NEASE: a Method for Gene Ontology Subclassification of High-throughput Gene Expression Data

Bioinformatics (Oxford, England). Mar, 2012  |  Pubmed ID: 22247278

High-throughput technologies can identify genes whose expression profiles correlate with specific phenotypes; however, placing these genes into a biological context remains challenging. To help address this issue, we developed nested Expression Analysis Systematic Explorer (nEASE). nEASE complements traditional gene ontology enrichment approaches by determining statistically enriched gene ontology subterms within a list of genes based on co-annotation. Here, we overview an open-source software version of the nEASE algorithm. nEASE can be used either stand-alone or as part of a pathway discovery pipeline. AVAILABILITY: nEASE is implemented within the Multiple Experiment Viewer software package available at http://www.tm4.org/mev. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Senescence and Age-specific Trade-offs Between Reproduction and Survival in Female Asian Elephants

Ecology Letters. Mar, 2012  |  Pubmed ID: 22248152

Although studies on laboratory species and natural populations of vertebrates have shown reproduction to impair later performance, little is known of the age-specific associations between reproduction and survival, and how such findings apply to the ageing of large, long-lived species. Herein we develop a framework to examine population-level patterns of reproduction and survival across lifespan in long-lived organisms, and decompose those changes into individual-level effects, and the effects of age-specific trade-offs between fitness components. We apply this to an extensive longitudinal dataset on female semi-captive Asian timber elephants (Elephas maximus) and report the first evidence of age-specific fitness declines that are driven by age-specific associations between fitness components in a long-lived mammal. Associations between reproduction and survival are positive in early life, but negative in later life with up to 71% of later-life survival declines associated with investing in the production of offspring within this population of this critically endangered species.

Psychological Entropy: A Framework for Understanding Uncertainty-related Anxiety

Psychological Review. Jan, 2012  |  Pubmed ID: 22250757

Entropy, a concept derived from thermodynamics and information theory, describes the amount of uncertainty and disorder within a system. Self-organizing systems engage in a continual dialogue with the environment and must adapt themselves to changing circumstances to keep internal entropy at a manageable level. We propose the entropy model of uncertainty (EMU), an integrative theoretical framework that applies the idea of entropy to the human information system to understand uncertainty-related anxiety. Four major tenets of EMU are proposed: (a) Uncertainty poses a critical adaptive challenge for any organism, so individuals are motivated to keep it at a manageable level; (b) uncertainty emerges as a function of the conflict between competing perceptual and behavioral affordances; (c) adopting clear goals and belief structures helps to constrain the experience of uncertainty by reducing the spread of competing affordances; and (d) uncertainty is experienced subjectively as anxiety and is associated with activity in the anterior cingulate cortex and with heightened noradrenaline release. By placing the discussion of uncertainty management, a fundamental biological necessity, within the framework of information theory and self-organizing systems, our model helps to situate key psychological processes within a broader physical, conceptual, and evolutionary context. (PsycINFO Database Record (c) 2012 APA, all rights reserved).

Neuraminidase Inhibitors for Preventing and Treating Influenza in Healthy Adults and Children

Cochrane Database of Systematic Reviews (Online). 2012  |  Pubmed ID: 22258996

Planning for outbreaks of influenza is a high priority public health issue for national governments. Neuraminidase inhibitors (NIs) are thought to help reduce the symptoms of influenza with several possible mechanisms proposed. NIs have been stockpiled with a view to their widespread use in the event of a pandemic. However, the evidence base for this class of agents remains a source of debate. In a previous review we have documented substantial risks of publication bias of trials of NIs for influenza (60% of patient data from phase III treatment trials of oseltamivir have never been published) and reporting bias in the published trials. Our confidence in the conclusions of previous versions of this review has been subsequently undermined. Since we have become aware of a large number of unpublished trials of NIs in the management of influenza, this review updates and merges existing reviews in this area.

