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Articles by Andrew L. Ready in JoVE

 JoVE Neuroscience

Intact Histological Characterization of Brain-implanted Microdevices and Surrounding Tissue

1Weldon School of Biomedical Engineering, Purdue University, 2Department of Biological Sciences, Purdue University


JoVE 50126

Here we present a histological method for capturing, labeling, optically clearing, and imaging the intact brain tissue interface around chronically implanted microdevices in rodent brain tissue. Results from the techniques comprising this method are useful for understanding the impact of various penetrating brain-implants on their surrounding tissue.

Other articles by Andrew L. Ready on PubMed

Age Differences in the Organization of Emotion Knowledge: Effects Involving Valence and Time Frame

Older and younger adults attend to and remember emotion information differently. The present study builds on this work by investigating age-related differences in the schematic organization of emotion knowledge. Younger and older adults reported on their experiences of positive and negative affect, both today and in general. Of primary interest was judgment speed as a function of matches (e.g., positive-positive) or mismatches (e.g., negative-positive) in valence and time frame across consecutive trials. Older adults exhibited stronger valence-related priming effects and weaker time-frame-related priming effects, relative to younger adults. Results remained significant when controlling for individual differences in speed, speed variability, motor priming, temperament, and life satisfaction. The discussion focuses on the manner in which age differences in the schematic organization of emotion knowledge might contribute to age differences in the self-concept, affective processing, and emotional experience.

New Chief Brings Welcome Change to US Cancer Agency

A Systematic Review and Economic Model of the Clinical and Cost-effectiveness of Immunosuppressive Therapy for Renal Transplantation in Children

To review the clinical and cost-effectiveness of basiliximab, daclizumab, tacrolimus, mycophenolate mofetil (MMF), mycophenolate sodium (MPS) and sirolimus as possible immunosuppressive therapies for renal transplantation in children.

Iron-catalyzed Carbometalation of Propargylic and Homopropargylic Alcohols

Nucleophilic addition to alkynes represents an attractive approach to the synthesis of olefins. Obstacles to this strategy include the low reactivity of alkynes toward many organometallic reagents and difficulties associated with controlling the regioselectivity of addition. Here we demonstrate that Fe(III) salts are effective precatalysts for the carbometalation of alkynes. Primary and secondary propargylic and homopropargylic alcohols react with alkyl and aryl Grignard reagents to provide Z-allylic and -homoallylic alcohols as single stereo and regioisomers. Alkylation and arylation occur distal to the alcohol. Common oxygen protecting groups and tertiary nitrogens are tolerated. The intermediate vinyl magnesium or iron species can be trapped with a variety of electrophiles including aldehydes, allyl bromide, and N-bromosuccinimide. Diyne substrates undergo an unusual addition/cyclization reaction to generate cyclic dienes. A brief discussion of mechanism is included.

Rapamycin Biosynthesis: Elucidation of Gene Product Function

The function of gene products involved in the biosynthesis of the clinically important polyketide rapamycin were elucidated by biotransformation and gene complementation.

Insight and Cognitive Impairment: Effects on Quality-of-life Reports from Mild Cognitive Impairment and Alzheimer's Disease Patients

This study follows previous work to determine the effect of patient insight and cognitive impairment on the reliability and validity of self-reported quality of life (QOL) from patients diagnosed with Alzheimer's disease (AD) and mild cognitive impairment (MCI). AD and MCI patients (N = 68) and their caregivers participated. Patients with impaired insight provided QOL ratings that were less reliable than those provided by patients with better insight. Patient-caregiver agreement for. QOL reports was used as an index of validity. Neither better insight nor lesser cognitive impairment suggested better agreement. Thus, even when patient insight is intact, patient reports are unlikely to agree with caregiver reports. Patient and caregiver reports about patient QOL may represent 2 unique, yet potentially valid, perspectives.

Susceptibility to Breast Cancer: Hereditary Syndromes and Low Penetrance Genes

Several genes are associated with hereditary susceptibility to breast cancer. Most notably these include BRCA1 and BRCA2; however, other less common gene mutations which confer elevated breast cancer risk are associated with Cowden syndrome, Li-Fraumeni syndrome, Peutz-Jeghers syndrome, ataxia-telangiectasia heterozygosity and hereditary diffuse gastric cancer. In this article we highlight the genetic epidemiology, gene function, genotype-phenotype correlations, cancer risks and clinicopathologic findings for the cancer susceptibility genes related to these syndromes. We also examine genes, such as CHEK2, which confer a lower penetrance for breast cancer in comparison to these highly penetrant genes.

Serial Changes in the Expression of CXCR3 and CCR5 on Peripheral Blood Lymphocytes Following Human Renal Transplantation

In animal models of transplantation, chemokine receptors have been shown to direct the infiltration of T cells in immune responses and inflammation and to be critical in cellular recruitment. Although the chemokine receptors CXCR3 and CCR5 and their ligands have been found during acute rejection in transplanted human kidneys, the kinetics of expression on peripheral blood lymphocytes is unknown.

Integrating Patient and Informant Reports on the Cornell-Brown Quality-of-Life Scale

Patients with mild cognitive impairment and mild to moderate Alzheimer's disease can provide information about their quality of life. This study determined whether aggregating patient and informant quality-of-life reports on the Cornell-Brown Scale for Quality of Life in Dementia can provide a broader perspective on the quality of life relative to patient or informant reports separately. Aggregated Cornell-Brown Scale for Quality of Life in Dementia scores were hypothesized to correlate more strongly with both patient and informant perspectives of patient's memory, function, and neuropsychiatric symptoms than the unaggregated measures. Results indicated that aggregated Cornell-Brown Scale for Quality of Life in Dementia scores reflected a blend of patient and informant perspectives on patient function. This study contributes to a growing line of research that recommends integrating patient and informant perspectives to achieve the most complete assessment of quality of life.

Use of Oxidized Zirconium Hemiarthroplasty in Hip Fractures: Clinical Results and Spectrum Analysis

Oxidized zirconium may have improved wear characteristics against polyethylene, but its performance against native cartilage is unknown. Between 1996 and 1998, 52 patients received an oxidized zirconium hemiarthroplasty for the treatment of a hip fracture. Twelve patients (23%) died within 1 year of surgery, and 24 (46%) were surviving at 5 years. In 38 patients with minimum 2-years follow-up, clinical evaluation after surgery averaged 4.5 years with Harris hip scores averaging 78 (range, 55-92). Three patients radiographically showed acetabular protrusion or significant wear, with 2 undergoing revision surgery. An explanted prosthesis demonstrated no appreciable damage by spectrum analysis. Because of the high mortality rate after hip fracture, the clinical benefits of oxidized zirconium hemiarthroplasty in this population, if existent, are difficult to appreciate and currently show no benefits over standard prostheses.

Discovery of Small-molecule Inhibitors of Tyrosinase

To identify novel inhibitors of tyrosinase, a fluorescent assay was developed which is suitable for high-throughput screening. In the assay, oxidation of the substrate by tyrosinase leads to the release of a fluorescent coumarin. Several small molecules were identified that inhibited mushroom tyrosinase in vitro and human tyrosinase in cell culture. These compounds may represent lead structures for therapies targeted at disorders of hyperpigmentation.

BRCA1 and BRCA2 Genetic Testing in Hispanic Patients: Mutation Prevalence and Evaluation of the BRCAPRO Risk Assessment Model

The BRCAPRO model, used to predict a family's likelihood of carrying a BRCA1 or BRCA2 mutation, was designed using mutation frequencies of white and Ashkenazi Jewish populations, and may not be applicable to other populations. BRCAPRO was recently validated in African Americans, although has yet to be examined in Hispanics. This retrospective study reports the mutation frequency and spectrum of BRCA1 and BRCA2 mutations in a Hispanic population and evaluates the BRCAPRO model in Hispanics.

Magnetic Resonance Imaging-guided Percutaneous Biopsy of Musculoskeletal Lesions

Bone, soft-tissue, and articular lesions are often well visualized by magnetic resonance imaging. Our goal was to evaluate the diagnostic performance of magnetic resonance imaging-guided biopsies of selected musculoskeletal lesions.

Directed Hydrozirconation of Propargylic Alcohols

Image-guided Percutaneous Thermal Ablation for the Palliative Treatment of Chest Wall Masses

To evaluate the palliative benefits of image-guided thermal ablation for the treatment of painful tumors affecting the chest wall.

Science at the Interface of Chemistry and Biology at the University of Texas Southwestern Medical Center

Light Exposure Causes Functional Changes in the Retina: Increased Photoreceptor Cation Channel Permeability, Photoreceptor Apoptosis, and Altered Retinal Metabolic Function

Light exposure induces retinal photoreceptor degeneration and retinal remodeling in both the normal rat retina and in animal models of retinal degeneration. Although cation entry is one of the triggers leading to apoptosis, it is unclear if this event occurs in isolation, or whether a number of pathways lead to photoreceptor apoptosis following light exposure. Following light exposure, we investigated the characteristics of cation entry, apoptotic markers [using terminal deoxynucleotidyl transferase (EC 2.7.7.31) dUTP nick-end labeling (TUNEL) labeling] and metabolic properties of retina from Sprague-Dawley (SD) rats and a rat model of retinitis pigmentosa [proline-23-histidine (P23H) rat]. Assessment of cation channel permeability using agmatine (AGB) labeling showed that excessive cation gating accompanied the series of anomalies that occur prior to photoreceptor loss. Increased AGB labeling in photoreceptors was seen in parallel with the appearance of apoptotic photoreceptors detected by TUNEL labeling with only a smaller proportion of cells colocalizing both markers. However, SD and P23H retinal photoreceptors differed in the amounts and colocalization of AGB gating and TUNEL labeling as a function of light exposure. Finally, reduced retinal lactate dehydrogenase levels were found in SD and P23H rat retinas after a 24-h light exposure period. Short-term (2 h) exposure of the P23H rat retina caused an increase in lactate dehydrogenase activity suggesting increased metabolic demand. These results suggest that energy availability may be exacerbated during the early stages of light exposure in susceptible retinas. Also, the concomitant observation of increased ion gating and TUNEL labeling suggest the existence of at least two possible mechanisms in light-damaged retinas in both SD and the P23H rat retina.

Commentary on "Health Economics and the Value of Therapy in Alzheimer's Disease." Patient-reported Outcomes in Clinical Trials for Alzheimer's Disease

Make Your Company a Talent Factory

Despite the great sums of money companies dedicate to talent management systems, many still struggle to fill key positions - limiting their potential for growth in the process. Virtually all the human resource executives in the authors' 2005 survey of 40 companies around the world said that their pipeline of high-potential employees was insufficient to fill strategic management roles. The survey revealed two primary reasons for this. First, the formal procedures for identifying and developing next-generation leaders have fallen out of sync with what companies need to grow or expand into new markets. To save money, for example, some firms have eliminated positions that would expose high-potential employees to a broad range of problems, thus sacrificing future development opportunities that would far outweigh any initial savings from the job cuts. Second, HR executives often have trouble keeping top leaders' attention on talent issues, despite those leaders' vigorous assertions that obtaining and keeping the best people is a major priority. If passion for that objective doesn't start at the top and infuse the culture, say the authors, talent management can easily deteriorate into the management of bureaucratic routines. Yet there are companies that can face the future with confidence. These firms don't just manage talent, they build talent factories. The authors describe the experiences of two such corporations - consumer products icon Procter & Gamble and financial services giant HSBC Group -that figured out how to develop and retain key employees and fill positions quickly to meet evolving business needs. Though each company approached talent management from a different direction, they both maintained a twin focus on functionality (rigorous talent processes that support strategic and cultural objectives) and vitality (management's emotional commitment, which is reflected in daily actions).

Internal Iliac Artery Pseudoaneurysm Following Renal Transplant Biopsy Successfully Treated with Endovascular Stenting and Thrombosis: a Case Report

A 49-year-old man underwent living donor renal transplantation in November 2005. The transplant renal artery was anastomosed to the right internal iliac artery with an end-to-end anastomosis. The patient achieved immediate graft function and the allograft was normally perfused. Seven weeks later, renal allograft function deteriorated with a serum creatinine level increased to 244 micromol/L. An ultrasound scan revealed adequate perfusion to the kidney and the absence of hydronephrosis. A transplant biopsy revealed Banff IB rejection, which was treated with high-dose prednisolone. Following biopsy, the patient's renal function rapidly deteriorated with a serum creatinine level increased to 627 micromol/L, requiring hemodialysis. A computed tomography (CT) angiogram demonstrated a 6-cm diameter pseudoaneurysm arising from the internal iliac artery with absence of kidney perfusion. The aneurysm was accessed percutaneously with a 4-F catheter and 1000 U of human thrombin injected, resulting in partial thrombosis of the pseudoaneurysm. A balloon expandable covered metal stent was then placed across the site of the transplant renal artery anastomosis, resulting in successful occlusion of the aneurysm. Intrarenal blood flow was established by dilating 2 intrarenal branches with 3-mm diameter balloons. The serum creatinine level started to decrease within 24 hours of the procedure and renal function improved rapidly to a level achieved immediately after transplantation. Three months later the patient had a well-functioning allograft with a serum creatinine level of 176 micromol/L, follow-up CT scan demonstrated good perfusion of the transplanted kidney with no further change in the pseudoaneurysm. At 12 months follow-up the patient remains with a well-functioning allograft.

MRI-guided Percutaneous Cryotherapy for Soft-tissue and Bone Metastases: Initial Experience

We sought to determine the safety and feasibility of percutaneous MRI-guided cryotherapy in the care of patients with refractory or painful metastatic lesions of soft tissue and bone adjacent to critical structures.

Predicting Early Renal Allograft Function Using Clinical Variables

Suboptimal early graft function following renal transplantation remains a significant challenge. It is suggested that clinical variables (or scoring systems based thereon) may predict the occurrence of delayed graft function (DGF), defined as post-operative dialysis requirement. However, data is conflicting, and suboptimal renal function not requiring dialysis has been little investigated. This study tested the ability of clinical variables to predict suboptimal early function variably assessed by: (i) DGF (dialysis requirement during the first week); (ii) DGF duration; (iii) slow graft function (creatinine>3 mg/dl on day 5); (iv) creatinine reduction ratio on day 2.

Paging All Doctors

Veterans Seeking Treatment for Posttraumatic Stress Disorder: What About Comorbid Chronic Pain?

Our primary aim was to document the rate of comorbidity of physician-diagnosed chronic pain conditions in veterans who were seeking treatment for posttraumatic stress disorder (PTSD). Chronic pain diagnoses (e.g., chronic low-back pain and osteoarthritis) were examined with retrospective chart review. Of the patients with PTSD, 66% had chronic pain diagnoses at pretreatment. These findings are consistent with previous studies that documented the high comorbidity of chronic pain and PTSD using samples of pain patients. Our secondary aim was to examine pain ratings before, during, and after PTSD treatment. Using data that were a part of clinical practice, we found that patients with more pain before treatment reported reductions in pain over the course of PTSD treatment and in the 4 months following treatment. While our results must be interpreted cautiously because of multiple confounding factors and the absence of experimental manipulation, they highlight the importance of PTSD and pain comorbidity.

Myosin V, Rab11, and DRip11 Direct Apical Secretion and Cellular Morphogenesis in Developing Drosophila Photoreceptors

Sensory neuron terminal differentiation tasks apical secretory transport with delivery of abundant biosynthetic traffic to the growing sensory membrane. We recently showed Drosophila Rab11 is essential for rhodopsin transport in developing photoreceptors and asked here if myosin V and the Drosophila Rab11 interacting protein, dRip11, also participate in secretory transport. Reduction of either protein impaired rhodopsin transport, stunting rhabdomere growth and promoting accumulation of cytoplasmic rhodopsin. MyoV-reduced photoreceptors also developed ectopic rhabdomeres inappropriately located in basolateral membrane, indicating a role for MyoV in photoreceptor polarity. Binary yeast two hybrids and in vitro protein-protein interaction predict a ternary complex assembled by independent dRip11 and MyoV binding to Rab11. We propose this complex delivers morphogenic secretory traffic along polarized actin filaments of the subcortical terminal web to the exocytic plasma membrane target, the rhabdomere base. A protein trio conserved across eukaryotes thus mediates normal, in vivo sensory neuron morphogenesis.

The Effect of Amalgam Exposure on Mercury- and Antibiotic-resistant Bacteria

Antibiotic resistance genes can be found on the same mobile genetic elements as genes coding for resistance to metals such as mercury (Hg). Amalgam restorations contain ca. 50% Hg and, therefore, it could be expected that exposure to such dental restorative materials may promote Hg resistance and thereby antibiotic resistance. An in vitro biofilm model was used to grow microcosm dental plaques on enamel or amalgam substrata. The number and proportion of Hg-resistant organisms over time were determined by viable counts. Microcosm dental plaques grown in the presence of amalgam had a higher number and proportion of Hg-resistant bacteria than those grown on enamel. The levels of these Hg-resistant bacteria remained elevated for a period of 48 h, however after 72 h the proportions returned to baseline levels. Of the 42 Hg-resistant bacteria isolated, 98% were streptococci, with Streptococcus mitis predominating. A high proportion of the Hg-resistant isolates (71%) were also resistant to a range of antibiotics, with resistance to tetracycline being encountered most frequently. The results of this in vitro study indicate that placement of amalgam restorations may play a role in promoting the levels of Hg- and antibiotic-resistant bacteria present in the oral cavity.

Gene Polymorphisms and the Prevalence of Key Periodontal Pathogens

Growing evidence suggests that individual genetic susceptibility may influence the host's response to infections. The aim of this project was to study whether gene polymorphisms of inflammatory markers are associated with the presence of viable periodontopathogenic bacteria. We extracted genomic DNA from 45 young adults diagnosed with generalized aggressive periodontitis to study Fc receptors, formyl peptide receptor, Interleukin-6, tumor necrosis factor-alpha, and vitamin D receptor polymorphisms. The presence and viable numbers of Actinobacillus actinomycetemcomitans, Porphyromonas gingivalis, and Tannerella forsythensis were determined by culture, and their identities confirmed by PCR. Multiple logistic regressions revealed that both Fcgamma receptor and IL-6 -174 polymorphisms were associated with increased odds of detecting A. actinomycetemcomitans, P. gingivalis, and T. forsythensis after adjustment for age, ethnicity, smoking, and periodontitis extent. These findings support the hypothesis that complex interactions between the microbiota and host genome may be at the basis of susceptibility to aggressive periodontitis.

A Multi-center Phase II Study of Weekly Topotecan As Second-line Therapy for Small Cell Lung Cancer

To determine the response rate, toxicity, failure free and overall survival of weekly topotecan in patients with relapsed small cell lung cancer who received one prior platinum based chemotherapy.

