however, their developmental and genetic etiologies currently remain largely unknown. In contrast, there is extensive literature describing cerebellar malformations in the mouse. During the past decade, analysis of both spontaneous and gene-targeted neurological mutant mice has provided significant insight into the molecular and cellular mechanisms that regulate cerebellar development. Cerebellar development occurs in several distinct but interconnected steps. These include the establishment of the cerebellar territory along anterior-posterior and dorsal-ventral axes of the embryo, initial specification of the cerebellar cell types, their subsequent proliferation, differentiation and migration, and, finally, the interconnection of the cerebellar circuitry. Our understanding of the basis of these developmental processes is certain to provide insight into the nature of human cerebellar malformations.

Paraneoplastic Neurological Disorders in Breast Cancer

Breast (Edinburgh, Scotland). Jun, 2003  |  Pubmed ID: 14659327

Paraneoplastic syndromes are the rarest neurological complications in patients with cancer. The neurological paraneoplastic syndromes that are mainly associated with breast cancer are subacute cerebellar degeneration, paraneoplastic retinopathy, opsoclonus-myoclonus syndrome, lower motor neuron diseases and Stiff-man syndrome. The aim of this paper is to briefly outline these paraneoplastic neurological syndromes and consider their relation to breast carcinoma.

Establishing Health Informatics As a Recognised and Respected Profession in the UK National Health Service

Studies in Health Technology and Informatics. 2003  |  Pubmed ID: 14664092

The delivery of healthcare is an information dependent process. National government modernisation targets, and drives to improve the effectiveness and efficiency of care delivery systems and processes have the better use of information and IT at their heart. If we are to realise the benefits information and IT developments can bring, we have to ensure we have a suitable cadre of well educated, proactive professional specialists who understand the business of healthcare. The English NHS has an attrition rate of something like 43% amongst its ICT specialists, and there are recruitment and retention problems in a range of other informatics disciplines like medical records, project management and strategic management. A 1999-2000 survey indicated the reasons for recruitment and retention problems. One agreed solution has been to work towards establishing health informatics as a recognised and respected national profession. This is in addition to other national work to establish career pathways, make health informatics as a profession "mainstream", and to provide development opportunities at all levels. This paper sets out the background to the establishment of a profession in UK health services, outlines progress to date, and summarises other national development activity to support health informatics professionals.

Antibody-mediated Neutralization of Pertussis Toxin-induced Mitogenicity of Human Peripheral Blood Mononuclear Cells

Infection and Immunity. Jan, 2004  |  Pubmed ID: 14688147

Antibody-mediated neutralization of pertussis toxin-induced proliferation of human peripheral blood mononuclear cells (PBMC) was assessed using alamarBlue and compared with results from the Chinese hamster ovary (CHO) cell assay using sera from vaccinated adults and convalescent children. Neutralization values for the CHO assay were similar for vaccinated and convalescent subjects; however. the convalescent group had higher titers in the PBMC assay. Results for pertussis toxin neutralization with the CHO assay appear to be distinct from those with the PBMC assay.

Dietary Patterns, Smoking, and Subclinical Heart Disease in Women: Opportunities for Primary Prevention from the Framingham Nutrition Studies

Journal of the American Dietetic Association. Feb, 2004  |  Pubmed ID: 14760568

To investigate the relationship between a heart-healthy dietary pattern and subclinical heart disease in women, and to identify potential opportunities for primary prevention.

Gating of CFTR by the STAS Domain of SLC26 Transporters

Nature Cell Biology. Apr, 2004  |  Pubmed ID: 15048129

Chloride absorption and bicarbonate secretion are vital functions of epithelia, as highlighted by cystic fibrosis and diseases associated with mutations in members of the SLC26 chloride-bicarbonate exchangers. Many SLC26 transporters (SLC26T) are expressed in the luminal membrane together with CFTR, which activates electrogenic chloride-bicarbonate exchange by SLC26T. However, the ability of SLC26T to regulate CFTR and the molecular mechanism of their interaction are not known. We report here a reciprocal regulatory interaction between the SLC26T DRA, SLC26A6 and CFTR. DRA markedly activates CFTR by increasing its overall open probablity (NP(o)) sixfold. Activation of CFTR by DRA was facilitated by their PDZ ligands and binding of the SLC26T STAS domain to the CFTR R domain. Binding of the STAS and R domains is regulated by PKA-mediated phosphorylation of the R domain. Notably, CFTR and SLC26T co-localize in the luminal membrane and recombinant STAS domain activates CFTR in native duct cells. These findings provide a new understanding of epithelial chloride and bicarbonate transport and may have important implications for both cystic fibrosis and diseases associated with SLC26T.

Relation Between Intake of Vitamins C and E and Risk of Diabetic Retinopathy in the Atherosclerosis Risk in Communities Study

The American Journal of Clinical Nutrition. May, 2004  |  Pubmed ID: 15113727

The potential protective effect of vitamins C and E against the development of diabetic retinopathy has not been thoroughly evaluated in epidemiologic studies.

Bioactivation of 1,1-dichloroethylene by CYP2E1 and CYP2F2 in Murine Lung

The Journal of Pharmacology and Experimental Therapeutics. Sep, 2004  |  Pubmed ID: 15123768

1,1-Dichloroethylene (DCE) exposure evokes lung toxicity with selective damage to bronchiolar Clara cells. Recent in vitro studies have implicated CYP2E1 and CYP2F2 in the bioactivation of DCE to 2-S-glutathionyl acetate [C], a putative conjugate of DCE epoxide with glutathione. An objective of this study was to test the hypothesis that bioactivation of DCE is catalyzed by both CYP2E1 and CYP2F2 in murine lung. Western blot analysis of lung microsomal proteins from DCE-treated CD-1 mice showed time-dependent loss of immunodetectable CYP2F2 and CYP2E1 protein. Dose-dependent formation of conjugate [C] was observed in the lungs of CD-1 mice treated with DCE (75-225 mg/kg), but it was not detected after pretreatment with 5-phenyl-1-pentyne (5-PIP). Treatment of mice with 5-PIP and also with diallyl sulfone (DASO2) significantly inhibited hydroxylation of p-nitrophenol (PNP) and chlorzoxazone (CHZX). Incubation of recombinant CYP2F3 (a surrogate for CYP2F2) and recombinant CYP2E1 with PNP and CHZX confirmed that they are substrates for both of the recombinant enzymes. Incubation of the recombinant enzymes with DASO2 or 5-PIP significantly inhibited hydroxylation of both PNP and CHZX. Bronchiolar injury was elicited in CD-1 mice treated with DCE (75 mg/kg), but it was abrogated with 5-PIP pretreatment. Bronchiolar toxicity also was manifested in the lungs of CYP2E1-null and wild-type mice treated with DCE (75 mg/kg), but protection ensued after pretreatment with 5-PIP or DASO2. These results showed that bioactivation of DCE in murine lung occurred via the catalytic activities of both CYP2E1 and CYP2F2 and that bioactivation by these enzymes mediated the lung toxicity.

Control of Roof Plate Formation by Lmx1a in the Developing Spinal Cord

Development (Cambridge, England). Jun, 2004  |  Pubmed ID: 15148302

Numerous studies have identified the roof plate as an embryonic signaling center critical for dorsal central nervous system patterning, but little is known about mechanisms that control its formation and its separation from clonally related neural crest cells and dI1 sensory interneurons. We demonstrate that the LIM homeodomain transcription factor, Lmx1a, mutated in the dreher mouse, acts to withdraw dorsal spinal cord progenitors from the cell cycle and simultaneously direct their differentiation into functional roof plate cells. Lmx1a cell-autonomously represses the dI1 progenitor fate, distinguishing the roof plate and dI1 interneuron programs, two major developmental programs of the dorsal neural tube. Lmx1a is not directly involved in neural crest development. We establish that Bmp signaling from epidermal ectoderm is necessary and sufficient for inducing Lmx1a and other co-factors that also regulate the extent of roof plate induction. We conclude that Lmx1a controls multiple aspects of dorsal midline patterning and is a major mediator of early Bmp signaling in the developing spinal cord.

Use of Vitamin, Mineral, Nonvitamin, and Nonmineral Supplements in the United States: The 1987, 1992, and 2000 National Health Interview Survey Results

Journal of the American Dietetic Association. Jun, 2004  |  Pubmed ID: 15175592

To describe trends in use of specific vitamin and mineral (VM) supplements.

Roof Plate and Dorsal Spinal Cord Dl1 Interneuron Development in the Dreher Mutant Mouse

Developmental Biology. Jun, 2004  |  Pubmed ID: 15183721

The establishment of neural circuits in the spinal cord depends on the differentiation of functionally distinct types of neurons in the embryonic neural tube. A number of genes have recently been shown to control the generation of dorsal interneurons through inductive signals provided by the roof plate. The roof plate is a transient signaling center on the dorsal midline of the neural tube that coordinates dorsal CNS development through the action of local peptide signals, primarily the bone morphogenic proteins (BMPs) and the Wingless-related genes (Wnts). The role of the roof plate has become evident through studies of mutations of genes in these gene families, and through several spontaneously occurring mouse mutants, including dreher(J) (dr(J)), all of which cause dorsal neural tube defects. We previously demonstrated that the roof plate is missing in the dreher mouse. Positional cloning of the dreher locus demonstrated that an inactivating point mutation in the LIM homeodomain (HD) transcription factor encoded by the Lmx1a gene, is responsible for the dreher(J) phenotype [Nature, 403 (2000) 764]. Here we report that Lmx1a is first expressed at E8.5 in a small number of cells in the lateral neural plate. As the neural tube closes, Lmx1a expression is restricted to the roof plate. In dr(J)/dr(J), although non-functional Lmx1a is correctly expressed at E8.5-E9.5, its expression is lost in the spinal cord roof plate by E10.5. Coincident with the loss of Lmx1a expression, Bmp expression fails, and the generation and differentiation of the dorsal-most spinal cord neurons, the dl1 interneurons, is abnormal. In dr(J)/dr(J) embryos, defects are evident in the number of dl1 progenitors, as well as in their migration to form the lateral and medial nuclei, and axon patterning, through mechanisms that apparently involve defects in early steps of neuronal polarity. Consistent with the general hypothesis that a failure of roof plate formation and function results in deficits in dorsal patterning of the neural tube, the dreher affects the generation and differentiation of the dl1 interneuron population.

Diet and Melanoma in a Case-control Study

Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology. Jun, 2004  |  Pubmed ID: 15184262

Malignant melanoma has been one of the most rapidly increasing cancers within the United States with few modifiable risk factors. This study investigates risk related to dietary factors, which are potentially modifiable.

Control of Roof Plate Development and Signaling by Lmx1b in the Caudal Vertebrate CNS

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. Jun, 2004  |  Pubmed ID: 15215291

Numerous studies have identified the roof plate as an important signaling center controlling dorsal interneuron specification and differentiation in the developing spinal cord. Currently, the molecular pathways of roof plate formation and function are poorly understood. We determined that the LIM-homeodomain transcription factor Lmx1b is sufficient to induce functional roof plate in the early chick developing spinal cord. In the chick, Lmx1b acts upstream of Lmx1a in the roof plate developmental program. Once the roof plate forms, we show that Bmp and Wnt signaling are the major components of Lmx1a/b-dependent roof plate dorsal patterning activity. The roof plate function of Lmx1b is not conserved across vertebrates because Lmx1b is not expressed in mouse roof plate progenitors. Instead, mouse caudal CNS roof plate formation relies entirely on Lmx1a. Lmx1b can, however, partially rescue roof plate development in dreher (Lmx1a-/-) mice, indicating that Lmx1b has some functional redundancy to Lmx1a. Furthermore, we demonstrate that the roof plate-inducing activity of Lmx1b can be suppressed by Mash1 (Cash1), which is normally expressed in intermediate neural tube in both chick and mouse. Our data identify Lmx1b as a key regulator of spinal cord roof plate induction and function.

Effects of Aluminum on Phosphate Metabolism in Rats: a Possible Interaction with Vitamin D3 Renal Production

Archives of Toxicology. Nov, 2004  |  Pubmed ID: 15221202

The effect of chronic aluminum (Al) administration on the phosphorous (Pi) metabolism of different target tissues was studied. Male Wistar rats received aluminum lactate for 3 months (5.75 mg/kg bodyweight of Al, i.p., three times per week). The animals were studied at the end of the 1st, 2nd and 3rd month of treatment. They were housed individually in metabolic cages for 4 days to study Pi and calcium (Ca) balance. Daily food and water intakes were recorded for all animals and urine and feces were collected for Pi and calcium assays. After 3 months the Pi intestinal absorption and the Pi deposition in bone were studied using 32Pi. Another group of rats was treated daily for 7 days with calcitriol (0.08 microg/kg body weight in sesame oil, i.p.) and the Pi balance was studied for the last 4 days. The results indicated that chronic administration of Al affected simultaneously the Pi and calcium balance, with a significant diminution of calcium and increased Pi accretion in bones, together with a diminution in the intestinal absorption of Pi. The treatment of the rats with calcitriol promoted a normalized Pi balance in Al treated rats. These findings suggest that Al could modify the Pi metabolism acting directly on intestine, kidney and bone, or indirectly through possible changes in the levels of vitamin D3.

Correlates of Serum Lutein + Zeaxanthin: Findings from the Third National Health and Nutrition Examination Survey

The Journal of Nutrition. Sep, 2004  |  Pubmed ID: 15333733

The determinants of blood levels of carotenoids were previously investigated in small or select samples. The relations of serum lutein + zeaxanthin to possible diet, lifestyle, and physiological determinants in 7059 participants of the Third National Health and Nutrition Examination Survey (1988-1994), > or = 40 y old, were examined. In a fully adjusted, multiple linear regression model, lower serum lutein + zeaxanthin was significantly associated with smoking, heavy drinking, being white, female, or not being physically active, having lower dietary lutein + zeaxanthin, higher fat-free mass, a higher percentage of fat mass, a higher waist-hip ratio, lower serum cholesterol, a higher white blood cell count, and high levels of C-reactive protein (P < 0.05). The model explained 24% of the variation present in serum lutein + zeaxanthin for the current sample. The correlation between dietary and serum lutein + zeaxanthin was 0.17 and increased to 0.18 after adjusting for the effects of given covariates. Each 10% increase in dietary lutein + zeaxanthin was associated with a 1% increase in serum conditional on other terms in the model. Many factors that influence the level of serum lutein + zeaxanthin remain unknown.

Heterozygous Deletion of the Linked Genes ZIC1 and ZIC4 is Involved in Dandy-Walker Malformation

Nature Genetics. Oct, 2004  |  Pubmed ID: 15338008

Dandy-Walker malformation (DWM; OMIM #220200) is a common but poorly understood congenital cerebellar malformation in humans. Through physical mapping of 3q2 interstitial deletions in several individuals with DWM, we defined the first critical region associated with DWM, encompassing two adjacent Zinc finger in cerebellum genes, ZIC1 and ZIC4. Mice with a heterozygous deletion of these two linked genes have a phenotype that closely resembles DWM, providing a mouse model for this malformation.

What's in Store for Medical Students? Awareness and Utilization of Expert Nutrition Guidelines Among Medical School Preceptors

Preventive Medicine. Oct, 2004  |  Pubmed ID: 15351542

Instruction of physicians and other health professionals in medical nutrition sciences is among the expert recommendations to promote population health and reduce risks for cancer and other major causes of morbidity and mortality in the population. However, formal training in nutrition in United States medical schools is still lacking compared to the gains in basic and applied medical nutrition sciences. We sought to understand the awareness and current utilization of expert nutrition recommendations and practice guidelines among medical student faculty preceptors.

Registration and Regulation of Health Informatics Professionals in the UK National Health Service

Studies in Health Technology and Informatics. 2004  |  Pubmed ID: 15360944

Whilst good health informatics can contribute directly to the delivery of effective patient care, bad informatics can kill. The UK is establishing a regulatory body to register health informatics specialists who can demonstrate that they meet agreed standards of professional practice: the UK Council for Health Informatics Professions (UKCHIP). UKCHIP will also manage the introduction of a Code of Conduct (based on the IMIA Code) and processes for continuous professional development, appeals, and removal from the Register. The challenge has been to design a process that provides a suitable structure for all informatics staff, including records, coding, audit, library and knowledge management, ICT, systems, information management and clinical management specialists. The contention is that this inclusive model of regulation has international applicability.

Mechanisms of Roof Plate Formation in the Vertebrate CNS

Nature Reviews. Neuroscience. Oct, 2004  |  Pubmed ID: 15378040

The roof plate is an embryonic organizing centre that occupies the dorsal midline of the vertebrate neural tube. During early CNS development, the roof plate produces secreted factors, which control the specification and differentiation of dorsal neuronal cell types. An appreciation of the signalling properties of the roof plate has prompted an enhanced interest in this important organizing centre, and several recent studies have begun to illuminate the molecular mechanisms of roof plate development.

A Novel Assay for Replicative Lifespan in Saccharomyces Cerevisiae

FEMS Yeast Research. Nov, 2004  |  Pubmed ID: 15489200

The replicative lifespan of Saccharomyces cerevisiae is determined by both genetic and environmental factors. Many of the same factors determine the lifespan of metazoan animals. The lack of fast and reliable lifespan assays has limited the pace of yeast aging research. In this study we describe a novel strategy for assaying replicative lifespan in yeast, and apply it in a screening of mutants that are resistant to pro-oxidants. The assay reproduces the lifespan-shortening effects of deleting SIR2 and of growth in the presence of paraquat, a pro-oxidant. The lifespan-increasing activity of resveratrol is also reproduced. Compared to current assays, this new strategy promises to significantly increase the possible number of replicative-lifespan determinations.

Acellular Pertussis Vaccines and Complement Killing of Bordetella Pertussis

Infection and Immunity. Dec, 2004  |  Pubmed ID: 15557666

Antibody-dependent complement killing of Bordetella pertussis after immunization with a three-component acellular pertussis vaccine was characterized. Postimmunization activity was unchanged for about half of the adult vaccine recipients. The responses of the other individuals were complex, with evidence of both beneficial and antagonistic responses occurring, sometimes in the same individual.

Roof Plate-dependent Patterning of the Vertebrate Dorsal Central Nervous System

Developmental Biology. Jan, 2005  |  Pubmed ID: 15617675

In the vertebrate central nervous system (CNS), diverse cellular types are generated in response to inductive signals provided by specialized cellular groups that act as organizing centers. The roof plate is a critical dorsal signaling center that occupies the dorsal midline of the developing CNS along its entire anterior-posterior axis. During caudal neural tube development, the roof plate produces proteins of the Bmp and Wnt families controlling proliferation, specification, migration, and axon guidance of adjacent dorsal interneurons. Although primarily investigated in the developing spinal cord, a growing number of studies indicate that roof plate-derived signals are also critical for the patterning of dorsal structures in more rostral regions of CNS including the hindbrain, diencephalon and telencephalon. In this review, we discuss recent progress towards understanding the molecular and cellular mechanisms of roof plate-dependent patterning of the dorsal CNS.

Cytidine Deaminase in Polymyalgia Rheumatica and Elderly Onset Rheumatoid Arthritis

Clinical Rheumatology. Sep, 2005  |  Pubmed ID: 15666033

Serum cytidine deaminase (CD) as a marker of inflammatory disease was assessed in 44 patients and 47 controls to differentiate polymyalgia rheumatica (PMR) from elderly onset rheumatoid arthritis (EORA). The patients were divided into four groups: PMR with and without synovitis and seropositive and seronegative EORA. No statistically significant differences were found when serum CD levels of seropositive EORA patients were compared with serum CD of PMR patients without synovitis, neither when serum CD levels of all PMR patients were compared with a seronegative EORA group, nor when serum CD levels of PMR patients with synovitis were compared with those with EORA. Nevertheless, statistically significant differences were detected between EORA's serum CD levels and the control group (p=0.023). This difference was 10% when comparing CD levels of PMR patients with the control group (p=0.070). We did not demonstrate that serum CD levels could be a useful tool to differentiate PMR from EORA, but these findings could nevertheless reflect the presence of an inflammatory disease.

The ZIC Gene Family in Development and Disease

Clinical Genetics. Apr, 2005  |  Pubmed ID: 15733262

The human ZIC gene family is comprised of five members encoding zinc-finger transcription factors, which are the vertebrate homologs of the Drosophila odd-paired gene. Mutations in ZIC genes in humans have recently been implicated in a wide variety of congenital malformations, including Dandy-Walker malformation, holoprosencephaly, neural tube defects, and heterotaxy. Mutant analysis of these genes in mice has underscored the conserved developmental roles of these genes. Further, this analysis has begun to elucidate the molecular and developmental mechanisms underlying these important birth defects.

Identification and Characterization of PDE4A11, a Novel, Widely Expressed Long Isoform Encoded by the Human PDE4A CAMP Phosphodiesterase Gene

Molecular Pharmacology. Jun, 2005  |  Pubmed ID: 15738310

PDE4A11 is a novel cAMP-specific phosphodiesterase that is conserved in humans, mouse, rat, pig, and bat. Exon-1(4A11) encodes its unique, 81 amino acid N-terminal region. Reverse-transcriptase polymerase chain reaction performed across the splice junction, plus identification of expressed sequence tags, identifies PDE4A11 as a long isoform possessing UCR1 and UCR2 regulatory domains. Transcript analysis shows that PDE4A11 is widely expressed compared with PDE4A10 and PDE4A4B long isoforms. Truncation analysis identifies a putative promoter in a 250-base pair region located immediately upstream of the start site in Exon-1(4A11). Recombinant PDE4A11, expressed in COS-7 cells, is a 126-kDa protein localized predominantly around the nucleus and in membrane ruffles. PDE4A11 exhibits a K(m) for cAMP hydrolysis of 4 microM, with relative V(max) similar to that of PDE4A10 and PDE4A4B. PDE4A11 is dose-dependently inhibited by rolipram, 4-[(3-butoxy-4-methoxyphenyl)-methyl]-2-imidazolidinone (Ro 20-1724), cilomilast, roflumilast, and denbufylline, with IC(50) values of 0.7, 0.9, 0.03, 0.004, and 0.3 microM, respectively. Soluble and particulate PDE4A11 exhibit distinct rates of thermal inactivation (55 degrees C; T((0.5)) = 2.5 and 4.4 min, respectively). Elevating cAMP levels in COS-7 cells activates PDE4A11 concomitant with its phosphorylation at Ser119 by protein kinase A (PKA). PDE4A11 differs from PDE4A4 in sensitivity to cleavage by caspase-3, interaction with LYN SH3 domain, redistribution upon long-term rolipram challenge, and sensitivity to certain PDE4 inhibitors. PDE4A11, PDE4A10, and PDE4A4 all can interact with betaarrestin. PDE4A11 is a novel, widely expressed long isoform that is activated by PKA phosphorylation and shows a distinct intracellular localization, indicating that it may contribute to compartmentalized cAMP signaling in cells in which it is expressed.

