Vibronic quantized tunneling controlled photoinduced electron transfer in an organic solar cell subjected to an external electric field.
In this work, vibration-resolved photoinduced electron transfer of an organic conjugated DA system subjected to an external electric field was theoretically investigated. The ground and excited state vibrational relaxation energies were quantitatively characterized. The effective high frequency, ωeff, could be estimated from the variation in energy of the excited-state equilibrium geometries of acceptor and donor sites as well as the analysis of the vibrational modes upon electron transfer. For a PCDTBT:PC70BM blend in an external electric field, the vibronic modes affected the charge separation process differently from the charge recombination process. The simulated results indicated that the vibrational quantum tunneling effect facilitated the charge recombination process to a large extent. Thus, for electron transfer reactions, considering the vibrational excitation influence and perturbed nucleus-electron interactions is essential. These results provide a feasible way to enhance the efficiency in yielding the electron transfer process products.


Phase II study of capecitabine and oxaliplatin for advanced adenocarcinoma of the small bowel and ampulla of Vater.
Adenocarcinomas of the small bowel and ampulla of Vater represent rare cancers that have limited data regarding first-line therapy. We conducted a phase II trial to evaluate the benefit of capecitabine in combination with oxaliplatin (CAPOX) in patients with advanced adenocarcinoma of small bowel or ampullary origin. Eligible patients with metastatic or unresectable tumors and no prior systemic chemotherapy for advanced disease participated in this phase II trial. CAPOX was administered as a 21-day cycle with oxaliplatin 130 mg/m(2) on day 1 and capecitabine 750 mg/m(2) twice a day on days 1 through 14. The primary end point was overall response rate as assessed by Response Evaluation Criteria in Solid Tumors. Thirty-one patients were enrolled onto the study, and 30 patients received study treatment. The confirmed overall response rate was 50%; three patients with metastatic disease achieved complete responses. The median time to progression (TTP) was 11.3 months, and the median overall survival (OS) was 20.4 months. Subset analysis of patients with metastatic disease only (n = 25) revealed a median TTP of 9.4 months and median OS of 15.5 months. The most common grades 3 or 4 toxicities included fatigue (30%), peripheral neuropathy (10%), vomiting (10%), diarrhea (10%), and neutropenia (10%). When administered to patients with good performance status, CAPOX is well tolerated and produces a superior response rate and longer OS compared with other regimens in the literature. CAPOX should be considered a new standard regimen for advanced small bowel and ampullary adenocarcinomas.


Use of the modified frailty index to predict 30-day morbidity and mortality from spine surgery.
OBJECTIVE Limited tools exist to stratify perioperative risk in patients undergoing spinal procedures. The modified frailty index (mFI) based on the Canadian Study of Health and Aging Frailty Index (CSHA-FI), constructed from standard demographic variables, has been applied to various other surgical populations for risk stratification. The authors hypothesized that it would be predictive of postoperative morbidity and mortality in patients undergoing spine surgery. METHODS The 2006-2010 National Surgical Quality Improvement Program (NSQIP) data set was accessed for patients undergoing spine surgeries based on Current Procedural Terminology (CPT) codes. Sixteen preoperative clinical NSQIP variables were matched to 11 CSHA-FI variables (changes in daily activities, gastrointestinal problems, respiratory problems, clouding or delirium, hypertension, coronary artery and peripheral vascular disease, congestive heart failure, and so on). The outcomes assessed were 30-day occurrences of adverse events. These were then summarized in groups: any infection, wound-related complication, Clavien IV complications (life-threatening, requiring ICU admission), and mortality. RESULTS A total of 18,294 patients were identified. In 8.1% of patients with an mFI of 0 there was at least one morbid complication, compared with 24.3% of patients with an mFI of ≥ 0.27 (p < 0.001). An mFI of 0 was associated with a mortality rate of 0.1%, compared with 2.3% for an mFI of ≥ 0.27 (p < 0.001). Patients with an mFI of 0 had a 1.7% rate of surgical site infections and a 0.8% rate of Clavien IV complications, whereas patients with an mFI of ≥ 0.27 had rates of 4.1% and 7.1% for surgical site infections and Clavien IV complications, respectively (p < 0.001 for both). Multivariate analysis showed that the preoperative mFI and American Society of Anesthesiologists classification of ≥ III had a significantly increased risk of leading to Clavien IV complications and death. CONCLUSIONS A higher mFI was associated with a higher risk of postoperative morbidity and mortality, providing an additional tool to improve perioperative risk stratification.