Ternary Arsenides A2Zn2As3 (A = Sr, Eu) and Their Stuffed Derivatives A2Ag2ZnAs3

Inorganic Chemistry. Feb, 2012  |  Pubmed ID: 22272660

The ternary arsenides A(2)Zn(2)As(3) and the quaternary derivatives A(2)Ag(2)ZnAs(3) (A = Sr, Eu) have been prepared by stoichiometric reaction of the elements at 800 °C. Compounds A(2)Zn(2)As(3) crystallize with the monoclinic Ba(2)Cd(2)Sb(3)-type structure (Pearson symbol mC28, space group C2/m, Z = 4; a = 16.212(5) Å, b = 4.275(1) Å, c = 11.955(3) Å, β = 126.271(3)° for Sr(2)Zn(2)As(3); a = 16.032(4) Å, b = 4.255(1) Å, c = 11.871(3) Å, β = 126.525(3)° for Eu(2)Zn(2)As(3)) in which CaAl(2)Si(2)-type fragments, built up of edge-sharing Zn-centered tetrahedra, are interconnected by homoatomic As-As bonds to form anionic slabs [Zn(2)As(3)](4-) separated by A(2+) cations. Compounds A(2)Ag(2)ZnAs(3) crystallize with the monoclinic Yb(2)Zn(3)Ge(3)-type structure (Pearson symbol mC32, space group C2/m; a = 16.759(2) Å, b = 4.4689(5) Å, c = 12.202(1) Å, β = 127.058(1)° for Sr(2)Ag(2)ZnAs(3); a = 16.427(1) Å, b = 4.4721(3) Å, c = 11.9613(7) Å, β = 126.205(1)° for Eu(2)Ag(2)ZnAs(3)), which can be regarded as a stuffed derivative of the Ba(2)Cd(2)Sb(3)-type structure with additional transition-metal atoms in tetrahedral coordination inserted to link the anionic slabs together. The Ag and Zn atoms undergo disorder but with preferential occupancy over four sites centered in either tetrahedral or trigonal planar geometry. The site distribution of these metal atoms depends on a complex interplay of size and electronic factors. All compounds are Zintl phases. Band structure calculations predict that Sr(2)Zn(2)As(3) is a narrow band gap semiconductor and Sr(2)Ag(2)ZnAs(3) is a semimetal. Electrical resistivity measurements revealed band gaps of 0.04 eV for Sr(2)Zn(2)As(3) and 0.02 eV for Eu(2)Zn(2)As(3), the latter undergoing an apparent metal-to-semiconductor transition at 25 K.

Genetic Marking and Characterization of Tac2-expressing Neurons in the Central and Peripheral Nervous System

Molecular Brain. 2012  |  Pubmed ID: 22272772

The neurocircuits that process somatic sensory information in the dorsal horn of the spinal cord are still poorly understood, with one reason being the lack of Cre lines for genetically marking or manipulating selective subpopulations of dorsal horn neurons. Here we describe Tac2-Cre mice that were generated to express the Cre recombinase gene from the Tac2 locus. Tachykinin 2 (Tac2) encodes a neurotransmitter, neurokinin B (NKB).

Increase in Cardiac M(2)-muscarinic Receptor Expression is Regulated by GATA Binding Protein 4 (GATA-4) in Streptozotocin-induced Diabetic Rats

International Journal of Cardiology. Jan, 2012  |  Pubmed ID: 22293779

BACKGROUND: An increase in cardiac M2-muscarinic receptor (M2-mAChR) expression in diabetic rats has been observed, but the molecular mechanism of this increase remains unclear. The transcriptional activity of GATA binding protein 4 (GATA-4) has been documented to regulate the expression of M2-mAChR genes. In this study, we were interested in identifying the role of GATA-4 in the increase in M2-mAChR in diabetic rats and a primary culture of cardiomyocytes. METHODS: Streptozotocin-induced diabetic rats (STZ-rats) and high-glucose (D-glucose 30mM, 24h)-treated primary cultures of cardiomyocytes from neonatal rats were used to investigate the role of GATA-4 in the change in M2-mAChR. The protein expression was determined by Western blot analysis. Phlorizin (Na(+)-glucose co-transport inhibitor), insulin, tiron (radical scavenger), PD98059 (ERK inhibitor) and SB203580 (p38 inhibitor) were used. We also silenced GATA-4 by RNAi to investigate the changes in M2-mAChR expression. RESULTS: The cardiac output was reduced in STZ-rats with a higher expression of M2-mAChR or phosphorylated GATA-4 in the heart. These changes were reversed after correction of the blood sugar level. In cardiomyocytes, high glucose treatment also increased M2-mAChR expression and GATA-4 phosphorylation. These changes were reversed by tiron (ROS scavenger) or PD98059 (MEK/ERK inhibitor). However, an increase in M2-mAChR expression was not observed when GATA-4 was silenced by small interfering RNA (siRNA) in cardiomyocytes. CONCLUSIONS: We suggest that hyperglycemia can cause a higher expression of M2-mAChR in cardiomyocytes mainly through ROS to enhance MEK/ERK for phosphorylation of GATA-4.