Copper-promoted Cycloaddition of Diazocarbonyl Compounds and Acetylides

Factor Structure of Patient and Caregiver Ratings on the Dementia Quality of Life Instrument

Preliminary evidence suggests that quality of life reports from patients diagnosed with mild cognitive impairment (MCI) and mild Alzheimer's disease (AD) are as reliable and valid as data provided by caregivers. To date, no studies compared the factor structure of data provided by caregivers and patients. Factor analyses are important to conduct because they are an indicator of validity. This study compared the factor structure of patient and caregiver reports on the Dementia Quality of Life scale (DQoL). Participants (N=67) were patients diagnosed with amnestic MCI or mild AD and their caregivers. Principal axis factor analyses were run separately on patient and caregiver report data. The three-factor solutions for patient and caregiver data were nearly identical. Three factors corresponding to positive affect, negative affect, and aesthetics emerged reliably from analyses. Thus, data from patients demonstrated a factor structure that was highly consistent with caregiver report data and conformed to meaningful psychological constructs.

Phase I Study of the Farnesyltransferase Inhibitor Lonafarnib with Weekly Paclitaxel in Patients with Solid Tumors

To establish the maximum tolerated dose of the farnesyltransferase inhibitor lonafarnib (Sarasar, Schering-Plough Corp., Kenilworth, NJ) in combination with weekly paclitaxel in patients with solid tumors. Tolerability, pharmacokinetics, safety, and dose-limiting toxicity were characterized.

Characterization of a 3;6 Translocation Associated with Renal Cell Carcinoma

The most frequent cause of familial clear cell renal cell carcinoma (RCC) is von Hippel-Lindau disease and the VHL tumor suppressor gene (TSG) is inactivated in most sporadic clear cell RCC. Although there is relatively little information on the mechanisms of tumorigenesis of clear cell RCC without VHL inactivation, a subset of familial cases harbors a balanced constitutional chromosome 3 translocation. To date nine different chromosome 3 translocations have been associated with familial or multicentric clear cell RCC; and in three cases chromosome 6 was also involved. To identify candidate genes for renal tumorigenesis we characterized a constitutional translocation, t(3;6)(q22;q16.1) associated with multicentric RCC without evidence of VHL target gene dysregulation. Analysis of breakpoint sequences revealed a 1.3-kb deletion on chromosome 6 within the intron of a 2 exon predicted gene (NT_007299.434). However, RT-PCR analysis failed to detect the expression of this gene in lymphoblast, fibroblast, or kidney tumor cell lines. No known genes were disrupted by the translocation breakpoints but several candidate TSGs (e.g., EPHB1, EPHA7, PPP2R3A RNF184, and STAG1) map within close proximity to the breakpoints.

Emotional Complexity in Younger, Midlife, and Older Adults

Questions pertaining to emotional complexity in adult development are being pursued from a number of vantage points. The current studies sought to clarify the study of emotional complexity by comparing and contrasting 2 dominant perspectives on emotional complexity in different age groups (i.e., covariation and absolute-level approaches). Results indicate that emotional complexity is a multifaceted construct and that methodology will impact substantive findings and developmental trends that emerge from the data. Recommendations and considerations for future research are discussed, including, for example, within- versus cross-domain ideas of emotional complexity.

Directed Hydrozirconation of Homopropargylic Alcohols

Homopropargylic alcohols undergo directed hydrozirconation with Schwartz reagent (Cp(2)ZrHCl) to generate vinyl-metal species in which the metal fragment is proximal to the alkoxide. Electrophilic trapping yields tri-substituted olefins in good yields with good control of regio- and stereochemistry. Experiments with a homopropargylic ether confirmed the role of the hydroxyl group in the directed hydrometalation.

Winning the Race for Talent in Emerging Markets. New Research Shows How to Attract and Retain the Best Employees in Developing Economies

Quantum Dots As Enhancers of the Efficacy of Bacterial Lethal Photosensitization

Because of the increasing resistance of bacteria to antibiotics there is considerable interest in light-activated antimicrobial agents (LAAAs) as alternatives to antibiotics for treating localized infections. The purpose of this study was to determine whether CdSe/ZnS quantum dots (QD) could enhance the antibacterial activity of the LAAA, toluidine blue O (TBO). Suspensions of Staphylococcus aureus and Streptococcus pyogenes were exposed to white light (3600 lux) and TBO (absorbance maximum = 630 nm) in the presence and absence of 25 nm diameter QD (emission maximum = 627 nm). When the TBO:QD ratio was 2667:1, killing of Staph. aureus was enhanced by 1.72log(10) units. In the case of Strep. pyogenes, an enhanced kill of 1.55log(10) units was achieved using TBO and QD in the ratio 267:1. Singlet oxygen and fluorescence measurements showed that QD suppress the formation of singlet oxygen from TBO and that QD fluorescence is significantly quenched in the presence of TBO (70-90%). Enhanced killing appears to be attributable to a non-Förster resonance energy transfer mechanism, whereby the QD converts part of the incident light to the absorption maximum for TBO; hence more light energy is harvested, resulting in increased concentrations of bactericidal radicals. QD may, therefore, be useful in improving the efficacy of antimicrobial photodynamic therapy.

Leishmaniasis Emergence and Climate Change

Spatio-temporal modelling of the distributions of the leishmaniases and their sandfly vectors is reviewed in relation to climate change. Many leishmaniases are rural zoonoses, and so there is a foundation of descriptive ecology and qualitative risk assessment. Dogs are widespread reservoir hosts of veterinary importance. Recent statistical modelling has not always produced novel general conclusions, exemplifying the difficulty of applying models outside the original geographical region. Case studies are given for transmission cycles involving both cutaneous and visceral leishmaniasis in the Old World and the Americas. An important challenge is to integrate statistical spatial models based mainly on climate with more explanatory biological models. Ecological niche models pose difficulties because of the number of assumptions. A positive association has been reported between the El Niño cycle and the annual incidence of visceral leishmaniasis in Brazil, but more basic research is needed before tackling other climate-change scenarios, including leishmaniasis emergence in northern Europe.

Air-borne Microbial Contamination of Surfaces in a UK Dental Clinic

Little is known about the number, type, or antibiotic resistance profiles, of air-borne microbes present in hospital settings yet such information is important in designing effective measures to reduce cross-infection. In this study settle plates were used to identify and quantify the air-borne microbes present in a dental clinic. All isolates were identified to species level using partial 16S ribosomal RNA gene sequencing and their susceptibility to ampicillin, chloramphenicol, erythromycin, gentamicin, penicillin, tetracycline or vancomycin was performed. The mean numbers of viable bacteria detected for each sampling occasion during periods of clinical activity and in the absence of such activity were 21.9 x 10(2 )cfu/m2/h and 2.3 x 10(2 )cfu/m2/h respectively. One hundred ninety-three distinct colony morphotypes, comprising 73 species, were isolated during the study and 48% of these were resistant to at least one antibiotic. The mean numbers of different morphotypes detected per sampling occasion were 14.3 and 5 during periods of clinical activity and inactivity respectively. Propionibacterium acnes, Micrococcus luteus and Staphylococcus epidermidis were frequently isolated regardless of whether any clinical activities were taking place. These findings highlight the importance of preventing surfaces from becoming reservoirs of antibiotic-resistant bacteria and thereby contributing to cross-infection in the dental clinic.

PCR Detection and Sequencing of Parasite ITS-rDNA Gene from Reservoirs Host of Zoonotic Cutaneous Leishmaniasis in Central Iran

Leishmania major is the causative agent of zoonotic cutaneous leishmaniasis (ZCL) in which gerbils are the reservoir host. ZCL is of great public health importance in Iran. In the current investigation, nested polymerase chain reaction (PCR) protocols were used to amplify a region of the ribosomal RNA amplicon of Leishmania (ITS1-5.8S rRNA gene). The PCR assays detected L. major in three rodent species: Rhombomis opimus, Meriones lybicus and, for first time, Meriones persicus. L. major parasite was found in Natanz, Isfahan Province in the center of Iran in a focus of rural zoonotic cutaneous leishmaniasis. Four L. major infections were detected in R. opimus species, three in M. Lybicus, and two in M. persicus. All nine rodent infections of L. major were found to be the same haplotype based on the PCR detection and sequencing of parasite ITS-ribosomal DNA gene. In addition, also for the first time, the nested PCR assays detected Leishmania tropica only in one M. persicus. Allied to studies in country, the new findings mean that past conclusions about the reservoir of L. major in Iran must be treated with caution. Finding two Leishmania species in different rodent species as reservoir in Iran, therefore, careful molecular eco-epidemiological investigations will be an essential part of modeling the roles of different gerbil species in maintaining and spreading ZCL foci.

AZD7762, a Novel Checkpoint Kinase Inhibitor, Drives Checkpoint Abrogation and Potentiates DNA-targeted Therapies

Insights from cell cycle research have led to the hypothesis that tumors may be selectively sensitized to DNA-damaging agents resulting in improved antitumor activity and a wider therapeutic margin. The theory relies on the observation that the majority of tumors are deficient in the G1-DNA damage checkpoint pathway resulting in reliance on S and G2 checkpoints for DNA repair and cell survival. The S and G2 checkpoints are regulated by checkpoint kinase 1, a serine/threonine kinase that is activated in response to DNA damage; thus, inhibition of checkpoint kinase 1 signaling impairs DNA repair and increases tumor cell death. Normal tissues, however, have a functioning G1 checkpoint signaling pathway allowing for DNA repair and cell survival. Here, we describe the preclinical profile of AZD7762, a potent ATP-competitive checkpoint kinase inhibitor in clinical trials. AZD7762 has been profiled extensively in vitro and in vivo in combination with DNA-damaging agents and has been shown to potentiate response in several different settings where inhibition of checkpoint kinase results in the abrogation of DNA damage-induced cell cycle arrest. Dose-dependent potentiation of antitumor activity, when AZD7762 is administered in combination with DNA-damaging agents, has been observed in multiple xenograft models with several DNA-damaging agents, further supporting the potential of checkpoint kinase inhibitors to enhance the efficacy of both conventional chemotherapy and radiotherapy and increase patient response rates in a variety of settings.

Ca2+-dependent Metarhodopsin Inactivation Mediated by Calmodulin and NINAC Myosin III

Phototransduction in flies is the fastest known G protein-coupled signaling cascade, but how this performance is achieved remains unclear. Here, we investigate the mechanism and role of rhodopsin inactivation. We determined the lifetime of activated rhodopsin (metarhodopsin = M( *)) in whole-cell recordings from Drosophila photoreceptors by measuring the time window within which inactivating M( *) by photoreisomerization to rhodopsin could suppress responses to prior illumination. M( *) was inactivated rapidly (tau approximately 20 ms) under control conditions, but approximately 10-fold more slowly in Ca2+-free solutions. This pronounced Ca2+ dependence of M( *) inactivation was unaffected by mutations affecting phosphorylation of rhodopsin or arrestin but was abolished in mutants of calmodulin (CaM) or the CaM-binding myosin III, NINAC. This suggests a mechanism whereby Ca2+ influx acting via CaM and NINAC accelerates the binding of arrestin to M( *). Our results indicate that this strategy promotes quantum efficiency, temporal resolution, and fidelity of visual signaling.

Disease Severity Associated with Presence in Subgingival Plaque of Porphyromonas Gingivalis, Aggregatibacter Actinomycetemcomitans, and Tannerella Forsythia, Singly or in Combination, As Detected by Nested Multiplex PCR

This study used a nested multiplex PCR method to detect three periodontal pathogens in subgingival plaque collected before treatment and at 2 and 6 months posttreatment from 107 patients with severe, generalized periodontitis. The proportions of the patients who harbored these bacteria before periodontal treatment were as follows: Tannerella forsythia, 81%; Porphyromonas gingivalis, 78%; and Aggregatibacter (formerly Actinobacillus) actinomycetemcomitans, 47%. At 2 months posttreatment there was a significant reduction in the numbers of patients harboring P. gingivalis (46%; P < 0.001) or T. forsythia (63%; P = 0.043) but not A. actinomycetemcomitans (50%) compared to pretreatment data. At 6 months posttreatment, significantly fewer patients harbored P. gingivalis (43%; P < 0.001); A. actinomycetemcomitans, (31%; P = 0.025), or T. forsythia (63%; P = 0.030). Interestingly, at baseline and at 2 months posttherapy, subjects who harbored only a single pathogen had a greater level of periodontal disease than subjects who harbored two, or all three, of these periodontal pathogens. These data suggest that a reduction in the number of species present may be associated with an increase in the severity of periodontal diseases.

Synthesis of Cyclopentenones from Cyclopropanes and Silyl Ynol Ethers

Direct and Stereospecific Synthesis of Allenes Via Reduction of Propargylic Alcohols with Cp2Zr(H)Cl

Allenes can be synthesized via the direct SN2' addition of hydride to propargylic alcohols. Previous examples of this approach, however, have involved harsh reaction conditions and have suffered from incomplete transfer of central chirality to axial chirality. Here we show that Cp2Zr(H)Cl can react with the zinc or magnesium alkoxides of propargylic alcohols to generate allenes in good yield and in high optical purity. Dialkyl-, alkyl-aryl-, and diaryl-allenes are accessible by this method. Furthermore, the reaction can provide silyl-substituted allenes, trisubstituted allenes, and terminal allenes.

Risk Factors for Acute Rejection in Renal Transplant Recipients Experiencing Delayed Graft Function

Acute rejection (AR) superimposed upon delayed graft function (DGF) following renal transplantation worsens graft outcomes. However, risk factors for AR in patients displaying DGF remain unclear. In this study, 71 patients displaying DGF >/= 5 d were investigated. All received cyclosporine, adjunctive azathioprine or mycophenolate mofetil (MMF), and corticosteroids, with 43 receiving anti-CD25 monoclonal antibody induction. AR episodes were seen in 20 of 71 (28%) patients. Higher C2 levels at days 3 and 5 and the use of MMF were associated with a reduced incidence of AR, with increased HLA-DR mismatch associated with an increased risk for AR. C2 levels at days 3 and 5 below 885 and 1096 ng/mL, respectively, showed best discriminatory values for AR. C2 levels showed no correlation with DGF duration. This study suggests that optimizing immunosuppression in patients with DGF (by ensuring adequate calcineurin inhibitor exposure and the use of potent adjunctive immunosuppression) may reduce the incidence of AR without prolonging the duration of dialysis requirement.

Primary Total Hip Replacement in Childhood, Adolescence and Young Patients: Quality and Outcome of Clinical Studies

The present meta-analysis illustrates relevant information about hip replacement in young patients that has been published during the past 3 decades.

Nested PCRs and Sequencing of Nuclear ITS-rDNA Fragments Detect Three Leishmania Species of Gerbils in Sandflies from Iranian Foci of Zoonotic Cutaneous Leishmaniasis

To identify and understand the natural transmission cycles of Leishmania in Iranian sandflies.

A Prospective Study of Bowel Motility and Related Factors on Breast Cancer Risk

Estrogen is an established risk factor for breast cancer. Greater bowel motility has been associated with increased estrogen excretion and lower serum estrogen levels, suggesting that it may influence breast cancer risk. However, only one other epidemiologic study thus far, to our knowledge, has examined the relation between bowel motility and breast cancer risk.

Branch Retinal Artery Occlusion: Visual Prognosis

To evaluate the visual prognosis in eyes with branch retinal artery occlusion (BRAO).

Calcium-activated Myosin V Closes the Drosophila Pupil

Approximately 40 years ago, an elegant automatic-gain control was revealed in compound eye photoreceptors: In bright light, an assembly of small pigment granules migrates to the cytoplasmic face of the photosensitive membrane organelle, the rhabdomere, where they attenuate waveguide propagation along the rhabdomere. This migration results in a "longitudinal pupil" that reduces rhodopsin exposure by a factor of 0.8 log units. Light-induced elevation of cytosolic free Ca(2+) triggers the migration of pigment granules, and pigment granules fail to migrate in a mutant deficient in photoactivated TRP calcium channels. However, the mechanism that moves photoreceptor pigment granules remains elusive. Are the granules actively pulled toward the rhabdomere upon light, or are they instead actively pulled into the cytoplasm in the absence of light? Here we show that Ca(2+)-activated Myosin V (MyoV) pulls pigment granules to the rhabdomere. Thus, one of MyoV's several functions is also as a sensory-adaptation motor. In vitro, Ca(2+) both activates and inhibits MyoV motility; in vivo, its role is undetermined. This first demonstration of an in vivo role for Ca(2+) in MyoV activity shows that in Drosophila photoreceptors, Ca(2+) stimulates MyoV motility.

Assessment of Antimicrobial Microspheres As a Prospective Novel Treatment Targeted Towards the Repair of Perianal Fistulae

None of the proposed materials tested for the management of perianal fistulae has proven to be a definitive treatment.

Two Leishmania Species Circulating in the Kaleybar Focus of Infantile Visceral Leishmaniasis, Northwest Iran: Implications for Deltamethrin Dog Collar Intervention

Leishmania infantum is the causative agent of infantile visceral leishmaniasis (IVL) in the Mediterranean Basin and, based on isoenzyme typing of a few isolates from patients and domestic dogs, this parasite was considered to predominate in the Kaleybar focus of IVL in northwest Iran. However, in the current investigation only one out of five sandfly infections was found to be L. infantum, based on PCR detection and sequencing of parasite internal transcribed spacer (ITS) rDNA infecting Phlebotomus perfiliewi transcaucasicus. The four other infections were of haplotypes of L. tropica, the causative agent of anthroponotic cutaneous leishmaniasis in the Middle East and a parasite occasionally detected in the viscera of dogs and patients in Iran and elsewhere. The widespread distribution of L. tropica in the Kaleybar focus suggests that this parasite is not a transient introduction. Kaleybar has been used for a deltamethrin dog collar intervention to reduce the biting rates of the vectors of L. infantum and this has significantly reduced the incidence of Leishmania infections both in children and the domestic dog, the usual reservoir host of IVL. The implications of finding L. tropica widespread in the heart of the intervention area are discussed. Extensive and intensive typing of natural Leishmania infections is a characteristic of epidemiological investigations in the Neotropics and the current report indicates that this will also be necessary in some regions of the Old World.

Musculoskeletal Biopsies Using Computed Tomography Fluoroscopy

To determine the diagnostic yield, accuracy, and safety of computed tomography (CT) fluoroscopy guidance for musculoskeletal biopsies.

Preparation of Substituted Enol Derivatives from Terminal Alkynes and Their Synthetic Utility

Stereodefined enol derivatives of aldehydes are prepared from terminal alkynes. Specifically, terminal alkynes are known to undergo Cp2ZrCl2-catalyzed methylalumination. Here, we show that the resultant vinylalanes can be oxygenated with peroxyzinc species to generate trisubstituted enolates. Electrophilic trapping with carboxylic anydrides or silyl triflates yields trisubstituted enol esters or silanes, respectively. The tandem carbometalation/oxygenation tolerates free and protected alcohols, heterocycles, olefins, and nitriles. Stereodefined enol esters can undergo asymmetric dihydroxylation to yield optically active alpha-hydroxy aldehydes. Reduction with NaBH4 provides the diols of 1,1-disubstituted olefins in excellent ee. An application of this methodology to the enantioselective synthesis of the insect pheromone frontalin is presented. Finally, alpha-hydroxy aldehydes are shown to undergo homologation to a terminal alkyne, reductive amination, oxidation and olefination. Preliminary results indicate that tandem carbometalation/amination can be accomplished with azodicarboxylates. In this way, ene-hydrazines are formed in excellent yield.