Dietary Patterns and the Metabolic Syndrome in Obese and Non-obese Framingham Women

Obesity Research. Jan, 2005  |  Pubmed ID: 15761175

To examine the relationship between habitual dietary patterns and the metabolic syndrome (MetS) in women and to identify foci for preventive nutrition interventions.

Improvement of Coping Abilities in Patients with Systemic Lupus Erythematosus: a Prospective Study

Annals of the Rheumatic Diseases. Nov, 2005  |  Pubmed ID: 15829575

To evaluate a novel specific psychological intervention aimed at improving coping in patients with systemic lupus erythematosus (SLE).

Pulmonary Bioactivation of Trichloroethylene to Chloral Hydrate: Relative Contributions of CYP2E1, CYP2F, and CYP2B1

Drug Metabolism and Disposition: the Biological Fate of Chemicals. Oct, 2005  |  Pubmed ID: 15987776

Pulmonary cytotoxicity induced by trichloroethylene (TCE) is associated with cytochrome P450-dependent bioactivation to reactive metabolites. In this investigation, studies were undertaken to test the hypothesis that TCE metabolism to chloral hydrate (CH) is mediated by cytochrome P450 enzymes, including CYP2E1, CYP2F, and CYP2B1. Recombinant rat CYP2E1 catalyzed TCE metabolism to CH with greater affinity than did the recombinant P450 enzymes, rat CYP2F4, mouse CYP2F2, rat CYP2B1, and human CYP2E1. The catalytic efficiencies of recombinant rat CYP2E1 (V(max)/K(m) = 0.79) for generating CH was greater than those of recombinant CYP2F4 (V(max)/K(m) = 0.27), recombinant mouse CYP2F2 (V(max)/K(m) = 0.11), recombinant rat CYP2B1 (V(max)/K(m) = 0.07), or recombinant human CYP2E1 (V(max)/K(m) = 0.02). Decreases in lung microsomal immunoreactive CYP2E1, CYP2F2, and CYP2B1 were manifested at varying time points after TCE treatment. The loss of immunoreactive CYP2F2 occurred before the loss of immunoreactive CYP2E1 and CYP2B1. These protein decreases coincided with marked reduction of lung microsomal p-nitrophenol hydroxylation and pentoxyresorufin O-dealkylation. Rates of CH formation in the microsomal incubations were time-dependent and were incremental from 5 to 45 min. The production of CH was also determined in human lung microsomal incubations. The rates were low and were detected in only three of eight subjects. These results showed that, although CYP2E1, CYP2F, and CYP2B1 are all capable of generating CH, TCE metabolism is mediated with greater affinity by recombinant rat CYP2E1 than by recombinant CYP2F, CYP2B1, or human CYP2E1. Moreover, the rates of CH production were substantially higher in murine than in human lung.

Compliance with Expert Population-based Dietary Guidelines and Lower Odds of Carotid Atherosclerosis in Women: the Framingham Nutrition Studies

The American Journal of Clinical Nutrition. Jul, 2005  |  Pubmed ID: 16002816

Carotid stenosis, an indicator of subclinical atherosclerosis, predicts future coronary artery disease (CAD) and stroke and provides a noninvasive method to identify candidates for primary prevention. The relation between diet and stenosis is relatively unexplored, particularly in women.

Alterations of the Renal Function and Oxidative Stress in Renal Tissue from Rats Chronically Treated with Aluminium During the Initial Phase of Hepatic Regeneration

Journal of Inorganic Biochemistry. Sep, 2005  |  Pubmed ID: 16129492

Various indices of renal functions during the early stage of hepatic injury were studied in rats chronically treated with aluminum (Al) lactate. Tubular and hemodynamic parameters were analyzed four days after producing a 65% partial hepatectomy (PH). Water and sodium balances were also studied. Oxidative stress and the activity of Na-K-ATPase were determined in renal tissue. The rats were distributed in four groups: control, Al, PH, Al+PH. Al did not modify the hemodynamic renal functions and the PH-group reduced the glomerular filtrate rate (GFR). The Al + PH group presented a decrease in the renal blood flow and accentuated the GFR fall as compared with PH. The fractional excretion (FE) of water and sodium increased in the PH group. The rats chronically treated with Al and then submitted to the PH protocol developed a further increase in FE of water but a reduction in FE of sodium. Both PH and Al promoted an increase in the aldosterone. PH and Al induced a similar increase of the lipoperoxidation status with reduction of glutathione (GSH) and the activity of glutathione peroxidase (GSH-Px). The data indicated that Al is an inhibitor of catalase. The GSH and GSH-Px activity in the Al + PH group demonstrated a synergic effect of Al and PH. This work demonstrates that rats treated chronically with Al and submitted to another injury (such as hepatic damage) can aggravate renal functions, probably by increasing the oxidative state, at least in kidneys.

Giant Magnetoresistive Sensors and Superparamagnetic Nanoparticles: a Chip-scale Detection Strategy for Immunosorbent Assays

Analytical Chemistry. Oct, 2005  |  Pubmed ID: 16223243

Thin structures of alternating magnetic and nonmagnetic layers with a total thickness of a few hundred nanometers exhibit a phenomenon known as giant magnetoresistance. The resistance of microfabricated giant magnetoresistors (GMRs) is dependent on the strength of an external magnetic field. This paper examines magnetic labeling methodologies and surface derivatization approaches based on protein-protein binding that are aimed at forming a general set of protocols to move GMR concepts into the bioanalytical arena. As such, GMRs have been used to observe and quantify the immunological interaction between surface-bound mouse IgG and alpha-mouse IgG coated on superparamagnetic particles. Results show the response of a GMR network connected together as a set of two sense GMRs and two reference GMRs in a Wheatstone bridge as a means to compensate for temperature effects. The response can be readily correlated to the amount of the magnetically labeled alpha-mouse IgG that is captured by an immobilized layer of mouse IgG, the presence of which is confirmed with X-ray photoelectron spectroscopy and atomic force microscopy. These results, along with a detailed description of the experimental testing platform, are described in terms of sensitivity, detection limits, and potential for multiplexing.

Unique Dietary Patterns and Chronic Disease Risk Profiles of Adult Men: the Framingham Nutrition Studies

Journal of the American Dietetic Association. Nov, 2005  |  Pubmed ID: 16256756

To identify the dietary patterns of adult men and examine their relationships with nutrient intake and chronic disease risk over long-term follow-up.

Pulmonary Bronchiolar Cytotoxicity and Formation of Dichloroacetyl Lysine Protein Adducts in Mice Treated with Trichloroethylene

The Journal of Pharmacology and Experimental Therapeutics. Feb, 2006  |  Pubmed ID: 16269531

This study was undertaken to test the hypothesis that bronchiolar damage induced by trichloroethylene (TCE) is associated with bioactivation within the Clara cells with the involvement of CYP2E1 and CYP2F2. Histopathology confirmed dose-dependent Clara cell injury and disintegration of the bronchiolar epithelium in CD-1 mice treated with TCE doses of 500 to 1000 mg/kg i.p. Immunohistochemical studies, using an antibody that recognizes dichloroacetyl lysine adducts, revealed dose-dependent formation of adducts in the bronchiolar epithelium. Localization of dichloroacetyl adducts in the Clara cells coincided with damage to this cell type in TCE-treated mice. Pretreatment of CD-1 mice with diallyl sulfone, an inhibitor of CYP2E1 and CYP2F2, abrogated the formation of the dichloroacetyl adducts and protected against TCE-induced bronchiolar cytotoxicity. Treatment of wild-type and CYP2E1-null mice with TCE (750 mg/kg i.p.) also elicited bronchiolar damage that correlated with the formation of adducts in the Clara cells. Immunoblotting, using lung microsomes from TCE-treated CD-1 mice, showed dose-dependent production of dichloroacetyl adducts that comigrated with CYP2E1 and CYP2F2. However, TCE treatment resulted in a loss of immunoreactive CYP2E1 and CYP2F2 proteins and p-nitrophenol hydroxylation, a catalytic activity associated with both cytochrome P450 enzymes. The TCE metabolite, chloral hydrate, was formed in incubations of TCE with lung microsomes from CD-1, wild-type, and CYP2E1-null mice. The levels were higher in CD-1 than in either wild-type or CYP2E1-null mice, although levels were higher in CYP2E1-null than in wild-type mice. These findings supported the contention that TCE bioactivation within the Clara cells, predominantly involving CYP2F2, correlated with bronchiolar cytotoxicity in mice.

The National Cancer Institute Diet History Questionnaire: Validation of Pyramid Food Servings

American Journal of Epidemiology. Feb, 2006  |  Pubmed ID: 16339051

The performance of the National Cancer Institute's food frequency questionnaire, the Diet History Questionnaire (DHQ), in estimating servings of 30 US Department of Agriculture Food Guide Pyramid food groups was evaluated in the Eating at America's Table Study (1997-1998), a nationally representative sample of men and women aged 20-79 years. Participants who completed four nonconsecutive, telephone-administered 24-hour dietary recalls (n = 1,301) were mailed a DHQ; 965 respondents completed both the 24-hour dietary recalls and the DHQ. The US Department of Agriculture's Pyramid Servings Database was used to estimate intakes of pyramid servings for both diet assessment tools. The correlation (rho) between DHQ-reported intake and true intake and the attenuation factor (lambda) were estimated using a measurement error model with repeat 24-hour dietary recalls as the reference instrument. Correlations for energy-adjusted pyramid servings of foods ranged from 0.43 (other starchy vegetables) to 0.84 (milk) among women and from 0.42 (eggs) to 0.80 (total dairy food) among men. The mean rho and lambda after energy adjustment were 0.62 and 0.60 for women and 0.63 and 0.66 for men, respectively. This food frequency questionnaire validation study of foods measured in pyramid servings allowed for a measure of food intake consistent with national dietary guidance.

A Debriefing Session with a Nutritionist Can Improve Dietary Assessment Using Food Diaries

The Journal of Nutrition. Feb, 2006  |  Pubmed ID: 16424125

The objective of the current study was to evaluate the effect of a debriefing call on nutrient intake estimates using two 3-d food diaries among women participating in the Women's Health and Interview Study (WISH) Diet Validation Study. Subjects were 207 women with complete data and six 24-h recalls (24-HR) by telephone over 8 mo followed by two 3-d food diaries during the next 4 mo. Nutrient intake was assessed using the food diaries before and after a debriefing session by telephone. The purpose of the debriefing call was to obtain more detailed information on the types and amounts of fat in the diet. However, due to the ubiquitous nature of fat in the diet, the debriefing involved providing more specific detail on many aspects of the diet. There was a significant difference in macronutrient and micronutrient intake estimates after the debriefing. Estimates of protein, carbohydrate, and fiber intake were significantly higher and total fat, monounsaturated fat, saturated fat, vitamin A, vitamin C, alpha-tocopherol, folic acid, and calcium intake were significantly lower after the debriefing (P < 0.05). The limits of agreement between the food diaries before and after the debriefing were especially large for total fat intake, which could be under- or overestimated by approximately 15 g/d. The debriefing call improved attenuation coefficients associated with measurement error for vitamin C, folic acid, iron, alpha tocopherol, vitamin A, and calcium estimates. A hypothetical relative risk (RR) = 2.0 could be attenuated to 1.16 for folic acid intake assessed without a debriefing but to only 1.61 with a debriefing. Depending on the nutrients of interest, the inclusion of a debriefing can reduce the potential attenuation of RR in studies evaluating diet disease associations.

Hypoxia-induced Remodelling of PDE4 Isoform Expression and CAMP Handling in Human Pulmonary Artery Smooth Muscle Cells

European Journal of Cell Biology. Jul, 2006  |  Pubmed ID: 16458997

Human pulmonary artery smooth muscle cells (hPASM cells) express PDE4A10, PDE4A11, PDE4B2, PDE4C and PDE4D5 isoforms. Hypoxia causes a transient up-regulation of PDE4B2 that reaches a maximum after 7 days and sustained up-regulation of PDE4A10/11 and PDE4D5 over 14 days in hypoxia. Seven days in hypoxia increases both intracellular cAMP levels, protein kinase A (PKA) activity and activated, phosphorylated extracellular signal regulated kinase (pERK) but does not alter either PKA isoform expression or total cAMP phosphodiesterase-4 (PDE4) activity or cAMP phosphodiesterase-3 (PDE3) activity. Both the cyclooxygenase inhibitor, indomethacin and the ERK inhibitors, UO126 and PD980589 reverse the hypoxia-induced increase in intracellular cAMP levels back to those seen in normoxic hPASM cells. Challenge of normoxic hPASM cells with prostaglandin E(2) (PGE(2)) elevates cAMP to levels comparable to those seen in hypoxic cells but fails to increase intracellular cAMP levels in hypoxic hPASM cells. The adenylyl cyclase activator, forskolin increases cAMP levels in both normoxic and hypoxic hPASM cells to comparable elevated levels. Challenge of hypoxic hPASM cells with indomethacin attenuates total PDE4 activity whilst challenge with UO126 increases total PDE4 activity. We propose that the hypoxia-induced activation of ERK initiates a phospholipase A(2)/COX-driven autocrine effect whereupon PGE(2) is generated, causing the activation of adenylyl cyclase and increase in intracellular cAMP. Despite the hypoxia-induced increases in the expression of PDE4A10/11, PDE4B2 and PDE4D5 and activation of certain of these long PDE4 isoforms through PKA phosphorylation, we suggest that the failure to see any overall increase in PDE4 activity is due to ERK-mediated phosphorylation and inhibition of particular PDE4 long isoforms. Such hypoxia-induced increase in expression of PDE4 isoforms known to interact with certain signalling scaffold proteins may result in alterations in compartmentalised cAMP signalling. The hypoxia-induced increase in cAMP may represent a compensatory protective mechanism against hypoxia-induced mitogens such as endothelin-1 and serotonin.

Urinary Concentrating Mechanism and Aquaporin-2 Abundance in Rats Chronically Treated with Aluminum Lactate

Toxicology. Jun, 2006  |  Pubmed ID: 16675087

The aim of this work was to study the effects of chronic administration of aluminum (Al) on the urinary concentrating and diluting mechanisms in the distal tubules and collecting ducts. Male Wistar rats were chronically treated with aluminum lactate for 12 weeks (0.575 mg Al/100g of body weight, i.p., three times per week). After 12 weeks, renal function of control and Al-treated rats was evaluated by clearance techniques. To study urinary concentrating mechanisms, renal function was also measured in control and Al-treated rats deprived of water, after the administration of desmopressin (vasopressin agonist) and after the infusion of hypertonic saline at increasing infusion rates. Sodium and water balance were impaired. We found decreased urinary concentrating ability in situations in which endogenous (thirst or infusion of hypertonic saline) or exogenous plasma antidiuretic hormone was increased. Solute-free water formation, measured during the infusion of hypotonic saline showed normal transport in the thick ascending limb. Aquaporin-2 (AQP2) expression was measured by Western blot to evaluate water permeability in collecting ducts. We found that Al produced downregulation of AQP2 in plasma membranes and intracellular vesicles, that could account for the impaired water handling. Administration of desmopressin increased AQP2 in plasma membranes, suggesting that Al did not impair trafficking of this protein, but could interfere with AQP2 synthesis.

Tissue-specific Thyroid Hormone Deprivation and Excess in Monocarboxylate Transporter (mct) 8-deficient Mice

Endocrinology. Sep, 2006  |  Pubmed ID: 16709608

Mutations of the X-linked thyroid hormone (TH) transporter (monocarboxylate transporter, MCT8) produce in humans unusual abnormalities of thyroid function characterized by high serum T3 and low T4 and rT3. The mechanism of these changes remains obscure and raises questions regarding the regulation of intracellular availability and metabolism of TH. To study the pathophysiology of MCT8 deficiency, we generated Mct8 knockout mice. Male mice deficient in Mct8 (Mct8(-/y)) replicate the thyroid abnormalities observed in affected men. TH deprivation and replacement with L-T3 showed that suppression of TSH required higher serum levels T3 in Mct8(-/y) than wild-type (WT) littermates, indicating hypothalamus and/or thyrotroph resistance to T3. Furthermore, T4 is required to maintain the high serum T3 level because the latter was not different between the two genotypes during administration of T3. Mct8(-/y) mice have 2.3-fold higher T3 content in liver associated with 6.1- and 3.1-fold increase in deiodinase 1 mRNA and enzymatic activity, respectively. The relative T3 excess in liver of Mct8(-/y) mice produced a decrease in serum cholesterol (79 +/- 18 vs. 137 +/- 38 mg/dl in WT) and an increase in alkaline phosphatase (107 +/- 23 vs. 58 +/- 3 U/liter in WT) levels. In contrast, T3 content in cerebrum was 1.8-fold lower in Mct8(-/y) mice, associated with a 1.6- and 10.6-fold increase in D2 mRNA and enzymatic activity, respectively, as previously observed in TH-deprived WT mice. We conclude that cell-specific differences in intracellular TH content due to differences in contribution of the various TH transporters are responsible for the unusual clinical presentation of this defect, in contrast to TH deficiency.

The Roof Plate Regulates Cerebellar Cell-type Specification and Proliferation

Development (Cambridge, England). Aug, 2006  |  Pubmed ID: 16790481

During embryogenesis, the isthmic organizer, a well-described signaling center at the junction of the mid-hindbrain, establishes the cerebellar territory along the anterior/posterior axis of the neural tube. Mechanisms specifying distinct populations within the early cerebellar anlage are less defined. Using a newly developed gene expression map of the early cerebellar anlage, we demonstrate that secreted signals from the rhombomere 1 roof plate are both necessary and sufficient for specification of the adjacent cerebellar rhombic lip and its derivative fates. Surprisingly, we show that the roof plate is not absolutely required for initial specification of more distal cerebellar cell fates, but rather regulates progenitor proliferation and cell position within the cerebellar anlage. Thus, in addition to the isthmus, the roof plate represents an important signaling center controlling multiple aspects of cerebellar patterning.

Apoptotic Index in Breast Carcinoma Cells Following Tamoxifen Treatment

International Journal of Gynaecology and Obstetrics: the Official Organ of the International Federation of Gynaecology and Obstetrics. Oct, 2006  |  Pubmed ID: 16828763

Nutritional Risk and the Metabolic Syndrome in Women: Opportunities for Preventive Intervention from the Framingham Nutrition Study

The American Journal of Clinical Nutrition. Aug, 2006  |  Pubmed ID: 16895895

Diet is recognized as a key factor in the cause and management of the metabolic syndrome (MetS). However, policies to guide preventive clinical nutrition interventions of the condition are limited.

Loss of Cyclin D1 Impairs Cerebellar Development and Suppresses Medulloblastoma Formation

Development (Cambridge, England). Oct, 2006  |  Pubmed ID: 16943274

Medulloblastoma, the most common malignant brain tumor of childhood, is believed to derive from immature granule neuron precursors (GNPs) that normally proliferate in the external granule layer before exiting the cell cycle and migrating to their mature location in the inner granule layer. In this study, we examined the expression of D type cyclins in GNPs during cerebellar development and showed that GNPs in early development expressed only cyclin D1, whereas later GNPs expressed both cyclins D1 and D2. Coinciding with the period of cyclin D1-only expression, Ccnd1(-/-) mice showed reduced proliferation of GNPs and impaired growth of the cerebellum. Interestingly, removal of cyclin D1 was sufficient to drastically reduce the incidence of medulloblastoma in Ptch1(+/-) mice, despite the fact that these tumors showed upregulation of both cyclins D1 and D2. We showed that cyclin D1 has an earlier role in tumorigenesis: in the absence of cyclin D1, the incidence and overall volume of ;preneoplastic' lesions were significantly decreased. We propose a model that links a role of cyclin D1 in normal GNP proliferation with its early role in tumorigenesis.

Molecular Definition of an Allelic Series of Mutations Disrupting the Mouse Lmx1a (dreher) Gene

Mammalian Genome : Official Journal of the International Mammalian Genome Society. Oct, 2006  |  Pubmed ID: 17019651

Mice homozygous for the dreher (dr) mutation are characterized by pigmentation and skeletal abnormalities and striking behavioral phenotypes, including ataxia, vestibular deficits, and hyperactivity. The ataxia is associated with a cerebellar malformation that is remarkably similar to human Dandy-Walker malformation. Previously, positional cloning identified mutations in LIM homeobox transcription factor 1 alpha gene (Lmx1a) in three dr alleles. Two of these alleles, however, are extinct and unavailable for further analysis. In this article we report a new spontaneous dr allele and describe the Lmx1a mutations in this and six additional dr alleles. Strikingly, deletion null, missense, and frameshift mutations in these alleles all cause similar cerebellar malformations, suggesting that all dr mutations analyzed to date are null alleles.

What's Happening in Health Informatics?

New Journal (Institute of Health Record & Information Management). Jun, 2006  |  Pubmed ID: 17278547

A Kinetic and Thermodynamic Study of the Glycosidic Bond Cleavage in Deoxyuridine

The Journal of Physical Chemistry. B. Apr, 2007  |  Pubmed ID: 17388517

Density functional theory was used to study the thermodynamics and kinetics for the glycosidic bond cleavage in deoxyuridine. Two reaction pathways were characterized for the unimolecular decomposition in vacuo. However, these processes are associated with large reaction barriers and highly endothermic reaction energies, which is in agreement with experiments that suggest a (water) nucleophile is required for the nonenzymatic glycosidic bond cleavage. Two (S(N)1 and S(N)2) reaction pathways were characterized for direct hydrolysis of the glycosidic bond by a single water molecule; however, both pathways also involve very large barriers. Activation of the water nucleophile via partial proton abstraction steadily decreases the barrier and leads to a more exothermic reaction energy as the proton affinity of the molecule interacting with water increases. Indeed, our data suggests that the barrier heights and reaction energies range from that for hydrolysis by water to that for hydrolysis by the hydroxyl anion, which represents the extreme of (full) water activation (deprotonation). Hydrogen bonds between small molecules (hydrogen fluoride, water, or ammonia) and the nucleobase were found to further decrease the barrier and overall reaction energy but not to the extent that the same hydrogen-bonding interactions increase the acidity of the nucleobase. Our results suggest that the nature of the nucleophile plays a more important role in reducing the barrier to glycosidic bond cleavage than the nature of the small molecule bound, and models with more than one hydrogen fluoride molecule interacting with the nucleobase provide further support for this conclusion. Our results lead to a greater fundamental understanding of the effects of the nucleophile, activation of the nucleophile, and interactions with the nucleobase for this important biological reaction.