A review of the literature: the economic impact of preventive dental hygiene services.
The contributions of dental hygiene as a discipline of prevention, the inception of systemic fluoride in community water systems, the continual research conducted by the National Institute of Dental and Craniofacial Research (NIDCR), and the success of dental sealants have all contributed to the decrease in incidences of dental diseases. The prevalence of employer-based dental insurance must also be recognized as contributing to a substantial paradigm shift on the utilization of oral health preventive services. This review of the economic impact of oral health preventive services on the consumer and the private dental practice suggests that these services have had a significant impact. Dentistry's challenge remains to extend these considerable gains in oral health status to the 150 million U.S. citizens who do not have access to oral health care services identified in the 2000 Oral Health in America: A Report of the Surgeon General. Utilizing preventive, therapeutic, and educational aspects of dental hygiene services, reaching communities without fluoridation of the public water supply, and incorporating mass pediatric dental sealant programs analogous to immunization programs would improve the oral health status of underserved populations.


Predicting genetic interactions from Boolean models of biological networks.
Genetic interaction can be defined as a deviation of the phenotypic quantitative effect of a double gene mutation from the effect predicted from single mutations using a simple (e.g., multiplicative or linear additive) statistical model. Experimentally characterized genetic interaction networks in model organisms provide important insights into relationships between different biological functions. We describe a computational methodology allowing us to systematically and quantitatively characterize a Boolean mathematical model of a biological network in terms of genetic interactions between all loss of function and gain of function mutations with respect to all model phenotypes or outputs. We use the probabilistic framework defined in MaBoSS software, based on continuous time Markov chains and stochastic simulations. In addition, we suggest several computational tools for studying the distribution of double mutants in the space of model phenotype probabilities. We demonstrate this methodology on three published models for each of which we derive the genetic interaction networks and analyze their properties. We classify the obtained interactions according to their class of epistasis, dependence on the chosen initial conditions and the phenotype. The use of this methodology for validating mathematical models from experimental data and designing new experiments is discussed.


Radiation therapy for hepatobiliary malignancies.
Hepatobiliary malignancies represent a heterogeneous group of diseases, which often arise in a background of underlying hepatic dysfunction complicating their local management. Surgical resection continues to be the standard of care for hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC); unfortunately the majority of patients are inoperable at presentation. The aggressiveness of these lesions makes locoregional control of particular importance. Historical experience with less sophisticated radiotherapy resulted in underwhelming efficacy and oftentimes prohibitive liver toxicity. However, with the advent of extremely conformal and precise radiotherapy delivery, dose escalation to the tumor with sparing of surrounding normal tissue has yielded notable improvements in efficacy for this modality of treatment. Dose escalation has come in a variety of forms most notably as stereotactic body radiation therapy (SBRT) and hypofractionated proton therapy. As radiation techniques continue to improve, their proper incorporation into the local management of hepatobiliary malignancies will be paramount in improving the prognosis of what is a grave diagnosis.