Protection of Prenylated Flavonoids from Mori Cortex Radicis (Moraceae) Against Nitric Oxide-induced Cell Death in Neuroblastoma SH-SY5Y Cells

Archives of Pharmacal Research. Jan, 2012  |  Pubmed ID: 22297755

Seven prenylated flavanoids, licoflavone C (1), cyclomulberrin (2), neocyclomorusin (3), sanggenon I (4), morusin (5), kuwanon U (6) and kuwanon E (7), and three 2-arylbenzofurans, moracin P (8), moracin O (9), and mulberrofuran Q (10) were isolated from the MeOH extract of Mori Cortex Radicis. Among these, compounds 2-7 enhanced cell viability in a dose-dependent manner against sodium nitroprusside-induced cell death in neuroblastoma SH-SY5Y cells, which was measured by MTT reduction assay (EC(50) values of 4.4, 5.6, 8.0, 6.4, 8.7, and 11.9 μg/mL, respectively). Among 10 compounds, C-3 prenylated flavones (2, 3, and 5) and prenylated flavanones (4, 6, and 7) showed cell protection. However, compound 1 which lacks the prenyl group at C-3 and three 2-arylbenzofurans (8-10) did not show protective effect. The order of cell protection was as follow: C-3 prenylated flavones (2, 3, and 5) > prenylated flavanones (4, 6, and 7) > 2-arylbenzofurans (8-10) and flavone (1). From this result, we show that some prenylated flavones and flavanones might protect neuronal cells against nitrosative stress-mediated cell death. Even though further evaluations are necessary in vitro and in vivo study, we carefully suggest that some prenylated flavonoids from Mori Cortex Radicis might protect neuronal cells from neurodegenerative diseases.

Genome-wide SiRNA Screen for Mediators of NF-κB Activation

Proceedings of the National Academy of Sciences of the United States of America. Feb, 2012  |  Pubmed ID: 22308454

Although canonical NFκB is frequently critical for cell proliferation, survival, or differentiation, NFκB hyperactivation can cause malignant, inflammatory, or autoimmune disorders. Despite intensive study, mammalian NFκB pathway loss-of-function RNAi analyses have been limited to specific protein classes. We therefore undertook a human genome-wide siRNA screen for novel NFκB activation pathway components. Using an Epstein Barr virus latent membrane protein (LMP1) mutant, the transcriptional effects of which are canonical NFκB-dependent, we identified 155 proteins significantly and substantially important for NFκB activation in HEK293 cells. These proteins included many kinases, phosphatases, ubiquitin ligases, and deubiquinating enzymes not previously known to be important for NFκB activation. Relevance to other canonical NFκB pathways was extended by finding that 118 of the 155 LMP1 NF-κB activation pathway components were similarly important for IL-1β-, and 79 for TNFα-mediated NFκB activation in the same cells. MAP3K8, PIM3, and six other enzymes were uniquely relevant to LMP1-mediated NFκB activation. Most novel pathway components functioned upstream of IκB kinase complex (IKK) activation. Robust siRNA knockdown effects were confirmed for all mRNAs or proteins tested. Although multiple ZC3H-family proteins negatively regulate NFκB, ZC3H13 and ZC3H18 were activation pathway components. ZC3H13 was critical for LMP1, TNFα, and IL-1β NFκB-dependent transcription, but not for IKK activation, whereas ZC3H18 was critical for IKK activation. Down-modulators of LMP1 mediated NFκB activation were also identified. These experiments identify multiple targets to inhibit or stimulate LMP1-, IL-1β-, or TNFα-mediated canonical NFκB activation.