Young Adult Attitudes About Alzheimer's Disease

The current generation of young adults will be greatly affected by Alzheimer's disease(AD), but little is known about their attitudes toward persons with Alzheimer's disease. The current study assessed attitudes about Alzheimer's disease in young adults with varying levels of contact with the disease. It was hypothesized that participants who had a high level of contact with someone with Alzheimer's disease previously, in the form of a close relationship, would report more positive attitudes than participants with a low level of contact or no contact. Results revealed that participants who had a high level of contact with persons with AD were more willing to make personal sacrifices for Alzheimer's disease than those who had no contact. Younger persons may realize a greater need to support persons with Alzheimer's disease if they have been personally affected by the disease through a close relationship.

Response Bias in "remembering" Emotional Stimuli: a New Perspective on Age Differences

Older adults sometimes show a recall advantage for emotionally positive, rather than neutral or negative, stimuli (S. T. Charles, M. Mather, & L. L. Carstensen, 2003). In contrast, younger adults respond "old" and "remember" more often to negative materials in recognition tests. For younger adults, both effects are due to response bias changes rather than to enhanced memory accuracy (S. Dougal & C. M. Rotello, 2007). We presented older and younger adults with emotional and neutral stimuli in a remember-know paradigm. Signal-detection and model-based analyses showed that memory accuracy did not differ for the neutral, negative, and positive stimuli, and that "remember" responses did not reflect the use of recollection. However, both age groups showed large and significant response bias effects of emotion: Younger adults tended to say "old" and "remember" more often in response to negative words than to positive and neutral words, whereas older adults responded "old" and "remember" more often to both positive and negative words than to neutral stimuli.

A Field Test of Group Based Exposure Therapy with 102 Veterans with War-related Posttraumatic Stress Disorder

Group-based exposure therapy (GBET) was field-tested with 102 veterans with war-related posttraumatic stress disorder (PTSD). Nine to 11 patients attended 3 hours of group therapy per day twice weekly for 16-18 weeks. Stress management and a minimum of 60 hours of exposure was included (3 hours of within-group war-trauma presentations per patient, 30 hours of listening to recordings of patient's own war-trauma presentations and 27 hours of hearing other patients' war-trauma presentations). Analysis of assessments conducted by treating clinicians pre-, post- and 6-month posttreatment suggests that GBET produced clinically significant and lasting reductions in PTSD symptoms for most patients on both clinician symptoms ratings (6-month posttreatment effect size delta = 1.22) and self-report measures with only three dropouts.

Interleukin-6 Polymorphisms Are Associated with Pathogenic Bacteria in Subjects with Periodontitis

Growing evidence suggests that individual genetic susceptibility may influence the host's response to infections. Previously, we showed that a common variation in the interleukin (IL)-6 gene was associated with increased odds of detection of common periodontal pathogens from individuals with aggressive periodontitis. The aim of this study was to investigate the association between IL-6 polymorphisms and periodontopathogenic bacteria in a larger, ethnically mixed population of subjects with periodontitis.

Small Cell Lung Cancer

Leishmania Manipulates Sandfly Feeding to Enhance Its Transmission

Malaria parasites manipulate mosquitoes to ensure transmission between mammalian hosts; painstaking experiments have now demonstrated that another medically important protozoan, Leishmania, enhances its transmission through the adaptive manipulation of one of its sandfly vectors, Lutzomyia longipalpis. Experimental Leishmania infections specifically increased sandfly biting persistence and feeding on multiple hosts, but only if the parasites produced infective forms and a gel plug of filamentous proteophosphoglycan in the anterior midgut of the sandfly. This fundamental research is relevant to vaccine development.

Evolution of a Synthetic Strategy: Total Synthesis of (+/-)-welwitindolinone A Isonitrile

An efficient and highly stereoselective total synthesis of the natural product (+/-)-welwitindolinone A isonitrile (1) is described. The bicyclo[4.2.0]octane core of 1 was established by a regio- and diastereoselective [2+2] ketene cycloaddition. The C12 quaternary center and vicinal stereogenic chlorine were installed in a single operation with excellent stereocontrol via a chloronium ion mediated semipinacol rearrangement. Described strategies for construction of the spiro-oxinole include a SmI2-LiCl mediated reductive cyclization and a novel anionic cyclization that simultaneously constructs the spiro-oxindole and vinyl isonitrile moieties.

Patient and Caregiver Quality of Life in Huntington's Disease

Little is known about subjective perceptions of quality of life (QOL) in Huntington's disease (HD). The current study determined correlates of patient and caregiver QOL and assessed change over time. Participants were 22 patient-caregiver dyads, who rated QOL at baseline and 6 months later. Overall, patients' functional and cognitive impairment were significantly correlated with patient and caregiver QOL. Neuropsychiatric symptoms had differential impact on patient and caregiver QOL. Furthermore, when patients recalled their QOL about a previous time, their recall may have been negatively biased. Clinical implications of results are discussed. Future work is needed because subjective QOL is an important outcome measure in therapeutic trials.

Quantity Representation in Children and Rhesus Monkeys: Linear Versus Logarithmic Scales

The performances of 4- and 5-year-olds and rhesus monkeys were compared using a computerized task for quantity assessment. Participants first learned two quantity anchor values and then responded to intermediate values by classifying them as similar to either the large anchor or the small anchor. Of primary interest was an assessment of where the point of subjective equality (PSE) occurred for each species across four different sets of anchors to determine whether the PSE occurred at the arithmetic mean or the geometric mean. Both species produced PSEs that were closer to the geometric mean for three of four anchor sets. This indicates that monkeys and children access either a logarithmic scale for quantity representation or a linear scale that is subject to scalar variability, both of which are consistent with Weber's law and representation of quantity that takes the form of analog magnitudes.

NSAID Use and Breast Cancer Risk in the VITAL Cohort

We prospectively evaluated the association between average 10-year use of NSAIDs and invasive breast cancer.

Concurrent Chemoradiotherapy with Weekly Paclitaxel and Carboplatin for Locally Advanced Head and Neck Cancer: Long-term Follow-up of a Brown University Oncology Group Phase II Study (HN-53)

A phase II study was conducted using concurrent paclitaxel, carboplatin, and external beam radiotherapy (RT) in patients with advanced head and neck cancer.

Calciphylaxis Following Kidney Transplantation: a Case Report

Calciphylaxis occurring after kidney transplantation is rare and rarely reported. It results in chronic non-healing wounds and is associated with a poor prognosis and is often fatal. We present a case of proximal lower limb calciphylaxis that occurred early after kidney transplantation. The patient had no classic associated risk factors. He had previously had a total parathyroidectomy but had normal serum calcium-phosphate product and parathyroid hormone levels. The clinical outcome of this case was favorable and highlights some fundamental issues relating to management.

Characterizing the Clinical Relevance of an Embryonic Stem Cell Phenotype in Lung Adenocarcinoma

Cancer cells possess traits reminiscent of those ascribed to normal stem cells. It is unclear whether these phenotypic similarities are the result of a common biological phenotype, such as regulatory pathways.

Deconvolution of Complex NMR Spectra in Small Molecules by Multi Frequency Homonuclear Decoupling (MDEC)

A new technique to deconvolute complex (1)H NMR spectra of small molecules has been developed that utilizes shape selective pulses to simultaneously decouple multiple protons. A limitation in the assignment of the relative configuration of small molecules is the ability to accurately obtain coupling constants. Other methods such as the E.COSY and the 2D J-resolved are available to obtain complicated coupling constants; the multiple homonuclear decoupling method (MDEC) described is a rapid and simple technique. Three examples of increasing spectral complexity, menthol, cholesteryl acetate and a C(16) fatty acid, demonstrate the utility of the technique. Increasing the experimental utility, the single pulse MDEC experiment can be incorporated in other 1D experiments, such as a 1D-TOCSY to solve specific problems.

Distribution of Tetracycline and Erythromycin Resistance Genes Among Human Oral and Fecal Metagenomic DNA

We have analyzed the total metagenomic DNA from both human oral and fecal samples derived from healthy volunteers from six European countries to determine the molecular basis for tetracycline and erythromycin resistance. We have determined that tet(M) and tet(W) are the most prevalent tetracycline resistance genes assayed for in the oral and fecal metagenomes, respectively. Additionally, tet(Q), tet(O), and tet(O/32/O) have been shown to be common. We have also shown that erm(B), erm(V), and erm(E) are common erythromycin resistance genes present in these environments. Further, we have demonstrated the ubiquitous presence of the Tn916 integrase in the oral metagenomes and the Tn4451 and Tn1549 integrase genes within the fecal metagenomes.

Allenes in Asymmetric Catalysis: Asymmetric Ring Opening of Meso-epoxides Catalyzed by Allene-containing Phosphine Oxides

Unsymmetrically substituted allenes (1,2-dienes) are inherently chiral and can be prepared in optically pure form. Nonetheless, to date the allene framework has not been incorporated into ligands for asymmetric catalysis. Since allenes project functionality differently than either tetrahedral carbon or chiral biaryls, they may create complementary chiral environments. This study demonstrates that optically active, C(2)-symmetric allene-containing bisphosphine oxides can catalyze the addition of SiCl(4) to meso-epoxides with high enantioselectivity. The epoxide opening likely involves generation of a Lewis acidic, cationic (bisphosphine oxide)SiCl(3) complex. The fact that high asymmetric induction is observed suggests that allenes may represent a new platform for the development of ligands and catalysts for asymmetric synthesis.

Contemporary Root Canal Irrigants Are Able to Disrupt and Eradicate Single- and Dual-species Biofilms

Clinical/microbiological studies have consistently revealed the persistence of some bacteria after conventional root canal debridement. Although this was originally attributed to the complexity of the root canal anatomy and the difficulty of delivering antibacterial agents effectively, it has emerged that the biofilm encasement of bacterial cells may confer a further mechanism of resistance. The purpose of this study was to investigate the relative disruption and bactericidal effects of root canal irrigants on single- and dual-species biofilms of root canal isolates.

Langerhans Cell Histiocytosis Following Acute Leukemia in an Adult

Local Recurrence After Surgery for Early Stage Lung Cancer: an 11-year Experience with 975 Patients

The objective of the current study was to evaluate the actuarial risk of local failure (LF) after surgery for stage I to II nonsmall cell lung cancer (NSCLC) and assess surgical and pathologic factors affecting this risk.

Bilateral Papillomacular Retinal Folds

Phylogeography of Androctonus Species (Scorpiones: Buthidae) in Tunisia: Diagnostic Characters for Linking Species to Scorpionism

A fragment of the mitochondrial (mt) 16S ribosomal RNA gene was amplified by PCR and sequenced from individual adult scorpions of the genus Androctonus, which were sampled from central and southern Tunisia and identified using an explicit set of morphological characters. Phylogenetic analyses placed the mtDNA haplotypes in three well-supported monophyletic lineages, corresponding to the morphospecies Androctonusaeneas, Androctonusamoreuxi and Androctonusaustralis. The latter species was the most abundant and widespread, and it was characterized by two mtDNA sub-lineages each of which predominated only north or south of the Chott el Jerid, a seasonally flooded saline depression that divides non-Mediterranean Tunisia. The divergence of the two mtDNA lineages was dated by mtDNA molecular clocks, indicating that the formation of the Chott el Jerid is unlikely to have been the barrier generating the vicariant evolution of the two lineages of A. australis, although it may have impeded their mixing following secondary contact. Both regional mtDNA lineages were found in A. australis hector and A. australisgarzonii, indicating that these two morphological forms are neither monophyletic nor geographically isolated and, therefore, should not be treated as species or subspecies. It is recommended that no subspecies of A. australis should be recognized in North Africa and toxicologists should cease the taxonomic error of referring to a species "Androctonus australis Hector". The morphological form "hector" has no proven association with an increased risk of scorpionism compared with "garzonii". However, it might be prudent to produce anti-venom in Tunisia by using both morphological forms of A. australis collected each side of the Chott el Jerid, because of the evidence for regional variation in toxins. The highest risk for scorpion stings occurs in the central region, where the new diagnostic markers should be used to discover any association between Androctonus species and scorpionism.

Antibody-dependent Cell-mediated Cytotoxicity Effector-enhanced EphA2 Agonist Monoclonal Antibody Demonstrates Potent Activity Against Human Tumors

EphA2 is a receptor tyrosine kinase that has been shown to be overexpressed in a variety of human tumor types. Previous studies demonstrated that agonist monoclonal antibodies targeting EphA2 induced the internalization and degradation of the receptor, thereby abolishing its oncogenic effects. In this study, the in vitro and in vivo antibody-dependent cell-mediated cytotoxicity (ADCC) activity of EphA2 effector-enhanced agonist monoclonal antibodies was evaluated. With tumor cell lines and healthy human peripheral blood monocytes, the EphA2 antibodies demonstrated approximately 80% tumor cell killing. In a dose-dependent manner, natural killer (NK) cells were required for the in vitro ADCC activity and became activated as demonstrated by the induction of cell surface expression of CD107a. To assess the role of NK cells on antitumor efficacy in vivo, the EphA2 antibodies were evaluated in xenograft models in severe compromised immunodeficient (SCID) mice (which have functional NK cells and monocytes) and SCID nonobese diabetic (NOD) mice (which largely lack functional NK cells and monocytes). Dosing of EphA2 antibody in the SCID murine tumor model resulted in a 6.2-fold reduction in tumor volume, whereas the SCID/nonobese diabetic model showed a 1.6-fold reduction over the isotype controls. Together, these results demonstrate that the anti-EphA2 monoclonal antibodies may function through at least two mechanisms of action: EphA2 receptor activation and ADCC-mediated activity. These novel EphA2 monoclonal antibodies provide additional means by which host effector mechanisms can be activated for selective destruction of EphA2-expressing tumor cells.

Preoperative Chemotherapy Versus Preoperative Chemoradiotherapy for Stage III (N2) Non-small-cell Lung Cancer

To compare preoperative chemotherapy (ChT) and preoperative chemoradiotherapy (ChT-RT) in operable Stage III non-small-cell lung cancer.

Emotion in Younger and Older Adults: Retrospective and Prospective Associations with Sleep and Physical Activity

Older adults may have superior emotion regulation skills than younger adults and the authors suggest that as emotion regulation capacities increase with age, emotions may be less swayed by external events or even by internal traits. The current retrospective and prospective study further tested this hypothesis by determining if the emotions of younger adults were more reactive to two behaviors (i.e., physical activity, sleep) than for older adults. Results supported predictions. Specifically, retrospective self-reports and prospective diary data about physical activity and sleep exhibited stronger associations with emotion for younger than older persons. Implications for emotional well-being across the life span are discussed.

Visible and Near-infrared Radiative Properties of Vertically Aligned Multi-walled Carbon Nanotubes

This work investigates the reflection and scattering from vertically aligned carbon nanotubes, fabricated on silicon substrate using thermally enhanced chemical vapor deposition with both tip-growth and base-growth mechanisms. The directional-hemispherical reflectance in the visible and near-infrared wavelengths was measured with an integrating sphere. The polarization-dependent bidirectional reflectance distribution function was characterized with a laser scatterometer at the wavelength of 635 nm. The effective medium theory was used to elucidate the mechanism of high absorptance (greater than 0.97 in the spectral region from 400 to 1800 nm) of the multi-walled carbon nanotube samples. It is observed that scattering by impurities on the top of the nanotubes, by the nanotube tips, and by defects and misalignment can significantly increase the reflectance and introduce retroreflection. This study may facilitate application of carbon nanotubes in pyroelectric detectors as well as thermophotovoltaic emitters and absorbers.

Canada's Physical Activity Guide Recommendations Are a Low Benchmark for Manitoba Adults

Canada's Physical Activity Guide to Healthy Active Living (CPAG) is the national reference for messaging on physical activity for health benefits, yet few studies have examined population activity levels in relation to its recommendations. As part of the province-wide in motion initiative, we obtained a baseline measurement of the physical activity levels of adult Manitobans. Physical activity levels were benchmarked against CPAG recommendations and were compared with criteria used in previous surveys. A stratified random sample of adults from the 9 Regional Health Authorities outside of Winnipeg, and from the 12 Community Areas within the Winnipeg Health Region, was surveyed by telephone. Respondents (n = 6,536) reported all light, moderate, and vigorous physical activity of 10 min or more in the previous week. Intensity levels were corrected to reflect standard MET equivalents, using the Ainsworth Compendium. A total of 69.5% of respondents met the minimum CPAG requirements; however, only 29.1% of those did so with vigorous activity. Relative to energy expenditure, 18.3% were classified as inactive (<1.50 kcal.kg-1.day-1 (KKD)), 16.4% as moderately active (1.50 to 2.99 KKD), and 65.3% as active (>or=3.00 KKD). When assessed against the CPAG recommendations, which promote integration of physical activity into one's daily routine, a higher proportion of Manitobans met recommended physical activity levels than that reported in previous surveys, which focused on leisure activity. Given the corresponding increase in levels of obesity and chronic disease, and equivocal nutrient intake data, we recommend that the CPAG recommendations be reviewed, especially with respect to the inclusion of routine baseline activities of daily living.

Mitochondrial Complex Activity in Donor Renal Grafts, Cold Ischemia Time, and Recovery of Graft Function

Indexed mitochondrial complex activities (MCAi) were determined in biopsies obtained from 52 donor kidneys at the end of cold ischemia (8-32 hr) to see if longer anoxia affected MCAi and accounted for the increased risk of delayed graft function (DGF) in recipients of grafts with longer cold ischemia time (CIT) or from non-heart-beating donors (NHBD). CITs were significantly different between those with and without DGF (P=0.02), being shorter in the latter, but MCAi were similar. CIT was correlated (r=0.43, P=0.003) with the time taken for creatinine concentration to fall to half the perioperative value (Crt(1/2)) but not with MCAi. Frequency of DGF, greater in NHBD, was significantly different from that of heart-beating donors (P=0.04), but CIT and MCAi were similar. However, Crt(1/2), was significantly different being longer in NHBD. Thus, the frequency of DGF increased and the speed of recovery diminished with longer CIT, whereas MCAi remained stable suggesting other factors determined tissue recovery.