Association Between Vitamin D and Age-related Macular Degeneration in the Third National Health and Nutrition Examination Survey, 1988 Through 1994

Archives of Ophthalmology. May, 2007  |  Pubmed ID: 17502506

To evaluate the associations between levels of vitamin D (25-hydroxyvitamin D) in serum and prevalent age-related macular degeneration (AMD).

Dietary Patterns: Challenges and Opportunities in Dietary Patterns Research an Experimental Biology Workshop, April 1, 2006

Journal of the American Dietetic Association. Jul, 2007  |  Pubmed ID: 17604756

Transducing Agonist Binding to Channel Gating Involves Different Interactions in 5-HT3 and GABAC Receptors

The Journal of Biological Chemistry. Aug, 2007  |  Pubmed ID: 17606617

5-hydroxytryptamine (5-HT)3 and gamma-aminobutyric acid, type C (GABAC) receptors are members of the Cys-loop superfamily of neurotransmitter receptors, which also includes nicotinic acetylcholine, GABAA, and glycine receptors. The details of how agonist binding to these receptors results in channel opening is not fully understood but is known to involve charged residues at the extracellular/transmembrane interface. Here we have examined the roles of such residues in 5-HT3 and GABAC receptors. Charge reversal experiments combined with data from activation by the partial agonist beta-alanine show that in GABAC receptors there is a salt bridge between Glu-92 (in loop 2) and Arg-258 (in the pre-M1 region), which is involved in receptor gating. The equivalent residues in the 5-HT3 receptor are important for receptor expression, but charge reversal experiments do not restore function, indicating that there is not a salt bridge here. There is, however, an interaction between Glu-215 (loop 9) and Arg-246 (pre-M1) in the 5-HT3 receptor, although the coupling energy determined from mutant cycle analysis is lower than might be expected for a salt bridge. Overall the data show that charged residues at the extracellular/transmembrane domain interfaces in 5-HT3 and GABAC receptors are important and that specific, but not equivalent, molecular interactions between them are involved in the gating process. Thus, we propose that the molecular details of interactions in the transduction pathway between the binding site and the pore can differ between different Cys-loop receptors.

Tobacco Control Priorities for Arabic Speakers: Key Findings from a Baseline Telephone Survey of Arabic Speakers Residing in Sydney's South-west

Health Promotion Journal of Australia : Official Journal of Australian Association of Health Promotion Professionals. Aug, 2007  |  Pubmed ID: 17663647

The Arabic-speaking population is a priority for tobacco control in Sydney's south-west. Current smoking prevalence and smokers' preferences for evidence-based cessation therapies are reported for this population.

Mapping of Deletion and Translocation Breakpoints in 1q44 Implicates the Serine/threonine Kinase AKT3 in Postnatal Microcephaly and Agenesis of the Corpus Callosum

American Journal of Human Genetics. Aug, 2007  |  Pubmed ID: 17668379

Deletions of chromosome 1q42-q44 have been reported in a variety of developmental abnormalities of the brain, including microcephaly (MIC) and agenesis of the corpus callosum (ACC). Here, we describe detailed mapping studies of patients with unbalanced structural rearrangements of distal 1q4. These define a 3.5-Mb critical region extending from RP11-80B9 to RP11-241M7 that we hypothesize contains one or more genes that lead to MIC and ACC when present in only one functional copy. Next, mapping of a balanced reciprocal t(1;13)(q44;q32) translocation in a patient with postnatal MIC and ACC demonstrated a breakpoint within this region that is situated 20 kb upstream of AKT3, a serine-threonine kinase. The murine orthologue Akt3 is required for the developmental regulation of normal brain size and callosal development. Whereas sequencing of AKT3 in a panel of 45 patients with ACC did not demonstrate any pathogenic variations, whole-mount in situ hybridization confirmed expression of Akt3 in the developing central nervous system during mouse embryogenesis. AKT3 represents an excellent candidate for developmental human MIC and ACC, and we suggest that haploinsufficiency causes both postnatal MIC and ACC.

Cilia Proteins Control Cerebellar Morphogenesis by Promoting Expansion of the Granule Progenitor Pool

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. Sep, 2007  |  Pubmed ID: 17804638

Although human congenital cerebellar malformations are common, their molecular and developmental basis is still poorly understood. Recently, cilia-related gene deficiencies have been implicated in several congenital disorders that exhibit cerebellar abnormalities such as Joubert syndrome, Meckel-Gruber syndrome, Bardet-Biedl syndrome, and Orofaciodigital syndrome. The association of cilia gene mutations with these syndromes suggests that cilia may be important for cerebellar development, but the nature of cilia involvement has not been elucidated. To assess the importance of cilia-related proteins during cerebellar development, we studied the effects of CNS-specific inactivation of two mouse genes whose protein products are critical for cilia formation and maintenance, IFT88, (also known as polaris or Tg737), which encodes intraflagellar transport 88 homolog, and Kif3a, which encodes kinesin family member 3a. We showed that loss of either of these genes caused severe cerebellar hypoplasia and foliation abnormalities, primarily attributable to a failure of expansion of the neonatal granule cell progenitor population. In addition, granule cell progenitor proliferation was sensitive to partial loss of IFT function in a hypomorphic mutant of IFT88 (IFT88(orpk)), an effect that was modified by genetic background. IFT88 and Kif3a were not required for the specification and differentiation of most other cerebellar cell types, including Purkinje cells. Together, our observations constitute the first demonstration that cilia proteins are essential for normal cerebellar development and suggest that granule cell proliferation defects may be central to the cerebellar pathology in human cilia-related disorders.

A Developmental Classification of Malformations of the Brainstem

Annals of Neurology. Dec, 2007  |  Pubmed ID: 17924529

With advances in imaging and genetics, malformations of the brainstem are being more commonly identified. We describe and classify brainstem anomalies in 138 patients ascertained over a period of 10 years

A Study of Temperature Rise in the Pulp Chamber During Composite Polymerization with Different Light-curing Units

The Journal of Contemporary Dental Practice. 2007  |  Pubmed ID: 17994152

The study compared pulp temperature rise during polymerization of resin-based composites (RBCs) using halogen and LED light-curing units (LCUs).

Fruit and Vegetable Intake and Prevalence of Colorectal Adenoma in a Cancer Screening Trial

The American Journal of Clinical Nutrition. Dec, 2007  |  Pubmed ID: 18065596

Research on the association between fruit and vegetable intake and risk of colorectal adenoma is inconclusive.

Proprioceptive Sensory Neuropathy in Mice with a Mutation in the Cytoplasmic Dynein Heavy Chain 1 Gene

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. Dec, 2007  |  Pubmed ID: 18160659

Mice heterozygous for the radiation-induced Sprawling (Swl) mutation display an early-onset sensory neuropathy with muscle spindle deficiency. The lack of an H reflex despite normal motor nerve function in the hindlimbs of these mutants strongly suggests defective proprioception. Immunohistochemical analyses reveal that proprioceptive sensory neurons are severely compromised in the lumbar dorsal root ganglia of newborn Swl/+ mice, whereas motor neuron numbers remain unaltered even in aged animals. We have used positional cloning to identify a nine base-pair deletion in the cytoplasmic dynein heavy chain 1 gene (Dync1h1) in this mutant. Furthermore, we demonstrate that Loa/+ mice, which have previously been shown to carry a missense point mutation in Dync1h1 that results in late-onset motor neuron loss, also present with a severe, early-onset proprioceptive sensory neuropathy. Interestingly, in contrast to the Loa mutation, the Swl mutation does not delay disease progression in a motor neuron disease mouse model overexpressing a human mutant superoxide dismutase (SOD1(G93A)) transgene. Together, we provide in vivo evidence that distinct mutations in cytoplasmic dynein can either result in a pure sensory neuropathy or in a sensory neuropathy with motor neuron involvement.

Effects of Hydrogen-bonding and Stacking Interactions with Amino Acids on the Acidity of Uracil

The Journal of Physical Chemistry. B. Feb, 2007  |  Pubmed ID: 17256895

The effects of hydrogen-bonding interactions with amino acids on the (N1) acidity of uracil are evaluated using (B3LYP) density functional theory. Many different binding arrangements of each amino acid to three uracil binding sites are considered. The effects on the uracil acidity are found to significantly depend upon the nature of the amino acid and the binding orientation, but weakly depend on the binding site. Our results reveal that in some instances small models for the amino acids can be used, while for other amino acids larger models are required to properly describe the binding to uracil. The gas-phase acidity of uracil is found to increase by up to approximately 60 kJ mol(-1) due to discrete hydrogen-bonding interactions. Although (MP2) stacking interactions with aromatic amino acids decrease the acidity of uracil, unexpected increases in the acidity are found when any of the aromatic amino acids, or the backbone, hydrogen bond to uracil. Consideration of enzymatic and aqueous environments leads to decreases in the effects of the amino acids on the acidity of uracil. However, we find that the magnitude of the decrease varies with the nature of the molecule bound, as well as the (gas-phase) binding orientations and strengths, and therefore solvation effects should be considered on a case-by-case basis in future work. Nevertheless, the effects of amino acid interactions within enzymatic environments are as much as approximately 35 kJ mol(-1). The present study has general implications for understanding the nature of active site amino acids in enzymes, such as DNA repair enzymes, that catalyze reactions involving anionic nucleobase intermediates.

Zic1 and Zic4 Regulate Zebrafish Roof Plate Specification and Hindbrain Ventricle Morphogenesis

Developmental Biology. Feb, 2008  |  Pubmed ID: 18191121

During development, the lumen of the neural tube develops into a system of brain cavities or ventricles, which play important roles in normal CNS function. We have established that the formation of the hindbrain (4th) ventricle in zebrafish is dependent upon the pleiotropic functions of the genes implicated in human Dandy Walker Malformation, Zic1 and Zic4. Using morpholino knockdown we show that zebrafish Zic1 and Zic4 are required for normal morphogenesis of the 4th ventricle. In Zic1 and/or Zic4 morphants the ventricle does not open properly, but remains completely or partially fused from the level of rhombomere (r) 2 towards the posterior. In the absence of Zic function early hindbrain regionalization and neural crest development remain unaffected, but dorsal hindbrain progenitor cell proliferation is significantly reduced. Importantly, we find that Zic1 and Zic4 are required for development of the dorsal roof plate. In Zic morphants expression of roof plate markers, including lmx1b.1 and lmx1b.2, is disrupted. We further demonstrate that zebrafish Lmx1b function is required for both hindbrain roof plate development and 4th ventricle morphogenesis, confirming that roof plate formation is a critical component of ventricle development. Finally, we show that dorsal rhombomere boundary signaling centers depend on Zic1 and Zic4 function and on roof plate signals, and provide evidence that these boundary signals are also required for ventricle morphogenesis. In summary, we conclude that Zic1 and Zic4 control zebrafish 4th ventricle morphogenesis by regulating multiple mechanisms including cell proliferation and fate specification in the dorsal hindbrain.

Linkage to Chromosome 2q36.1 in Autosomal Dominant Dandy-Walker Malformation with Occipital Cephalocele and Evidence for Genetic Heterogeneity

Human Genetics. Apr, 2008  |  Pubmed ID: 18204864

We previously reported a Vietnamese-American family with isolated autosomal dominant occipital cephalocele. Upon further neuroimaging studies, we have recharacterized this condition as autosomal dominant Dandy-Walker with occipital cephalocele (ADDWOC). A similar ADDWOC family from Brazil was also recently described. To determine the genetic etiology of ADDWOC, we performed genome-wide linkage analysis on members of the Vietnamese-American and Brazilian pedigrees. Linkage analysis of the Vietnamese-American family identified the ADDWOC causative locus on chromosome 2q36.1 with a multipoint parametric LOD score of 3.3, while haplotype analysis refined the locus to 1.1 Mb. Sequencing of the five known genes in this locus did not identify any protein-altering mutations. However, a terminal deletion of chromosome 2 in a patient with an isolated case of Dandy-Walker malformation also encompassed the 2q36.1 chromosomal region. The Brazilian pedigree did not show linkage to this 2q36.1 region. Taken together, these results demonstrate a locus for ADDWOC on 2q36.1 and also suggest locus heterogeneity for ADDWOC.

Computational and Experimental Evidence for the Structural Preference of Phenolic C-8 Purine Adducts

The Journal of Physical Chemistry. A. Apr, 2008  |  Pubmed ID: 18376879

The structural and spectral properties of (ortho and para) C8-aryl-purine adducts formed from carbon attachment by phenolic toxins were investigated through DFT calculations and UV-vis absorbance and emission studies. The global minima of both the deoxyadenosine (dA) and deoxyguanosine (dG) adducts adopted a syn conformation about the glycosidic bond due to the presence of an O5'-H...N3 hydrogen bond, where the anti minima are 20-30 kJ mol-1 higher in energy. While the nucleobase adducts are planar, the presence of the deoxyribose sugar induces a twist about the carbon-carbon bond connecting the phenol and nucleobase rings. ortho-Phenolic adducts are less twisted than the corresponding para adducts due to stabilization provided by an intramolecular O-H...N7 bond. Solvation calculations, in combination with UV-vis studies, demonstrate that the structural preference is solvent dependent, where solvents with hydrogen-bonding abilities disrupt the intramolecular O-H...N7 hydrogen bond such that a greater degree of twist is observed, and less polar solvents stabilize the planar structure. Indeed, the ratio of twisted to planar conformers is estimated to be as large as 50:50 in some aprotic solvents. Thus, the combined experimental and computational approach has provided a greater understanding of the structure of the ortho- and para-dA and dG C-bonded phenoxyl adducts as the first step to understanding the biological consequences of this form of DNA damage.

The Effect of Diagnostic Delays on the Drop-out Rate and the Total Delay to Diagnosis of Tuberculosis

PloS One. 2008  |  Pubmed ID: 18398459

Numerous patient and healthcare system-related delays contribute to the overall delay experienced by patients from onset of TB symptoms to diagnosis and treatment. Such delays are critical as infected individuals remain untreated in the community, providing more opportunities for transmission of the disease and adversely affecting the epidemic.

Assessment of Vitamin D in Population-based Studies. Preface

The American Journal of Clinical Nutrition. Apr, 2008  |  Pubmed ID: 18400737

Vitamin D Assessment in Population-based Studies: a Review of the Issues

The American Journal of Clinical Nutrition. Apr, 2008  |  Pubmed ID: 18400742

In the past decade, research on the relation between vitamin D exposure and disease in population-based studies has increased exponentially. These studies have involved measurement of vitamin D exposure by means of several methods: blood assays, self-reported dietary and supplemental intakes, and sunlight exposure questionnaires or diaries. As with all exposure measurements, researchers must consider the validity of their assessment tools for capturing vitamin D exposure. The purpose of this article is to summarize our current understanding of the various approaches to measuring vitamin D status within populations as reviewed at the 2007 Experimental Biology symposium, "Assessment of Vitamin D in Population-Based Studies." In summary, serum 25-hydroxyvitamin D is the accepted biomarker for short-term vitamin D status, but estimates of long-term dietary and supplemental intakes of vitamin D and long-term sunlight exposure may be the most logistically feasible indicators of lifetime vitamin D exposure in population-based studies. Also discussed are issues investigators should consider when analyzing relations between vitamin D exposure and disease outcomes in population-based studies as well as research avenues that need further exploration. The best method for assessing vitamin D status in population-based studies will depend primarily on the research question asked and the critical window of vitamin D exposure hypothesized to be most important.

Compliance with Recommended Cancer Screening Among Emergency Department Patients: a Multicenter Survey

Academic Emergency Medicine : Official Journal of the Society for Academic Emergency Medicine. May, 2008  |  Pubmed ID: 18439206

The objectives were to measure compliance with, and possible sociodemographic disparities for, cancer screening among emergency department (ED) patients.

Prion Protein Complexed to N2a Cellular RNAs Through Its N-terminal Domain Forms Aggregates and is Toxic to Murine Neuroblastoma Cells

The Journal of Biological Chemistry. Jul, 2008  |  Pubmed ID: 18456654

Conversion of the cellular prion protein (PrP(C)) into its altered conformation, PrP(Sc), is believed to be the major cause of prion diseases. Although PrP is the only identified agent for these diseases, there is increasing evidence that other molecules can modulate the conversion. We have found that interaction of PrP with double-stranded DNA leads to a protein with higher beta-sheet content and characteristics similar to those of PrP(Sc). RNA molecules can also interact with PrP and potentially modulate PrP(C) to PrP(Sc) conversion or even bind differentially to both PrP isoforms. Here, we investigated the interaction of recombinant murine PrP with synthetic RNA sequences and with total RNA extracted from cultured neuroblastoma cells (N2aRNA). We found that PrP interacts with N2aRNA with nanomolar affinity, aggregates upon this interaction, and forms species partially resistant to proteolysis. RNA does not bind to N-terminal deletion mutants of PrP, indicating that the N-terminal region is important for this process. Cell viability assays showed that only the N2aRNA extract induces PrP-RNA aggregates that can alter the homeostasis of cultured cells. Small RNAs bound to PrP give rise to nontoxic small oligomers. Nuclear magnetic resonance measurements of the PrP-RNA complex revealed structural changes in PrP, but most of its native fold is maintained. These results indicate that there is selectivity in the species generated by interaction with different molecules of RNA. The catalytic effect of RNA on the PrP(C)-->PrP(Sc) conversion depends on the RNA sequence, and small RNA molecules may exert a protective effect.

Implications and Impact of the New US Centers for Disease Control and Prevention HIV Testing Guidelines

Current Infectious Disease Reports. May, 2008  |  Pubmed ID: 18462591

Of the 1.2 million Americans estimated to be living with HIV in the United States, approximately 250,000 are unaware of their diagnosis and therefore unable to access clinical care and life-sustaining treatment. The revised 2006 US Centers for Disease Control and Prevention's guidelines for HIV testing recommend universal, routine, and voluntary HIV screening in public and private health care settings for all adults and adolescents between 13 and 64 years old. These major revisions present new challenges for health care providers, hospitals, government agencies, and community advocacy groups. In this review, we discuss the important issues in diverse care venues such as opt-out testing, consent and confidentiality, barriers to treatment, and financial impact. The implications of the revised recommendations for HIV testing are addressed in the context of a fragmented, overstressed, underfunded US health care system.

Leukocyte Trafficking and Pain Behavioral Responses to a Hydrogen Sulfide Donor in Acute Monoarthritis

American Journal of Physiology. Regulatory, Integrative and Comparative Physiology. Sep, 2008  |  Pubmed ID: 18667709

Hydrogen sulfide (H(2)S) is an endogenous gaseous mediator with the ability to modulate tissue inflammation and pain. The aim of this study was to determine the effect of an H(2)S donor (Na(2)S) on leukocyte-endothelium interactions, blood flow, and pain sensation in acutely inflamed knee joints. Acute arthritis was induced in urethane anesthetized C57bl/6 mice by intra-articular injection of kaolin/carrageenan (24-h recovery), and the effect of local administration of Na(2)S on leukocyte trafficking was measured by intravital microscopy. Synovial blood flow was measured in inflamed knees by laser Doppler perfusion imaging. Finally, the effect of an intra-articular injection of Na(2)S on joint pain in control and inflamed rats was determined by hindlimb incapacitance and von Frey hair algesiometry. Local administration of an H(2)S donor to inflamed knees caused a dose-dependent reduction in leukocyte adherence and an increase in leukocyte velocity. These effects could be inhibited by coadministration of the ATP-sensitive K(+) channel blocker glibenclamide. Local administration of Na(2)S to inflamed joints caused a pronounced vasoconstrictor response; however, there was no observable effect of Na(2)S on joint pain. These findings establish H(2)S as a novel signaling molecule in rodent knee joints. H(2)S exhibits potent anti-inflammatory properties, but with no detectable effect on joint pain.

The Luminal N-terminus of Yeast Nvj1 is an Inner Nuclear Membrane Anchor

Traffic (Copenhagen, Denmark). Sep, 2008  |  Pubmed ID: 18694438

The endoplasmic reticulum (ER) in Saccharomyces cerevisiae is largely divided between perinuclear and cortical compartments. Yeast Nvj1 localizes exclusively to small patches on the perinuclear ER where it interacts with Vac8 in the vacuole membrane to form nucleus-vacuole (NV) junctions. Three regions of Nvj1 mediate the biogenesis of NV junctions. A membrane-spanning domain targets the protein to the ER. The C-terminus binds Vac8 in the vacuole membrane, which induces the clustering of both proteins into NV junctions. The luminal N-terminus is required for strict perinuclear localization. Three-dimensional cryo-electron tomography reveals that Nvj1 clamps the separation between the two nuclear membranes to half the width of bulk nuclear envelope. The N-terminus contains a hydrophobic sequence bracketed by basic residues that resembles outer mitochondrial membrane signal-anchors. The hydrophobic sequence can be scrambled or reversed without affecting function. Mutations that reduce the hydrophobicity of the core sequence or affect the distribution of basic residues cause mislocalization to the cortical ER. We conclude that the N-terminus of Nvj1 is a retention sequence that bridges the perinuclear lumen and inserts into the inner nuclear membrane.