Methylenedioxy- and Ethylenedioxy-Fused Indolocarbazoles. Potent Human Topoisomerase I Inhibitors and Antitumor Agents

Anti-cancer Agents in Medicinal Chemistry. Feb, 2012  |  Pubmed ID: 22339065

The indolo[2,3-a]carbazole alkaloids constitute an important class of natural products with interesting and diverse biological activities. A series of novel ring-fused indolocarbazoles were synthesized and evaluated for inhibition of topoisomerase I-mediated relaxation of supercoiled DNA and in vitro antitumor activity. The derivatives bearing a methylenedioxy or an ethylenedioxy ring the fused onto the nonglycosylated indole (1a, 1b) demonstrated more potent anti-topoisomerase I activity. The isopropylenedioxy analogue 1c was approximately half as active as 1a, while the O-dimethoxy analogue 1d and the regioisomers 2a and 2b were essentially devoid of measurable activity, implying that the stacking with the intact DNA strand has been impeded by these compounds due to steric hindrance. The newly synthesized indolocarbazoles were screened against the NCI's 60 tumor cell lines. The order of activity, based on the mean GI50 values, is as follows: 1a > 2a ~ 1d > 1b > MCR-47 > 2b. Though in general the analogues that showed potent activity against topoisomerase I (1a, 1b) also showed potent in vitro inhibition of tumor cell growth, the antitumor activity of the anti-topoisomerase I inactive 1d and 2a were intriguing. COMPARE analyses confirmed that the topoisomerase I is the primary target for 1a and 1b; however, other target(s) or pathway(s) may also be involved, with PLD1 and MERTK suggested. Further investigation of these molecular targets against these indolocarbazoles is warranted.

Diagnostic Imaging in the Evaluation of Leg Pain in Athletes

Clinics in Sports Medicine. Apr, 2012  |  Pubmed ID: 22341013

The causes of leg pain in the athlete are diverse. Pain can relate to more common etiologies, such as musculotendinous injury to the hamstrings and Achilles tendon as well as stress injury to bone, with tibial stress injuries comprising the most common cause for lower leg pain in athletes. Less-common causes include chronic exertional compartment syndrome and popliteal artery entrapment syndrome, both of which cause pain as a result of muscle ischemia. Radiologic evaluation plays an important role in differentiating among the many possible causes of leg pain and is often essential in determining degree of injury as well as in documenting healing before patient return to athletic activity. With PAES and hamstring and Achilles injuries, imaging may be helpful in surgical planning as well as in determining an underlying anatomic cause for injury. Several of these conditions can be evaluated with multiple different imaging modalities. The imaging modality of choice should be selected based on the sensitivity and specificity of the imaging examination but should also be tailored to each individual patient after determining comorbidities that may preclude certain types of imaging as well as assessing the patient's ability to undergo such testing.

Sequencing Histone-modifying Enzymes Identifies UTX Mutations in Acute Lymphoblastic Leukemia

Leukemia : Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K. Mar, 2012  |  Pubmed ID: 22377896

Acylated Kaempferol Glycosides from Laurus Nobilis Leaves and Their Inhibitory Effects on Na+/K+-adenosine Triphosphatase

Biological & Pharmaceutical Bulletin. 2012  |  Pubmed ID: 22382332

Na(+)/K(+)-adenosine triphosphatase (ATPase) inhibitors have considerable therapeutic potential against some heart diseases like congestive heart failure and cardiac arrhythmias. Through bioassay-guided separation of the leaf extract of Laurus nobilis, six acylated kaempferol glycosides (compounds 1-6) were isolated. Their structures were determined on the basis of spectroscopic analysis and comparison with reported data. All the isolates were subjected to in vitro bioassays to evaluate their inhibitory activities against Na(+)/K(+)-ATPase from porcine cerebral cortex and bacterial growth. These studies led to the identification of compounds 1-6 as potent Na(+)/K(+)-ATPase inhibitors, with IC(50) values in the range of 4.0 ± 0.1-10.4 ± 0.6 μM. These compounds also exhibited a broad spectrum of antibacterial activity. In particular, compounds 4 and 6 showed potent inhibitory activities against several bacterial strains, except Escherichia coli, with minimum inhibitory concentration (MIC) values in the range of 0.65-2.08 μg/mL. Thus, L. nobilis-derived acylated kaempferol glycosides may have a potential to be leads for the development of Na(+)/K(+) ATPase inhibitors (1-6) and antibacterial agents (4, 6).