Molecular Genetic Analysis of Populations of Wohlfahrt's Wound Myiasis Fly, Wohlfahrtia Magnifica, in Outbreak Populations from Greece and Morocco

Wohlfahrt's wound myiasis fly, Wohlfahrtia magnifica (Schiner) (Diptera: Sarcophagidae), is the most important cause of traumatic myiasis in the southern Palaearctic region. Larval stages are obligate parasites and the wounds caused by infestations are very similar to those caused by Old and New World screwworm flies. During the last decade, W. magnifica appears to have expanded its range to parts of northern and central Morocco, and to Crete, Greece. Specimens of W. magnifica were collected in Morocco and Crete either as larvae (preserved in 80% ethanol) or as adults (dry-pinned). Comparison specimens were collected in Spain, Hungary and mainland Greece. A DNA fragment containing the 3' 715 base pairs of the mitochondrial cytochrome b gene was amplified by polymerase chain reaction from each of 132 larvae or adults of W. magnifica and the amplicons were directly sequenced and analysed phylogeographically. Twelve cytochrome b haplotypes were detected. All haplotypes from Morocco belonged to a lineage that included specimens from the Iberian peninsula, and restricted mixing of central and northern populations in Morocco was demonstrated. Cytochrome b haplotyping combined with an analysis of larval size provided clear evidence of multiple infestations of hosts in all geographical areas, with one quarter of wounds containing larvae from two to at least four females. More than 80% of specimens from Crete contained a haplotype predominating in mainland Greece and Hungary. Our survey indicated that wohlfahrtiosis was more widespread in northern and central Morocco than previously recorded by government veterinarians. However, the prevalence of wohlfahrtiosis was low (< 1%). The high genetic diversity of Moroccan populations is consistent with longterm endemicity, rather than recent introduction. Crete showed a higher prevalence of wohlfahrtiosis (< or = 15%) and less genetic diversity of W. magnifica, which is consistent with a recent introduction. The western and eastern Mediterranean lineages may have been isolated in different Pleistocene ice-age refugia, from which there has been limited post-glacial dispersal.

Morphological and Mitochondrial DNA Characters for Identification and Phylogenetic Analysis of the Myiasis-causing Flesh Fly Wohlfahrtia Magnifica and Its Relatives, with a Description of Wohlfahrtia Monegrosensis Sp. N. Wyatt & Hall

Wohlfahrtia magnifica (Schiner) (Diptera: Sarcophagidae) is a major cause of traumatic myiasis in livestock in Central and Eastern Europe and in countries bordering the Mediterranean. The present study explored the utility of external body characters, genitalia characters and mitochondrial DNA characters for identification of this and related species in the subfamily Paramacronychiinae. Sequence analyses of the 3' terminal 273 bp of the mitochondrial cytochrome b gene revealed two lineages of W. magnifica, one from Spain and France and the other from the rest of Eurasia, differing by only two base pairs. Phylogenetic analysis of cytochrome b showed that W. magnifica and Wohlfahrtia vigil Walker were sister species; this conclusion was not contradicted by a phylogenetic analysis of the morphological characters. Based on cytochrome b, the genetic distance between specimens of W. vigil from Europe and North America was sufficiently large to justify the recognition of more than one species. A new species, Wohlfahrtia monegrosensis, from northern Spain, was described, based on morphology and cytochrome b. A unique combination of external body characters of males or females were diagnostic for W. magnifica, the W. vigil group and Wohlfahrtia bella, but only the genitalia characters were diagnostic for all nine species studied.

Genetic Diversity of Populations of Old World Screwworm Fly, Chrysomya Bezziana, Causing Traumatic Myiasis of Livestock in the Gulf Region and Implications for Control by Sterile Insect Technique

Fly larvae were collected from 181 cases of traumatic myiasis in livestock in 10 regions of four countries in the Middle East Gulf region: Iran, Iraq, Saudi Arabia and Oman. The predominant fly species responsible for cases was the Old World screwworm (OWS) fly, Chrysomya bezziana Villeneuve (Diptera: Calliphoridae). In cases from Iran and Oman, which included non-OWS fly species, OWS fly was found solely responsible for 67.6% of cases and jointly with other fly species for a further 12.7% of cases. The major hosts were sheep and goats, together comprising 84.6% of the total, which reflects their predominance among the livestock of these Gulf countries. The major site of wounding on sheep and goats was the tail (40.3%), followed by female genitalia (14.0%). The 3' terminal 715 nucleotides of the mitochondrial cytochrome b gene were sequenced for 178 larvae of OWS. Five haplotypes were identified: three had been recorded previously in the region (two were common throughout and one was unique to Oman), and two were newly identified, one from southern Iraq and the other from Saudi Arabia, both in regions sampled for the first time. The haplotypes varied from one another only at one or two nucleotide sites, equivalent to an intraspecific difference of 0.14-0.28% across the entire 715-bp fragment. There was a single statistically significant association between host species and haplotype in Saudi Arabia, a first such record for OWS fly. The small degree of genetic diversity between geographical populations of OWS fly within the Gulf region suggests that a single Gulf colony could be used to implement the sterile insect technique within an integrated control programme.

Phylogeography and Recent Emergence of the Old World Screwworm Fly, Chrysomya Bezziana, Based on Mitochondrial and Nuclear Gene Sequences

A previous study had identified an African and an Asian race of the Old World screwworm fly, Chrysomya bezziana Villeneuve (Diptera: Calliphoridae), based on the 3' terminal 279 basepairs (bp) of the mitochondrial cytochrome b gene. The current study improved the phylogeographic resolution of cytochrome b for this species by characterizing more of the gene (the 3' terminal 715 bp) and by sampling more geographical populations, including Oman, Iran, Hong Kong and the Indonesian islands of Sulawesi and East Sumba. Strong support was found for recognizing an African race, but not for a monophyletic Asian race. The cladistic and genealogical relationships among the Asian populations were complex. There was sufficient genetic homogeneity throughout separate regions (mainland Asia and each Indonesian island) to suggest that there are no reproductive barriers within each region that might necessitate the production of more than one strain for control by the sterile insect technique (SIT). Primers were designed for the amplification by polymerase chain reaction of two nuclear loci, the highly conserved elongation factor-1alphagene and the less conserved white gene, and the preliminary results indicated that these genes showed the same pattern of small-scale regional variation as cytochrome b. The cytochrome b haplotypes are useful markers for identifying the geographical origins of any emerging infestations of the species: the absence of Indonesian and African haplotypes in the Middle East demonstrates that the large-scale transport of livestock is not spreading Old World screwworm.

U.S. High School Curriculum: Three Phases of Contemporary Research and Reform

Valerie Lee and Douglas Ready explore the influences of the high school curriculum on student learning and the equitable distribution of that learning by race and socioeconomic status. They begin by tracing the historical development of the U.S. comprehensive high school and then examine the curricular reforms of the past three decades. During the first half of the twentieth century, the authors say, public high schools typically organized students into rigid curricular "tracks" based largely on students' past academic performance and future occupational and educational plans. During the middle of the century, however, high schools began to provide students with a choice among courses that varied in both content and academic rigor. Although the standards movement of the 1980s limited these curricular options somewhat, comprehensive curricula remained, with minority and low-income students less often completing college-prep courses. During the 1990s, say the authors, researchers who examined the associations between course-taking and student learning reported that students completing more advanced coursework learned more, regardless of their social or academic backgrounds. Based largely on this emerging research consensus favoring college-prep curriculum, in 1997 public high schools in Chicago began offering exclusively college-prep courses. To address the needs of the city's many low-performing ninth graders, schools added extra coursework in subjects in which their performance was deficient. A recent study of this reform, however, found that these approaches made little difference in student achievement. Lee and Ready hypothesize that "selection bias" may explain the divergent conclusions reached by the Chicago study and previous research. Earlier studies rarely considered the unmeasured characteristics of students who completed college-prep courses-characteristics such as motivation, access to academic supports, and better teachers-that are also positively related to student learning. Although the Chicago evaluation is only one study of one city, its findings raise the worrisome possibility that the recent push for "college-prep for all" may not generate the improvements for which researchers and policy makers had hoped.

Calcineurin Inhibitor Sparing with Mycophenolate in Kidney Transplantation: a Systematic Review and Meta-analysis

Limiting the exposure of kidney transplant recipients to calcineurin inhibitors (CNIs) has potential merit, but there is no clear consensus on the utility of current strategies. In an attempt to aid clarification, we conducted a systematic review and meta-analysis of randomized trials that assessed CNI sparing (minimization or elimination) with mycophenolate as sole adjunctive immunosuppression.

Identification of the Optimal Donor Quality Scoring System and Measure of Early Renal Function in Kidney Transplantation

The early identification of kidney allografts at risk of later dysfunction has implications for clinical practice. Donor quality scoring systems (preoperative) and measures of early allograft function (first week postoperative) have previously shown practical utility. This study aimed to determine the optimal parameter(s) (preoperative and postoperative) with greatest predictive power for the development of subsequent allograft dysfunction.

Perception of Screening and Risk Reduction Surgeries in Patients Tested for a BRCA Deleterious Mutation

Women at a high risk for breast cancer are offered choices for screening or prophylactic surgeries. The aim of this study was to evaluate opinions regarding screening and surgical strategies in high-risk women.

Susceptibility of MRSA Biofilms to Denture-cleansing Agents

Methicillin-resistant Staphylococcus aureus (MRSA) is an important nosocomial pathogen, which is responsible for considerable morbidity and mortality in the United Kingdom. The major reservoir of this organism is thought to be the anterior nares, but there is increasing evidence that this pathogen is present in the oral cavity, particularly in denture wearers. The purpose of this study was to determine whether MRSA, grown as biofilms on denture acrylic resin, could be eradicated using commercially available agents. EMRSA-15 or EMRSA-16 was grown in a model system on the surface of denture acrylic resin for 4, 24 or 120 h before the samples were exposed to a range of disinfectants for time intervals of 1, 5 and 10 min. All of the agents reduced the number of cultivable MRSA bacteria present on the acrylic resin surface at 4 h, with 2% sodium hypochlorite (NaOCl) eliminating MRSA below the level of detection after an exposure of 1 min. However, the established MRSA biofilms (24 and 120 h) were more resistant to killing by the agents, although 2% NaOCl was still able to eradicate all ages of MRSA biofilms within 1 min of exposure.

Accuracy of the BRCAPRO Model Among Women with Bilateral Breast Cancer

The likelihood of identifying a BRCA mutation was often calculated using the BRCAPRO model. A previous study suggested that this model may overestimate the chance of detecting a BRCA mutation among women diagnosed with bilateral breast cancer. Studies also suggested that few patients with bilateral breast cancer whose age at first diagnosis is >40 years were mutation carriers. The objectives of this study were to determine the accuracy of the BRCAPRO model among women with bilateral breast cancer and to determine whether their mutation status was dependent on their age at first diagnosis.

Phase I and Pharmacokinetic Study of Gimatecan Given Orally Once a Week for 3 of 4 Weeks in Patients with Advanced Solid Tumors

A phase I study was conducted to determine the dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) of gimatecan, a lipophilic camptothecin analogue, administered orally once a week for 3 weeks.

Controlled Delivery of Antimicrobial Gallium Ions from Phosphate-based Glasses

Gallium-doped phosphate-based glasses (PBGs) have been recently shown to have antibacterial activity. However, the delivery of gallium ions from these glasses can be improved by altering the calcium ion concentration to control the degradation rate of the glasses. In the present study, the effect of increasing calcium content in novel gallium (Ga2O3)-doped PBGs on the susceptibility of Pseudomonas aeruginosa is examined. The lack of new antibiotics in development makes gallium-doped PBG potentially a highly promising new therapeutic agent. The results show that an increase in calcium content (14, 15 and 16 mol.% CaO) cause a decrease in degradation rate (17.6, 13.5 and 7.3 microg mm(-2) h(-1)), gallium ion release and antimicrobial activity against planktonic P. aeruginosa. The most potent glass composition (containing 14 mol.% CaO) was then evaluated for its ability to prevent the growth of biofilms of P. aeruginosa. Gallium release was found to reduce biofilm growth of P. aeruginosa with a maximum effect (0.86 log(10) CFU reduction compared to Ga2O3-free glasses) after 48 h. Analysis of the biofilms by confocal microscopy confirmed the anti-biofilm effect of these glasses as it showed both viable and non-viable bacteria on the glass surface. Results of the solubility and ion release studies show that this glass system is suitable for controlled delivery of Ga3+. 71Ga NMR and Ga K-edge XANES measurements indicate that the gallium is octahedrally coordinated by oxygen atoms in all samples. The results presented here suggest that PBGs may be useful in controlled drug delivery applications, to deliver gallium ions in order to prevent infections due to P. aeruginosa biofilms.

The Impacts of Knowledge of the Past on Preferences for Future Landscape Change

In this paper, we investigate whether people's knowledge of the past influences their preferences and values towards future landscape change. "Knowledge of the past" is one aspect of the information set held by individuals, and a well-established finding in economics is that changes in information can change preferences and values. The particular aspects of knowledge of the past we work with here are: (i) awareness of past landuse, as represented by woodland cover and (ii) awareness of differing and sometimes contradictory literary impressions of this past landscape. The case studies used here relate to prospective changes in woodland cover in two UK national parks, the Lake District and the Trossachs. We find that people who are made aware that the landscape has changed over time, or that perceptions of the landscape have changed over time, are more likely to favour changes to the current landscape (are less likely to favour the status quo). Knowledge of the past therefore seems to have an impact on preferences for future landscapes. We also investigate the impacts on preferences of how "special", how "wild" and how "worked in" people perceive the landscapes of these two national parks to be.

Clinical Assessment of Breast Cancer Risk Based on Family History

Family history is a key component of breast cancer risk assessment. Family history provides clues as to the likelihood of a hereditary breast cancer syndrome and the need for a cancer genetics referral and can be used in the setting of a breast cancer risk assessment model to estimate a woman's risk. Appropriate breast cancer screening and risk reduction management plans rely on an accurate assessment of a patient's family history. This article reviews the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Breast Cancer Risk Reduction and provides insight into the application of the guidelines in clinical practice.

Arrestin Translocation is Stoichiometric to Rhodopsin Isomerization and Accelerated by Phototransduction in Drosophila Photoreceptors

Upon illumination, visual arrestin translocates from photoreceptor cell bodies to rhodopsin and membrane-rich photosensory compartments, vertebrate outer segments or invertebrate rhabdomeres, where it quenches activated rhodopsin. Both the mechanism and function of arrestin translocation are unresolved and controversial. In dark-adapted photoreceptors of the fruitfly Drosophila, confocal immunocytochemistry shows arrestin (Arr2) associated with distributed photoreceptor endomembranes. Immunocytochemistry and live imaging of GFP-tagged Arr2 demonstrate rapid reversible translocation to stimulated rhabdomeres in stoichiometric proportion to rhodopsin photoisomerization. Translocation is very rapid in normal photoreceptors (time constant <10 s) and can also be resolved in the time course of electroretinogram recordings. Genetic elimination of key phototransduction proteins, including phospholipase C (PLC), Gq, and the light-sensitive Ca2+-permeable TRP channels, slows translocation by 10- to 100-fold. Our results indicate that Arr2 translocation in Drosophila photoreceptors is driven by diffusion, but profoundly accelerated by phototransduction and Ca2+ influx.

Hand-assisted Laparoscopic Donor Nephrectomy in Patients with Aberrant Inferior Vena Caval Anatomy

Hand-assisted laparoscopic donor nephrectomy has become an established technique for live-donor organ retrieval. In most cases, the left kidney is removed because of its more favorable anatomic relations, particularly with the major abdominal vessels.

Aggregatibacter (Actinobacillus) Actinomycetemcomitans: a Triple A* Periodontopathogen?

Chemoradiotherapy and Gefitinib in Stage III Non-small Cell Lung Cancer with Epidermal Growth Factor Receptor and KRAS Mutation Analysis: Cancer and Leukemia Group B (CALEB) 30106, a CALGB-stratified Phase II Trial

This study evaluated the addition of gefitinib to sequential or concurrent chemoradiotherapy (CRT) in unresectable stage III non-small cell lung cancer.

Association Between Interleukin-6 -174 Polymorphism and Aggregatibacter Actinomycetemcomitans in Chronic Periodontitis

We previously demonstrated an association between interleukin-6 (IL-6) polymorphisms and the detection of periodontopathogenic bacteria in aggressive and chronic periodontitis on a patient basis (pooled samples). The aim of this study is to comprehensively analyze the relative contribution of IL-6 genetic factors and local (tooth and site) factors on the detection of Aggregatibacter actinomycetemcomitans (previously Actinobacillus actinomycetemcomitans) and Porphyromonas gingivalis in patients with chronic periodontitis.

Personal Factors, Perceived Environment, and Objectively Measured Walking in Old Age

This study examined the associations between walking behavior and the perceived environment and personal factors among older adults. Sixty participants age 65 yr or older (mean 77 +/- 7.27, range 65-92) wore pedometers for 3 consecutive days. Perceived environment was assessed using the Neighborhood Environment Walkability Scale (abbreviated version). Physical function was measured using the timed chair-stands test. The mean number of steps per day was 5,289 steps (SD = 4,029). Regression analyses showed a significant association between personal factors, including physical function (relative rate = 1.05, p < .01) and income (RR = 1.43, p < .05) and the average daily number of steps taken. In terms of perceived environment, only access to services was significantly related to walking at the univariate level, an association that remained marginally significant when controlling for personal characteristics. These results suggest that among this sample of older adults, walking behavior was more related to personal and intrinsic physical capabilities than to the perceived environment.

Factors Affecting the Decision of Breast Cancer Patients to Undergo Contralateral Prophylactic Mastectomy

Increasing numbers of women with breast cancer are electing for contralateral prophylactic mastectomy (CPM) to reduce the risk of developing contralateral breast cancer. The objective of this study was to identify factors that may affect a patient's decision to undergo CPM. We identified 2,504 women with stage 0 to III unilateral primary breast cancer who underwent breast surgery at our institution from January 2000 to August 2006 from a prospectively maintained database. We did logistic regression analyses to determine which factors were associated with undergoing CPM. Of 2,504 breast cancer patients, 1,223 (48.8%) underwent total mastectomy. Of the 1,223 patients who underwent mastectomy, 284 (23.2%) underwent immediate or delayed CPM. There were 33 patients (1.3%) who had genetic testing before the surgery, with the use of testing increasing in the latter years of the study (0.1% in 2000-2002 versus 2.0% in 2003-2006; P < 0.0001). Multivariable analysis revealed several factors that were associated with a patient undergoing CPM: age younger than 50 years, white ethnicity, family history of breast cancer, BRCA1/2 mutation testing, invasive lobular histology, clinical stage, and use of reconstruction. We identified specific patient and tumor characteristics associated with the use of CPM. Although genetic testing is increasing, most women undergoing CPM did not have a known genetic predisposition to breast cancer. Evidence-driven models are needed to better inform women of their absolute risk of contralateral breast cancer as well as their competing risk of recurrence from the primary breast cancer to empower them in their active decision making.