Piecemeal Microautophagy of the Nucleus Requires the Core Macroautophagy Genes

Molecular Biology of the Cell. Oct, 2008  |  Pubmed ID: 18701704

Autophagy is a diverse family of processes that transport cytoplasm and organelles into the lysosome/vacuole lumen for degradation. During macroautophagy cargo is packaged in autophagosomes that fuse with the lysosome/vacuole. During microautophagy cargo is directly engulfed by the lysosome/vacuole membrane. Piecemeal microautophagy of the nucleus (PMN) occurs in Saccharomyces cerevisiae at nucleus-vacuole (NV) junctions and results in the pinching-off and release into the vacuole of nonessential portions of the nucleus. Previous studies concluded macroautophagy ATG genes are not absolutely required for PMN. Here we report using two biochemical assays that PMN is efficiently inhibited in atg mutant cells: PMN blebs are produced, but vesicles are rarely released into the vacuole lumen. Electron microscopy of arrested PMN structures in atg7, atg8, and atg9 mutant cells suggests that NV-junction-associated micronuclei may normally be released from the nucleus before their complete enclosure by the vacuole membrane. In this regard PMN is similar to the microautophagy of peroxisomes (micropexophagy), where the side of the peroxisome opposite the engulfing vacuole is capped by a structure called the "micropexophagy-specific membrane apparatus" (MIPA). The MIPA contains Atg proteins and facilitates terminal enclosure and fusion steps. PMN does not require the complete vacuole homotypic fusion genes. We conclude that a spectrum of ATG genes is required for the terminal vacuole enclosure and fusion stages of PMN.

Performance of a Method for Identifying the Unique Dietary Patterns of Adult Women and Men: the Framingham Nutrition Studies

Journal of the American Dietetic Association. Sep, 2008  |  Pubmed ID: 18755317

Identification of population dietary patterns has been recommended by experts as a key to developing innovative and targeted nutrition interventions and achieving long-term dietary behavior changes for health promotion and chronic disease risk reduction. Essential in this task is the evaluation of methods to accurately identify these unique dietary patterns.

YDNA Versus XDNA Pyrimidine Nucleobases: Computational Evidence for Dependence of Duplex Stability on Spacer Location

The Journal of Physical Chemistry. B. Oct, 2008  |  Pubmed ID: 18771305

The structural and binding properties of the natural and x- and y-pyrimidines were compared using computational methods. Our calculations show that although the x-pyrimidines favor different orientations about the glycosidic bond compared to the natural pyrimidines, which could have implications for the formation and resulting stability of xDNA duplexes and jeopardize the selectivity of expanded nucleobases, y-pyrimidines have rotational profiles more similar to the natural bases. Increasing the pyrimidine size using a benzene spacer leads to relatively minor changes in the hydrogen-bond strength of isolated Watson-Crick base pairs. However, differences in the anomeric carbon distances in pairs composed of x- or y-pyrimidines suggest yDNA may yield a more optimal expanded structure. By stacking two monomers via their centers of mass, we find that the expanded nucleobases stack much stronger than the natural bases. Additionally, although replacing xT by yT changes the stacking energy by less than 5 kJ mol (-1), replacing xC by yC significantly strengthens complexes with the natural nucleobases (by up to 30%). Calculations on larger duplex models composed of four nucleobases reveal that x- and y-pyrimidines can increase duplex stability of natural helices by strengthening both the intra and interstrand stacking interactions. Furthermore, when the total stability (sum of all hydrogen-bonding and (intrastrand and interstrand) stacking interactions) of the larger models is considered, y-pyrimidines lead to more stable complexes than x-pyrimidines for all but three duplex sequences. Thus, through analysis of a variety of properties, our calculations suggest that the location of the benzene spacer affects the properties of expanded nucleobases and the stability of expanded duplexes, and therefore should be carefully considered when designing future expanded analogues.

Review. Studying Cumulative Cultural Evolution in the Laboratory

Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences. Nov, 2008  |  Pubmed ID: 18799419

Cumulative cultural evolution is the term given to a particular kind of social learning, which allows for the accumulation of modifications over time, involving a ratchet-like effect where successful modifications are maintained until they can be improved upon. There has been great interest in the topic of cumulative cultural evolution from researchers from a wide variety of disciplines, but until recently there were no experimental studies of this phenomenon. Here, we describe our motivations for developing experimental methods for studying cumulative cultural evolution and review the results we have obtained using these techniques. The results that we describe have provided insights into understanding the outcomes of cultural processes at the population level. Our experiments show that cumulative cultural evolution can result in adaptive complexity in behaviour and can also produce convergence in behaviour. These findings lend support to ideas that some behaviours commonly attributed to natural selection and innate tendencies could in fact be shaped by cultural processes.

Giant Magnetoresistance Sensors. 1. Internally Calibrated Readout of Scanned Magnetic Arrays

Analytical Chemistry. Nov, 2008  |  Pubmed ID: 18826239

This paper describes efforts aimed at setting the stage for the application of giant magnetoresistance sensor (GMRs) networks as readers for quantification of biolytes selectively captured and then labeled with superparamagnetic particles on a scanned chip-scale array. The novelty and long-range goal of this research draws from the potential development of a card-swipe instrument through which an array of micrometer-sized, magnetically tagged addresses (i.e., a sample stick) can be interrogated in a manner analogous to a credit card reader. This work describes the construction and testing of a first-generation instrument that uses a GMR sensor network to read the response of a "simulated" sample stick. The glass sample stick is composed of 20-nm-thick films of permalloy that have square or rectangular lateral footprints of up to a few hundred micrometers. Experiments were carried out to gain a fundamental understanding of the dependence of the GMR response on the separation between, and planarity of, the scanned sample stick and sensor. Results showed that the complex interplay between these experimentally controllable variables strongly affect the shape and magnitude of the observed signal and, ultimately, the limit of detection. This study also assessed the merits of using on-sample standards as internal references as a facile means to account for small variations in the gap between the sample stick and sensor. These findings were then analyzed to determine various analytical figures of merit (e.g., limit of detection in terms of the amount of magnetizable material on each address) for this readout strategy. An in-depth description of the first-generation test equipment is presented, along with a brief discussion of the potential widespread applicability of the concept.

Giant Magenetoresistive Sensors. 2. Detection of Biorecognition Events at Self-referencing and Magnetically Tagged Arrays

Analytical Chemistry. Nov, 2008  |  Pubmed ID: 18826241

Microfabricated devices formed from alternating layers of magnetic and nonmagnetic materials at combined thicknesses of a few hundred nanometers exhibit a phenomenon known as the giant magnetoresistance effect. Devices based on this effect are known as giant magnetoresistive (GMR) sensors. The resistance of a GMR is dependent on the strength of an external magnetic field, which has resulted in the widespread usage of such platforms in high-speed, high-data density storage drives. The same attributes (i.e., sensitivity, small size, and speed) are also important embodiments of many types of bioanalytical sensors, pointing to an intriguing opportunity via an integration of GMR technology, magnetic labeling strategies, and biorecognition elements (e.g., antibodies). This paper describes the utilization of GMRs for the detection of streptavidin-coated magnetic particles that are selectively captured by biotinylated gold addresses on a 2 x 0.3 cm sample stick. A GMR sensor network reads the addresses on a sample stick in a manner that begins to emulate that of a "card-swipe" system. This study also takes advantage of on-sample magnetic addresses that function as references for internal calibration of the GMR response and as a facile means to account for small variations in the gap between the sample stick and sensor. The magnetic particle surface coverage at the limit of detection was determined to be approximately 2%, which corresponds to approximately 800 binding events over the 200 x 200 microm capture address. These findings, along with the potential use of streptavidin-coated magnetic particles as a universal label for antigen detection in, for example, heterogeneous assays, are discussed.

Molecular Mechanisms Involved in Vascular Interactions of the Lyme Disease Pathogen in a Living Host

PLoS Pathogens. 2008  |  Pubmed ID: 18833295

Hematogenous dissemination is important for infection by many bacterial pathogens, but is poorly understood because of the inability to directly observe this process in living hosts at the single cell level. All disseminating pathogens must tether to the host endothelium despite significant shear forces caused by blood flow. However, the molecules that mediate tethering interactions have not been identified for any bacterial pathogen except E. coli, which tethers to host cells via a specialized pillus structure that is not found in many pathogens. Furthermore, the mechanisms underlying tethering have never been examined in living hosts. We recently engineered a fluorescent strain of Borrelia burgdorferi, the Lyme disease pathogen, and visualized its dissemination from the microvasculature of living mice using intravital microscopy. We found that dissemination was a multistage process that included tethering, dragging, stationary adhesion and extravasation. In the study described here, we used quantitative real-time intravital microscopy to investigate the mechanistic features of the vascular interaction stage of B. burgdorferi dissemination. We found that tethering and dragging interactions were mechanistically distinct from stationary adhesion, and constituted the rate-limiting initiation step of microvascular interactions. Surprisingly, initiation was mediated by host Fn and GAGs, and the Fn- and GAG-interacting B. burgdorferi protein BBK32. Initiation was also strongly inhibited by the low molecular weight clinical heparin dalteparin. These findings indicate that the initiation of spirochete microvascular interactions is dependent on host ligands known to interact in vitro with numerous other bacterial pathogens. This conclusion raises the intriguing possibility that fibronectin and GAG interactions might be a general feature of hematogenous dissemination by other pathogens.

High Symptom Reporters Are Less Interoceptively Accurate in a Symptom-related Context

Journal of Psychosomatic Research. Nov, 2008  |  Pubmed ID: 18940371

We investigated the role of a symptom interpretation frame on the accuracy of interoception and on retrospective symptom reporting in nonclinical high and low reporters of medically unexplained symptoms.

A Cation-pi Interaction in the Binding Site of the Glycine Receptor is Mediated by a Phenylalanine Residue

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. Oct, 2008  |  Pubmed ID: 18945901

Cys-loop receptor binding sites characteristically contain many aromatic amino acids. In nicotinic ACh and 5-HT3 receptors, a Trp residue forms a cation-pi interaction with the agonist, whereas in GABA(A) receptors, a Tyr performs this role. The glycine receptor binding site, however, contains predominantly Phe residues. Homology models suggest that two of these Phe side chains, Phe159 and Phe207, and possibly a third, Phe63, are positioned such that they could contribute to a cation-pi interaction with the primary amine of glycine. Here, we test this hypothesis by incorporation of a series of fluorinated Phe derivatives using unnatural amino acid mutagenesis. The data reveal a clear correlation between the glycine EC(50) value and the cation-pi binding ability of the fluorinated Phe derivatives at position 159, but not at positions 207 or 63, indicating a single cation-pi interaction between glycine and Phe159. The data thus provide an anchor point for locating glycine in its binding site, and demonstrate for the first time a cation-pi interaction between Phe and a neurotransmitter.

Lmx1a is Required for Segregation of Sensory Epithelia and Normal Ear Histogenesis and Morphogenesis

Cell and Tissue Research. Dec, 2008  |  Pubmed ID: 18985389

At embryonic day 8.5, the LIM-homeodomain factor Lmx1a is expressed throughout the otic placode but becomes developmentally restricted to non-sensory epithelia of the ear (endolymphatic duct, ductus reuniens, cochlea lateral wall). We confirm here that the ears of newborn dreher (Lmx1a (dr)) mutants are dysmorphic. Hair cell markers such as Atoh1 and Myo7 reveal, for the first time, that newborn Lmx1a mutants have only three sensory epithelia: two enlarged canal cristae and one fused epithelium comprising an amalgamation of the cochlea, saccule, and utricle (a "cochlear-gravistatic" endorgan). The enlarged anterior canal crista develops by fusion of horizontal and anterior crista, whereas the posterior crista fuses with an enlarged papilla neglecta that may extend into the cochlear lateral wall. In the fused endorgan, the cochlear region is distinguished from the vestibular region by markers such as Gata3, the presence of a tectorial membrane, and cochlea-specific innervation. The cochlea-like apex displays minor disorganization of the hair and supporting cells. This contrasts with the basal half of the cochlear region, which shows a vestibular epithelium-like organization of hair cells and supporting cells. The dismorphic features of the cochlea are also reflected in altered gene expression patterns. Fgf8 expression expands from inner hair cells in the apex to most hair cells in the base. Two supporting cell marker proteins, Sox2 and Prox1, also differ in their cellular distribution between the base and the apex. Sox2 expression expands in mutant canal cristae prior to their enlargement and fusion and displays a more diffuse and widespread expression in the base of the cochlear region, whereas Prox1 is not detected in the base. These changes in Sox2 and Prox1 expression suggest that Lmx1a expression restricts and sharpens Sox2 expression, thereby defining non-sensory and sensory epithelium. The adult Lmx1a mutant organ of Corti shows a loss of cochlear hair cells, suggesting that the long-term maintenance of hair cells is also disrupted in these mutants.

Cerebellar Development and Disease

Current Opinion in Neurobiology. Feb, 2008  |  Pubmed ID: 18513948

The molecular control of cell-type specification within the developing cerebellum as well as the genetic causes of the most common human developmental cerebellar disorders have long remained mysterious. Recent genetic lineage and loss-of-function data from mice have revealed unique and nonoverlapping anatomical origins for GABAergic neurons from ventricular zone precursors and glutamatergic cell from rhombic lip precursors, mirroring distinct origins for these neurotransmitter-specific cell types in the cerebral cortex. Mouse studies elucidating the role of Ptf1a as a cerebellar ventricular zone GABerigic fate switch were actually preceded by the recognition that PTF1A mutations in humans cause cerebellar agenesis, a birth defect of the human cerebellum. Indeed, several genes for congenital human cerebellar malformations have recently been identified, including genes causing Joubert syndrome, Dandy-Walker malformation, and pontocerebellar hypoplasia. These studies have pointed to surprisingly complex roles for transcriptional regulation, mitochondrial function, and neuronal cilia in patterning, homeostasis, and cell proliferation during cerebellar development. Together, mouse and human studies are synergistically advancing our understanding of the developmental mechanisms that generate the uniquely complex mature cerebellum.

Eight-week, Placebo-controlled, Double-blind Comparison of the Antidepressant Efficacy and Tolerability of Bupropion XR and Venlafaxine XR

Journal of Psychopharmacology (Oxford, England). Jul, 2009  |  Pubmed ID: 18635695

The efficacy, safety and tolerability of bupropion XR and venlafaxine XR was assessed and compared with placebo in adult outpatients with major depressive disorder (MDD). Adults meeting DSM-IV criteria for MDD with a minimum Hamilton Depression Rating Scale (HAMD) 17-Item total score of > or =18 were randomized to eight weeks of double-blind treatment with either bupropion XR (150 mg/day), venlafaxine XR (75 mg/day) or placebo. At the end of the fourth week of treatment, a dosage increase to bupropion XR 300 mg/day or venlafaxine XR 150 mg/day was allowed if, in the opinion of the investigator, response was inadequate. The primary efficacy endpoint was mean change from baseline at week 8 in the Montgomery-Asberg Depression Rating Scale (MADRS) total score last observation carried forward (LOCF). Mean changes from baseline at week 8 (LOCF) in MADRS total score were statistically significant for bupropion XR and venlafaxine XR patients compared to the placebo group: -16.0 for bupropion XR (P = 0.006 vs placebo), -17.1 for venlafaxine XR (P < 0.001 vs placebo) and -13.5 for placebo. Secondary outcomes (including CGI-S, HAM-A, MEI, Q-LES-Q-SF, responder and remitter analyses) also improved significantly for both active treatment groups compared with placebo. The most frequently reported adverse events were dry mouth and insomnia for bupropion XR, and nausea, hyperhidrosis, fatigue, and insomnia for venlafaxine XR. In this double-blind, placebo-controlled trial, bupropion XR at doses up to 300 mg/day and venlafaxine XR at doses up to 150 mg/day demonstrated comparable antidepressant efficacy.

A Developmental and Genetic Classification for Midbrain-hindbrain Malformations

Brain : a Journal of Neurology. Dec, 2009  |  Pubmed ID: 19933510

Advances in neuroimaging, developmental biology and molecular genetics have increased the understanding of developmental disorders affecting the midbrain and hindbrain, both as isolated anomalies and as part of larger malformation syndromes. However, the understanding of these malformations and their relationships with other malformations, within the central nervous system and in the rest of the body, remains limited. A new classification system is proposed, based wherever possible, upon embryology and genetics. Proposed categories include: (i) malformations secondary to early anteroposterior and dorsoventral patterning defects, or to misspecification of mid-hindbrain germinal zones; (ii) malformations associated with later generalized developmental disorders that significantly affect the brainstem and cerebellum (and have a pathogenesis that is at least partly understood); (iii) localized brain malformations that significantly affect the brain stem and cerebellum (pathogenesis partly or largely understood, includes local proliferation, cell specification, migration and axonal guidance); and (iv) combined hypoplasia and atrophy of putative prenatal onset degenerative disorders. Pertinent embryology is discussed and the classification is justified. This classification will prove useful for both physicians who diagnose and treat patients with these disorders and for clinical scientists who wish to understand better the perturbations of developmental processes that produce them. Importantly, both the classification and its framework remain flexible enough to be easily modified when new embryologic processes are described or new malformations discovered.

Incident Invasive Breast Cancer, Geographic Location of Residence, and Reported Average Time Spent Outside

Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology. Feb, 2009  |  Pubmed ID: 19190147

There have been reports of greater breast cancer incidence and mortality at northern compared with southern latitudes postulated to be related to vitamin D exposure. Among 71,662 participants in the Women's Health Initiative Observational Study (WHIOS) free of cancer at baseline (1993-1998), associations were explored between incident invasive postmenopausal breast cancer (n = 2,535), over approximately 8.6 years follow-up, and the following: (a) region of residence at birth, age 15 years, age 35 years; (b) region of residence at WHIOS baseline; and (c) clinic center solar irradiance. Hazard ratios and 95% confidence intervals (CI) for breast cancer were estimated after adjustment for individual level confounders. There was no difference in breast cancer risk by region of earlier life, baseline residence, or solar irradiance measured in Langelys (gm-cal) per cm(2). There was an observed 15% decreased risk among women residing in areas of low versus high solar irradiance measured in Watts per m(2) (95% CI, 2-26%). However, the associated P(trend) of 0.20 was not significant. Conversely, women who reported spending on average <30 minutes versus >2 hours outside in daylight year round at WHIOS year 4 follow-up (n = 46,926), had a 20% (95% CI, 2-41%; P(trend) = 0.001) increased risk of breast cancer. In conclusion, region of residence and geographic solar irradiance are not consistently related to risk of breast cancer and may not be sufficient proxy measures for sunlight/vitamin D exposure. The observed association between time spent outside and breast cancer risk support the hypothesis that vitamin D may protect against breast cancer.

A Vapor Cell Based on Dispensers for Laser Spectroscopy

The Review of Scientific Instruments. Jan, 2009  |  Pubmed ID: 19191423

We describe a simple strontium vapor cell for laser spectroscopy experiments. Strontium vapor is produced using an electrically heated commercial dispenser source. The sealed cell operates at room temperature, and without a buffer gas or vacuum pump. The cell was characterized using laser spectroscopy, and was found to offer stable and robust operation, with an estimated lifetime of >10 000 h. By changing the dispenser, this technique can be readily extended to other alkali and alkaline earth elements.

Case Report of Self-injurious Behaviour (SIB) Presenting As Gingivitis Artefacta Major

British Dental Journal. Feb, 2009  |  Pubmed ID: 19218945

The case report described here discusses gingivitis artefacta major, an oral presentation of self-injurious behaviour, in an adolescent. On presentation, the patient knew well the ramifications of her gum scratching behaviour, however, was unable to stop. At further presentations new lesions had appeared with further bone loss. The cause of her behaviour seemed to be of psychological origin and therefore no interventive dental treatment was possible until this issue was resolved. A more preventive approach was adopted in the meantime. Referral to appropriate services from the dental profession also proved to be challenging. In conclusion, gingivitis artefacta, although rarely seen to this extent, is extremely challenging to diagnose and treat fully in a dental setting.

Genetic Variation and Population Substructure in Outbred CD-1 Mice: Implications for Genome-wide Association Studies

PloS One. 2009  |  Pubmed ID: 19266100

Outbred laboratory mouse populations are widely used in biomedical research. Since little is known about the degree of genetic variation present in these populations, they are not widely used for genetic studies. Commercially available outbred CD-1 mice are drawn from an extremely large breeding population that has accumulated many recombination events, which is desirable for genome-wide association studies. We therefore examined the degree of genome-wide variation within CD-1 mice to investigate their suitability for genetic studies. The CD-1 mouse genome displays patterns of linkage disequilibrium and heterogeneity similar to wild-caught mice. Population substructure and phenotypic differences were observed among CD-1 mice obtained from different breeding facilities. Differences in genetic variation among CD-1 mice from distinct facilities were similar to genetic differences detected between closely related human populations, consistent with a founder effect. This first large-scale genetic analysis of the outbred CD-1 mouse strain provides important considerations for the design and analysis of genetic studies in CD-1 mice.

Lipoteichoic Acid Induces Unique Inflammatory Responses when Compared to Other Toll-like Receptor 2 Ligands

PloS One. 2009  |  Pubmed ID: 19440307

Toll-like receptors (TLRs) recognize evolutionarily-conserved molecular patterns originating from invading microbes. In this study, we were interested in determining if microbial ligands, which use distinct TLR2-containing receptor complexes, represent unique signals to the cell and can thereby stimulate unique cellular responses. Using the TLR2 ligands, R-FSL1, S-FSL1, Pam2CSK4, Pam3CSK4, and lipoteichoic acid (LTA), we demonstrate that these ligands activate NF-kappaB and MAP Kinase pathways with ligand-specific differential kinetics in murine macrophages. Most strikingly, LTA stimulation of these pathways was substantially delayed when compared with the other TLR2 ligands. These kinetics differences were associated with a delay in the LTA-induced expression of a subset of genes as compared with another TLR2 ligand, R-FSL1. However, this did not translate to overall differences in gene expression patterns four hours following stimulation with different TLR2 ligands. We extended this study to evaluate the in vivo responses to distinct TLR2 ligands using a murine model of acute inflammation, which employs intravital microscopy to monitor leukocyte recruitment into the cremaster muscle. We found that, although R-FSL1, S-FSL1, Pam2CSK4, and Pam3CSK4 were all able to stimulate robust leukocyte recruitment in vivo, LTA remained functionally inert in this in vivo model. Therefore distinct TLR2 ligands elicit unique cellular responses, as evidenced by differences in the kinetic profiles of signaling and gene expression responses in vitro, as well as the physiologically relevant differences in the in vivo responses to these ligands.