Beneficial effects of androgen-primed chemotherapy in the Dunning R3327 G model of prostatic cancer.
The objective of this study was to test the hypothesis that androgen administration prior to chemotherapy (androgen priming) may potentiate tumor cytotoxicity in hormone-responsive prostate cancer. Accordingly, six groups of Copenhagen rats bearing small (i.e., 40-mm3 median volume) Dunning R3327 G tumors were left untreated or received castration, chemotherapy, or a combination of the two, with or without androgen priming. Groups without priming included: intact untreated, castrate alone, intact plus chemotherapy, and castrate plus chemotherapy (cyclophosphamide, 30 mg/kg/day, for 2 days, with repeat cycle in 24 days) (Cx). To specifically evaluate the effect of androgen priming on Cx cytotoxicity, two additional castrate groups were studied. One received testosterone propionate (4 mg/kg/day) for 2 days prior to Cx and the other after Cx. Treatment effect was evaluated by quantitating tumor volume as well as animal survival to an ethically allowable, maximal tumor burden. As expected, castration and Cx produced a retardation of tumor growth and prolongation of survival when compared to untreated animals. The addition of androgen priming prior to but not after Cx enhanced the degree of tumor suppression. Specifically, 26 days after the second Cx cycle, all androgen-primed tumors had regressed; 70% of tumors had disappeared and those remaining were barely palpable. At this same time point, tumors in all the other groups were actively growing and had volumes greater than initial values (P less than 0.01). Although tumor regrowth occurred, median survival for the androgen-primed group was significantly prolonged, to 186 days versus 39 days (P less than 0.01) for untreated animals and 153 days for the non-primed castrate plus Cx animals (P less than 0.01). These data suggested that androgen priming potentiates the effects of Cx in castrate animals bearing R3327 G tumors.


Biochemically based design of cyclooxygenase-2 (COX-2) inhibitors: facile conversion of nonsteroidal antiinflammatory drugs to potent and highly selective COX-2 inhibitors.
All nonsteroidal antiinflammatory drugs (NSAIDs) inhibit the cyclooxygenase (COX) isozymes to different extents, which accounts for their anti-inflammatory and analgesic activities and their gastrointestinal side effects. We have exploited biochemical differences between the two COX enzymes to identify a strategy for converting carboxylate-containing NSAIDs into selective COX-2 inhibitors. Derivatization of the carboxylate moiety in moderately selective COX-1 inhibitors, such as 5,8,11,14-eicosatetraynoic acid (ETYA) and arylacetic and fenamic acid NSAIDs, exemplified by indomethacin and meclofenamic acid, respectively, generated potent and selective COX-2 inhibitors. In the indomethacin series, esters and primary and secondary amides are superior to tertiary amides as selective inhibitors. Only the amide derivatives of ETYA and meclofenamic acid inhibit COX-2; the esters are either inactive or nonselective. Inhibition kinetics reveal that indomethacin amides behave as slow, tight-binding inhibitors of COX-2 and that selectivity is a function of the time-dependent step. Site-directed mutagenesis of murine COX-2 indicates that the molecular basis for selectivity differs from the parent NSAIDs and from diarylheterocycles. Selectivity arises from novel interactions at the opening and at the apex of the substrate-binding site. Lead compounds in the present study are potent inhibitors of COX-2 activity in cultured inflammatory cells. Furthermore, indomethacin amides are orally active, nonulcerogenic, anti-inflammatory agents in an in vivo model of acute inflammation. Expansion of this approach can be envisioned for the modification of all carboxylic acid-containing NSAIDs into selective COX-2 inhibitors.


Lensfree optofluidic plasmonic sensor for real-time and label-free monitoring of molecular binding events over a wide field-of-view.
We demonstrate a high-throughput biosensing device that utilizes microfluidics based plasmonic microarrays incorporated with dual-color on-chip imaging toward real-time and label-free monitoring of biomolecular interactions over a wide field-of-view of >20 mm(2). Weighing 40 grams with 8.8 cm in height, this biosensor utilizes an opto-electronic imager chip to record the diffraction patterns of plasmonic nanoapertures embedded within microfluidic channels, enabling real-time analyte exchange. This plasmonic chip is simultaneously illuminated by two different light-emitting-diodes that are spectrally located at the right and left sides of the plasmonic resonance mode, yielding two different diffraction patterns for each nanoaperture array. Refractive index changes of the medium surrounding the near-field of the nanostructures, e.g., due to molecular binding events, induce a frequency shift in the plasmonic modes of the nanoaperture array, causing a signal enhancement in one of the diffraction patterns while suppressing the other. Based on ratiometric analysis of these diffraction images acquired at the detector-array, we demonstrate the proof-of-concept of this biosensor by monitoring in real-time biomolecular interactions of protein A/G with immunoglobulin G (IgG) antibody. For high-throughput on-chip fabrication of these biosensors, we also introduce a deep ultra-violet lithography technique to simultaneously pattern thousands of plasmonic arrays in a cost-effective manner.