Discovery of a Proneurogenic, Neuroprotective Chemical

An in vivo screen was performed in search of chemicals capable of enhancing neuron formation in the hippocampus of adult mice. Eight of 1000 small molecules tested enhanced neuron formation in the subgranular zone of the dentate gyrus. Among these was an aminopropyl carbazole, designated P7C3, endowed with favorable pharmacological properties. In vivo studies gave evidence that P7C3 exerts its proneurogenic activity by protecting newborn neurons from apoptosis. Mice missing the gene encoding neuronal PAS domain protein 3 (NPAS3) are devoid of hippocampal neurogenesis and display malformation and electrophysiological dysfunction of the dentate gyrus. Prolonged administration of P7C3 to npas3(-/-) mice corrected these deficits by normalizing levels of apoptosis of newborn hippocampal neurons. Prolonged administration of P7C3 to aged rats also enhanced neurogenesis in the dentate gyrus, impeded neuron death, and preserved cognitive capacity as a function of terminal aging. PAPERCLIP:

Are You a High Potential?

Comparing Virtual Reality Exposure Therapy to Present-centered Therapy with 11 U.S. Vietnam Veterans with PTSD

Eleven Vietnam veterans with war-related posttraumatic stress disorder (PTSD) were randomly assigned to 10 sessions of either virtual reality exposure (VRE) therapy within a computer-generated virtual Vietnam environment or present-centered therapy (PCT) that avoided traumatic content and utilized a problem-solving approach. Participants were assessed at pretreatment, posttreatment, and 6 months posttreatment by an independent assessor blind to treatment condition. Nine participants completed treatment with one dropout per condition. No significant differences emerged between treatments, likely due to insufficient power. Although comparison of mean changes in PTSD symptoms for the VRE and PCT conditions yielded a moderate effect size (d = 0.56) in favor of VRE at 6 months posttreatment, changes in PTSD scores were more variable, and therefore less reliable, within the VRE condition. The utility of VRE with older veterans with PTSD is discussed.

Energy Expenditure During Golfing and Lawn Mowing in Older Adult Men

This study compared the intensity and energy cost of playing 9 holes of golf with 40 min of lawn mowing in older men and determined whether both met the current recommendations for health benefits. Eighteen men (age 71.2 +/- 4.4 yr, BMI 27.3 +/- 2.3; M +/- SD) completed a graded treadmill test. During golfing and lawn-mowing field tests, oxygen consumption and walking velocity and distance were measured using a portable metabolic system and global positioning system receiver. The net energy costs of golfing and lawn mowing were 310 and 246 kcal, respectively. The average intensities in metabolic equivalents of golfing and lawn mowing were 2.8 +/- 0.5 and 5.5 +/- 0.9, respectively. Both lawn mowing and golfing met the original intensity and energy expenditure requirements for health benefits specified by the American College of Sports Medicine in 1998, but only lawn mowing met the 2007 intensity recommendations.

Knowledge, Attitudes, and Clinical Experience of Physicians Regarding Preimplantation Genetic Diagnosis for Hereditary Cancer Predisposition Syndromes

Approximately 5-10% of cancers are caused by an inherited predisposition. Individuals affected by hereditary cancer are often concerned about transmitting a predisposition to cancer to their children. Preimplantation genetic diagnosis (PGD) is a technology that allows embryos without a deleterious mutation associated with a hereditary cancer syndrome to be identified and implanted. The aim of this study is to assess the knowledge, attitudes, and clinical experience of physicians regarding PGD for hereditary cancer predisposition syndromes. Hereditary Breast and Ovarian Cancer (HBOC) and Familial Adenomatous Polyposis (FAP) are two hereditary cancer syndromes highlighted in this present study. A survey assessing physicians' attitudes, knowledge, and clinical practice was completed by a total of 373 gynecologic oncologists (GYN ONCs) and obstetrics and gynecologists (OB/GYNs). Physicians had a limited knowledge of PGD for hereditary cancer; however, physicians reported PGD was an appropriate option for patients with either HBOC or FAP. Although GYN ONCs were more likely to care for patients with hereditary cancer (P < 0.001), they were less likely than OB/GYNs to refer their patients to a PGD specialist (P = 0.004). While 80% of GYN ONCs and 91% of OB/GYNs would refer patients to a PGD specialist, clinical experience indicates that only 29% actually referred their patients. Since 68% of physicians had incorrect or limited knowledge of PGD for hereditary cancer, there is a need for additional education.

Leishmaniasis Emergence in Europe

Leishmaniasis emergence in Europe is reviewed, based on a search of literature up to and including 2009. Topics covered are the disease, its relevance, transmission and epidemiology, diagnostic methods, treatment, prevention, current geographical distribution, potential factors triggering changes in distribution, and risk prediction. Potential factors triggering distribution changes include vectorial competence, importation or dispersal of vectors and reservoir hosts, travel, and climatic/environmental change. The risk of introducing leishmaniasis into the European Union (EU) and its spread among Member States was assessed for the short (2-3 years) and long term (15-20 years). There is only a low risk of introducing exotic Leishmania species because of the absence of proven vectors and/or reservoir hosts. The main threat comes from the spread of the two parasites endemic in the EU, namely Leishmania infantum, which causes zoonotic visceral and cutaneous leishmaniasis in humans and the domestic dog (the reservoir host), and L. tropica, which causes anthroponotic cutaneous leishmaniasis. The natural vector of L. tropica occurs in southern Europe, but periodic disease outbreaks in Greece (and potentially elsewhere) should be easily contained by surveillance and prompt treatment, unless dogs or other synanthropic mammals prove to be reservoir hosts. The northward spread of L. infantum from the Mediterranean region will depend on whether climate and land cover permit the vectors to establish seasonal biting rates that match those of southern Europe. Increasing dog travel poses a significant risk of introducing L. infantum into northern Europe, and the threat posed by non-vectorial dog-to-dog transmission should be investigated.

Use of Biofilm Model Systems to Study Antimicrobial Susceptibility

There are many laboratory biofilm models available which can be used to assess the susceptibility of these distinctive resistant phenotypes. The complexities of these models vary considerably and indeed, the antimicrobial susceptibility of biofilms grown in these different models are also not standardised. It is clear that such methods are necessary for the testing of antibiotics and antimicrobial agents since these persistent communities are far more resistant than their planktonic counterparts. Therefore, it is now apparent that standardised tests such as MIC are no longer appropriate on their own to fully characterise susceptibility. There has also been a growing realisation that bacteria are growing as biofilms in almost every health-care setting and are, thus, a major contributing factor to the difficulty of treating infections. There is a pressing need for the models outlined in this chapter to test both current and novel anti-biofilm compounds and materials.

Environmental Risk Mapping of Canine Leishmaniasis in France

Canine leishmaniasis (CanL) is a zoonotic disease caused by Leishmania infantum, a Trypanosomatid protozoan transmitted by phlebotomine sandflies. Leishmaniasis is endemic in southern France, but the influences of environmental and climatic factors on its maintenance and emergence remain poorly understood. From a retrospective database, including all the studies reporting prevalence or incidence of CanL in France between 1965 and 2007, we performed a spatial analysis in order to i) map the reported cases in France, and ii) produce an environment-based map of the areas at risk for CanL. We performed a Principal Component Analysis (PCA) followed by a Hierarchical Ascendant Classification (HAC) to assess if the locations of CanL could be grouped according to environmental variables related to climate, forest cover, and human and dog densities. For each group, the potential distribution of CanL in France was mapped using a species niche modelling approach (Maxent model).

Organ Trafficking for Live Donor Kidney Transplantation in Indoasians Resident in the West Midlands: High Activity and Poor Outcomes

Some Indoasian (IA) patients with established renal failure travel abroad for commercial kidney transplantation. We compared the 1-year outcomes of IA patients from one UK region who received overseas transplants with IA patients receiving local living donor (LD) kidney transplantation, deceased donor (DD) transplantation, and dialysis.

Is Exposure to Mercury a Driving Force for the Carriage of Antibiotic Resistance Genes?

The mercury resistance gene merA has often been found together with antibiotic resistance genes in human commensal Escherichia coli. To study this further, we analysed mercury resistance in collections of strains from various populations with different levels of mercury exposure and various levels of antibiotic resistance. The first population lived in France and had no known mercury exposure. The second lived in French Guyana and included a group of Wayampi Amerindians with a known high exposure to mercury. Carriage rates of mercury resistance were assessed by measuring the MIC and by detecting the merA gene. Mercury-resistant E. coli was found significantly more frequently in the populations that had the highest carriage rates of antibiotic-resistant E. coli and in parallel antibiotic resistance was higher in the population living in an environment with a high exposure to mercury, suggesting a possible co-selection. Exposure to mercury might be a specific driving force for the acquisition and maintenance of mobile antibiotic resistance gene carriage in the absence of antibiotic selective pressure.

Transfer of Antibiotic Resistance by Transformation with EDNA Within Oral Biofilms

We demonstrate that live donor Veillonella dispar cells can transfer the conjugative transposon Tn916 to four different Streptococcus spp. recipients in a multispecies oral consortium growing as a biofilm in a constant depth film fermentor. Additionally, we demonstrate that purified V. dispar DNA can transform Streptococcus mitis to tetracycline resistance in this experimental system. These data show that transfer of conjugative transposon-encoded antibiotic resistance can occur by transformation in addition to conjugation in biofilms.

Clinical Application of Breast Cancer Risk Assessment Models

With the evolving availability of testing for genetic cancer syndromes, oncologists now are increasingly expected to review family histories and to give a genetic risk assessment as part of their care for breast cancer. The most important of these breast cancer genetic syndromes identified to date have been those associated with the BRCA1 and BRCA2 genes. Therefore, the proper identification of potentially affected families and providing risk assessment estimates will be ever more essential. This review outlines several different available breast cancer risk assessment models. Risk models for the development of breast cancer as well as risk models that estimate the chance of having a genetic cancer syndrome are discussed. Their clinical applications are also outlined and clinical situations appropriate for each model are reviewed.

Obstetrics/gynecology Residents' Knowledge of Hereditary Breast and Ovarian Cancer and Lynch Syndrome

Although there have been many studies regarding physicians' knowledge of hereditary cancer syndromes, very little information exists regarding medical residents' knowledge of hereditary cancer syndromes. Obstetrics/gynecology residents completed a test which evaluated their knowledge of hereditary breast and ovarian cancer and Lynch syndrome. Areas of relative deficit were identified. Residents indicated a desire and need for more education regarding this topic. Cancer genetics education programs should place more emphasis on the areas in which residents' appeared to be deficient in order to aid future physicians in the identification of high-risk individuals.

Long-term Outcome in Patients with Adrenal Metastases Following Resection of Colorectal Liver Metastases (Br J Surg 2009; 96: 935-940)

Carboplatin with Weekly Docetaxel and Ifosfamide in Advanced Head and Neck Cancers: a Phase I Brown University Oncology Group Dose Escalation Study (HN-93)

A phase I study was performed to determine the maximally tolerated dose of carboplatin, ifosfamide, and docetaxel in advanced head and neck cancers.

In Vitro Antibacterial Efficacy of Tetracycline Hydrochloride Adsorbed Onto Bio-Oss Bone Graft

Local delivery of antibiotics may provide the advantage of reducing the potential side effects associated with their systemic administration. This study assessed, in vitro, the antimicrobial efficacy of tetracycline hydrochloride (TCH) adsorbed onto Bio-Oss bone grafts against a range of pathogenic bacteria. Various levels of TCH were adsorbed onto Bio-Oss granules by immersing in TCH aqueous solutions of different initial concentrations for 48 h at room temperature. TCH release was assessed in phosphate buffered saline at 37 degrees C, and its antimicrobial efficacy, up to 96 h, was tested against two Gram-negative bacteria associated with periodontal diseases: Aggregatibacter (formerly Actinobacillus) actinomycetemcomitans, and Porphyromonas gingivalis, and one Gram-positive bacterium associated with soft-tissue and bone infections: Staphylococcus aureus. The range of TCH concentrations studied was also assessed for cytotoxicity against osteoblast-like human osteosarcoma cell lines. The amount of TCH adsorbed and released from Bio-Oss was concentration dependent. All TCH adsorbed Bio-Oss resulted in a reduction of A. actinomycetemcomitans, P. gingivalis, and S. aureus and higher concentrations were generally more effective in reducing or eliminating bacterial growth. The proliferation of HOS cells was not substantially reduced except for the maximum concentration of TCH. In addition to its osteoconductive role, TCH adsorbed Bio-Oss could also be functional in negating systemically antibiotic prophylactic treatment in the prevention of implant or biomaterial related infections.

Retinal Metabolic State of the Proline-23-histidine Rat Model of Retinitis Pigmentosa

We determined the metabolic changes that precede cell death in the dystrophic proline-23-histidine (P23H) line 3 (P23H-3) rat retina compared with the normal Sprague-Dawley (SD) rat retina. Metabolite levels and metabolic enzymes were analyzed early in development and during the early stages of degeneration in the P23H-3 retina. Control and degenerating retinas showed an age-dependent change in metabolite levels and enzymatic activity, particularly around the time when phototransduction was activated. However, lactate dehydrogenase (LDH) activity was significantly higher in P23H-3 than SD retina before the onset of photoreceptor death. The creatine/phosphocreatine system did not contribute to the increase in ATP, because phosphocreatine levels, creatine kinase, and expression of the creatine transporter remained constant. However, Na(+)-K(+)-ATPase and Mg(2+)-Ca(2+)-ATPase activities were increased in the developing P23H-3 retina. Therefore, photoreceptor apoptosis in the P23H-3 retina occurs in an environment of increased LDH, ATPase activity, and higher-than-normal ATP levels. We tested the effect of metabolic challenge to the retina by inhibiting monocarboxylate transport with alpha-cyano-4-hydroxycinnamic acid or systemically administering the phosphodiesterase inhibitor sildenafil. Secondary to monocarboxylate transport inhibition, the P23H-3 retina did not demonstrate alterations in metabolic activity. However, administration of sildenafil significantly reduced LDH activity in the P23H-3 retina and increased the number of terminal deoxynucleotidyl transferase biotin-dUPT nick end-labeled photoreceptor cells. Photoreceptor cells with a rhodopsin mutation display an increase in apoptotic markers secondary to inhibition of a phototransduction enzyme (phosphodiesterase), suggesting increased susceptibility to altered cation entry.

Phlebotomus Caucasicus and Phlebotomus Mongolensis (Diptera: Psychodidae): Indistinguishable by the Mitochondrial Cytochrome B Gene in Iran

Diagnostic molecular markers for the females of Phlebotomus (Paraphlebotomus) caucasicus and P. mongolensis were sought by characterizing from individual Iranian specimens a gene fragment, namely mitochondrial cytochrome b, that had previously proven useful for the taxonomy of phlebotomine sandflies. Males of both species were used as reference material because their external genitalia provide the only diagnostic morphological characters. A phylogenetic analysis of the new sequences, and those previously reported for P. grimmi, found no support for recognizing more than one species (P. caucasicus s.l.) in Iran. Most of the genetic variation was geographical. An absence of lineage sorting was demonstrated, and it is proposed that any search for species-specific molecular markers for these three taxonomic species should be continued by applied biologists only if there is better evidence for associating any one of them with phenotypes important for understanding the transmission of Leishmania species in foci of zoonotic cutaneous leishmaniasis.

Cetuximab, Paclitaxel, Carboplatin, and Radiation for Head and Neck Cancer: a Toxicity Analysis

To determine the feasibility and toxicity of the addition of cetuximab to paclitaxel, carboplatin, and concurrent radiation for patients with head and neck cancer.

Music As Language

This article is an inquiry into the potential role of music in helping to address and to articulate complex emotional states such as the feelings patients might experience during the process of an illness or while undergoing bereavement. The article is centered on the role music played in structuring and articulating the cancer treatment experience of my infant nephew. What is woven around that central core is a synthesis and analysis of various philosophical perspectives, autobiographical vignettes, and empirical research. The writer postulates that music has an essential, inherent capacity to scaffold and contain emotions. Music is also considered a means to help facilitate the expression of difficult emotions such as lamentation, longing, and fear of the unknown that are often otherwise isolating, ineffable, or unbearable for patients. A major point of inquiry in this article is whether music can serve as a nurturing love object, or as a transitional object, for a patient during times of intense distress. What is also woven throughout this article is a subexploration of various philosophical perspectives on the cultural meanings and metaphors of illness.

Emotion and Executive Functioning: the Effect of Normal Mood States on Fluency Tasks

Induced positive affect (PA) can improve verbal fluency performance, and induced negative affect (NA) can increase design fluency performance (Bartolic, Basso, Schefft, Glauser, & Titanic-Schefft, 1999). Building on this, the current study investigated associations between everyday mood states and executive functions. Participants (N = 74, mean age = 51.19 years) completed verbal and design fluency tasks and a self-report affect task. PA was associated with better verbal fluency performance, although NA was not associated with design fluency. Variations in everyday PA may be associated with cognitive performance, whereas greater shifts in NA might be needed to establish associations with executive functioning.

The Power of Collective Ambition

In the past few years, some companies have not just weathered the economic storm: They've emerged stronger than ever. How did such players as Four Seasons, Sephora, and Standard Chartered Bank defy conventional logic? Instead of pursuing a single ambition, such as profits, employees defined a collective ambition. As a result, those organizations deepened their engagement with employees and other stakeholders and became sustainably profitable. Purpose, a company's reason for existence, is the central element of collective ambition. The other elements--vision, targets and milestones, strategic and operational priorities, brand promise, core values, and leader behaviors--must be aligned to serve the company's purpose. Articulating the elements of collective ambition can give everyone in the organization a better sense of the company's purpose and how they can contribute to it. Purpose does not have to be about saving the world; providing excellent entertainment or banking services is just as meaningful a purpose as improving health care in emerging economies--as long as it is an authentic representation of why the company exists. To shape and then achieve a collective ambition, companies must strengthen their organizational glue (the collaborative engagement that creates a unified culture) and grease (the disciplined execution that enterprisewide change initiatives require).

Local Failure in Resected N1 Lung Cancer: Implications for Adjuvant Therapy

PURPOSE: To evaluate actuarial rates of local failure in patients with pathologic N1 non-small-cell lung cancer and to identify clinical and pathologic factors associated with an increased risk of local failure after resection. METHODS AND MATERIALS: All patients who underwent surgery for non-small-cell lung cancer with pathologically confirmed N1 disease at Duke University Medical Center from 1995-2008 were identified. Patients receiving any preoperative therapy or postoperative radiotherapy or with positive surgical margins were excluded. Local failure was defined as disease recurrence within the ipsilateral hilum, mediastinum, or bronchial stump/staple line. Actuarial rates of local failure were calculated with the Kaplan-Meier method. A Cox multivariate analysis was used to identify factors independently associated with a higher risk of local recurrence. RESULTS: Among 1,559 patients who underwent surgery during the time interval, 198 met the inclusion criteria. Of these patients, 50 (25%) received adjuvant chemotherapy. Actuarial (5-year) rates of local failure, distant failure, and overall survival were 40%, 55%, and 33%, respectively. On multivariate analysis, factors associated with an increased risk of local failure included a video-assisted thoracoscopic surgery approach (hazard ratio [HR], 2.5; p = 0.01), visceral pleural invasion (HR, 2.1; p = 0.04), and increasing number of positive N1 lymph nodes (HR, 1.3 per involved lymph node; p = 0.02). Chemotherapy was associated with a trend toward decreased risk of local failure that was not statistically significant (HR, 0.61; p = 0.2). CONCLUSIONS: Actuarial rates of local failure in pN1 disease are high. Further investigation of conformal postoperative radiotherapy may be warranted.