HemaMaxâ„¢, a Recombinant Human Interleukin-12, is a Potent Mitigator of Acute Radiation Injury in Mice and Non-human Primates

PloS One. 2012  |  Pubmed ID: 22383962

HemaMax, a recombinant human interleukin-12 (IL-12), is under development to address an unmet medical need for effective treatments against acute radiation syndrome due to radiological terrorism or accident when administered at least 24 hours after radiation exposure. This study investigated pharmacokinetics, pharmacodynamics, and efficacy of m-HemaMax (recombinant murine IL-12), and HemaMax to increase survival after total body irradiation (TBI) in mice and rhesus monkeys, respectively, with no supportive care. In mice, m-HemaMax at an optimal 20 ng/mouse dose significantly increased percent survival and survival time when administered 24 hours after TBI between 8-9 Gy (p<0.05 Pearson's chi-square test). This survival benefit was accompanied by increases in plasma interferon-γ (IFN-γ) and erythropoietin levels, recovery of femoral bone hematopoiesis characterized with the presence of IL-12 receptor β2 subunit-expressing myeloid progenitors, megakaryocytes, and osteoblasts. Mitigation of jejunal radiation damage was also examined. At allometrically equivalent doses, HemaMax showed similar pharmacokinetics in rhesus monkeys compared to m-HemaMax in mice, but more robustly increased plasma IFN-γ levels. HemaMax also increased plasma erythropoietin, IL-15, IL-18, and neopterin levels. At non-human primate doses pharmacologically equivalent to murine doses, HemaMax (100 ng/Kg and 250 ng/Kg) administered at 24 hours after TBI (6.7 Gy/LD(50/30)) significantly increased percent survival of HemaMax groups compared to vehicle (p<0.05 Pearson's chi-square test). This survival benefit was accompanied by a significantly higher leukocyte (neutrophils and lymphocytes), thrombocyte, and reticulocyte counts during nadir (days 12-14) and significantly less weight loss at day 12 compared to vehicle. These findings indicate successful interspecies dose conversion and provide proof of concept that HemaMax increases survival in irradiated rhesus monkeys by promoting hematopoiesis and recovery of immune functions and possibly gastrointestinal functions, likely through a network of interactions involving dendritic cells, osteoblasts, and soluble factors such as IL-12, IFN-γ, and cytoprotectant erythropoietin.

Causes and Correlates of Calf Mortality in Captive Asian Elephants (Elephas Maximus)

PloS One. 2012  |  Pubmed ID: 22396757

Juvenile mortality is a key factor influencing population growth rate in density-independent, predation-free, well-managed captive populations. Currently at least a quarter of all Asian elephants live in captivity, but both the wild and captive populations are unsustainable with the present fertility and calf mortality rates. Despite the need for detailed data on calf mortality to manage effectively populations and to minimize the need for capture from the wild, very little is known of the causes and correlates of calf mortality in Asian elephants. Here we use the world's largest multigenerational demographic dataset on a semi-captive population of Asian elephants compiled from timber camps in Myanmar to investigate the survival of calves (n = 1020) to age five born to captive-born mothers (n = 391) between 1960 and 1999. Mortality risk varied significantly across different ages and was higher for males at any age. Maternal reproductive history was associated with large differences in both stillbirth and liveborn mortality risk: first-time mothers had a higher risk of calf loss as did mothers producing another calf soon (<3.7 years) after a previous birth, and when giving birth at older age. Stillbirth (4%) and pre-weaning mortality (25.6%) were considerably lower than those reported for zoo elephants and used in published population viability analyses. A large proportion of deaths were caused by accidents and lack of maternal milk/calf weakness which both might be partly preventable by supplementary feeding of mothers and calves and work reduction of high-risk mothers. Our results on Myanmar timber elephants with an extensive keeping system provide an important comparison to compromised survivorship reported in zoo elephants. They have implications for improving captive working elephant management systems in range countries and for refining population viability analyses with realistic parameter values in order to predict future population size of the Asian elephant.