Melatonin Reduces Oxidative Damage Induced by Aluminium in Rat Kidney

Toxicology Letters. Oct, 2009  |  Pubmed ID: 19539013

We evaluated the effect of melatonin (Mel), in male Wistar rats which received aluminium (Al) lactate for 12 weeks (0.57 mg Al/100g body weight (b.w.), i.p. three times per week). Moreover rats received Mel (10 mg/kg b.w. i.p. 5 days/weeks) for 12 weeks. At the end of the treatment water and sodium balances were studied, and nephrogenic cyclic adenosine monophosphate (cAMP) was also measured. Urinary osmolality was measured after the administration of desmopressin (vasopressin agonist) to assess concentrating capacity. Oxidative stress in renal tissue and Na(+)-K(+)ATPase and gamma-glutamyl transferase (GGT) activities in whole plasma membrane were determined. Sodium and water balances were impaired by Al. We found decreased urinary concentrating ability and nephrogenic cAMP excretion. Al increased the Na(+)-K(+)ATPase activity, and serum aldosterone concentration. Mel normalized serum aldosterone level, the Na(+)-K(+)ATPase activity and potassium urinary without improving water and sodium excretion. Mel treatment did not improve the impaired urinary concentrating ability. Al reduced the GGT activity, an effect that persists in Al(+) Mel. Al exposure promoted oxidative stress with an increase in lipid peroxidation (LPO), and a decrease in glutathione (GSH) and glutathione peroxidase (GSH-Px) and catalase (CAT) activities. Mel markedly attenuated oxidative stress produced by Al. This may result from the higher efficacy of melatonin in scavenging various free radicals and also because of its ability in stimulating the antioxidant enzymes. However, it only reduced some alterations in the renal functions particularly related to the water and sodium excretion, which would be independent of the increased production of reactive oxygen substances.

Lmx1a Maintains Proper Neurogenic, Sensory, and Non-sensory Domains in the Mammalian Inner Ear

Developmental Biology. Sep, 2009  |  Pubmed ID: 19540218

Lmx1a is a LIM homeodomain-containing transcription factor, which is required for the formation of multiple organs. Lmx1a is broadly expressed in early stages of the developing inner ear, but its expression is soon restricted to the non-sensory regions of the developing ear. In an Lmx1a functional null mutant, dreher (dr(J)/dr(J)), the inner ears lack a non-sensory structure, the endolymphatic duct, and the membranous labyrinth is poorly developed. These phenotypes are consistent with Lmx1a's role as a selector gene. More importantly, while all three primary fates of the inner ear - neural, sensory, and non-sensory - are specified in dr(J)/dr(J), normal boundaries among these tissues are often violated. For example, the neurogenic domain of the ear epithelium, from which cells delaminate to form the cochleovestibular ganglion, is expanded. Within the neurogenic domain, the demarcation between the vestibular and auditory neurogenic domains is most likely disrupted as well, based on the increased numbers of vestibular neuroblasts and ectopic expression of Fgf3, which normally is associated specifically with the vestibular neurogenic region. Furthermore, aberrant and ectopic sensory organs are observed; most striking among these is vestibular-like hair cells located in the cochlear duct.

Differences Between Food Group Reports of Low-energy Reporters and Non-low-energy Reporters on a Food Frequency Questionnaire

Journal of the American Dietetic Association. Jul, 2009  |  Pubmed ID: 19559136

Low-energy reporters (LERs) and non-LERs differ with respect to several characteristics, including self-reported intake of foods. Limited data exist regarding food intake difference between LERs and non-LERs identified using doubly labeled water (DLW).

A Snapshot of Management Practices and Nutritional Recommendations Used by Feedlot Nutritionists in Brazil

Journal of Animal Science. Oct, 2009  |  Pubmed ID: 19574564

Feedlot consulting nutritionists were invited to participate in a survey of feedlot nutritional and management practices in Brazil. Thirty-one nutritionists completed the survey on a Web site that was designed for collection of survey data. The survey consisted of 94 questions that included general information (n = 10); commodity information (n = 12); and questions about the use of coproducts (n = 5), roughage source and levels (n = 5), finishing diet adaptation methods (n = 7), supplements and micronutrients (n = 8), feed mixers (n = 6), feeding management (n = 3), cattle management and type of cattle fed (n = 16), formulation practices (n = 17), information resources used for nutritional recommendations (n = 2), and 2 additional questions. One final question addressed the primary challenges associated with applying nutritional recommendations in practice. The number of animals serviced yearly by each nutritionist averaged 121,682 (minimum = 2,000; maximum = 1,500,000; mode = 120,000; total = 3,163,750). Twenty-two respondents (71%) worked with feedlots that feed less than 5,000 animals/yr. Labor, along with availability and precision of equipment, seemed to be the main challenges for the nutritionists surveyed. Most of the nutritionists surveyed used TDN as the primary energy unit for formulation. More than 50% of the clients serviced by the 31 nutritionists did not manage feed bunks to control the quantity of feed offered per pen, and 36.6% fed cattle more than 4 times daily. The NRC (1996) and Journal of Animal Science were the most used sources of information by these nutritionists. Overall, general practices and nutritional recommendations provided by the 31 nutritionists surveyed were fairly consistent. Present data should aid in development of new research, future National Research Council models, and recommendations for Brazilian feeding systems in which Bos indicus cattle predominate.

Multicenter Study of Knowledge About Human Papilloma Virus and Attitudes Among Emergency Department Patients

Journal of Pediatric and Adolescent Gynecology. Dec, 2009  |  Pubmed ID: 19576825

We sought to evaluate knowledge of human papilloma virus (HPV) and attitudes toward the HPV vaccine among emergency department (ED) patients.

Concerning the Hydrolytic Stability of 8-aryl-2'-deoxyguanosine Nucleoside Adducts: Implications for Abasic Site Formation at Physiological PH

The Journal of Organic Chemistry. Aug, 2009  |  Pubmed ID: 19603821

Direct addition of aryl radical species to the C(8)-site of 2'-deoxyguanosine (dG) affords C(8)-aryl-dG adducts that are produced by carcinogenic arylhydrazines, polycyclic aromatic hydrocarbons (PAHs), and certain phenolic toxins. A common property of C(8)-arylpurine adduction is the accompaniment of abasic site formation. To determine how the C(8)-aryl moiety contributes to sugar loss, UV-vis spectroscopy has been employed to determine N(7) pK(a1) values and hydrolysis kinetics, while density functional theory (DFT) calculations have been utilized to probe the structural features and stability of the C(8)-aryl-dG adducts bearing different para and ortho substituents. In all cases, the C(8)-aryl-dG adducts adopt a syn conformation containing a strong O(5)'-H...N(3) hydrogen bond with the aryl ring twisted with respect to the nucleobase. The adducts undergo N(7)-protonation with ionization constants and calculated N(7) proton affinity (PA) values similar to those measured for dG. The hydrolysis kinetics shows that C(8)-aryl-dG nucleoside adducts are more prone than dG to acid-catalyzed hydrolysis, with those bearing para substituents having k(1) values that are ca. 90- to 200-fold larger than k(1) for dG, while the effects for the ortho adducts are only ca. 9- to 60-fold larger. Changes in the rate of hydrolysis are further explained by calculations showing that glycosidic bond cleavage in the syn orientation of both neutral and N(7)-protonated dG has a lower barrier than the anti orientation, and the bulky (phenyl) group further decreases the barrier. Despite adduct reactivity in acidic media, all adducts are relatively stable at physiological pH with t(1/2) approximately 25 days, suggesting that they are unlikely intermediates leading to abasic site formation at physiological pH. This information has allowed development of a new rationale for the tendency of abasic site formation to accompany C(8)-arylpurine adduction within duplex DNA at neutral pH.

FOXC1 is Required for Normal Cerebellar Development and is a Major Contributor to Chromosome 6p25.3 Dandy-Walker Malformation

Nature Genetics. Sep, 2009  |  Pubmed ID: 19668217

Dandy-Walker malformation (DWM), the most common human cerebellar malformation, has only one characterized associated locus. Here we characterize a second DWM-linked locus on 6p25.3, showing that deletions or duplications encompassing FOXC1 are associated with cerebellar and posterior fossa malformations including cerebellar vermis hypoplasia (CVH), mega-cisterna magna (MCM) and DWM. Foxc1-null mice have embryonic abnormalities of the rhombic lip due to loss of mesenchyme-secreted signaling molecules with subsequent loss of Atoh1 expression in vermis. Foxc1 homozygous hypomorphs have CVH with medial fusion and foliation defects. Human FOXC1 heterozygous mutations are known to affect eye development, causing a spectrum of glaucoma-associated anomalies (Axenfeld-Rieger syndrome, ARS; MIM no. 601631). We report the first brain imaging data from humans with FOXC1 mutations and show that these individuals also have CVH. We conclude that alteration of FOXC1 function alone causes CVH and contributes to MCM and DWM. Our results highlight a previously unrecognized role for mesenchyme-neuroepithelium interactions in the mid-hindbrain during early embryogenesis.

Alcohol Consumption and Genetic Variation in Methylenetetrahydrofolate Reductase and 5-methyltetrahydrofolate-homocysteine Methyltransferase in Relation to Breast Cancer Risk

Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology. Sep, 2009  |  Pubmed ID: 19706843

It has been hypothesized that effects of alcohol consumption on one-carbon metabolism may explain, in part, the association of alcohol consumption with breast cancer risk. The methylenetetrahydrofolate reductase (MTHFR) and 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR) genes express key enzymes in this pathway. We investigated the association of polymorphisms in MTHFR (rs1801133 and rs1801131) and MTR (rs1805087) with breast cancer risk and their interaction with alcohol consumption in a case-control study--the Western New York Exposures and Breast Cancer study. Cases (n = 1,063) were women with primary, incident breast cancer and controls (n = 1,890) were frequency matched to cases on age and race. Odds ratios (OR) and 95% confidence intervals (95% CI) were estimated by unconditional logistic regression. We found no association of MTHFR or MTR genotype with risk of breast cancer. In the original case-control study, there was a nonsignificant increased odds of breast cancer among women with higher lifetime drinking. In the current study, there was no evidence of an interaction of genotype and alcohol in premenopausal women. However, among postmenopausal women, there was an increase in breast cancer risk for women who were homozygote TT for MTHFR C677T and had high lifetime alcohol intake (>or=1,161.84 oz; OR, 1.92; 95% CI, 1.13-3.28) and for those who had a high number of drinks per drinking day (>1.91 drinks/day; OR, 1.80; 95% CI, 1.03-3.28) compared with nondrinkers who were homozygote CC. Our findings indicate that among postmenopausal women, increased breast cancer risk with alcohol consumption may be as a result of effects on one-carbon metabolism.

Overlapping Function of Lmx1a and Lmx1b in Anterior Hindbrain Roof Plate Formation and Cerebellar Growth

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. Sep, 2009  |  Pubmed ID: 19741143

The roof plate is an organizing center in the dorsal CNS that controls specification and differentiation of adjacent neurons through secretion of the BMP and WNT signaling molecules. Lmx1a, a member of the LIM-homeodomain (LIM-HD) transcription factor family, is expressed in the roof plate and its progenitors at all axial levels of the CNS and is necessary and sufficient for roof plate formation in the spinal cord. In the anterior CNS, however, a residual roof plate develops in the absence of Lmx1a. Lmx1b, another member of the LIM-HD transcription factor family which is highly related to Lmx1a, is expressed in the roof plate in the anterior CNS. Although Lmx1b-null mice do not show a substantial deficiency in hindbrain roof plate formation, Lmx1a/Lmx1b compound-null mutants fail to generate hindbrain roof plate. This observation indicates that both genes act in concert to direct normal hindbrain roof plate formation. Since the requirement of Lmx1b function for normal isthmic organizer at the mid-hindbrain boundary complicates analysis of a distinct dorsal patterning role of this gene, we also used a conditional knock-out strategy to specifically delete dorsal midline Lmx1b expression. Phenotypic analysis of single and compound conditional mutants confirmed overlapping roles for Lmx1 genes in regulating hindbrain roof plate formation and growth and also revealed roles in regulating adjacent cerebellar morphogenesis. Our data provides the first evidence of overlapping function of the Lmx1 genes during embryonic CNS development.

Model Organisms Inform the Search for the Genes and Developmental Pathology Underlying Malformations of the Human Hindbrain

Seminars in Pediatric Neurology. Sep, 2009  |  Pubmed ID: 19778712

Congenital malformations of the human hindbrain, including the cerebellum, are poorly understood largely because their recognition is a relatively recent advance for imaging diagnostics. Cerebellar malformations are the most obvious and best characterized hindbrain malformations due to their relative ease of viewing by magnetic resonance imaging and the recent identification of several causative genes (Millen et al. Curr Opin Neurobiol 18:12-19, 2008). Malformations of the pons and medulla have also been described both in isolation and in association with cerebellar malformations (Barkovich et al. Ann Neurol 62:625-639, 2007). Although little is understood regarding the specific developmental pathologies underlying hindbrain malformations in humans, much is known regarding the mechanisms and genes driving hindbrain development in vertebrate model organisms. Thus, studies in vertebrate models provide a developmental framework in which to categorize human hindbrain malformations and serve to provide information regarding disrupted developmental processes and candidate genes. Here, we survey the basic principles of vertebrate hindbrain development and integrate our current knowledge of human hindbrain malformations into this framework.

Surveillance Beyond Camp Settings in Humanitarian Emergencies: Findings from the Humanitarian Health Information Management Working Group

Prehospital and Disaster Medicine. Jul-Aug, 2009  |  Pubmed ID: 19806541

Surveillance is an essential component of health and nutrition information management during humanitarian situations. Changes in the nature and scope of humanitarian assistance activities have created new challenges in health surveillance, particularly outside of camp-based settings.

Promoting Self-efficacy and Outcome Expectations to Enable Adherence to Resistance Training After Cardiac Rehabilitation

The Journal of Cardiovascular Nursing. Jul-Aug, 2009  |  Pubmed ID: 21206354

Resistance training offers clinical and functional benefits to cardiac patients, yet exercise adherence after cardiac rehabilitation (CR) is problematic. This study examined effects of an intervention targeting self-efficacy, outcome expectations, and adherence to upper-body resistance exercise after CR.

Differential Gene Expression in the Developing Lateral Geniculate Nucleus and Medial Geniculate Nucleus Reveals Novel Roles for Zic4 and Foxp2 in Visual and Auditory Pathway Development

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. Oct, 2009  |  Pubmed ID: 19864579

Primary sensory nuclei of the thalamus process and relay parallel channels of sensory input into the cortex. The developmental processes by which these nuclei acquire distinct functional roles are not well understood. To identify novel groups of genes with a potential role in differentiating two adjacent sensory nuclei, we performed a microarray screen comparing perinatal gene expression in the principal auditory relay nucleus, the medial geniculate nucleus (MGN), and principal visual relay nucleus, the lateral geniculate nucleus (LGN). We discovered and confirmed groups of highly ranked, differentially expressed genes with qRT-PCR and in situ hybridization. A functional role for Zic4, a transcription factor highly enriched in the LGN, was investigated using Zic4-null mice, which were found to have changes in topographic patterning of retinogeniculate projections. Foxp2, a transcriptional repressor expressed strongly in the MGN, was found to be positively regulated by activity in the MGN. These findings identify roles for two differentially expressed genes, Zic4 and Foxp2, in visual and auditory pathway development. Finally, to test whether modality-specific patterns of gene expression are influenced by extrinsic patterns of input, we performed an additional microarray screen comparing the normal MGN to "rewired" MGN, in which normal auditory afferents are ablated and novel retinal inputs innervate the MGN. Data from this screen indicate that rewired MGN acquires some patterns of gene expression that are present in the developing LGN, including an upregulation of Zic4 expression, as well as novel patterns of expression which may represent unique processes of cross-modal plasticity.

Social Learning Mechanisms and Cumulative Cultural Evolution. Is Imitation Necessary?

Psychological Science. Dec, 2009  |  Pubmed ID: 19891752

Cumulative cultural evolution has been suggested to account for key cognitive and behavioral attributes that distinguish modern humans from their anatomically similar ancestors, but researchers have yet to establish which cognitive mechanisms are responsible for this kind of learning and whether they are unique to humans. Here, we show that human participants' cumulative learning is not always reliant on sources of social information commonly assumed to be essential. Seven hundred participants were organized into 70 microsocieties and completed a task involving building a paper airplane. We manipulated the availability of opportunities for imitation (reproducing actions), emulation (reproducing end results), and teaching. Each condition was independently sufficient for participants to show cumulative learning. Because emulative learning can elicit cumulative culture on this task, we conclude that accounts of the unusual complexity of human culture in terms of species-unique learning mechanisms do not currently provide complete explanations and that other factors may be involved.

Looking at Cerebellar Malformations Through Text-mined Interactomes of Mice and Humans

PLoS Computational Biology. Nov, 2009  |  Pubmed ID: 19893633

We have generated and made publicly available two very large networks of molecular interactions: 49,493 mouse-specific and 52,518 human-specific interactions. These networks were generated through automated analysis of 368,331 full-text research articles and 8,039,972 article abstracts from the PubMed database, using the GeneWays system. Our networks cover a wide spectrum of molecular interactions, such as bind, phosphorylate, glycosylate, and activate; 207 of these interaction types occur more than 1,000 times in our unfiltered, multi-species data set. Because mouse and human genes are linked through an orthological relationship, human and mouse networks are amenable to straightforward, joint computational analysis. Using our newly generated networks and known associations between mouse genes and cerebellar malformation phenotypes, we predicted a number of new associations between genes and five cerebellar phenotypes (small cerebellum, absent cerebellum, cerebellar degeneration, abnormal foliation, and abnormal vermis). Using a battery of statistical tests, we showed that genes that are associated with cerebellar phenotypes tend to form compact network clusters. Further, we observed that cerebellar malformation phenotypes tend to be associated with highly connected genes. This tendency was stronger for developmental phenotypes and weaker for cerebellar degeneration.

Measuring Piecemeal Microautophagy of the Nucleus in Saccharomyces Cerevisiae

Autophagy. Jan, 2009  |  Pubmed ID: 18989095

Piecemeal microautophagy of the nucleus (PMN) selectively removes and degrades small fragments of the Saccharomyces cerevisiae nucleus. Inter-organelle contact sites called nucleus-vacuole (NV) junctions determine the selectivity of PMN by establishing a platform for the biogenesis of PMN blebs and vesicles. PMN structures can be observed by fluorescence microscopy using GFP-tagged reporters; however, this approach is best supported with quantitative immunoblot assays of PMN-specific cargo degradation. Together, these assays should facilitate the further study of this fascinating but poorly understood autophagic process in different genetic backgrounds, physiological states, and environmental conditions.

DNA Hypermethylation and Clinicopathological Features in Breast Cancer: the Western New York Exposures and Breast Cancer (WEB) Study

Breast Cancer Research and Treatment. Apr, 2009  |  Pubmed ID: 18463976

Aberrant DNA hypermethylation of gene promoter regions has been increasingly recognized as a common molecular alteration in carcinogenesis. We evaluated the association between major clinicopathological features and hypermethylation of genes in tumors among 803 incidence breast cancer cases from a large population-based case-control study conducted in Western New York State. DNA samples were isolated from archive paraffin embedded tumor tissue and were analyzed for hypermethylation status of the E-cadherin, p16, and RAR-beta(2) genes using real time methylation-specific polymerase chain reaction. The frequencies of hypermethylation were 20.0% for E-cadherin, 25.9% for p16, and 27.5% for RAR-beta(2) genes. For postmenopausal women, hypermethylation of E-cadherin tended to be more likely in progesterone receptor (PR) negative than in PR-positive tumors (odds ratio (OR), 1.41; 95% confidence interval (CI), 0.91-2.18). Hypermethylation of p16 tended to be more frequent among estrogen receptor (ER) negative cases than ER-positive cases (OR, 1.51; 95% CI, 1.01-2.32). Hypermethylation of RAR-beta(2) gene was inversely associated with histological and nuclear grade of breast cancer.

Diet Quality and Obesity in Women: the Framingham Nutrition Studies

The British Journal of Nutrition. Apr, 2010  |  Pubmed ID: 19930766

Obesity affects one in three American adult women and is associated with overall mortality and major morbidities. A composite diet index to evaluate total diet quality may better assess the complex relationship between diet and obesity, providing insights for nutrition interventions. The purpose of the present investigation was to determine whether diet quality, defined according to the previously validated Framingham nutritional risk score (FNRS), was associated with the development of overweight or obesity in women. Over 16 years, we followed 590 normal-weight women (BMI < 25 kg/m2), aged 25 to 71 years, of the Framingham Offspring and Spouse Study who presented without CVD, cancer or diabetes at baseline. The nineteen-nutrient FNRS derived from mean ranks of nutrient intakes from 3 d dietary records was used to assess nutritional risk. The outcome was development of overweight or obesity (BMI > or = 25 kg/m2) during follow-up. In a stepwise multiple logistic regression model adjusted for age, physical activity and smoking status, the FNRS was directly related to overweight or obesity (P for trend = 0.009). Women with lower diet quality (i.e. higher nutritional risk scores) were significantly more likely to become overweight or obese (OR 1.76; 95 % CI 1.16, 2.69) compared with those with higher diet quality. Diet quality, assessed using a comprehensive composite nutritional risk score, predicted development of overweight or obesity. This finding suggests that overall diet quality be considered a key component in planning and implementing programmes for obesity risk reduction and treatment recommendations.