Persistent N2 Disease After Neoadjuvant Chemotherapy for Non-small-cell Lung Cancer

Patients achieving a mediastinal pathologic complete response with neoadjuvant chemotherapy have improved outcomes compared with patients with persistent N2 disease. How to best manage this latter group of patients is unknown, prompting a review of our institutional experience.

Small Cell Lung Cancer

Chiral Allene-containing Phosphines in Asymmetric Catalysis

We demonstrate that allenes, chiral 1,2-dienes, appended with basic functionality can serve as ligands for transition metals. We describe an allene-containing bisphosphine that, when coordinated to Rh(I), promotes the asymmetric addition of arylboronic acids to α-keto esters with high enantioselectivity. Solution and solid-state structural analysis reveals that one olefin of the allene can coordinate to transition metals, generating bi- and tridentate ligands.

Cisplatin, Irinotecan, and Bevacizumab for Untreated Extensive-stage Small-cell Lung Cancer: CALGB 30306, a Phase II Study

The efficacy of cisplatin, irinotecan, and bevacizumab was evaluated in patients with extensive-stage small-cell lung cancer (ES-SCLC).

Apolipoprotein E-e4, Processing Speed, and White Matter Volume in a Genetically Enriched Sample of Midlife Adults

Healthy midlife children of a parent with Alzheimer's disease ([AD] N = 23; 9 male) participated in neuropsychological testing, and magnetic resonance imaging (MRI) of brain volumetrics were obtained. In all, 35% of the sample were apolipoprotein E (ApoE)-e4 positive (n = 8; 5 male). The ApoE-e4 group exhibited significantly slower performances on an executive function and processing speed measure and had less white matter volume than the non-ApoE-e4 group. Lesser white matter volume was significantly correlated with slower processing speed. Processing speed and changes in white matter volume might be indicators of preclinical decline in AD.

An Education-service Partnership to Achieve Safety and Quality Improvement Competencies in Nursing

The Institute of Medicine recommends that educational and service organizations develop partnerships to promote and prioritize competency development for nurses. This article describes a collaborative project between a college of nursing and a regional health care system. The project's aim was to foster the development of safety and quality by creating a curriculum based on the 10 core competencies identified by the Massachusetts Department of Higher Education Nurse of the Future Competency Committee. To accomplish this goal, learning experiences were created to address competency development. Competency-based education will help ensure that nursing graduates are adequately prepared to meet the current and future health care needs of our population.

Predicting the Distribution of Canine Leishmaniasis in Western Europe Based on Environmental Variables

SUMMARYThe domestic dog is the reservoir host of Leishmania infantum, the causative agent of zoonotic visceral leishmaniasis endemic in Mediterranean Europe. Targeted control requires predictive risk maps of canine leishmaniasis (CanL), which are now explored. We databased 2187 published and unpublished surveys of CanL in southern Europe. A total of 947 western surveys met inclusion criteria for analysis, including serological identification of infection (504, 369 dogs tested 1971-2006). Seroprevalence was 23·2% overall (median 10%). Logistic regression models within a GIS framework identified the main environmental predictors of CanL seroprevalence in Portugal, Spain, France and Italy, or in France alone. A 10-fold cross-validation approach determined model capacity to predict point-values of seroprevalence and the correct seroprevalence class (<5%, 5-20%, >20%). Both the four-country and France-only models performed reasonably well for predicting correctly the <5% and >20% seroprevalence classes (AUC >0·70). However, the France-only model performed much better for France than the four-country model. The four-country model adequately predicted regions of CanL emergence in northern Italy (<5% seroprevalence). Both models poorly predicted intermediate point seroprevalences (5-20%) within regional foci, because surveys were biased towards known rural foci and Mediterranean bioclimates. Our recommendations for standardizing surveys would permit higher-resolution risk mapping.

Integrated Mapping of Establishment Risk for Emerging Vector-borne Infections: a Case Study of Canine Leishmaniasis in Southwest France

Zoonotic visceral leishmaniasis is endemic in the Mediterranean Basin, where the dog is the main reservoir host. The disease's causative agent, Leishmania infantum, is transmitted by blood-feeding female sandflies. This paper reports an integrative study of canine leishmaniasis in a region of France spanning the southwest Massif Central and the northeast Pyrenees, where the vectors are the sandflies Phlebotomus ariasi and P. perniciosus.

Pathologic Response After Neoadjuvant Carboplatin and Weekly Paclitaxel for Early-stage Lung Cancer: a Brown University Oncology Group Phase II Study

Pathologic complete response (pCR) to neoadjuvant chemotherapy is associated with improved survival in solid tumors. Southwest Oncology Group 9,900 demonstrated a 9% pCR after three cycles of paclitaxel/carboplatin every 21 days. We evaluated pCR rate with intensive weekly paclitaxel in a phase II study.

Quality of Life in Prodromal HD: Qualitative Analyses of Discourse from Participants and Companions

Persons who are at risk for Huntington's Disease (HD) can be tested for the HD gene expansion before symptom onset. People with the gene expansion, but no clinical diagnosis, are in the prodromal phase of HD. This study explored quality of life (QOL) in prodromal HD. Interviews about QOL, conducted with 9 prodromal HD participants and 6 companions, were transcribed. Discourse was coded for emotional valence, content (e.g., coping, spirituality, interpersonal relationships, HD in others, and employment), and time frame (e.g., current, past, and future). Respondents were more positive than negative about the present, which was their major focus. The most common statements were about positive attitudes. Positive statements were made about spirituality, and negative statements were made about HD in other people. Relationships, employment, and coping with HD reflected both positivity and negativity. Participants and companions spoke of the future with different concerns. Applicability of findings to the clinical management of HD are discussed.

Communication of BRCA1 and BRCA2 Genetic Test Results to Health Care Providers Following Genetic Testing at a Tertiary Care Center

Individuals at high risk for hereditary cancers often receive genetic counseling and testing at tertiary care centers; however, they may receive care for long-term management of their cancer risk in community settings. Communication of genetic test results to health care providers outside of tertiary care settings can facilitate the long-term management of high risk individuals. This study assessed women's communication of BRCA1/BRCA2 genetic test results to health care providers outside of tertiary care settings (termed "outside" health care providers, or OHCPs) and women's perceptions regarding communication of results. Women (n = 312) who underwent BRCA1/BRCA2 genetic counseling and testing completed a questionnaire assessing whether or not they shared test results with OHCPs and perceptions regarding the communication of test results to OHCPs. Most (72%) shared genetic test results with OHCPs. Women with no personal history of cancer were more likely to have shared results compared to women with a personal history of cancer. Mutation status did not significantly predict sharing of genetic information. Most reported positive perceptions regarding the disclosure of genetic test results to OHCPs. The majority did not report any concerns about potential insurance discrimination (88%) and indicated that OHCPs were able to appropriately address their questions (81%). Although most women shared their genetic test results with OHCPs, those with a personal history of cancer may need further encouragement to share this information. Tertiary care centers should facilitate outreach and education with OHCPs in order to assure appropriate long-term cancer risk management for high risk populations.

Enantioselective Total Synthesis of (-)-kibdelone C

The kibdelones are aromatic polyketide natural products featuring isoquinolinone and tetrahydroxanthone ring systems. They display potent cytotoxicity toward a range of human cancer cell lines. Here, we present an enantioselective total synthesis of kibdelone C that utilizes a Shi epoxidation to establish the absolute and relative stereochemistry, an acid-catalyzed cyclization to form the tetrahydroxanthone, and a C-H arylation to complete the hexacyclic skeleton.

Current and Future Patterns of Global Marine Mammal Biodiversity

Quantifying the spatial distribution of taxa is an important prerequisite for the preservation of biodiversity, and can provide a baseline against which to measure the impacts of climate change. Here we analyse patterns of marine mammal species richness based on predictions of global distributional ranges for 115 species, including all extant pinnipeds and cetaceans. We used an environmental suitability model specifically designed to address the paucity of distributional data for many marine mammal species. We generated richness patterns by overlaying predicted distributions for all species; these were then validated against sightings data from dedicated long-term surveys in the Eastern Tropical Pacific, the Northeast Atlantic and the Southern Ocean. Model outputs correlated well with empirically observed patterns of biodiversity in all three survey regions. Marine mammal richness was predicted to be highest in temperate waters of both hemispheres with distinct hotspots around New Zealand, Japan, Baja California, the Galapagos Islands, the Southeast Pacific, and the Southern Ocean. We then applied our model to explore potential changes in biodiversity under future perturbations of environmental conditions. Forward projections of biodiversity using an intermediate Intergovernmental Panel for Climate Change (IPCC) temperature scenario predicted that projected ocean warming and changes in sea ice cover until 2050 may have moderate effects on the spatial patterns of marine mammal richness. Increases in cetacean richness were predicted above 40° latitude in both hemispheres, while decreases in both pinniped and cetacean richness were expected at lower latitudes. Our results show how species distribution models can be applied to explore broad patterns of marine biodiversity worldwide for taxa for which limited distributional data are available.

Use of a Retrograde Pedicled Double-barreled Osteocutaneous Fibula Flap for Reconstruction of Distal Tibia and Soft-tissue Defects

Habitats of the Sandfly Vectors of Leishmania Tropica and L. Major in a Mixed Focus of Cutaneous Leishmaniasis in Southeast Tunisia

From 2009 to 2010, 3129 sandflies were caught in CDC light traps placed in various habitats in Ghomrassen, Tataouine governorate, southeast Tunisia, a mixed focus of human cutaneous leishmaniasis caused by Leishmania tropica and Leishmania major. Species diversity was quantified in anthropogenic, semi-anthropogenic and semi-natural locations. Sandflies were identified according to morphological characters and also by the comparative sequence analysis of a fragment of the mitochondrial cytochrome b gene to distinguish between two putative local vectors of L. tropica, namely Phlebotomus chabaudi and Phlebotomus riouxi. The lowest sandfly diversities were found in L. major sites, where the incriminated vector P. papatasi predominated in the burrows of the rodent reservoir hosts (Meriones) as well as inside and outside houses of human cases. In L. tropica sites, the incriminated peri-domestic vector Phlebotomus sergenti was the most abundant species inside houses, whereas P. riouxi or P. chabaudi was the dominant species in the semi-natural rocky habitats favoured by the putative rodent reservoir, Ctenodactylus gundi. All specimens of P. chabaudi identified molecularly had the diagnostic cytochrome b characters of P. riouxi, indicating either that the latter represents only a geographical variant of P. chabaudi or that these two species may sometimes hybridize.

Selective Organ Preservation in Operable Locally Advanced Head and Neck Squamous Cell Carcinomas Guided by Primary Site Restaging Biopsy: Long-term Results of Two Sequential Brown University Oncology Group Chemoradiotherapy Studies

The long-term outcomes of selective organ preservation in operable, locally advanced head and neck cancers in two sequential chemoradiotherapy (CRT) protocols (HN-53, HN-67) are reported.

Age-group Differences in Facets of Positive and Negative Affect

The higher order structure of Positive Affect (PA) and Negative Affect (NA) is comparable in self-report affect data from younger and older adults. The current study advances this work by comparing the factor structure of facets of PA and NA in older and younger adults using exploratory and confirmatory factor analyses.

Ectoplasm, Ghost in the R Cell Machine?

Drosophila photoreceptors (R cells) are an extreme instance of sensory membrane amplification via apical microvilli, a widely deployed and deeply conserved operation of polarized epithelial cells. Developmental rotation of R cell apices aligns rhabdomere microvilli across the optical axis and enables enormous membrane expansion in a new, proximal distal dimension. R cell ectoplasm, the specialized cortical cytoplasm abutting the rhabdomere is likewise enormously amplified. Ectoplasm is dominated by the actin-rich terminal web, a conserved operational domain of the ancient vesicle-transport motor, Myosin V. R cells harness Myosin V to move two distinct cargoes, the biosynthetic traffic that builds the rhabdomere during development, and the migration of pigment granules that mediates the adaptive "longitudinal pupil" in adults, using two distinct Rab proteins. Ectoplasm further shapes a distinct cortical endosome compartment, the subrhabdomeral cisterna (SRC), vital to normal cell function. Reticulon, a protein that promotes endomembrane curvature, marks the SRC. R cell visual arrestin 2 (Arr2) is predominantly cytoplasmic in dark-adapted photoreceptors but on illumination it translocates to the rhabdomere, where it quenches ongoing photosignaling by binding to activated metarhodopsin. Arr2 translocation is "powered" by diffusion; a motor is not required to move Arr2 and ectoplasm does not obstruct its rapid diffusion to the rhabdomere.

The Structure and Validity of Self-reported Affect in Mild Cognitive Impairment and Mild Alzheimer's Disease

ABSTRACTBackground: This study determined the reliability, validity, and factor structure of self-report emotions in persons with mild Alzheimer's disease (AD) and mild cognitive impairment (MCI) relative to controls.Methods: Participants (mild AD, n = 73; MCI, n = 159; controls, n = 96) rated current emotions with the Visual Analogue Mood Scales (Stern, 1997).Results: Internal consistency reliabilities were comparable across groups, as were the factor structures of emotion. Persons with AD reported more negative affect (NA) than persons with MCI and controls. The emotion that most differentiated groups was confusion. NA and PA may be more bipolar in persons with AD than for persons with MCI and controls.Conclusions: The underlying structure of affect was similar in persons with mild AD, MCI, and controls. Further, persons with MCI appeared to be "transitional" between cognitive health and dementia with regard to mood and affect. That is, participants with MCI tended to have affect scores that were intermediate between those with AD and controls. Implications for interventions to improve emotional well-being in AD and MCI are discussed.

Should Sand Fly Taxonomy Predict Vectorial and Ecological Traits?

I review species concepts, the taxonomy of phlebotomine sand flies, and some transmission cycles of leishmaniasis in order to illustrate the difficulties of classifying these vectors in a way that will be ideal both for medical parasitologists and sand fly specialists. Choices will have to be made between different classifications, either maintaining a practical one containing few vectorial genera (mostly Phlebotomus for the Old World and Lutzomyia for the Neotropics) or changing the generic names of many vectors so that the classification represents an evolutionary hypothesis. However, sand flies also transmit arboviruses and members of other sand fly genera bite humans, and so vectorial status alone might not provide the criteria for recognizing only a few genera. Vectorial roles are often determined by species-level co-evolution of susceptibility to Leishmania species, with selection being initiated and maintained by ecological contacts. There is only imperfect co-cladogenesis of genus-level groups or subgeneric complexes of sand flies and Leishmania species. Natural hybridization between sand fly species has been recorded in several species complexes, and this highlights the need to focus on gene flow and the distribution of phenotypes of biomedical importance, not on taxa.

Nonoperative Versus Prophylactic Treatment of Bisphosphonate-associated Femoral Stress Fractures

Several studies have identified a specific fracture in the proximal diaphysis of the femur in patients treated with bisphosphonates. The fractures typically are sustained after a low-energy mechanism with the presence of an existing characteristic stress fracture. However, it is unclear whether these patients are best treated nonoperatively or operatively.

Titanium-mediated Oxidative Arylation of Homoallylic Alcohols

The Prevalence of Opportunistic Pathogens Associated with Intraoral Implants

The aim of this study was to determine the prevalence and proportions of opportunistic pathogens harboured on orthodontic retainers.

How Well Does the New Lung Cancer Staging System Predict for Local/regional Recurrence After Surgery?: A Comparison of the TNM 6 and 7 Systems

To evaluate how well the tumor, node, metastasis (TNM) 6 and TNM 7 staging systems predict rates of local/regional recurrence (LRR) after surgery alone for non-small cell lung cancer.

Trauma Reactivity, Avoidant Coping, and PTSD Symptoms: a Moderating Relationship?

In the immediate aftermath of a traumatic event, many individuals experience physiological reactivity in response to reminders of the traumatic event that typically lessens over time. However, an overreliance on avoidant coping strategies may interfere with the natural recovery process, particularly for those who are highly reactive to trauma reminders. In the current investigation, we examined avoidant coping as a moderator of the association between heart rate reactivity to a trauma monologue measured shortly after a traumatic event and severity of posttraumatic stress disorder (PTSD) symptoms measured several months later. Fifty-five female survivors of assault completed PTSD diagnostic interviews and a self-report coping measure and participated in a trauma monologue procedure that included continuous heart rate measurement. These procedures were completed within 1 month of the assault and again 3 months postassault. After we controlled for the effect of initial symptom levels, the interaction of heart rate reactivity to the trauma monologue and avoidant coping measured at Time 1 was associated with PTSD symptom severity at Time 2. Individuals who are relatively highly reliant on avoidant coping strategies and relatively highly reactive to trauma reminders may be at greatest risk of maintaining or potentially increasing their PTSD symptoms within the first few months following the trauma. These findings may help inform early intervention efforts for survivors of traumatic events.

Hand-assisted Laparoscopic Donor Nephrectomy: Are Hand Port Devices Really Necessary?

Hand port devices (HPD) are used routinely for hand-assisted laparoscopic surgery including hand-assisted laparoscopic donor nephrectomy (HALDN). However, the cost of such devices may prove prohibitive, particularly in centers with financial constraints. The authors aimed to identify any adverse effects of performing device-free HALDN.

Cancer Risk Management Decisions of Women with BRCA1 or BRCA2 Variants of Uncertain Significance

Double-blind, Placebo-controlled, Randomized Phase 2 Study of the Proapoptotic Agent AT-101 Plus Docetaxel, in Second-line Non-small Cell Lung Cancer

AT-101 is an inhibitor of Bcl-2 family proteins including Bcl-2, Bcl-xL, Mcl-1, and Bcl-w. In vivo and in vitro studies have exhibited broad activity of AT-101, including synergy with docetaxel in non-small cell lung cancer tumor models.