Welding and lung cancer in a pooled analysis of case-control studies.
Several epidemiologic studies have indicated an increased risk of lung cancer among welders. We used the SYNERGY project database to assess welding as a risk factor for developing lung cancer. The database includes data on 15,483 male lung cancer cases and 18,388 male controls from 16 studies in Europe, Canada, China, and New Zealand conducted between 1985 and 2010. Odds ratios and 95% confidence intervals between regular or occasional welding and lung cancer were estimated, with adjustment for smoking, age, study center, and employment in other occupations associated with lung cancer risk. Overall, 568 cases and 427 controls had ever worked as welders and had an odds ratio of developing lung cancer of 1.44 (95% confidence interval: 1.25, 1.67) with the odds ratio increasing for longer duration of welding. In never and light smokers, the odds ratio was 1.96 (95% confidence interval: 1.37, 2.79). The odds ratios were somewhat higher for squamous and small cell lung cancers than for adenocarcinoma. Another 1,994 cases and 1,930 controls had ever worked in occupations with occasional welding. Work in any of these occupations was associated with some elevation of risk, though not as much as observed in regular welders. Our findings lend further support to the hypothesis that welding is associated with an increased risk of lung cancer.


Photocatalytic inactivation of Vibrio fischeri using Fe2O3-TiO2-based nanoparticles.
Biofouling is a major problem in water membrane processes, especially in seawater reverse osmosis plants. Inactivation of Vibrio fischeri (a well-known marine bacterium forming biofilm) through photocatalysis via visible light was investigated in this work using active Fe2O3-TiO2 nanoparticles. Five Fe2O3-TiO2 photocatalysts with different weight percentage of Fe2O3 (0-5 wt%) were synthesized using an ultrasonic-assisted co-precipitation method. The photocatalysts were characterized by powder X-ray diffraction (XRD), BET surface area, transmission electron Æ (TEM) plus selected area electron diffraction (SAED) patterns, scanning electron microscopy (SEM), energy-dispersive X-ray spectroscopy (EDX) and diffuse-reflectance spectroscopy (DRS). Based on the design of experiments, the synthesized photocatalysts were tested for inactivation of V. fischeri under visible light irradiation at different temperatures (25-35 °C) and different photocatalyst dosage (0.1-2 g/L). The photocatalytic microbial inactivation experiments were performed in artificial seawater appropriate for growth of the marine bacterium. The results revealed that the highest inactivation efficiency of V. fischeri was achieved when 1 g/L of 2.5 wt% Fe2O3-TiO2 were used, at 35 °C. Photocatalytic inactivation of microorganisms using visible light-driven Fe2O3-TiO2 photocatalysts, could introduce an innovative green method in pretreatment units of reverse osmosis plants to control the membrane biofouling.


Budesonide delivered by Turbuhaler is effective in a dose-dependent fashion when used in the treatment of adult patients with chronic asthma.
Airway inflammation is a hallmark of asthma, therefore current treatment recommendations include the use of inhaled glucocorticosteroids (GCS). However, there is little evidence that the effects of inhaled GCS are dose dependent. The objective of this study was to assess the efficacy and safety of a second-generation GCS, budesonide, delivered by Turbuhaler, in adults with chronic asthma. In a 12-week, randomized, double-blind, multicenter, parallel-group study, 473 subjects 18 to 70 years of age received either placebo or budesonide (200, 400, 800, or 1600 microg total daily dose) administered twice daily. Primary efficacy end points were mean change from baseline for FEV1 and morning peak expiratory flow. Safety was assessed by reported adverse events and by a cosyntropin-stimulation test. The mean baseline FEV1 was 63% to 66% of predicted normal value between groups. All doses of budesonide were more effective than placebo (p < 0.001). The mean changes in morning peak expiratory flow were 12, 22, 27, and 30 L/min in the 200, 400, 800, and 1600 microg budesonide total daily dose groups, respectively, and -27 L/min for the placebo group. A statistically significant dose-response effect for the mean change from baseline over the 12-week study was seen for both morning peak expiratory flow and FEV1. Budesonide-treated subjects also demonstrated significant reduction in asthma symptoms and bronchodilator use compared with placebo. There were no clinically significant differences in treatment-related adverse experiences among groups. Budesonide administered by Turbuhaler exhibited a dose response and was effective at low doses. It was well tolerated and significantly more effective than placebo.