Identification and Characterization of the Carbohydrate Ligands Recognized by Pertussis Toxin Via a Glycan Microarray and Surface Plasmon Resonance

Biochemistry. Jul, 2010  |  Pubmed ID: 20515023

Binding of pertussis toxin (PTx) was examined by a glycan microarray; 53 positive hits fell into four general groups. One group represents sialylated biantennary compounds with an N-glycan core terminating in alpha2-6-linked sialic acid. The second group consists of multiantennary compounds with a canonical N-glycan core, but lacking terminal sialic acids, which represents a departure from the previous understanding of PTx binding to N-glycans. The third group consists of Neu5Acalpha2-3(lactose or N-acetyllactosamine) forms that lack the branched mannose core found in N-glycans; thus, their presentation is more similar to that of O-linked glycans and glycolipids. The fourth group of compounds consists of Neu5Acalpha2-8Neu5Acalpha2-8Neu5Ac, which is seen in the c series gangliosides and some N-glycans. Quantitative analysis by surface plasmon resonance of the relative affinities of PTx for terminal Neu5Acalpha2-3 versus Neu5Acalpha2-6, as well as the affinities for the trisaccharide Neu5Acalpha2-8Neu5Acalpha2-8Neu5Ac versus disaccharide, revealed identical global affinities, even though the amount of bound glycan varied by 4-5-fold. These studies suggest that the conformational space occupied by a glycan can play an important role in binding, independent of affinity. Characterization of N-terminal and C-terminal binding sites on the S2 and S3 subunits by mutational analysis revealed that binding to all sialylated compounds was mediated by the C-terminal binding sites, and binding to nonsialylated N-linked glycans is mediated by the N-terminal sites present on both the S2 and S3 subunits. A detailed understanding of the glycans recognized by pertussis toxin is essential to understanding which cells are targeted in clinical disease.

Healthy Diets and the Subsequent Prevalence of Nuclear Cataract in Women

Archives of Ophthalmology. Jun, 2010  |  Pubmed ID: 20547952

To assess the association between healthy diet scores and prevalence of nuclear cataract in women.

Signal Detection and Placebo Response in Schizophrenia: Parallels with Depression

Psychopharmacology Bulletin. 2010  |  Pubmed ID: 20581800

OBJECTIVE: Placebo response and the rate of failed clinical trials are increasing in schizophrenia, resembling previous experience with antidepressant clinical trials. In depression, the percent of patients randomized to placebo was shown to be strongly associated with drug-placebo differences (signal detection).We hypothesized that this factor would also be important in recent schizophrenia clinical trials. To test this hypothesis a database of acute schizophrenia placebo-controlled studies conducted between 1997 and 2008 was constructed. The database contained 27 studies, with 79 active treatment arms. As percentage of patients randomized to placebo increased, mean placebo improvement decreased (p = 0.047) and mean drug-placebo differences tended to increase (p = 0.166). The frequency of significant contrasts from studies with ≥ 25% randomized to placebo was 83.3%, compared with 58.3% in studies with <25% randomized to placebo. Caveats to these findings include limited data and confounding of potentially influential factors. These limitations prevent definitive conclusions. However, results are consistent with previous findings in depression where having a higher percent of patients randomized to placebo increased drug-placebo differences.

Human Cumulative Culture in the Laboratory: Effects of (micro) Population Size

Learning & Behavior. Aug, 2010  |  Pubmed ID: 20628168

Traditionally, experiments on social learning (in both humans and nonhumans) involve dyads, with an experimenter or experimenter-trained conspecific serving as the demonstrator and the participant as the observer. But social learning in nature often involves multiple potential models, and the models themselves were once learners. We discuss our studies of social learning by adult humans in interactive group settings in the absence of formal demonstrations by experimenters, which tracked transmission over multiple learner generations. In these experiments, we found evidence for cumulative learning over generations. This has allowed us to manipulate learning conditions in order to test hypotheses regarding the necessary conditions for cumulative culture. We also report results from a further experiment using similar methods, which compared conditions of varying cohort size. Participants were given the task to build a paper airplane to fly as far as possible. Contrary to expectations, there was no advantage for larger cohort sizes, in terms of the cumulative effects observed.

Dietary Behavior Assessment: Historical and Recent Innovations

Journal of the American Dietetic Association. Aug, 2010  |  Pubmed ID: 20656091

The Cystic Fibrosis-causing Mutation DeltaF508 Affects Multiple Steps in Cystic Fibrosis Transmembrane Conductance Regulator Biogenesis

The Journal of Biological Chemistry. Nov, 2010  |  Pubmed ID: 20667826

The deletion of phenylalanine 508 in the first nucleotide binding domain of the cystic fibrosis transmembrane conductance regulator is directly associated with >90% of cystic fibrosis cases. This mutant protein fails to traffic out of the endoplasmic reticulum and is subsequently degraded by the proteasome. The effects of this mutation may be partially reversed by the application of exogenous osmolytes, expression at low temperature, and the introduction of second site suppressor mutations. However, the specific steps of folding and assembly of full-length cystic fibrosis transmembrane conductance regulator (CFTR) directly altered by the disease-causing mutation are unclear. To elucidate the effects of the ΔF508 mutation, on various steps in CFTR folding, a series of misfolding and suppressor mutations in the nucleotide binding and transmembrane domains were evaluated for effects on the folding and maturation of the protein. The results indicate that the isolated NBD1 responds to both the ΔF508 mutation and intradomain suppressors of this mutation. In addition, identification of a novel second site suppressor of the defect within the second transmembrane domain suggests that ΔF508 also effects interdomain interactions critical for later steps in the biosynthesis of CFTR.

Cerebellar Hypoplasia and Cohen Syndrome: a Confirmed Association

American Journal of Medical Genetics. Part A. Sep, 2010  |  Pubmed ID: 20683995

Phenotypic and Genetic Analysis of the Cerebellar Mutant Tmgc26, a New ENU-induced ROR-alpha Allele

The European Journal of Neuroscience. Sep, 2010  |  Pubmed ID: 20722722

ROR-alpha is an orphan nuclear receptor, inactivation of which cell-autonomously blocks differentiation of cerebellar Purkinje cells with a secondary loss of granule neurons. As part of our ENU mutagenesis screen we isolated the recessive tmgc26 mouse mutant, characterized by early-onset progressive ataxia, cerebellar degeneration and juvenile lethality. Detailed analysis of the tmgc26-/- cerebella revealed Purkinje cell and granule cell abnormalities, and defects in molecular layer interneurons and radial glia. Chimera studies suggested a cell-autonomous effect of the tmgc26 mutation in Purkinje cells and molecular layer interneurons, and a non-cell-autonomous effect in granule cells. The mutation was mapped to a 13-Mb interval on chromosome 9, a region that contains the ROR-alpha gene. Sequencing of genomic DNA revealed a T-to-A transition in exon 5 of the ROR-alpha gene, resulting in a nonsense mutation C257X and severe truncation of the ROR-alpha protein. Together, our data identify new roles for ROR-alpha in molecular layer interneurons and radial glia development and suggest tmgc26 as a novel ROR-alpha allele that may be used to further delineate the molecular mechanisms of ROR-alpha action.

An Obesity Dietary Quality Index Predicts Abdominal Obesity in Women: Potential Opportunity for New Prevention and Treatment Paradigms

Journal of Obesity. 2010  |  Pubmed ID: 20798863

Background. Links between dietary quality and abdominal obesity are poorly understood. Objective. To examine the association between an obesity-specific dietary quality index and abdominal obesity risk in women. Methods. Over 12 years, we followed 288 Framingham Offspring/Spouse Study women, aged 30-69 years, without metabolic syndrome risk factors, cardiovascular disease, cancer, or diabetes at baseline. An 11-nutrient obesity-specific dietary quality index was derived using mean ranks of nutrient intakes from 3-day dietary records. Abdominal obesity (waist circumference >88 cm) was assessed during follow-up. Results. Using multiple logistic regression, women with poorer dietary quality were more likely to develop abdominal obesity compared to those with higher dietary quality (OR 1.87; 95% CI, 1.01, 3.47; P for trend = .048) independent of age, physical activity, smoking, and menopausal status. Conclusions. An obesity-specific dietary quality index predicted abdominal obesity in women, suggesting targets for dietary quality assessment, intervention, and treatment to address abdominal adiposity.

Effect of Watson-Crick and Hoogsteen Base Pairing on the Conformational Stability of C8-phenoxyl-2'-deoxyguanosine Adducts

The Journal of Physical Chemistry. B. Oct, 2010  |  Pubmed ID: 20853889

Bulky DNA addition products (adducts) formed through attack at the C8 site of guanine can adopt the syn orientation about the glycosidic bond due to changes in conformational stability or hydrogen-bonding preferences directly arising from the bulky group. Indeed, the bulky substituent may improve the stability of (non-native) Hoogsteen pairs. Therefore, such adducts often result in mutations upon DNA replication. This work examines the hydrogen-bonded pairs between the Watson-Crick and Hoogsteen faces of the ortho or para C8-phenoxyl-2'-deoxyguanosine adduct and each natural (undamaged) nucleobase with the goal to clarify the conformational preference of this type of damage, as well as provide insight into the likelihood of subsequent mutation events. B3LYP/6-311+G(2df,p)//B3LYP/6-31G(d) hydrogen-bond strengths were determined using both nucleobase and nucleoside models for adduct pairs, as well as the corresponding complexes involving natural 2'-deoxyguanosine. In addition to the magnitude of the binding strengths, the R(C1'···C1') distances and ∠(N9C1'C1') angles, as well as the degree of propeller-twist and buckle distortions, were carefully compared to the values observed in natural DNA strands. Due to structural changes in the adduct monomer upon inclusion of the sugar moiety, the monomer deformation energy significantly affects the relative hydrogen-bond strengths calculated with the nucleobase and nucleoside models. Therefore, we recommend the use of at least a nucleoside model to accurately evaluate hydrogen-bond strengths of base pairs involving flexible, bulky nucleobase adducts. Our results also emphasize the importance of considering both the magnitude of the hydrogen-bond strength and the structure of the base pair when predicting the preferential binding patterns of nucleobases. Using our best models, we conclude that the Watson-Crick face of the ortho phenoxyl adduct forms significantly more stable complexes than the Hoogsteen face, which implies that the anti orientation of the damaged base will be favored by hydrogen bonding in DNA helices. Additionally, regardless of the hydrogen-bonding face involved, cytosine forms the most stable base pair with the ortho adduct, which implies that misincorporation due to this type of damage is unlikely. Similarly, cytosine is the preferred binding partner for the Watson-Crick face of the para adduct. However, Hoogsteen interactions with the para adduct are stronger than those with natural 2'-deoxyguanosine or the ortho adduct, and this form of damage binds with nearly equal stability to both cytosine and guanine in the Hoogsteen orientation. Therefore, the para adduct may adopt multiple orientations in DNA helices and potentially cause mutations by forming pairs with different natural bases. Models of oligonucleotide duplexes must be used in future work to further evaluate other factors (stacking, major groove contacts) that may influence the conformation and binding preference of these adducts in DNA helices.

A Unique Redox-sensing Sensor II Motif in TorsinA Plays a Critical Role in Nucleotide and Partner Binding

The Journal of Biological Chemistry. Nov, 2010  |  Pubmed ID: 20861018

Early onset dystonia is commonly associated with the deletion of one of a pair of glutamate residues (ΔE302/303) near the C terminus of torsinA, a member of the AAA+ protein family (ATPases associated with a variety of cellular activities) located in the endoplasmic reticulum lumen. The functional consequences of the disease-causing mutation, ΔE, are not currently understood. By contrast to other AAA+ proteins, torsin proteins contain two conserved cysteine residues in the C-terminal domain, one of which is located in the nucleotide sensor II motif. Depending on redox status, an ATP hydrolysis mutant of torsinA interacts with lamina-associated polypeptide 1 (LAP1) and lumenal domain like LAP1 (LULL1). Substitution of the cysteine in sensor II diminishes the redox-regulated interaction of torsinA with these substrates. Significantly, the dystonia-causing mutation, ΔE, alters the ability of torsinA to mediate the redox-regulated interactions with LAP1 and LULL1. Limited proteolysis experiments reveal redox- and mutation-dependent changes in the local conformation of torsinA as a function of nucleotide binding. These results indicate that the cysteine-containing sensor II plays a critical role in redox sensing and the nucleotide and partner binding functions of torsinA and suggest that loss of this function of torsinA contributes to the development of DYT1 dystonia.

Two-electron Excitation of an Interacting Cold Rydberg Gas

Physical Review Letters. Nov, 2010  |  Pubmed ID: 21231300

We report the creation of an interacting cold Rydberg gas of strontium atoms. We show that the excitation spectrum of the inner valence electron is sensitive to the interactions in the Rydberg gas, even though they are mediated by the outer Rydberg electron. By studying the evolution of this spectrum we observe density-dependent population transfer to a state of higher angular momentum l. We determine the fraction of Rydberg atoms transferred, and identify the dominant transfer mechanism to be l-changing electron-Rydberg collisions associated with the formation of a cold plasma.

The Prevalence of Neck Pain in Migraine

Headache. Sep, 2010  |  Pubmed ID: 20100298

To determine the prevalence of neck pain at the time of migraine treatment relative to the prevalence of nausea, a defining associated symptom of migraine.

Evaluation of a Comprehensive Tobacco Control Project Targeting Arabic-speakers Residing in South West Sydney, Australia

Health Promotion International. Jun, 2010  |  Pubmed ID: 20189945

Tobacco control is a health promotion priority, but there is limited evidence on the effectiveness of campaigns targeting culturally and linguistically diverse (CALD) populations. Being the largest population of non-English-speaking smokers residing in New South Wales (NSW), Australia, Arabic-speakers are a priority population for tobacco control. We report findings from baseline and post-intervention cross-sectional telephone surveys evaluating a comprehensive social marketing campaign (SMC) specifically targeting Arabic-speakers residing in south west Sydney, NSW. The project was associated with a decline in self-reported smoking prevalence from 26% at baseline to 20.7% at post (p < 0.05) and an increase in self-reported smoke-free households from 67.1% at baseline to 74.9% at post (p < 0.05). This paper contributes evidence that comprehensive SMCs targeting CALD populations can reduce smoking prevalence and influence smoking norms in CALD populations.

Conformational Flexibility of C8-phenoxyl-2'-deoxyguanosine Nucleotide Adducts

The Journal of Physical Chemistry. B. Apr, 2010  |  Pubmed ID: 20201579

Previous computational work suggests that isolated C8-phenoxyl-2'-deoxyguanosine nucleoside adducts preferentially adopt a syn orientation about the glycosidic bond, which is the first step in the mechanism by which many bulky C8 adducts exert their mutagenic effects. Since it is not clear whether these results can be directly extrapolated to the preferred conformation in DNA helices, approaches that more accurately reflect the physiological environment were used in the present study to understand the anti/syn preference of the ortho and para C8-phenoxyl-2'-deoxyguanosine adducts. Using nucleoside models and methods (B3LYP) similar to those previously implemented, we determine that the syn conformer is less stable than previously predicted when geometries relevant to B-DNA are considered. This indicates that the conformational energy trend is model dependent and stresses the importance of considering models that better mimic the DNA environment when determining the conformational preference of damaged bases. Therefore, we expanded our computational model to include the 5'-monophosphate group. Since the correct anti/syn energy trend for 2'-deoxyguanosine (dG) 5'-monophosphate has only been found using very specific computational models and prior knowledge of the biologically relevant nucleotide conformation, which is unavailable for most damaged systems, we initially benchmark our computational approach by studying the natural nucleotide. Despite the wide use of gas-phase optimizations in the current literature, only through the implementation of solvation-phase optimizations, as well as the use of a counterion model for the phosphate backbone, is the correct anti/syn energy trend predicted. Indeed, this is the first time in the literature that a biologically relevant syn structure is characterized for dG using methods suitable for studying bulky DNA adducts. Subsequently, our newly identified approach for DNA lesions was used to study C8-phenoxyl DNA adducts. In contrast to previously published results, we predict that the ortho and para adducts may adopt both the anti and syn conformations in DNA helices. These results have implications for the base-pairing properties and mutagenicity of these adducts, which must be further considered in future work.

Predictors of Serum 25-hydroxyvitamin D Concentrations Among Postmenopausal Women: the Women's Health Initiative Calcium Plus Vitamin D Clinical Trial

The American Journal of Clinical Nutrition. May, 2010  |  Pubmed ID: 20219959

It is unclear how well surrogate markers for vitamin D exposure (eg, oral intake of vitamin D and estimates of sunlight exposure), with and without consideration of other potential predictors of 25-hydroxyvitamin D [25(OH)D] concentrations, similarly rank individuals with respect to 25(OH)D blood concentrations.

Novel Approaches to Studying the Genetic Basis of Cerebellar Development

Cerebellum (London, England). Sep, 2010  |  Pubmed ID: 20387026

The list of genes that when mutated cause disruptions in cerebellar development is rapidly increasing. The study of both spontaneous and engineered mouse mutants has been essential to this progress, as it has revealed much of our current understanding of the developmental processes required to construct the mature cerebellum. Improvements in brain imaging, such as magnetic resonance imaging (MRI) and the emergence of better classification schemes for human cerebellar malformations, have recently led to the identification of a number of genes which cause human cerebellar disorders. In this review we argue that synergistic approaches combining classical molecular techniques, genomics, and mouse models of human malformations will be essential to fuel additional discoveries of cerebellar developmental genes and mechanisms.

Diet Quality, Physical Activity, Smoking Status, and Weight Fluctuation Are Associated with Weight Change in Women and Men

The Journal of Nutrition. Jul, 2010  |  Pubmed ID: 20484553

The effect of diet quality on weight change, relative to other body weight determinants, is insufficiently understood. Furthermore, research on long-term weight change in U.S. adults is limited. We evaluated prospectively patterns and predictors of weight change in Framingham Offspring/Spouse (FOS) women and men (n = 1515) aged > or =30 y with BMI > or = 18.5 kg/m2 and without cardiovascular disease, diabetes, and cancer at baseline over a 16-y period. Diet quality was assessed using the validated Framingham Nutritional Risk Score. In women, older age (P < 0.0001) and physical activity (P < 0.05) were associated with lower weight gain. Diet quality interacted with former smoking status (P-interaction = 0.02); former smokers with lower diet quality gained an additional 5.2 kg compared with those with higher diet quality (multivariable-adjusted P-trend = 0.06). Among men, older age (P < 0.0001) and current smoking (P < 0.01) were associated with lower weight gain, and weight fluctuation (P < 0.01) and former smoking status (P < 0.0001) were associated with greater weight gain. Age was the strongest predictor of weight change in both women (partial R(2) = 11%) and men (partial R(2) = 8.6%). Normal- and overweight women gained more than obese women (P < 0.05) and younger adults gained more weight than older adults (P < 0.0001). Patterns and predictors of weight change differ by sex. Age in both sexes and physical activity among women as well as weight fluctuation and smoking status in men were stronger predictors of weight change than diet quality among FOS adults. Women who stopped smoking over follow-up and had poor diet quality gained the most weight. Preventive interventions need to be sex-specific and consider lifestyle factors.

Nutrient Database Development: a Historical Perspective from the Framingham Nutrition Studies

Journal of the American Dietetic Association. Jun, 2010  |  Pubmed ID: 20497779

Food frequency questionnaires (FFQs) are commonly used in nutritional epidemiology to assess habitual eating habits. Development of an appropriate food and nutrient database is required for translating information derived from FFQs into estimates of nutrient intake, dietary quality, or for absolute or rank-ordered nutritional risk assessment. We discuss the procedures used recently in designing a historical nutrient database to analyze an FFQ administered in 1984-1988 to Framingham Offspring-Spouse Study members. This systematic approach should inform other research in the field. The self-administered 145-item Framingham FFQ is semi-quantitative with seven nonoverlapping response categories to determine annual consumption frequency. The database development process included selection of the US Department of Agriculture's Nutrient Database for Standard Reference as the primary raw data source, expansion of the 145 FFQ line items to code individual foods to assign nutrient values, a selection process to match foods to appropriate nutrition codes for nutrient information, and a statistical model to calculate nutrient intakes. The historical database contains 449 foods and nutrient data for all 29 nutrients available in 1985. The adequacy with which an FFQ can provide reliable diet assessment data depends on the integrity of the underlying database. We outlined a systematic protocol to derive usual dietary intake from an FFQ using a robust nutrient database that is appropriate for the Framingham Offspring-Spouse Study FFQ and its assessment time-frame. The database can be updated to accommodate changes in the food supply and eating behaviors and creates a foundation for future nutrition research.

Lmx1a Regulates Fates and Location of Cells Originating from the Cerebellar Rhombic Lip and Telencephalic Cortical Hem

Proceedings of the National Academy of Sciences of the United States of America. Jun, 2010  |  Pubmed ID: 20498066

The cerebellar rhombic lip and telencephalic cortical hem are dorsally located germinal zones which contribute substantially to neuronal diversity in the CNS, but the mechanisms that drive neurogenesis within these zones are ill defined. Using genetic fate mapping in wild-type and Lmx1a(-/-) mice, we demonstrate that Lmx1a is a critical regulator of cell-fate decisions within both these germinal zones. In the developing cerebellum, Lmx1a is expressed in the roof plate, where it is required to segregate the roof plate lineage from neuronal rhombic lip derivatives. In addition, Lmx1a is expressed in a subset of rhombic lip progenitors which produce granule cells that are predominantly restricted to the cerebellar posterior vermis. In the absence of Lmx1a, these cells precociously exit the rhombic lip and overmigrate into the anterior vermis. This overmigration is associated with premature regression of the rhombic lip and posterior vermis hypoplasia in Lmx1a(-/-) mice. These data reveal molecular organization of the cerebellar rhombic lip and introduce Lmx1a as an important regulator of rhombic lip cell-fate decisions, which are critical for maintenance of the entire rhombic lip and normal cerebellar morphogenesis. In the developing telencephalon Lmx1a is expressed in the cortical hem, and in its absence cortical hem progenitors contribute excessively to the adjacent hippocampus instead of producing Cajal-Retzius neurons. Thus, Lmx1a activity is critical for proper production of cells originating from both the cerebellar rhombic lip and the telencephalic cortical hem.

Double-blind, Placebo-controlled Evaluation of Extended-release Bupropion in Elderly Patients with Major Depressive Disorder

Journal of Psychopharmacology (Oxford, England). Apr, 2010  |  Pubmed ID: 19164492

Major depressive disorder in the elderly is associated with increased morbidity and reduced quality of life. This 10 week, placebo-controlled study investigated the efficacy and tolerability of extended-release bupropion (150-300 mg once daily) in depressed patients aged 65 years or older. The statistical assumptions necessary for the validity of the protocol-specified analysis of covariance were not met for the analysis of the primary outcome variable (Montgomery-Asberg Depression Rating Scale total score at Week 10, last observation carried forward). Alternative statistical methods used for the analysis of this variable demonstrated statistical significance. Statistically significant improvements were observed on the majority of secondary end points when compared with placebo, including the health outcome measures for motivation and energy, and life satisfaction and contentment. Adverse events were generally mild to moderate and similar between treatment groups. This study demonstrated that the extended-release bupropion is an effective, well-tolerated treatment for major depression in the elderly.