A Quantitation Method for Mass Spectrometry Imaging

A new quantitation method for mass spectrometry imaging (MSI) with matrix-assisted laser desorption/ionization (MALDI) has been developed. In this method, drug concentrations were determined by tissue homogenization of five 10 µm tissue sections adjacent to those analyzed by MSI. Drug levels in tissue extracts were measured by liquid chromatography coupled to tandem mass spectrometry (LC/MS/MS). The integrated MSI response was correlated to the LC/MS/MS drug concentrations to determine the amount of drug detected per MSI ion count. The study reported here evaluates olanzapine in liver tissue. Tissue samples containing a range of concentrations were created from liver harvested from rats administered a single dose of olanzapine at 0, 1, 4, 8, 16, 30, or 100 mg/kg. The liver samples were then analyzed by MALDI-MSI and LC/MS/MS. The MALDI-MSI and LC/MS/MS correlation was determined for tissue concentrations of ~300 to 60,000 ng/g and yielded a linear relationship over two orders of magnitude (R(2) = 0.9792). From this correlation, a conversion factor of 6.3 ± 0.23 fg/ion count was used to quantitate MSI responses at the pixel level (100 µm). The details of the method, its importance in pharmaceutical analysis, and the considerations necessary when implementing it are presented.

First Surveys to Investigate the Presence of Canine Leishmaniasis and Its Phlebotomine Vectors in Hungary

Hungary is regarded as free of leishmaniasis because only a few imported cases have been reported. However, southern Hungary has a sub-Mediterranean climate, and so it was included in the EU FP6 EDEN project, which aimed to map the northern limits of canine leishmaniasis (CanL) in Europe. The numbers of traveling and imported dogs have increased in the last decade, raising concerns about the introduction of CanL caused by Leishmania infantum. Serum samples were collected from 725 dogs (22 localities, 6 counties) that had never traveled to endemic countries, as well as from other potential reservoir hosts (185 red foxes and 13 golden jackals). All sera were tested by the indirect fluorescent antibody test, but they were sero-negative using the OIE cut-off of 1:80 serum dilution except for those of two dogs resident since birth in southern Hungary. These had not received a blood transfusion, but the mode of transmission is unclear because no sandfly vectors were caught locally. From 2006 to 2009, phlebotomine sandflies were sampled in the summer months at 47 localities of 8 counties. They were trapped with castor-oil-impregnated sticky-paper, light, and CO(2)-baited traps. Small numbers of two vectors of Leishmania infantum were found. Phlebotomus neglectus occurred in three villages near to Croatia and one in north Hungary at latitude 47 °N, and Phlebotomus perfiliewi perfiliewi was trapped at two sites in a southeastern county close to the sites where it was first found in 1931-1932. Our report provides baseline data for future investigations into the northward spread of CanL into Hungary, which we conclude has yet to occur.

Randomized Controlled Trial of Toothbrushing to Reduce Ventilator-associated Pneumonia Pathogens and Dental Plaque in a Critical Care Unit

To investigate the effect of a powered toothbrush on colonization of dental plaque by ventilator-associated pneumonia (VAP)-associated organisms and dental plaque removal.

Development of Proneurogenic, Neuroprotective Small Molecules

Degeneration of the hippocampus is associated with Alzheimer's disease and occurs very early in the progression of the disease. Current options for treating the cognitive symptoms associated with Alzheimer's are inadequate, giving urgency to the search for novel therapeutic strategies. Pharmacologic agents that safely enhance hippocampal neurogenesis may provide new therapeutic approaches. We discovered the first synthetic molecule, named P7C3, which protects newborn neurons from apoptotic cell death, and thus promotes neurogenesis in mice and rats in the subgranular zone of the hippocampal dentate gyrus, the site of normal neurogenesis in adult mammals. We describe the results of a medicinal chemistry campaign to optimize the potency, toxicity profile, and stability of P7C3. Systematic variation of nearly every position of the lead compound revealed elements conducive toward increases in activity and regions subject to modification. We have discovered compounds that are orally available, nontoxic, stable in mice, rats, and cell culture, and capable of penetrating the blood-brain barrier. The most potent compounds are active at nanomolar concentrations. Finally, we have identified derivatives that may facilitate mode-of-action studies through affinity chromatography or photo-cross-linking.

Invasive Fungal Disease After Remote Inoculation in Transplant Recipients

We describe 3 cases of invasive fungal disease in the setting of transplantation-associated immunosuppression, developing months to years after clinically resolved penetrating soft-tissue injuries with wood fragments. Invasive fungal disease resulting from remote inoculation is a distinct syndrome in immunocompromised patients presenting with soft-tissue abnormalities in areas of prior trauma.

Asymmetric Synthesis of Tertiary Benzylic Alcohols

Vinyl, aryl, and alkynyl organometallics add to ketones containing a stereogenic sulfoxide. Tertiary alcohols are generated in diastereomerically and enantiomerically pure form. Reductive lithiation converts the sulfoxide into a variety of useful functional groups.

Multiple Genetic Divergences and Population Expansions of a Mediterranean Sandfly, Phlebotomus Ariasi, in Europe During the Pleistocene Glacial Cycles

Phlebotomus ariasi is one of the two sandflies transmitting the causative agent of zoonotic leishmaniasis, Leishmania infantum, in France and Iberia, and provides a rare case study of the postglacial re-colonization of France by a Mediterranean species. Four DNA sequences were analysed-mitochondrial cytochrome b (cyt b), nuclear elongation factor-1α (EF-1α) and two anonymous nuclear loci-for 14-15 French populations and single populations from northeast Spain, northwest Spain, Portugal and Morocco. The presence of cryptic sibling species was not revealed by phylogenetic analyses and testing for reproductive isolation between sympatric populations defined by the two most divergent cyt b haplogroups. No locus was shown to be under positive directional or balancing selection and, therefore, molecular variation was explained demographically. Each nuclear locus showed shallow isolation by distance from Portugal to the French Pyrenees, but for both cyt b and EF-1α there was then a step change to the upland Massif Central, where leading-edge populations showed low diversity at all loci. Multiple genetic divergences and population expansions were detected by analyses of cyt b and dated to the Pleistocene. Endemicity of one cyt b sub-lineage suggested the presence of a refuge north of the Pyrenees during the last glacial period. Monopolization of the Massif Central by genetically differentiated populations of P. ariasi might possibly hinder the northwards spread of leishmaniasis.

Predictors for Major Wound Complications Following Preoperative Radiotherapy and Surgery for Soft-Tissue Sarcoma of the Extremities and Trunk: Importance of Tumor Proximity to Skin Surface

PURPOSE: Preoperative and postoperative RT for the treatment of high-grade soft-tissue sarcoma result in similar local control and overall survival rates, but morbidities differ. Postoperative RT is associated with a higher rate of long-term fibrosis, edema, and joint stiffness. Preoperative RT is associated with higher rates of wound complications. It is important to identify predictors for major wound complications (MWC) and to develop strategies to minimize this outcome. We reviewed our experience to determine predictors for MWC following preoperative radiotherapy (RT) and surgery for soft-tissue sarcoma. METHODS: Between January 2006 and May 2011, 103 patients with soft-tissue sarcoma of the extremities and trunk were treated with preoperative RT followed by surgery. MWCs were defined as those requiring operative or prolonged nonoperative management. Fisher's exact test was used to compare rates. Logistic regression was used for multivariable analysis of factors potentially associated with MWCs. RESULTS: Median tumor size was 8.4 cm (range 2-25). All patients had wide or radical resections. Wound closures were primary in 70 %, a vascularized flap in 27 %, and split-thickness skin graft (STSG) in 3 %. There were 36 MWCs (35 %). Significant predictors for MWCs on univariate analysis included diabetes, tumors >10 cm, tumors <3 mm from skin surface, and vascularized flap/STSG closure. The same four variables were significant predictors on multivariable analysis. CONCLUSIONS: MWCs following preoperative RT and surgery were common. Tumor proximity to skin surface <3 mm is a previously unreported independent predictor, and further strategies to minimize wound complications are needed.

"Passageless" Administration of the Nelson-Denny Reading Comprehension Test: Associations With IQ and Reading Skills

There are few tests that assess reading comprehension in adults, but these tests are needed for a comprehensive assessment of reading disorders (RD). The Nelson-Denny Reading Test (NDRT) has a long-passage reading comprehension component that can be used with adolescents and adults. A problem with the NDRT is that reading comprehension test items can be answered correctly without reading the associated passage. The current study determined how IQ, verbal comprehension, and reading skills were associated with scores on a passageless administration of the NDRT. Results indicated that IQ, verbal comprehension, and broad reading skills were significantly associated with greater NDRT passageless scores. Results raise questions about the validity of the reading comprehension component of the NDRT and suggest that the test may have differential validity based on individual differences in vocabulary, general fund of knowledge, and broad reading skills.

Sequential Identification of a Degradable Phosphate Glass Scaffold for Skeletal Muscle Regeneration

Tissue engineering has the potential to overcome limitations associated with current management of skeletal muscle defects. This study aimed to sequentially identify a degradable phosphate glass scaffold for the restoration of muscle defects. A series of glass compositions were investigated for the potential to promote bacterial growth. Thereafter, the response of human craniofacial muscle-derived cells was determined. Glass compositions containing Fe4- and 5 mol% did not promote greater Staphylococcus aureus and Staphylococcus epidermidis growth compared to the control (p > 0.05). Following confirmation of myogenicity, further studies assessed the biocompatibility of glasses containing Fe5 mol%. Cells seeded on collagen-coated disks demonstrated comparable cellular metabolic activity to control. Upregulation of genes encoding for myogenic regulatory factors (MRFs) confirmed myofibre formation and there was expression of developmental MYH genes. The use of 3-D aligned fibre scaffolds supported unidirectional cell alignment and upregulation of MRF and developmental MYH genes. Compared to the 2-D disks, there was also expression of MYH2 and MYH7 genes, indicating further myofibre maturation on the 3-D scaffolds and confirming the importance of key biophysical cues. Copyright © 2012 John Wiley & Sons, Ltd.

Ultra Strong Silicon-coated Carbon Nanotube Nonwoven Fabric As a Multifunctional Lithium-ion Battery Anode

Materials that can perform simultaneous functions allow for reductions in the total system mass and volume. Developing technologies to produce flexible batteries with good performance in combination with high specific strength is strongly desired for weight- and power-sensitive applications such as unmanned or aerospace vehicles, high-performance ground vehicles, robotics, and smart textiles. State of the art battery electrode fabrication techniques are not conducive to the development of multifunctional materials due to their inherently low strength and conductivities. Here, we present a scalable method utilizing carbon nanotube (CNT) nonwoven fabric-based technology to develop flexible, electrochemically stable (∼494 mAh·g(-1) for 150 cycles) battery anodes that can be produced on an industrial scale and demonstrate specific strength higher than that of titanium, copper, and even a structural steel. Similar methods can be utilized for the formation of various cathode and anode composites with tunable strength and energy and power densities.

Neuroprotective Efficacy of Aminopropyl Carbazoles in a Mouse Model of Parkinson Disease

We previously reported the discovery of P7C3, an aminopropyl carbazole having proneurogenic and neuroprotective properties in newborn neural precursor cells of the dentate gyrus. Here, we provide evidence that P7C3 also protects mature neurons in brain regions outside of the hippocampus. P7C3 blocks 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-mediated cell death of dopaminergic neurons in the substantia nigra of adult mice, a model of Parkinson disease (PD). Dose-response studies show that the P7C3 analog P7C3A20 blocks cell death with even greater potency and efficacy, which parallels the relative potency and efficacy of these agents in blocking apoptosis of newborn neural precursor cells of the dentate gyrus. P7C3 and P7C3A20 display similar relative effects in blocking 1-methyl-4-phenylpyridinium (MPP(+))-mediated death of dopaminergic neurons in Caenorhabditis elegans, as well as in preserving C. elegans mobility following MPP(+) exposure. Dimebon, an antihistaminergic drug that is weakly proneurogenic and neuroprotective in the dentate gyrus, confers no protection in either the mouse or the worm models of PD. We further demonstrate that the hippocampal proneurogenic efficacy of eight additional analogs of P7C3 correlates with their protective efficacy in MPTP-mediated neurotoxicity. In vivo screening of P7C3 analogs for proneurogenic efficacy in the hippocampus may thus provide a reliable means of predicting neuroprotective efficacy. We propose that the chemical scaffold represented by P7C3 and P7C3A20 provides a basis for optimizing and advancing pharmacologic agents for the treatment of patients with PD.

Combining Group-based Exposure Therapy with Prolonged Exposure to Treat U.S. Vietnam Veterans with PTSD: a Case Study

Group-based exposure therapy (GBET) of 16-week duration was developed to treat combat-related posttraumatic stress disorder (PTSD) and decreased PTSD symptoms in 3 noncontrolled open trials with low attrition (0%-5%). Group-based exposure therapy has not produced as much PTSD symptom reduction as Prolonged Exposure (PE) within a U.S. Veterans Affairs PTSD treatment program, although PE had more dropouts (20%). This pilot study was of a model that combined key elements of GBET with components of PE in an effort to increase the effectiveness of a group-based treatment while reducing its length and maintaining low attrition. Twice per week, 8 Vietnam combat veterans with PTSD were treated for 12 weeks, with an intervention that included 2 within-group war trauma presentations per participant, 6 PE style individual imaginal exposure (IE) sessions per participant, daily listening to recorded IE sessions, and daily in vivo exposure exercises. All completed treatment and showed Significant reductions on all measures of PTSD with large effect sizes; 7 participants no longer met PTSD criteria on treating clinician administered interviews and a self-report measure at posttreatment. Significant reductions in depression with large effect sizes and moderate reductions in PTSD-related cognitions were also found. Most gains were maintained 6 months posttreatment.

Influence of IL-6 Haplotypes on Clinical and Inflammatory Response in Aggressive Periodontitis

OBJECTIVES: The aim of this study was to investigate the inflammatory response in aggressive periodontitis (AgP) patients after periodontal therapy and associate these changes to subjects' interleukin-6 (IL-6) genetic variants. MATERIALS AND METHODS: Twelve non-smoking UK Caucasian patients with AgP were selected based on their IL6 haplotypes (six haplotype positive and six haplotype negative based on polymorphisms rs 2069827 and rs 2069825) and underwent full mouth non-surgical periodontal therapy, followed by open flap surgery. Gingival crevicular fluid (GCF) and peripheral blood samples were taken at baseline and at six different time points after treatment. Gingival biopsy samples were harvested during surgery and underwent immunohistochemical analysis for identification of IL-6. RESULTS: An overall improvement in clinical periodontal parameters was observed following periodontal therapy. Haplotype status was associated with clinical presentation, Aggregatibacter actinomycetemcomitans counts in subgingival plaque samples, white cell count, neutrophils, red cell count and haemoglobin. GCF IL-6 concentrations increased dramatically 1 day after surgery and IL-6 haplotype-positive subjects exhibited a higher magnitude in this increase. CONCLUSIONS: IL6 haplotypes may have an effect on clinical presentation and magnitude and kinetics of local and systemic inflammatory responses following non-surgical and surgical periodontal therapy in aggressive periodontitis. CLINICAL RELEVANCE: Detecting IL-6 haplotype-positive periodontitis patients might become helpful in identifying subjects prone to excessive inflammatory response and increased periodontal breakdown.

Penicillin and Amoxicillin Resistance in Oral Veillonella Spp

Phylogenetics of the Old World Screwworm Fly and Its Significance for Planning Control and Monitoring Invasions in Asia

Phylogenetic, genealogical and population relationships of Chrysomya bezziana, the Old World screwworm fly (OWSF), were inferred from DNA sequences of mitochondrial cytochrome b (cyt b), nuclear elongation factor-1α (EF-1α) and nuclear white eye colour (white), using sequences of Chrysomya megacephala and Chrysomya rufifacies as outgroups. Cyt b (717bp, 754 specimens), EF-1α (361bp, 256 specimens) and white (577bp, 242 specimens) were analysed from up to two African and nine Asian countries, including 10 Indonesian islands. We show that OWSF occurs as distinctive African and Asian lineages based on cyt b and white, and that there is a marked differentiation between Sumatran and Javan populations in Indonesia, supported by the genealogy and analysis of molecular variance of cyt b alone. Four cyt b sub-lineages are recognised in Asia: only 2.1 occurs on the Asian mainland, from Yemen to Peninsular Malaysia; only 2.2, 2.3 and 2.4 occur in central Indonesia; 2.4 predominates on New Guinea; and 2.1 co-occurs with others only on Sumatra in western Indonesia. This phylogeography and the genetic distances between cyt b haplotypes indicate pre-historic, natural dispersal of OWSF eastwards into Indonesia and other Malesian islands, followed by vicariant evolution in New Guinea and central Indonesia. OWSF is absent from Australia, where there is surveillance for importation or natural invasion. Judged by cyt b haplotype markers, there is currently little spread of OWSF across sea barriers, despite frequent shipments of Australian livestock through Indonesian seas to the Middle East Gulf region. These findings will inform plans for integrated pest management, which could be applied progressively, for example starting in East Nusa Tenggara (central Indonesia) where OWSF has regional cyt b markers, and progressing westwards to Java where any invasion from Sumatra is unlikely. Cyt b markers would help identify the source of any re-emergence in treated areas.

A Phase I Study of Bevacizumab, Everolimus and Panitumumab in Advanced Solid Tumors

Preclinical data suggest concurrent inhibition of VEGF, mTOR and EGFR pathways may augment antitumor and antiangiogenic effects compared to inhibition of each pathway alone. This study evaluated the maximum tolerated dose/recommended phase II dose and safety and tolerability of bevacizumab, everolimus and panitumumab drug combination.

Lymphovascular Invasion in Non-small-cell Lung Cancer: Implications for Staging and Adjuvant Therapy

Lymphovascular space invasion (LVI) is an established negative prognostic factor and an indication for postoperative radiation therapy in many malignancies. The purpose of this study was to evaluate LVI in patients with early-stage non-small-cell lung cancer, undergoing surgical resection.

Psychological Well-Being in Persons Affected by Huntington's Disease: a Comparison of At-Risk, Prodromal, and Symptomatic Groups

In order to broaden knowledge of psychological functioning in Huntington's disease (HD), participants at-risk, prodromal, and symptomatic for HD reported on stress, negative affect, and depressive symptoms as well as life satisfaction, positive affect, and quality of life. Persons with symptomatic HD reported fewer psychological assets and greater stress, depressive symptoms, and negative affect than other groups. Positive affect in symptomatic persons did not significantly differ from other groups, and was higher in persons at-risk for HD than in controls. Greater attention to psychological assets in HD is warranted, particularly positive affect which may not decline early in the disease.