Metabolic and physiologic effects from consuming a hunter-gatherer (Paleolithic)-type diet in type 2 diabetes.
The contemporary American diet figures centrally in the pathogenesis of numerous chronic diseases--'diseases of civilization'--such as obesity and diabetes. We investigated in type 2 diabetes whether a diet similar to that consumed by our pre-agricultural hunter-gatherer ancestors ('Paleolithic' type diet) confers health benefits. We performed an outpatient, metabolically controlled diet study in type 2 diabetes patients. We compared the findings in 14 participants consuming a Paleo diet comprising lean meat, fruits, vegetables and nuts, and excluding added salt, and non-Paleolithic-type foods comprising cereal grains, dairy or legumes, with 10 participants on a diet based on recommendations by the American Diabetes Association (ADA) containing moderate salt intake, low-fat dairy, whole grains and legumes. There were three ramp-up diets for 7 days, then 14 days of the test diet. Outcomes included the following: mean arterial blood pressure; 24-h urine electrolytes; hemoglobin A1c and fructosamine levels; insulin resistance by euglycemic hyperinsulinemic clamp and lipid levels. Both groups had improvements in metabolic measures, but the Paleo diet group had greater benefits on glucose control and lipid profiles. Also, on the Paleo diet, the most insulin-resistant subjects had a significant improvement in insulin sensitivity (r = 0.40, P = 0.02), but no such effect was seen in the most insulin-resistant subjects on the ADA diet (r = 0.39, P = 0.3). Even short-term consumption of a Paleolithic-type diet improved glucose control and lipid profiles in people with type 2 diabetes compared with a conventional diet containing moderate salt intake, low-fat dairy, whole grains and legumes.


Comparative models of GABAA receptor extracellular and transmembrane domains: important insights in pharmacology and function.
Comparative models of the extracellular and transmembrane domains of GABAA receptors in the agonist-free state were generated based on the recently published structures of the nicotinic acetylcholine receptor. The models were validated by computational methods, and their reliability was estimated by analyzing conserved and variable elements of the cys-loop receptor topology. In addition, the methodological limits in the interpretation of such anion channel receptor models are discussed. Alignment ambiguities in the helical domain were resolved for helix 3 by placing two gaps into the linker connecting helices 2 and 3. The resulting models were shown to be consistent with a wide range of pharmacological and mutagenesis data from GABAA and glycine receptors. The loose packing of the models results in a large amount of solvent-accessible space and offers a natural explanation for the rich pharmacology and the great flexibility of these receptors that are known to exist in numerous drug-induced conformational states. Putative drug binding pockets found within and between subunits are described, and amino acid residues important for the action and subtype selectivity of volatile and intravenous anesthetics, barbiturates, and furosemide are shown to be part of these pockets. The entire helical domain, however, seems to be crucial not only for binding of drugs but also for transduction of binding to gating or of allosteric modulation. These models can now be used to design new experiments for clarification of pharmacological and structural questions as well as for investigating and visualizing drug induced conformational changes.


Combined contributions of feedforward and feedback inputs to bottom-up attention.
In order to deal with a large amount of information carried by visual inputs entering the brain at any given point in time, the brain swiftly uses the same inputs to enhance processing in one part of visual field at the expense of the others. These processes, collectively called bottom-up attentional selection, are assumed to solely rely on feedforward processing of the external inputs, as it is implied by the nomenclature. Nevertheless, evidence from recent experimental and modeling studies points to the role of feedback in bottom-up attention. Here, we review behavioral and neural evidence that feedback inputs are important for the formation of signals that could guide attentional selection based on exogenous inputs. Moreover, we review results from a modeling study elucidating mechanisms underlying the emergence of these signals in successive layers of neural populations and how they depend on feedback from higher visual areas. We use these results to interpret and discuss more recent findings that can further unravel feedforward and feedback neural mechanisms underlying bottom-up attention. We argue that while it is descriptively useful to separate feedforward and feedback processes underlying bottom-up attention, these processes cannot be mechanistically separated into two successive stages as they occur at almost the same time and affect neural activity within the same brain areas using similar neural mechanisms. Therefore, understanding the interaction and integration of feedforward and feedback inputs is crucial for better understanding of bottom-up attention.