Alcohol Consumption and Breast Tumor Mitochondrial DNA Mutations

Breast Cancer Research and Treatment. Jun, 2010  |  Pubmed ID: 19847642

Mitochondrial DNA (mtDNA) mutations are frequent in breast tumors, but the etiology of these mutations is unknown. We hypothesized that these mutations are associated with exposures that affect oxidative stress such as alcohol metabolism. Using archived tumor blocks from incident breast cancer cases in a case control study, the Western New York Exposures and Breast Cancer (WEB) study, analysis of mtDNA mutations was conducted on 128 breast cancer cases selected based on extremes of alcohol intake. Temporal temperature gradient gel electrophoresis (TTGE) was used to screen the entire mtDNA genome and sequencing was completed for all TTGE positive samples. Case-case comparisons were completed using unconditional logistic regression to determine the relative prevalence of the mutations by exposures including alcohol consumption, manganese superoxide dismutase (MnSOD) genotype, nutrient intake related to oxidative stress and established breast cancer risk factors. Somatic mtDNA mutations were found in 60 of the 128 tumors examined. There were no differences in the prevalence of mtDNA mutations by alcohol consumption, MnSOD genotype or dietary intake. The likelihood of mtDNA mutations was reduced among those with a positive family history for breast cancer (OR = 0.33, CI = 0.12-0.92), among postmenopausal women who used hormone replacement therapy (OR = 0.46, CI = 0.19-1.08, P = 0.08) and was increased for ER negative tumors (OR = 2.05, CI = 0.95-4.43, P = 0.07). Consistent with previous studies, we found that mtDNA mutations are a frequent occurrence in breast tumors. An understanding of the etiology of mtDNA mutations may provide insight into breast carcinogenesis.

Metabolic Parameters in Patients Treated with Olanzapine or Other Atypical Antipsychotics

Journal of Psychopharmacology (Oxford, England). May, 2011  |  Pubmed ID: 20498135

The relative risk of changes in metabolic parameters during treatment with atypical antipsychotics has not been fully investigated. Baseline-to-endpoint mean and anytime-categorical changes in metabolic parameters were evaluated in Lilly active comparator-controlled clinical trials. Olanzapine-treated patients gained significantly more baseline-to-endpoint weight versus risperidone- (3.3 kg [N = 713; median exposure [ME, days] = 68] versus 1.8 kg [N = 697; ME = 65], p < 0.001), ziprasidone-(2.8 kg [N = 463; ME = 168] versus -1.3 kg [N = 443; ME = 89], p < 0.001), and aripiprazole-treated patients (3.7 kg [N = 273; ME = 104] versus 0.5 kg [N = 275; ME = 187], p < 0.001). Significantly more olanzapine-treated patients gained ≥ 7% of their baseline weight versus risperidone-(30.6% [N = 713; ME = 169] versus 20.2% [N = 697; ME = 140], p < 0.001), ziprasidone-(30.0% [N = 463; ME = 147] versus 6.5% [N = 443; ME = 165], p < 0.001), and aripiprazole-treated patients (40.3% [N = 273; ME = 170] versus 16.4% [N = 275; ME = 154], p < 0.001). Olanzapine-treated patients had significantly greater baseline-to-endpoint changes in fasting triglycerides compared with ziprasidone- (0.24 mmol/L [N = 365; ME = 168] versus -0.24 mmol/L [N = 316; ME = 140], p < 0.001) and aripiprazole-treated patients (0.28 mmol/L [N = 215; ME = 195] versus -0.19 mmol/L [N = 210; ME = 194], p < 0.001). Olanzapine-treated patients had significantly greater baseline-to-endpoint changes in fasting glucose than ziprasidone-(0.25 mmol/L [N = 379; ME = 168] versus -0.04 mmol/L [N = 333; ME = 133], p = 0.016) and aripiprazole-treated patients (0.27 mmol/L [N = 227; ME = 195] versus 0.04 mmol/L [N = 220; ME = 194], p = 0.048). The study concluded that there are changes with varying frequencies and magnitude in some metabolic parameters in patients treated with olanzapine compared with other atypical antipsychotics.

An Indole-linked C8-deoxyguanosine Nucleoside Acts As a Fluorescent Reporter of Watson-Crick Versus Hoogsteen Base Pairing

Organic & Biomolecular Chemistry. Mar, 2011  |  Pubmed ID: 21240404

Pyrrole- and indole-linked C(8)-deoxyguanosine nucleosides act as fluorescent reporters of H-bonding specificity. Their fluorescence is quenched upon Watson-Crick H-bonding to dC, while Hoogsteen H-bonding to G enhances emission intensity. The indole-linked probe is ∼ 10-fold brighter and shows promise as a fluorescent reporter of Hoogsteen base pairing.

Multiple Developmental Programs Are Altered by Loss of Zic1 and Zic4 to Cause Dandy-Walker Malformation Cerebellar Pathogenesis

Development (Cambridge, England). Mar, 2011  |  Pubmed ID: 21307096

Heterozygous deletions encompassing the ZIC1;ZIC4 locus have been identified in a subset of individuals with the common cerebellar birth defect Dandy-Walker malformation (DWM). Deletion of Zic1 and Zic4 in mice produces both cerebellar size and foliation defects similar to human DWM, confirming a requirement for these genes in cerebellar development and providing a model to delineate the developmental basis of this clinically important congenital malformation. Here, we show that reduced cerebellar size in Zic1 and Zic4 mutants results from decreased postnatal granule cell progenitor proliferation. Through genetic and molecular analyses, we show that Zic1 and Zic4 have Shh-dependent function promoting proliferation of granule cell progenitors. Expression of the Shh-downstream genes Ptch1, Gli1 and Mycn was downregulated in Zic1/4 mutants, although Shh production and Purkinje cell gene expression were normal. Reduction of Shh dose on the Zic1(+/-);Zic4(+/-) background also resulted in cerebellar size reductions and gene expression changes comparable with those observed in Zic1(-/-);Zic4(-/-) mice. Zic1 and Zic4 are additionally required to pattern anterior vermis foliation. Zic mutant folial patterning abnormalities correlated with disrupted cerebellar anlage gene expression and Purkinje cell topography during late embryonic stages; however, this phenotype was Shh independent. In Zic1(+/-);Zic4(+/-);Shh(+/-), we observed normal cerebellar anlage patterning and foliation. Furthermore, cerebellar patterning was normal in both Gli2-cko and Smo-cko mutant mice, where all Shh function was removed from the developing cerebellum. Thus, our data demonstrate that Zic1 and Zic4 have both Shh-dependent and -independent roles during cerebellar development and that multiple developmental disruptions underlie Zic1/4-related DWM.

Co-transcription of the CelC Gene Cluster in Clostridium Thermocellum

Applied Microbiology and Biotechnology. Apr, 2011  |  Pubmed ID: 21318364

Clostridium thermocellum, an anaerobic, thermophilic, and ethanogenic bacterium produces a large cellulase complex termed the cellulosome and many free glycosyl hydrolases. Most cellulase genes scatter around the genome. We mapped the transcripts of the six-gene cluster celC-glyR3-licA-orf4-manB-celT and determined their transcription initiation sites by primer extension. Northern blot showed that celC-glyR3-licA were co-transcribed into a polycistronic messenger with the transcription initiation site at -20 bp. Furthermore, RT-PCR mapping showed that manB and celT, two cellulosomal genes immediately downstream, were co-transcribed into a bicistronic messenger with the initiation site at -233 bp. In contrast, rf4 was transcribed alone with the two initiation sites at -130 and -138 bp, respectively. Finally, quantitative RT-PCR analysis showed that celC, glyR3, and licA were coordinately induced by growing on laminarin, a β-1,3 glucan. Gene expression peaked at the late exponential phase. Taking together with our previous report that GlyR3 binds to the celC promoter in the absence of laminaribiose, a β-1,3 glucose dimer, these results indicate that celC, glyR3, and licA form an operon repressible by GlyR3 and inducible by laminaribiose, signaling the availability of β-1,3 glucan. The celC operon is the first glycosyl hydrolase operon reported in this bacterium.

Pretreatment Serum Concentrations of 25-hydroxyvitamin D and Breast Cancer Prognostic Characteristics: a Case-control and a Case-series Study

PloS One. 2011  |  Pubmed ID: 21386992

Results from epidemiologic studies on the relationship between vitamin D and breast cancer risk are inconclusive. It is possible that vitamin D may be effective in reducing risk only of specific subtypes due to disease heterogeneity.

Granulocyte-macrophage Colony-stimulating Factor (GM-CSF): a Chemoattractive Agent for Murine Leukocytes in Vivo

Journal of Leukocyte Biology. Jun, 2011  |  Pubmed ID: 21393420

GM-CSF is well recognized as a proliferative agent for hematopoietic cells and exerts a priming function on neutrophils. The aim of this study was to determine if GM-CSF has a role as a neutrophil chemoattractant in vivo and if it can contribute to recruitment during intestinal inflammation. Initial studies in vitro, using the under-agarose gel assay, determined that GM-CSF can induce neutrophil migration at a much lower molar concentration than the fMLP-like peptide WKYMVm (33.5-134 nM vs. 1-10 μM). GM-CSF-induced neutrophil migration was ablated (<95%) using neutrophils derived from GMCSFRβ(-/-) mice and significantly attenuated by 42% in PI3Kγ(-/-)neutrophils. In vivo, a significant increase in leukocyte recruitment was observed using intravital microscopy 4 h post-GM-CSF (10 μg/kg) injection, which was comparable with leukocyte recruitment induced by KC (40 μg/kg). GM-CSF-induced recruitment was abolished, and KC-induced recruitment was maintained in GMCSFRβ(-/-) mice. Furthermore, in vivo migration of extravascular leukocytes was observed toward a gel containing GM-CSF in WT but not GMCSFRβ(-/-) mice. Finally, in a model of intestinal inflammation (TNBS-induced colitis), colonic neutrophil recruitment, assessed using the MPO assay, was attenuated significantly in anti-GM-CSF-treated mice or GMCSFRβ(-/-) mice. These data demonstrate that GM-CSF is a potent chemoattractant in vitro and can recruit neutrophils from the microvasculature and induce extravascular migration in vivo in a β subunit-dependent manner. This property of GM-CSF may contribute significantly to recruitment during intestinal inflammation.

Duration of Physical Activity and Serum 25-hydroxyvitamin D Status of Postmenopausal Women

Annals of Epidemiology. Jun, 2011  |  Pubmed ID: 21414803

To investigate whether the association between physical activity and serum 25-hydroxyvitamin D (25(OH)D) concentrations is independent of sun exposure, body size, and other potential explanatory variables.

Impact of Reduction in Working Hours for Doctors in Training on Postgraduate Medical Education and Patients' Outcomes: Systematic Review

BMJ (Clinical Research Ed.). 2011  |  Pubmed ID: 21427046

To determine whether a reduction in working hours of doctors in postgraduate medical training has had an effect on objective measures of medical education and clinical outcome.

Vitamin D Status and Early Age-related Macular Degeneration in Postmenopausal Women

Archives of Ophthalmology. Apr, 2011  |  Pubmed ID: 21482873

The relationship between serum 25-hydroxyvitamin D (25[OH]D) concentrations (nmol/L) and the prevalence of early age-related macular degeneration (AMD) was investigated in participants of the Carotenoids in Age-Related Eye Disease Study.

A Multicenter, Inpatient, Phase 2, Double-blind, Placebo-controlled Dose-ranging Study of LY2140023 Monohydrate in Patients with DSM-IV Schizophrenia

Journal of Clinical Psychopharmacology. Jun, 2011  |  Pubmed ID: 21508856

The primary objective of this study was to test the hypothesis that 1 or more dose levels of LY2140023 monohydrate, an oral prodrug of the potent metabotropic glutamate (mGlu) 2/3 receptor agonist LY404039, given to patients with schizophrenia for 4 weeks would demonstrate significantly greater efficacy than placebo. The HBBI study was a multicenter, randomized, double-blind, parallel, placebo- and active-controlled trial. Male and female patients aged 18 to 65 years who met the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria for schizophrenia were randomized in a 2:2:2:2:2:1 ratio to receive 5-, 20-, 40-, or 80-mg LY2140023 monohydrate twice daily, placebo twice daily, or placebo (am) and 15 mg of olanzapine (pm) daily. Efficacy was defined as the change from baseline on the Positive and Negative Syndrome Scale (PANSS) total score assessed at 4 weeks. The primary analysis did not show that any of the 4 LY2140023 monohydrate doses were more efficacious than placebo as measured by the PANSS total score. Similarly, olanzapine did not significantly separate from placebo. A higher-than-anticipated treatment effect (14.6-point improvement) in the placebo group was observed on PANSS total score. LY2140023 monohydrate was generally well tolerated, although 4 patients reported the serious adverse event of convulsion. LY2140023 monohydrate-treated patients showed little change in dopamine-related adverse events and weight. The results of the HBBI study are considered to be inconclusive because LY2140023 monohydrate and the active control olanzapine did not separate from placebo in the treatment of patients with acutely exacerbated schizophrenia. Additional efficacy, safety, and tolerability testing are needed.

Three Methods for Constructing Parallel Gatekeeping Procedures in Clinical Trials

Journal of Biopharmaceutical Statistics. Jul, 2011  |  Pubmed ID: 21516568

This paper gives a review of three classes of parallel gatekeeping procedures that can be used in clinical trials with multiple objectives grouped into two or more families. We begin with a high-level summary of three methods for building parallel gatekeeping procedures proposed in the literature and provide a detailed comparison of the three methods. The comparison is based on analytical arguments as well as simulation studies and helps us develop general recommendations on the use of these methods in clinical trial applications. The methods discussed in this paper are illustrated using clinical trial examples with two families of objectives.

Melatonin Prevents Oxidative Stress in Ovariectomized Rats Treated with Aluminium

Biological Trace Element Research. Dec, 2011  |  Pubmed ID: 21537923

This study is designed to determine the simultaneous effect of aluminium (Al) and melatonin (Mel) treatment in intact and ovariectomized (Ovx) female rats on oxidative stress and their inter-organ relationship in the kidney and liver. Al-treated rats received an intra-peritoneal injection of solution of aluminium lactate (0.575 mg Al/100 g of body weight, three times a week), during 12 weeks. Mel groups received intra-peritoneal injections of melatonin at a dose of 10 mg/kg/day, 5 days/week, during 12 weeks. The results of this study showed that Al treatment in female rats modifies homeostasis of glutathione and the antioxidant capacity of the rat liver and kidney. The alteration of glutathione homeostasis and oxidative status was not associated with an increased lipid peroxidation in both organs with the exception of the increase observed in the liver of Ovx rats. Al also induced modifications in the activity of some enzymes related to the glutathione cycle: GSH-Px in the liver and kidney and glutathione reductase only in the kidney. Al exposure decreased CAT activity in both the kidney and liver of intact and Ovx groups. The administration of Mel in the intact and castrated females treated with Al seems to reduce oxidative changes in the liver and kidney of intact and Ovx rats.

Effects of Adding Polyclonal Antibody Preparations on Ruminal Fermentation Patterns and Digestibility of Cows Fed Different Energy Sources

Journal of Animal Science. Oct, 2011  |  Pubmed ID: 21551346

Nine ruminally cannulated cows fed different energy sources were used to evaluate an avian-derived polyclonal antibody preparation (PAP-MV) against the specific ruminal bacteria Streptococcus bovis, Fusobacterium necrophorum, Clostridium aminophilum, Peptostreptococcus anaerobius, and Clostridium sticklandii and monensin (MON) on ruminal fermentation patterns and in vivo digestibility. The experimental design was three 3 × 3 Latin squares distinguished by the main energy source in the diet [dry-ground corn grain (CG), high-moisture corn silage (HMCS), or citrus pulp (CiPu)]. Inside each Latin square, animals received one of the feed additives per period [none (CON), MON, or PAP-MV]. Dry matter intake and ruminal fermentation variables such as pH, total short-chain fatty acids (tSCFA), which included acetate, propionate, and butyrate, as well as lactic acid and NH(3)-N concentration were analyzed in this trial. Total tract DM apparent digestibility and its fractions were estimated using chromic oxide as an external marker. Each experimental period lasted 21 d. Ruminal fluid sampling was carried out on the last day of the period at 0, 2, 4, 6, 8, 10, and 12 h after the morning meal. Ruminal pH was higher (P = 0.006) 4 h postfeeding in MON and PAP-MV groups when compared with CON. Acetate:propionate ratio was greater in PAP-MV compared with MON across sampling times. Polyclonal antibodies did not alter (P > 0.05) tSCFA, molar proportion of acetate and butyrate, or lactic acid and NH(3)-N concentration. Ruminal pH was higher (P = 0.01), 4 h postfeeding in CiPu diets compared with CG and HMCS. There was no interaction between feed additive and energy source (P > 0.05) for any of the digestibility coefficients analyzed. Starch digestibility was less (P = 0.008) in PAP-MV when compared with CON and MON. In relation to energy sources, NDF digestibility was greater (P = 0.007) in CG and CiPu vs. the HMCS diet. The digestibility of ADF was greater (P = 0.002) in CiPu diets followed by CG and HMCS. Feeding PAP-MV or monensin altered ruminal fermentation patterns and digestive function in cows; however, those changes were independent of the main energy source of the diet.

Zac1 Plays a Key Role in the Development of Specific Neuronal Subsets in the Mouse Cerebellum

Neural Development. 2011  |  Pubmed ID: 21592321

The cerebellum is composed of a diverse array of neuronal subtypes. Here we have used a candidate approach to identify Zac1, a tumor suppressor gene encoding a zinc finger transcription factor, as a new player in the transcriptional network required for the development of a specific subset of cerebellar nuclei and a population of Golgi cells in the cerebellar cortex.

Wormless Without Wingless

Nature Medicine. Jun, 2011  |  Pubmed ID: 21647144

The Effect of Calcium Plus Vitamin D on Risk for Invasive Cancer: Results of the Women's Health Initiative (WHI) Calcium Plus Vitamin D Randomized Clinical Trial

Nutrition and Cancer. 2011  |  Pubmed ID: 21774589

In the Women's Health Initiative (WHI) trial of calcium plus vitamin D (CaD), we examined the treatment effect on incidence and mortality for all invasive cancers. Postmenopausal women (N = 36,282) were randomized to 1,000 mg of elemental calcium with 400 IU vitamin D3 or placebo. Cox models estimated risk of cancer incidence and mortality. After 7.0 yr, 1,306 invasive cancers were diagnosed in the supplement and 1,333 in the placebo group [hazard ratio (HR) = 0.98; CI = 0.90, 1.05, unweighted P = 0.54]. Mortality did not differ between supplement (315, annualized% = .26) and placebo [(347, 0.28%; P = 0.17; HR = 0.90 (0.77, 1.05)]. Significant treatment interactions on incident cancer were found for family history of cancer, personal total intake of vitamin D, smoking, and WHI dietary trial randomized group. Calcium/vitamin D supplementation did not reduce invasive cancer incidence or mortality. Supplementation lowered cancer risk in the WHI healthy diet trial arm and in women without a first-degree relative with cancer. The interactions are only suggestive given multiple testing considerations. The low vitamin D dose provided, limited adherence, and lack of serum 25(OH)D values should be considered when interpreting these findings.

Diet, the Global Obesity Epidemic, and Prevention

Journal of the American Dietetic Association. Aug, 2011  |  Pubmed ID: 21802558

Vitamin D Intake from Foods and Supplements and Depressive Symptoms in a Diverse Population of Older Women

The American Journal of Clinical Nutrition. Oct, 2011  |  Pubmed ID: 21865327

Vitamin D may plausibly reduce the occurrence of depression in postmenopausal women; however, epidemiologic evidence is limited, and few prospective studies have been conducted.

Fluorescent Properties and Conformational Preferences of C-linked Phenolic-DNA Adducts

Chemical Research in Toxicology. Oct, 2011  |  Pubmed ID: 21905681

Phenolic toxins and mutagenic diazoquinones generate C-linked adducts at the C8 site of 2'-deoxyguanosine (dG) through the intermediacy of radical species. We have previously reported the site-specific incorporation of these adducts into oligonucleotides using a postsynthetic palladium-catalyzed cross-coupling strategy [Omumi (2011 ) J. Am. Chem. Soc. 133 , 42 - 50 ]. We report here the structural impact of these lesions within two decanucleotide sequences containing either 5'- and 3'-flanking pyrimidines or purines. In the complementary strands, the base opposite (N) the C-linked adduct was varied to determine the possibility of mismatch stabilization by the modified nucleobases. The resulting adducted duplex structures were characterized using UV thermal denaturation studies, circular dichroism, fluorescence spectroscopy, and molecular dynamics (MD) simulations. The experimental data showed the C-linked adducts to destabilize the duplex when base paired with its normal partner C but to increase duplex stability within a G:G mismatch. The stabilization within the G:G mismatch was sequence dependent, with flanking purine bases playing a key role in the stabilizing influence of the adduct. MD simulations showed no large structural changes to the B form double helix, regardless of the (anti/syn) adduct preference. Consideration of H-bonding and stacking interactions derived from the MD simulations together with the thermal melting data and changes in fluorescent emission of the adducts upon hybridization to the complementary strands implied that the C-linked phenolic adducts preferentially adopt the syn-conformation within both duplexes regardless of the opposite base N. Given that biological outcome in terms of mutagenicity appears to be strongly correlated to the conformational preference of the corresponding N-linked C8-dG adducts, the potential biological implications of phenolic C-linked adducts are discussed.

Promoter Methylation of E-cadherin, P16, and RAR-β(2) Genes in Breast Tumors and Dietary Intake of Nutrients Important in One-carbon Metabolism

Nutrition and Cancer. Oct, 2011  |  Pubmed ID: 21916701

Aberrant DNA methylation plays a critical role in carcinogenesis, and the availability of dietary factors involved in 1-carbon metabolism may contribute to aberrant DNA methylation. We investigated the association of intake of folate, vitamins B(2), B(6), B(12), and methionine with promoter methylation of E-cadherin, p16, and RAR-β(2) genes in archived tumor tissues from incident, primary breast cancer cases in a population-based case-control study. Real-time methylation-specific PCR was performed on 803 paraffin-embedded samples; usual dietary intake was queried from a food frequency questionnaire. Unconditional logistic regression was used to derive adjusted odds ratios and 95% confidence intervals for likelihood of promoter methylation for high compared to low intake of those 1-carbon nutrients. Overall, in case-case comparisons, dietary intakes of folate, vitamins B(2), B(6), B(12), and methionine were not associated with likelihood of promoter methylation of E- cadherin, p16, and RAR-β(2) for all cases combined or within strata defined by menopausal status and estrogen receptor status in this study. This finding, however, does not exclude the possibility that intake of such nutrients might have the ability to modulate promoter methylation in normal or premalignant (dysplastic) breast tissue.