Leukodystrophies

Advances in Experimental Medicine and Biology. 2012  |  Pubmed ID: 22411242

Leukodystrophies comprise a broad group of progressive, inherited disorders affecting mainly myelin. They often present after a variable period of normalcy with a variety of neurologic problems. Though the ultimate diagnosis is not found in many patients with leukodystrophies, distinctive features unique to them aid in diagnosis, treatment and prognostication. The clinical characteristics, etiologies, diagnostic testing and treatment options are reviewed in detail for some of the major leukodystrophies: X-linked adrenoleukodystrophy, Krabbe disease, metachromatic leukodystrophy, Pelizaeus-Merzbacher disease, Alexander disease, Canavan disease, megalencephalic leukoencephalopathy with subcortical cysts and vanishing white matter disease.

Designer Dirac Fermions and Topological Phases in Molecular Graphene

Nature. Mar, 2012  |  Pubmed ID: 22422264

The observation of massless Dirac fermions in monolayer graphene has generated a new area of science and technology seeking to harness charge carriers that behave relativistically within solid-state materials. Both massless and massive Dirac fermions have been studied and proposed in a growing class of Dirac materials that includes bilayer graphene, surface states of topological insulators and iron-based high-temperature superconductors. Because the accessibility of this physics is predicated on the synthesis of new materials, the quest for Dirac quasi-particles has expanded to artificial systems such as lattices comprising ultracold atoms. Here we report the emergence of Dirac fermions in a fully tunable condensed-matter system-molecular graphene-assembled by atomic manipulation of carbon monoxide molecules over a conventional two-dimensional electron system at a copper surface. Using low-temperature scanning tunnelling microscopy and spectroscopy, we embed the symmetries underlying the two-dimensional Dirac equation into electron lattices, and then visualize and shape the resulting ground states. These experiments show the existence within the system of linearly dispersing, massless quasi-particles accompanied by a density of states characteristic of graphene. We then tune the quantum tunnelling between lattice sites locally to adjust the phase accrual of propagating electrons. Spatial texturing of lattice distortions produces atomically sharp p-n and p-n-p junction devices with two-dimensional control of Dirac fermion density and the power to endow Dirac particles with mass. Moreover, we apply scalar and vector potentials locally and globally to engender topologically distinct ground states and, ultimately, embedded gauge fields, wherein Dirac electrons react to 'pseudo' electric and magnetic fields present in their reference frame but absent from the laboratory frame. We demonstrate that Landau levels created by these gauge fields can be taken to the relativistic magnetic quantum limit, which has so far been inaccessible in natural graphene. Molecular graphene provides a versatile means of synthesizing exotic topological electronic phases in condensed matter using tailored nanostructures.

Effect of Methoxychlor on Ca(2+) Movement and Viability in MDCK Renal Tubular Cells

Basic & Clinical Pharmacology & Toxicology. Mar, 2012  |  Pubmed ID: 22458924

The effect of the insecticide methoxychlor on the physiology of renal tubular cells is unknown. This study aimed to explore the effect of methoxychlor on cytosolic Ca(2+) concentrations ([Ca(2+) ](i) ) in MDCK renal tubular cells by using the Ca(2+) -sensitive fluorescent dye fura-2. Methoxychlor at 5-20 μM increased [Ca(2+) ](i) in a concentration-dependent manner. The signal was reduced by 80% by removing extracellular Ca(2+) . Methoxychlor-induced Ca(2+) entry was not affected by nifedipine and SK&F96365 but was inhibited by econazole and protein kinase C modulators. In Ca(2+) -free medium, treatment with the endoplasmic reticulum Ca(2+) pump inhibitor thapsigargin or 2,5-di-tert-butylhydroquinone (BHQ) partly inhibited methoxychlor-induced [Ca(2+) ](i) rise. Incubation with methoxychlor also inhibited thapsigargin or BHQ-induced [Ca(2+) ](i) rise. Inhibition of phospholipase C with U73122 nearly abolished methoxychlor-induced [Ca(2+) ](i) rise. At 5-15 μM, methoxychlor slightly increased cell viability; whereas at 20 μM, it decreased viability. The cytotoxic effect of methoxychlor was not reversed by chelating cytosolic Ca(2+) with 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid/AM (BAPTA/AM). Annexin V-FITC data suggest that 10 μM methoxychlor inhibited apoptosis while 20 μM methoxychlor enhanced apoptosis. Methoxychlor (10 and 20 μM) increased the production of reactive oxygen species. Together, in renal tubular cells, methoxychlor induced [Ca(2+) ](i) rise by inducing phospholipase C-dependent Ca(2+) release from multiple stores and Ca(2+) entry via protein kinase C- and econazole-sensitive channels. Methoxychlor slightly enhanced or inhibited cell viability in a concentration-dependent, Ca(2+) -independent manner. Methoxychlor induced cell death that may involve apoptosis via mitochondrial pathways.