Heart rate variability and short duration spaceflight: relationship to post-flight orthostatic intolerance.
Upon return from space many astronauts experience symptoms of orthostatic intolerance. Research has implicated altered autonomic cardiovascular regulation due to spaceflight with further evidence to suggest that there might be pre-flight autonomic indicators of post-flight orthostatic intolerance. We used heart rate variability (HRV) to determine whether autonomic regulation of the heart in astronauts who did or did not experience post-flight orthostatic intolerance was different pre-flight and/or was differentially affected by short duration (8-16 days) spaceflight. HRV data from ten-minute stand tests collected from the 29 astronauts 10 days pre-flight, on landing day and three days post-flight were analysed using coarse graining spectral analysis. From the total power (PTOT), the harmonic component was extracted and divided into high (PHI: >0.15 Hz) and low (PLO: = 0.15 Hz) frequency power regions. Given the distribution of autonomic nervous system activity with frequency at the sinus node, PHI/PTOT was used as an indicator of parasympathetic activity; PLO/PTOT as an indicator of sympathetic activity; and, PLO/PHI as an estimate of sympathovagal balance. Twenty-one astronauts were classified as finishers, and eight as non-finishers, based on their ability to remain standing for 10 minutes on landing day. Pre-flight, non-finishers had a higher supine PHI/PTOT than finishers. Supine PHI/PTOT was the same pre-flight and on landing day in the finishers; whereas, in the non-finishers it was reduced. The ratio PLO/PHI was lower in non-finishers compared to finishers and was unaffected by spaceflight. Pre-flight, both finishers and non-finishers had similar supine values of PLO/PTOT, which increased from supine to stand. Following spaceflight, only the finishers had an increase in PLO/PTOT from supine to stand. Both finishers and non-finishers had an increase in sympathetic activity with stand on pre-flight, yet only finishers retained this response on landing day. Non-finishers also had lower sympathovagal balance and higher pre-flight supine parasympathetic activity than finishers. These results suggest pre-flight autonomic status and post-flight impairment in autonomic control of the heart may contribute to orthostatic intolerance. The mechanism by which higher pre-flight parasympathetic activity might contribute to post-flight orthostatic intolerance is not understood and requires further investigation.


Ratio of "A-type" to "B-type" proanthocyanidin interflavan bonds affects extra-intestinal pathogenic Escherichia coli invasion of gut epithelial cells.
Gut colonization by extra-intestinal pathogenic Escherichia coli (ExPEC) increases the risk of subsequent infections, including urinary tract infection and septicemia. Previous work suggests that cranberry proanthocyanidins (PAC) interact with bacterial surface factors, altering bacterial interaction with host cells. Methods were developed to determine if ratios of "A-type" to "B-type" interflavan bonds in PAC affect ExPEC agglutination and invasion of enterocytes. In cranberries, 94.5% of PAC contain one or more "A-type" bonds, whereas in apples, 88.3% of PAC contain exclusively "B-type" bonds. Results show that cranberry "A-type" PAC have greater bioactivity than apple "B-type" PAC for increasing ExPEC agglutination and decreasing ExPEC epithelial cell invasion.