A Subclass of Acylated Anti-inflammatory Mediators Usurp Toll-like Receptor 2 to Inhibit Neutrophil Recruitment Through Peroxisome Proliferator-activated Receptor Gamma

Proceedings of the National Academy of Sciences of the United States of America. Sep, 2011  |  Pubmed ID: 21930915

Toll-like receptors are host sentinel receptors that signal the presence of infectious nonself and initiate protective immunity. One of the primary immune defense mechanisms is the recruitment of neutrophils from the bloodstream into the infected tissue. Although neutrophils are important in host defense, they can also be responsible for damaging pathologies associated with excessive inflammation. Here, we report that the di-acylated TLR2 ligand lipoteichoic acid can directly inhibit neutrophil recruitment in vivo. This discovery allowed us to test the concept that conventional proinflammatory TLR2 ligands can be made to act as inhibitors through specific structural modifications. Indeed, lipopeptide TLR2 ligands, when modified at their acyl chains to contain linoleate, lose their capacity to induce inflammation and yield ligands that can directly inhibit the in vivo neutrophil recruitment initiated by a wide range of proinflammatory stimuli. The inhibitory capacity of LTA and these modified ligands requires the expression of TLR2, but is independent of the TLR2 signaling adaptor, MyD88. Instead, this inhibitory effect requires functional activity of the fatty acid and nuclear hormone receptor peroxisome proliferator-activated receptor γ (PPARγ). Therefore, these data support a model in TLR2 biology where structural modifications of these ligands can profoundly influence host-microbial interactions. These inhibitory TLR2 ligands also have broader implications with respect to their potential use in various inflammatory disease settings.

Conformational Flexibility of C8-phenoxylguanine Adducts in Deoxydinucleoside Monophosphates

The Journal of Physical Chemistry. B. Nov, 2011  |  Pubmed ID: 21942470

M06-2X/6-31G(d,p) is used to calculate the structure of all natural deoxydinucleoside monophosphates with G in the 5' or 3' position, the anti or syn conformation, and each natural (A, C, G, T) base in the corresponding flanking position. When the ortho or para C8-phenoxyl-2'-deoxyguanosine (C8-phenoxyl-dG) adduct replaces G in each model, there is little change in the relative base-base orientation or backbone conformation. However, the orientation of the C8-phenoxyl group can be characterized according to the position (5' versus 3'), conformation (anti versus syn), and isomer (ortho versus para) of damage. Although the degree of coplanarity between the phenoxyl ring and G base in the ortho adduct is highly affected by the sequence since the hydroxyl group can interact with neighboring bases, the para adduct generally does not exhibit discrete interactions with flanking bases. For both adducts, steric clashes between the phenoxyl group and the backbone or flanking base destabilize the anti conformation preferred by the natural nucleotide and thereby result in a clear preference for the syn conformation regardless of the sequence or position. This contrasts the conclusions drawn from smaller (nucleoside, nucleotide) models previously used in the literature, which stresses the importance of using models that address the steric constraints present due to the surrounding environment. Since replication errors for other C8-dG bulky adducts have been linked to a preference for the syn conformation, our findings provide insight into the possible mutagenicity of phenolic adducts.

Stability of the Framingham Nutritional Risk Score and Its Component Nutrients over 8 Years: the Framingham Nutrition Studies

European Journal of Clinical Nutrition. Oct, 2011  |  Pubmed ID: 21970940

Background/Objectives:Diet quality indices are increasingly used in nutrition epidemiology as dietary exposures in relation to health outcomes. However, literature on the long-term stability of these indices is limited. We aimed to assess the stability of the validated Framingham Nutritional Risk Score (FNRS) and its component nutrients over 8 years, as well as the validity of the follow-up FNRS.Subjects/Methods:Framingham Offspring/Spouse Study women and men (n=1734) aged 22-76 years were evaluated over 8 years. Individuals' nutrient intake and nutritional risk scores were assessed using 3-day dietary records administered at baseline (1984-1988) and at follow-up (1992-1996). Agreement between baseline and follow-up FNRS and nutrient intakes was evaluated by Bland-Altman method; stability was assessed using intra-class correlation (ICC) and weighted Kappa statistics. The effect of diet quality (as assessed by the FNRS) on cardiometabolic risk factors was evaluated using analysis of covariance.Results:Modest changes from baseline (15%) were observed in nutrient intake. The stability coefficients for the FNRS (ICC: women, 0.49; men, 0.46; P<0.0001) and many nutrients (ICC 0.3) were moderate. Over half of the women and men (58%) remained in the same or contiguous baseline and follow-up quartile of the FNRS and few (3-4%) shifted >1 quartile. The FNRS was directly associated with body mass index in women (P<0.01) and high-density lipoprotein cholesterol among both women (P<0.001) and men (P<0.01).Conclusions:The FNRS and its constituent nutrients remained relatively stable over 8 years of follow-up. The stability of diet quality has implications for prospective epidemiological investigations.European Journal of Clinical Nutrition advance online publication, 5 October 2011; doi:10.1038/ejcn.2011.167.

Alteration of CFTR Transmembrane Span Integration by Disease-causing Mutations

Molecular Biology of the Cell. Dec, 2011  |  Pubmed ID: 21998193

Many missense mutations in the cystic fibrosis transmembrane conductance regulator protein (CFTR) result in its misfolding, endoplasmic reticulum (ER) accumulation, and, thus, cystic fibrosis. A number of these mutations are located in the predicted CFTR transmembrane (TM) spans and have been projected to alter span integration. However, the boundaries of the spans have not been precisely defined experimentally. In this study, the ER luminal integration profiles of TM1 and TM2 were determined using the ER glycosylation machinery, and the effects of the CF-causing mutations G85E and G91R thereon were assessed. The mutations either destabilize the integrated conformation or alter the TM1 ER integration profile. G85E misfolding is based in TM1 destabilization by glutamic acid and loss of glycine and correlates with the temperature-insensitive ER accumulation of immature full-length CFTR harboring the mutation. By contrast, temperature-dependent misfolding owing to the G91R mutation depends on the introduction of the basic side chain rather than the loss of the glycine. This work demonstrates that CF-causing mutations predicted to have similar effects on CFTR structure actually result in disparate molecular perturbations that underlie ER accumulation and the pathology of CF.

Development of Gatekeeping Strategies in Confirmatory Clinical Trials

Biometrical Journal. Biometrische Zeitschrift. Nov, 2011  |  Pubmed ID: 22069199

This paper discusses multiplicity issues arising in confirmatory clinical trials with hierarchically ordered multiple objectives. In order to protect the overall type I error rate, multiple objectives are analyzed using multiple testing procedures. When the objectives are ordered and grouped in multiple families (e.g. families of primary and secondary endpoints), gatekeeping procedures are employed to account for this hierarchical structure. We discuss considerations arising in the process of building gatekeeping procedures, including proper use of relevant trial-specific information and criteria for selecting gatekeeping procedures. The methods and principles discussed in this paper are illustrated using a clinical trial in patients with type II diabetes mellitus.

Vitamin D Receptor Gene Polymorphisms Are Associated with Adiposity Phenotypes

The American Journal of Clinical Nutrition. Jan, 2011  |  Pubmed ID: 21048058

Emerging data suggest a role for the vitamin D receptor (VDR) in lipogenesis and adipocyte differentiation.

Neither Infants nor Toddlers Catch Yawns from Their Mothers

Biology Letters. Jun, 2011  |  Pubmed ID: 21123252

This study aimed to clarify whether infants and preschool children show susceptibility to contagious yawning, a well-known effect that has been demonstrated experimentally in older children and adults by exposing them to video sequences showing yawns. In a first study, parents kept a log of their child's yawns for a one week period. None of the log entries reported any contagious yawns by the children. Although less frequent than in older children and adults, spontaneous yawning by infants and preschoolers showed the typical morning, post-wakening peak, and an increase before bedtime in the evening. In an experimental study, infants and preschoolers watched a presentation that included many images of yawning and a repeated video clip of their own mother yawning, but there was no evidence of contagious yawning. The results suggest that, even when witnessing yawns by someone with whom they have a strong and positive emotional relationship, very young children do not show contagious yawning.

Healthy Lifestyles Related to Subsequent Prevalence of Age-related Macular Degeneration

Archives of Ophthalmology. Apr, 2011  |  Pubmed ID: 21149749

To investigate the relationships between lifestyle behaviors of diet, smoking, and physical activity and the subsequent prevalence of age-related macular degeneration (AMD).

Alcohol Consumption in Relation to Aberrant DNA Methylation in Breast Tumors

Alcohol (Fayetteville, N.Y.). Nov, 2011  |  Pubmed ID: 21168302

The mechanism for the observed association of alcohol consumption breast cancer risk is not known; understanding that mechanism could improve understanding of breast carcinogenesis and optimize prevention strategies. Alcohol may impact breast malignancies or tumor progression by altering DNA methylation. We examined promoter methylation of three genes, the E-cadherin, p16, and retinoic acid-binding receptor-β2 (RAR-β2) genes in archived breast tumor tissues from participants in a population-based case-control study. Real time methylation-specific PCR was performed on 803 paraffin-embedded samples, and lifetime alcohol consumption was queried. Unordered polytomous and unconditional logistic regression were used to derive adjusted odds ratios (ORs) and 95% confidence intervals (CIs). RAR-β2 methylation was not associated with drinking. Among premenopausal women, alcohol consumption was also not associated with promoter methylation for E-cadherin and p16 genes. In case-case comparisons of postmenopausal breast cancer, compared with lifetime never drinkers, promoter methylation likelihood was increased for higher alcohol intake for E-cadherin (OR=2.39; 95% CI, 1.15-4.96), in particular for those with estrogen receptor-negative tumors (OR=4.13; 95% CI, 1.16-14.72), and decreased for p16 (OR=0.52; 95% CI, 0.29-0.92). There were indications that the association with p16 was stronger for drinking at younger ages. Methylation was also associated with drinking intensity independent of total consumption for both genes. We found alcohol consumption was associated with DNA methylation in postmenopausal breast tumors, suggesting that the association of alcohol and breast cancer may be related, at least in part, to altered methylation, and may differ by drinking pattern.

Vestibular Migraine: Perspectives of Otology Versus Neurology

Otology & Neurotology : Official Publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology. Feb, 2011  |  Pubmed ID: 21178806

To compare the attitudes and opinions of otologists and neurologists regarding the cause, diagnosis, and management of vestibular migraine.

Weight Changes over Time in Adults Treated with the Oral or Depot Formulations of Olanzapine: a Pooled Analysis of 86 Clinical Trials

Journal of Psychopharmacology (Oxford, England). May, 2011  |  Pubmed ID: 20558497

Several analytical approaches were used to characterize time progression of weight changes observed in adults treated with olanzapine from a 12,425-patient database of 86 studies of oral and depot formulations of olanzapine (mean modal dose 13.3 mg/day). Descriptive mean profile plots for completer and modified completer groups showed weight increasing throughout each observed period, with apparent slowing in rate of change after 3 or 4 months. Mixed-effects model repeated measures analyses also showed that weight increased most rapidly early in treatment and slowed within 2 to 4 months. The slowing in rate of change was greatest for patients obese at baseline and least for patients underweight at baseline. This pattern was also observed in a nonparametric regression-based profile. Based on visual inspection of profile plots, 2, 3, 4, and 5 months were postulated as potential 'change points' beyond which rate of increase might slow, and the proportions of patients whose slope after each change point was ≤ 90% of the slope before change point were calculated. Over 85% of patients who gained weight showed slowing rate of weight change after each postulated change point. Potential consequences of weight gain should be considered prior to starting olanzapine. Olanzapine-treated patients should receive regular weight monitoring.

Maisonneuve Fracture

The Journal of Emergency Medicine. Jul, 2011  |  Pubmed ID: 19157747

A Practical Critique of Antifungal Treatment Guidelines for Haemato-oncologists

Critical Reviews in Microbiology. Feb, 2012  |  Pubmed ID: 22324737

The management of invasive fungal disease (IFD) in the haemato-oncology setting remains a challenge. This article reviews recent guidelines relating to IFD for their similarities and differences, as well as applying the Appraisal of Guidelines Research and Evaluation (AGREE) criteria. The guidelines' recommendations on antifungal prophylaxis, empirical and definitive treatment of candidiasis and aspergillosis are summarized; also, minimum standards for diagnosis and follow-up are discussed. This critique of the reviewed guidelines is a practical guide to physicians and commissioners in making local policies for IFD management.

Effects of Feeding a Multivalent Polyclonal Antibody Preparation on Feedlot Performance, Carcass Characteristics, Rumenitis and Blood Gas Profile in Bos Indicus Biotype Yearling Bulls

Journal of Animal Science. Feb, 2012  |  Pubmed ID: 22344322

The objective of this study was to evaluate effects of feeding monensin (MON) or a multivalent polyclonal antibody preparation (PAP) against several rumen microorganisms on feedlot performance, carcass characteristics, blood gas profile, and rumenitis of Bos indicus biotype (BT) yearling bulls. The study was designed as a completely randomized design with a 3 × 2 factorial arrangement, replicated four times, in which 32 yearling bulls of each of three BT evaluated (3-way-cross, TC; Canchim, CC; and Nellore, NE) were fed diets containing either MON at 300 mg•d(-1) or PAP at 10 mL•d(-1 )across three different periods. No significant (P > 0.10) feed additive (FA) main effects were observed for any of the feedlot performance variables and carcass characteristics with the exception of dressing percentage. Yearling bulls receiving PAP had a decreased (P = 0.047) dressing percentage when compared with yearling bulls receiving MON. Significant (P < 0.05) BT main effects were observed for all feedlot performance variables and carcass characteristics with the exception of kidney-pelvic fat expressed in kg (P = 0.49) and LM lipids content (P = 0.45). Crossbred yearling bulls (TC and CC) had greater (P < 0.001) ADG, DMI in kg, DMI as % of BW, and improved (P = 0.001) G:F when compared with NE yearling bulls. A tendency (P = 0.072) for a FA main effect was observed for rumenitis scores, in which yearling bulls receiving PAP had lesser rumenitis scores than those receiving MON. When the data was disposed as frequency percent, 55.6% and 45.7% of the rumens from yearling bulls fed PAP and MON were scored between 0 and 1, respectively (0 = no lesions, 10 = severe lesions). Likewise, a significant BT main effect was observed (P = 0.008), where NE yearling bulls had greater rumenitis scores than those of crossbred yearling bulls (TC and CC). No significant FA main effects were observed (P > 0.10) for any of the fatty acids measured in the subcutaneous adipose tissue, with the exception that yearling bulls receiving MON had greater (P < 0.05) concentrations of palmitic acid (16:0), margaric acid (17:0), docosapentaenoic acid (22:5) and docosahexaenoic acid (22:6) than those yearling bulls receiving PAP. Feeding PAP tended to decrease incidence of rumen lesions and led to similar feedlot performance compared with feeding MON. Thus, PAP is a new technology that presents a possible alternative for ionophores.

The Influence of Health and Lifestyle Characteristics on the Relation of Serum 25-Hydroxyvitamin D With Risk of Colorectal and Breast Cancer in Postmenopausal Women

American Journal of Epidemiology. Feb, 2012  |  Pubmed ID: 22362582

The authors' objective was to discern whether lifestyle or health-related factors were confounders, effect modifiers, or irrelevant with regard to understanding observational associations of serum 25-hydroxyvitamin D (25(OH)D) with colorectal and breast cancer. The authors conducted nested case-control studies of colorectal cancer (310 cases, 310 controls) and breast cancer (1,080 cases, 1,080 controls) in the Women's Health Initiative Calcium and Vitamin D Clinical Trial (1994-2005). Case-control matching factors included age, latitude, race/ethnicity, and blood collection date. Serum 25(OH)D was assayed in baseline fasting blood. Conditional logistic regression was used to estimate odds ratios for each cancer by serum 25(OH)D concentration, comparing the relative effects of successively adding body mass index, physical activity, and other health and lifestyle characteristics particular to each cancer. In models with matching factors only, low (vs. high) serum 25(OH)D was associated with a colorectal cancer odds ratio of 2.72 (95% confidence interval (CI): 1.55, 4.77) and a breast cancer odds ratio of 1.33 (95% CI: 1.02, 1.72). In multivariate-adjusted models for colorectal cancer, the association strengthened (OR = 4.45, 95% CI: 1.96, 10.10). However, in multivariate-adjusted breast cancer models, associations were no longer significant (OR = 1.06, 95% CI: 0.78, 1.43). Adjusting for health and lifestyle characteristics has differential effects depending on the cancer site; when modeling such relations, investigators should take these factors into account.

Consensus Paper: Pathological Role of the Cerebellum in Autism

Cerebellum (London, England). Feb, 2012  |  Pubmed ID: 22370873

There has been significant advancement in various aspects of scientific knowledge concerning the role of cerebellum in the etiopathogenesis of autism. In the current consensus paper, we will observe the diversity of opinions regarding the involvement of this important site in the pathology of autism. Recent emergent findings in literature related to cerebellar involvement in autism are discussed, including: cerebellar pathology, cerebellar imaging and symptom expression in autism, cerebellar genetics, cerebellar immune function, oxidative stress and mitochondrial dysfunction, GABAergic and glutamatergic systems, cholinergic, dopaminergic, serotonergic, and oxytocin-related changes in autism, motor control and cognitive deficits, cerebellar coordination of movements and cognition, gene-environment interactions, therapeutics in autism, and relevant animal models of autism. Points of consensus include presence of abnormal cerebellar anatomy, abnormal neurotransmitter systems, oxidative stress, cerebellar motor and cognitive deficits, and neuroinflammation in subjects with autism. Undefined areas or areas requiring further investigation include lack of treatment options for core symptoms of autism, vermal hypoplasia, and other vermal abnormalities as a consistent feature of autism, mechanisms underlying cerebellar contributions to cognition, and unknown mechanisms underlying neuroinflammation.

Comparison of Long-Term (At Least 24 Weeks) Weight Gain and Metabolic Changes Between Adolescents and Adults Treated with Olanzapine

Journal of Child and Adolescent Psychopharmacology. Feb, 2012  |  Pubmed ID: 22372514

Abstract Objective: The purpose of these analyses was to compare the weight and other metabolic changes between adolescents and adults during long-term (at least 24 weeks) olanzapine treatment. Method: The adult database included 86 studies with 12,425 patients with schizophrenia, schizoaffective disorder, depression, borderline personality disorder, or bipolar I disorder; the adolescent database comprised six studies with 489 patients with schizophrenia, schizoaffective disorder, borderline personality disorder, bipolar I disorder, or prodromal psychosis. Patients who had at least 24 weeks of olanzapine exposure (N=4,280 from adult database and N=179 from adolescent database) were analyzed in this study. Weight data were collected for all patients, fasting glucose and lipids data were collected in some patients. For weight gain, data in 34.5% adults (4,280/12,425) and 36.6% adolescents (179/489) were analyzed while for glucose and lipids, data in 8.4% (1,038/12,425) adults and 24.9% adolescents (122/489) were analyzed. Adult patients were treated with oral (5-20 mg/day) or depot formulations (doses equivalent to oral doses of 5-20 mg/day) of olanzapine and adolescent patients were treated with oral olanzapine (2.5-20 mg/day). The incidences of potentially clinically significant categorical changes in weight and metabolic parameters were calculated with a 95% confidence interval (CI). Nonoverlapping 95% CIs were considered as indicating a statistically significant difference. Weight, lipid, and glucose change comparisons are summarized. Results: The mean age for adolescents and adults was 15.8 and 38.8, respectively. The percentage of the male population was similar for both adults (58.5%) and adolescents (62.8%). The median duration of the follow-up period was 201 days for adolescent database and 280 days for adult database. The mean weight gain from baseline to endpoint in adolescents was 11.24 kg when compared with 4.81 kg in adults. The 95% CI for adolescents (10.1, 12.4) and adults (4.57, 5.04) are not overlapping, which indicates that the difference between adolescents and adults is statistically significant. The percentage of olanzapine-treated adolescents with ≥7% mean weight gain was 89.4% compared with 55.4% in adults (Number need to harm [NNH]=3). Mean changes from baseline to endpoint were also greater for adolescents than for adults in fasting total cholesterol (5.49 mg/dL vs. 2.06 mg/dL), LDL (5.41 mg/dL vs. 0.49 mg/dL), and triglycerides (20.49 mg/dL vs. 16.72 mg/dL), but overlapping 95% CIs were observed for all lipid parameters. Mean changes from baseline to endpoint in fasting glucose values were similar between adolescents and adults (3.13 mg/dL vs. 3.95 mg/dL). However, the incidence of treatment-emergent significant glucose changes was greater in adults. Among olanzapine-treated adults and adolescents, 8.9% and 0.9% experienced a shift from normal to high and 12.5% and 3.3% experienced a shift from normal/impaired glucose tolerance (IGT) to high fasting glucose, respectively. The incidence of IGT to high elevations in glucose was greater in adolescents, but overlapping 95% CI was observed. Conclusions: The types of metabolic changes during the long-term olanzapine treatment in adolescents were similar to those observed in adults. However, the magnitude of changes in weight and lipid parameters was greater in adolescents. Patients should receive regular monitoring of weight, fasting blood glucose, and lipid profile at the beginning of, and periodically during, treatment with olanzapine.

Emergency Provider Attitudes and Barriers to Universal HIV Testing in the Emergency Department

The Journal of Emergency Medicine. Jan, 2012  |  Pubmed ID: 19828278

The Centers for Disease Control and Prevention (CDC) recently published recommendations for routine, voluntary human immunodeficiency virus (HIV) testing of adults in all health care settings, including the emergency department (ED).