Do You Think It's a Disease? A Survey of Medical Students

BMC Medical Education. Apr, 2012  |  Pubmed ID: 22471875

ABSTRACT: BACKGROUND: The management of medical conditions is influenced by whether clinicians regard them as "disease" or "not a disease". The aim of the survey was to determine how medical students classify a range of conditions they might encounter in their professional lives and whether a different name for a condition would influence their decision in the categorisation of the condition as a 'disease' or 'not a disease'. METHODS: We surveyed 3 concurrent years of medical students to classify 36 candidate conditions into "disease" and "non-disease". The conditions were given a 'medical' label and a (lay) label and positioned where possible in alternate columns of the survey. RESULTS: The response rate was 96% (183 of 190 students attending a lecture): 80% of students concurred on 16 conditions as "disease" (eg diabetes, tuberculosis), and 4 as "non-disease" (eg baldness, menopause, fractured skull and heat stroke). The remaining 16 conditions (with 21-79% agreement) were more contentious (especially obesity, infertility, hay fever, alcoholism, and restless leg syndrome). Three pairs of conditions had both a more, and a less, medical label: the more medical labels (myalgic encephalomyelitis, hypertension, and erectile dysfunction) were more frequently classified as 'disease' than the less medical (chronic fatigue syndrome, high blood pressure, and impotence), respectively, significantly different for the first two pairs. CONCLUSIONS: Some conditions excluded from the classification of "disease" were unexpected (eg fractured skull and heat stroke). Students were mostly concordant on what conditions should be classified as "disease". They were more likely to classify synonyms as 'disease' if the label was medical. The findings indicate there is still a problem 30 years on in the concept of 'what is a disease'. Our findings suggest that we should be addressing such concepts to medical students.

The Group 2 Metabotropic Glutamate Receptor Agonist LY379268 Rescues Neuronal, Neurochemical and Motor Abnormalities in R6/2 Huntington's Disease Mice

Neurobiology of Disease. Mar, 2012  |  Pubmed ID: 22472187

Excitotoxic injury to striatum by dysfunctional cortical input or aberrant glutamate uptake may contribute to Huntington's disease (HD) pathogenesis. Since corticostriatal terminals possess mGluR2/3 autoreceptors, whose activation dampens glutamate release, we tested the ability of the mGluR2/3 agonist LY379268 to improve the phenotype in R6/2 HD mice with 120-125 CAG repeats. Daily subcutaneous injection of a maximum tolerated dose (MTD) of LY379268 (20mg/kg) had no evident adverse effects in WT mice, and diverse benefits in R6/2 mice, both in a cohort of mice tested behaviorally until the end of R6/2 lifespan and in a cohort sacrificed at 10weeks of age for blinded histological analysis. MTD LY379268 yielded a significant 11% increase in R6/2 survival, an improvement on rotarod, normalization and/or improvement in locomotor parameters measured in open field (activity, speed, acceleration, endurance, and gait), a rescue of a 15-20% cortical and striatal neuron loss, normalization of SP striatal neuron neurochemistry, and to a lesser extent enkephalinergic striatal neuron neurochemistry. Deficits were greater in male than female R6/2 mice, and drug benefit tended to be greater in males. The improvements in SP striatal neurons, which facilitate movement, are consistent with the improved movement in LY379268-treated R6/2 mice. Our data indicate that mGluR2/3 agonists may be particularly useful for ameliorating the morphological, neurochemical and motor defects observed in HD.