Discovery of Checkpoint Kinase Inhibitor (S)-5-(3-fluorophenyl)-N-(piperidin-3-yl)-3-ureidothiophene-2-carboxamide (AZD7762) by Structure-based Design and Optimization of Thiophenecarboxamide Ureas

Checkpoint kinases CHK1 and CHK2 are activated in response to DNA damage that results in cell cycle arrest, allowing sufficient time for DNA repair. Agents that lead to abrogation of such checkpoints have potential to increase the efficacy of such compounds as chemo- and radiotherapies. Thiophenecarboxamide ureas (TCUs) were identified as inhibitors of CHK1 by high throughput screening. A structure-based approach is described using crystal structures of JNK1 and CHK1 in complex with 1 and 2 and of the CHK1-3b complex. The ribose binding pocket of CHK1 was targeted to generate inhibitors with excellent cellular potency and selectivity over CDK1and IKKβ, key features lacking from the initial compounds. Optimization of 3b resulted in the identification of a regioisomeric 3-TCU lead 12a. Optimization of 12a led to the discovery of the clinical candidate 4 (AZD7762), which strongly potentiates the efficacy of a variety of DNA-damaging agents in preclinical models.

A Pilot Study of a 12-week Model of Group-based Exposure Therapy for Veterans with PTSD

Group-based exposure therapy (GBET) is an intensive group treatment that targets posttraumatic stress disorder (PTSD) symptoms through repeated imaginal and in vivo exposure. The purpose of the present study was to assess the feasibility and acceptability of a modified 12-week course of GBET (modified from the standard 16 weeks) and to examine its effectiveness in reducing veterans' PTSD symptoms. Participants were 10 male Operation Iraqi Freedom and Vietnam-era veterans recruited from a PTSD specialty clinic at a large Veterans Affairs Medical Center. All participants were retained and demonstrated clinically significant reductions in PTSD symptoms (η(2) = .84-.87) comparable to the standard protocol. The findings from this small sample indicate that the abbreviated 12-week GBET protocol is a potentially effective treatment for PTSD.

Outcomes and Prognostic Factors for a Consecutive Case Series of 115 Patients with Somatic Leiomyosarcoma

Leiomyosarcoma is an uncommon tumor that affects 500 to 1000 patients in the United States annually. The purpose of our study was to further define survival rates as well as to identify multivariable predictors of disease-specific mortality, local recurrence, and development of distant metastasis following surgical resection.

Cyclocondensation of Amino-propargyl Silanes

Amino-propargyl silanes condense with carbonyl compounds to form imines and subsequently cyclize to form allenylidene tetrahydroquinolines. The cyclocondensations are catalyzed by a variety of Brønsted acids, among which phosphoric acids provide the highest yields. Subsequent intramolecular and intermolecular additions to the allene moiety provide complex polycyclic amines.

Stereotactic Radiotherapy for Malignancies Involving the Trigeminal and Facial Nerves

Involvement of a cranial nerve caries a poor prognosis for many malignancies. Recurrent or residual disease in the trigeminal or facial nerve after primary therapy poses a challenge due to the location of the nerve in the skull base, the proximity to the brain, brainstem, cavernous sinus, and optic apparatus and the resulting complex geometry. Surgical resection caries a high risk of morbidity and is often not an option for these patients. Stereotactic radiosurgery and radiotherapy are potential treatment options for patients with cancer involving the trigeminal or facial nerve. These techniques can deliver high doses of radiation to complex volumes while sparing adjacent critical structures. In the current study, seven cases of cancer involving the trigeminal or facial nerve are presented. These patients had unresectable recurrent or residual disease after definitive local therapy. Each patient was treated with stereotactic radiation therapy using a linear accelerator based system. A multidisciplinary approach including neuroradiology and surgical oncology was used to delineate target volumes. Treatment was well tolerated with no acute grade 3 or higher toxicity. One patient who was reirradiated experienced cerebral radionecrosis with mild symptoms. Four of the seven patients treated had no evidence of disease after a median follow up of 12 months (range 2-24 months). A dosimetric analysis was performed to compare intensity modulated fractionated stereotactic radiation therapy (IM-FSRT) to a 3D conformal technique. The dose to 90% (D90) of the brainstem was lower with the IM-FSRT plan by a mean of 13.5 Gy. The D95 to the ipsilateral optic nerve was also reduced with IM-FSRT by 12.2 Gy and the D95 for the optic chiasm was lower with FSRT by 16.3 Gy. Treatment of malignancies involving a cranial nerve requires a multidisciplinary approach. Use of an IM-FSRT technique with a micro-multileaf collimator resulted in a lower dose to the brainstem, optic nerves and chiasm for each case examined.

Retraction: Characterizing the Clinical Relevance of an Embryonic Stem Cell Phenotype in Lung Adenocarcinoma

Anti-tuberculosis Prophylaxis Following Renal Transplantation: Acceptable Variations?

Guidelines suggest tuberculosis (TB) prophylaxis in renal transplant recipients originating in endemic areas or in those at risk from non-endemic countries. Concern remains that these guidelines may fail to provide adequate prophylaxis for a cohort of patients who remain at potential risk. We aimed to determine variation patterns among different transplant units within the United Kingdom (UK) with regard to TB prophylaxis policy.

Sickle Cell and Renal Transplant: a National Survey and Literature Review

Sickle cell disease is an inherited, structural hemoglobin defect with multisystemic sequelae including renal failure. Patients with sickle cell disease are thought to benefit from renal transplant, but the long-term outcomes in such patients are unclear and have not been supported by any large prospective studies. Similarly, the renal morbidity and outcome after transplant in patients with sickle cell trait is also unclear. There is little evidence concerning living donation in donors with sickle cell disease or sickle cell trait, either for the donor health or for the graft outcome, and there are no United Kingdom guidelines. The aim of this study is to review the evidence surrounding renal transplant in recipients and donors with sickle syndromes and to determine the attitudes and current practices of United Kingdom transplant centers to performing such operations.

No Association Between A Actinomycetemcomitans or P Gingivalis and Chronic or Aggressive Periodontitis Diagnosis

Only a few studies have attempted to detect differences in microbiologic profiles of patients with chronic periodontitis (CP) and aggressive periodontitis (AgP). The aim of this analysis was to assess if clinical diagnosis or other subject factors showed association with the presence of Actinobacillus actinomycetemcomitans and Porphyromonas gingivalis in a cohort of periodontitis patients.

Assessing the Added Value of Breast Tumor Markers in Genetic Risk Prediction Model BRCAPRO

The BRCAPRO model estimates carrier probabilities for the BRCA1 and BRCA2 genes, and was recently enhanced to use estrogen receptor (ER) and progesterone receptor (PR) status of breast cancer. No independent assessment of the added value of these markers exists. Moreover, earlier versions of BRCAPRO did not use human epidermal growth factor receptor 2 (Her-2/neu) status of breast cancer. Here, we incorporate Her-2/neu in BRCAPRO and validate all the markers. We trained the enhanced model on 406 germline tested individuals, and validated on a separate clinical cohort of 796 individuals for whom test results and family history are available. For model-building, we estimated joint probabilities of ER, PR, and Her-2/neu status for carriers and non-carriers of BRCA1/2 mutations. For validation, we obtained BRCAPRO predictions with and without markers. We calculated area under the receiver operating characteristic curve (AUC), sensitivity, specificity, predictive values, and correct reclassification rates. The AUC for predicting BRCA1 status among individuals who are carriers of at least one mutation improved when ER and PR were used. The AUC for predicting the presence of either mutation improved when Her-2/neu was added. Use of markers also produced highly significant correct reclassification improvements in both cases. Breast tumor markers are useful for prediction of BRCA1/2 mutation status. ER and PR improve discrimination between BRCA1 and BRCA2 mutation carriers while Her-2/neu helps discriminate between carriers and non-carriers, particularly among women who are ER positive and Her-2/neu negative. These results support the use of the enhanced version of BRCAPRO in clinical settings.

Prospective Trial of Synchronous Bevacizumab, Erlotinib, and Concurrent Chemoradiation in Locally Advanced Head and Neck Cancer

We assessed the safety and efficacy of synchronous VEGF and epidermal growth factor receptor (EGFR) blockade with concurrent chemoradiation (CRT) in locally advanced head and neck cancer (HNC).

Towards Ultrathick Battery Electrodes: Aligned Carbon Nanotube-enabled Architecture

Vapor deposition techniques were utilized to synthesize very thick (∼1 mm) Li-ion battery anodes consisting of vertically aligned carbon nanotubes coated with silicon and carbon. The produced anode demonstrated ultrahigh thermal (>400 W·m(-1) ·K(-1)) and high electrical (>20 S·m(-1)) conductivities, high cycle stability, and high average capacity (>3000 mAh·g(Si) (-1)). The processes utilized allow for the conformal deposition of other materials, thus making it a promising architecture for the development of Li-ion anodes and cathodes with greatly enhanced electrical and thermal conductivities.

A Little Help from Our Friends: Intra-operative Endoscopy for the Extraction of an Ingested Foreign Body

Knowledge and Attitudes Regarding Expanded Genetic Carrier Screening Among Women's Healthcare Providers

To determine women's healthcare providers' knowledge and attitudes regarding genetic disorders and expanded genetic screening.

Iniparib Nonselectively Modifies Cysteine-containing Proteins in Tumor Cells and is Not a Bona Fide PARP Inhibitor

PARP inhibitors are being developed as therapeutic agents for cancer. More than six compounds have entered clinical trials. The majority of these compounds are β-nicotinamide adenine dinucleotide (NAD(+))-competitive inhibitors. One exception is iniparib, which has been proposed to be a noncompetitive PARP inhibitor. In this study, we compare the biologic activities of two different structural classes of NAD(+)-competitive compounds with iniparib and its C-nitroso metabolite.

Predictive Factors for BRCA1/BRCA2 Mutations in Women with Ductal Carcinoma in Situ

It is unclear whether women with ductal carcinoma in situ (DCIS), like their counterparts with invasive breast cancer, warrant genetic risk assessment and testing on the basis of high-risk variables. The authors of this report identified predictive factors for mutations in the breast cancer-susceptibility genes BRCA1 and BRCA2 in women who were diagnosed with DCIS.

Earlier Age of Onset of BRCA Mutation-related Cancers in Subsequent Generations

Women who are diagnosed with a deleterious mutation in either breast cancer (BRCA) gene have a high risk of developing breast and ovarian cancers at young ages. In this study, the authors assessed age at diagnosis in 2 generations of families with known mutations to investigate for earlier onset in subsequent generations.

Emotional Complexity and Emotional Well-being in Older Adults: Risks of High Neuroticism

Older and midlife adults tend to report greater emotional complexity and greater emotional well-being than younger adults but there is variability in these factors across the lifespan. This study determined how the personality trait of neuroticism at baseline predicts emotional complexity and emotional well-being 10 years later; a goal was to determine if neuroticism is a stronger predictor of these emotion outcomes with increasing age in adulthood. Data were obtained from two waves of the MIDUS projects (N = 1503; aged 34-84). Greater neuroticism predicted less emotional complexity as indicated by associations between positive and negative affect, particularly for older participants. Neuroticism predicted lower emotional well-being and this association was stronger for older and midlife than for younger adults. Overall, high neuroticism may be a greater liability for poor emotion outcomes for older and perhaps for midlife adults than for younger persons. Clinical and theoretical implications of this conclusion are discussed.

Treatment-induced Changes in Vocal Cord Mobility and Subsequent Local Recurrence After Organ Preservation Therapy for Laryngeal Carcinoma

As multidisciplinary cancer treatment evolves, strategies to identify patients needing early resection/salvage are necessary. Some have suggested that vocal cord function after organ-preservation treatment may be an indicator.

Early Onset HER2-positive Breast Cancer is Associated with Germline TP53 Mutations

Germline TP53 mutations predispose to early onset breast cancer in women and are associated with Li-Fraumeni syndrome. Published data on the pathological characteristics of breast cancer among women with TP53 mutations is limited.

Weekly Paclitaxel and Carboplatin Induction Chemotherapy Followed by Concurrent Chemoradiotherapy in Locally Advanced Squamous Cell Carcinoma of the Head and Neck

To perform a phase II trial evaluating dose dense induction chemotherapy for locally advanced head and neck cancer.

PI(4,5)P2 Depletion Underlies Retinal Degeneration in Drosophila Trp Mutants

The prototypical Transient Receptor Potential (TRP) channel is the major light-sensitive, and Ca(2+) permeable channel in Drosophila's microvillar photoreceptors. TRP channels are activated following hydrolysis of phosphatidyl-inositol 4,5 bisphosphate (PIP(2)) by the key effector enzyme phospholipase C (PLC). Mutants lacking TRP channels undergo light-dependent retinal degeneration, as a consequence of the reduced Ca(2+) influx. It has been proposed that degeneration is caused by defects in the Ca(2+) dependent visual pigment cycle, which result in accumulation of toxic phosphorylated metarhodopsin-arrestin complexes (M(PP)-Arr2). Here we show that two interventions, which prevent accumulation of M(PP)-Arr2, namely rearing under red light or eliminating the C-terminal rhodopsin phosphorylation sites, both failed to rescue degeneration in trp mutants. Instead degeneration in trp mutants reared under red light was rescued by mutation of PLC. Degeneration correlated closely with the light-induced depletion of PIP(2) that occurs in trp mutants due to failure of Ca(2+) dependent inhibition of PLC. Severe retinal degeneration was also induced in the dark in otherwise wild-type flies by overexpression of a bacterial PIP(2) 4'-phosphatase (SigD) to deplete PIP(2). In degenerating trp photoreceptors, phosphorylated Moesin, a PIP(2)-regulated membrane-cytoskeleton linker essential for normal microvillar morphology, delocalizes from the rhabdomere and there is extensive microvillar actin depolymerization. The results suggest the compromised light-induced Ca(2+) influx due to loss of TRP channels leads to PIP(2) depletion, resulting in dephosphorylation of Moesin, actin depolymerization and disintegration of photoreceptor structure.

Biology of Phlebotomine Sand Flies As Vectors of Disease Agents

Phlebotomines are the sole or principal vectors of Leishmania, Bartonella bacilliformis, and some arboviruses. The coevolution of sand flies with Leishmania species of mammals and lizards is considered in relation to the landscape epidemiology of leishmaniasis, a neglected tropical disease. Evolutionary hypotheses are unresolved, so a practical phlebotomine classification is proposed to aid biomedical information retrieval. The vectors of Leishmania are tabulated and new criteria for their incrimination are given. Research on fly-parasite-host interactions, fly saliva, and behavioral ecology is reviewed in relation to parasite manipulation of blood feeding, vaccine targets, and pheromones for lures. Much basic research is based on few transmission cycles, so generalizations should be made with caution. Integrated research and control programs have begun, but improved control of leishmaniasis and nuisance-biting requires greater emphasis on population genetics and transmission modeling. Most leishmaniasis transmission is zoonotic, affecting the poor and tourists in rural and natural areas, and therefore control should be compatible with environmental conservation.

Small Cell Lung Cancer

Neuroendocrine tumors account for approximately 20% of lung cancers; most (≈15%) are small cell lung cancer (SCLC). These NCCN Clinical Practice Guidelines in Oncology for SCLC focus on extensive-stage SCLC because it occurs more frequently than limited-stage disease. SCLC is highly sensitive to initial therapy; however, most patients eventually die of recurrent disease. In patients with extensive-stage disease, chemotherapy alone can palliate symptoms and prolong survival in most patients; however, long-term survival is rare. Most cases of SCLC are attributable to cigarette smoking; therefore, smoking cessation should be strongly promoted.

Genotype in BRCA-associated Breast Cancers

Women with BRCA1 or 2 mutations are at high risk for breast cancer. For BRCA1, a trend of increasing risk has been associated with increasing downstream (3') location for mutations compared to the upstream (5') mutations in the gene. For BRCA2, an increased risk of breast cancer has been associated with mutations outside of the ovarian cancer cluster region (OCCR). We sought to determine the mutation position in BRCA-associated breast cancers and whether or not there was a genotype-phenotype correlation. Breast cancer patients with BRCA1/2 mutations were identified by a search of a prospectively maintained data base. Mutation site, patient, and tumor characteristics were determined through retrospective review. One hundred and sixty-four patients with BRCA1-associated breast cancer and 109 patients with BRCA2-associated breast cancer were identified. Among patients with BRCA1-associated cancers, 86 (52%) had mutations in the 5' half of the gene. Among patients with BRCA2-associated breast cancers, 40 (37%) had OCCR mutations. Although BRCA1-associated tumors were more likely to be ER/PR- than BRCA2-associated cancers (p < 0.0001), there was no difference in the tumor characteristics among BRCA1 or BRCA2-associated cancers based on mutation location. In this single-institution study, over half of BRCA1-associated and over a third of BRCA2-associated breast cancers were associated with putative lower risk mutations. Although we cannot exclude the possibility that mutations in these regions confer a lower relative risk for breast cancer, vigilance in cancer screening and prevention remains necessary. Further studies in genotype/phenotype correlation are needed to individualize prevention strategies.

Lubricin and Smooth Muscle α-actin-containing Myofibroblasts in the Pseudomembranes Around Loose Hip and Knee Prostheses

The objective was to evaluate the presence and distribution of the lubricating and anti-adhesion glycoprotein lubricin and cells containing the contractile isoform smooth muscle α-actin (SMA) in pseudomembranes around loose hip prostheses. Periprosthetic tissue was obtained at revision arthroplasty of eight aseptic, loose hip implants, and for comparison three loose knee prostheses. Immunohistochemical analysis was performed in 3 zones: zone 1, within 300μm of the edge of the implant-tissue interface; zone 2, between zones 1 and 3; zone 3, within 300μm of the resected/trimmed edge. The presence of lubricin was extensive in all samples: (1) as a discrete layer at the implant-tissue interface; (2) within the extracellular matrix (ECM); (3) intracellularly. There was significantly more high grade (>50%) lubricin surface staining at the implant-tissue interface compared with the resected edge. While there was also a significant effect of location of high grade ECM lubricin staining, there was no significant effect of implant type (i.e. hip versus knee). All but two hip pseudomembrane samples showed the presence of many SMA-containing cells. There was a significant effect of location on the number of SMA-expressing cells, but not of implant type. These findings might explain why the management of loose prosthesis is so challenging.

Recombinant Strains for the Enhanced Production of Bioengineered Rapalogs

The rapK gene required for biosynthesis of the DHCHC starter acid that initiates rapamycin biosynthesis was deleted from strain BIOT-3410, a derivative of Streptomyces rapamycinicus which had been subjected to classical strain and process development and capable of robust rapamycin production at titres up to 250mg/L. The resulting strain BIOT-4010 could no longer produce rapamycin, but when supplied exogenously with DHCHC produced rapamycin at titres equivalent to its parent strain. This strain enabled mutasynthetic access to new rapalogs that could not readily be isolated from lower titre strains when fed DHCHC analogs. Mutasynthesis of some rapalogs resulted predominantly in compounds lacking late post polyketide synthase biosynthetic modifications. To enhance the relative production of fully elaborated rapalogs, genes encoding late-acting biosynthetic pathway enzymes which failed to act efficiently on the novel compounds were expressed ectopically to give strain BIOT-4110. Strains BIOT-4010 and BIOT-4110 represent valuable tools for natural product lead optimization using biosynthetic medicinal chemistry and for the production of rapalogs for pre-clinical and early stage clinical trials.

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