Microbiological assessment of bile during cholecystectomy: is all bile infected?
To determine the prevalence of bactibilia in patients undergoing cholecystectomy and to relate the presence or absence of organisms to the preoperative and postoperative course. Patients undergoing cholecystectomy under the care of a single consultant surgeon during a continuous 5-year period were identified from a prospectively maintained departmental database. Symptoms, clinical signs, findings of investigations, details of treatment and postoperative care were noted. Risk factors for bactibilia (acute cholecystitis, common duct stones, emergency surgery, intraoperative findings and age > 70 years) were documented. Patients were divided according to the presence (B + ) or absence (B-) of bacteria on culture of their bile. In all, 128/180 (70%) of cholecystectomies had full data available for analysis. Bacteria were identified in the bile of 20 (15.6%) patients (B+ group). The B+ group was significantly older at 63.78+/-9.7 versus 61.62+/-13.9 (p<0.05) and contained significantly fewer females than the B- group (p<0.05). All 20 patients (100%) in the B+ group had > or = 1 risk factor, while these factors were present in only 29/108 (30.3%) of patients in the B- group (p<0.05). The overall incidence of infective complications was 20% in the B+ group compared with 0.9% in the B- group (p<0.05) and the bile-related infections were higher in the B+ group (p<0.05). The study demonstrated that while patients with complicated gallstone disease frequently exhibit bactibilia, patients with uncomplicated cholelithiasis have aseptic bile. The findings would suggest that prophylactic antibiotics should be limited to patients with risk factors for bactibilia.


Combining survey data, GIS and qualitative interviews in the analysis of health service access for persons with disabilities.
Equitable access to health services is a key ingredient in reaching health for persons with disabilities and other vulnerable groups. So far, research on access to health services in low- and middle-income countries has largely relied on self-reported survey data. Realizing that there may be substantial discrepancies between perceived and actual access, other methods are needed for more precise knowledge to guide health policy and planning. The objective of this article is to describe and discuss an innovative methodological triangulation where statistical and spatial analysis of perceived distance and objective measures of access is combined with qualitative evidence. The data for the study was drawn from a large household and individual questionnaire based survey carried out in Namibia and Malawi. The survey data was combined with spatial data of respondents and health facilities, key informant interviews and focus group discussions. To analyse access and barriers to access, a model is developed that takes into account both measured and perceived access. The geo-referenced survey data is used to establish four outcome categories of perceived and measured access as either good or poor. Combined with analyses of the terrain and the actual distance from where the respondents live to the health facility they go to, the data allows for categorising areas and respondents according to the four outcome categories. The four groups are subsequently analysed with respect to variation in individual characteristics and vulnerability factors. The qualitative component includes participatory map drawing and is used to gain further insight into the mechanisms behind the different combinations of perceived and actual access. Preliminary results show that there are substantial discrepancies between perceived and actual access to health services and the qualitative study provides insight into mechanisms behind such divergences. The novel combination of survey data, geographical data and qualitative data will generate a model on access to health services in poor contexts that will feed into efforts to improve access for the most vulnerable people in underserved areas.


The global burden of childhood coeliac disease: a neglected component of diarrhoeal mortality?
Coeliac disease has emerged as an increasingly recognised public health problem over the last half-century, and is now coming to be seen as a global phenomenon, despite a profound lack of globally representative epidemiological data. Since children with coeliac disease commonly present with chronic diarrhoea and malnutrition, diagnosis is often overlooked, particularly in poorer settings where children often fail to thrive and water-borne infectious diarrhoeas are common. This is the first attempt to make global estimates of the burden of coeliac disease in childhood. We built a relatively crude model of childhood coeliac disease, incorporating estimates of population prevalence, probability of non-diagnosis, and likelihood of mortality among the undiagnosed across all countries from 1970 to 2010, based around the few available data. All our assumptions are stated in the paper and the model is available as a supplementary file. Our model suggests that in 2010 there were around 2.2 million children under 5 years of age living with coeliac disease. Among these children there could be 42,000 deaths related to coeliac disease annually. In 2008, deaths related to coeliac disease probably accounted for approximately 4% of all childhood diarrhoeal mortality. Although coeliac disease may only account for a small proportion of diarrhoeal mortality, these deaths are not preventable by applying normal diarrhoea treatment guidelines, which may even involve gluten-based food supplements. As other causes of diarrhoeal mortality decline, coeliac disease will become a proportionately increasing problem unless consideration is given to trying gluten-free diets for children with chronic diarrhoea and malnutrition.


A proto-architecture for innate directionally selective visual maps.
Self-organizing artificial neural networks are a popular tool for studying visual system development, in particular the cortical feature maps present in real systems that represent properties such as ocular dominance (OD), orientation-selectivity (OR) and direction selectivity (DS). They are also potentially useful in artificial systems, for example robotics, where the ability to extract and learn features from the environment in an unsupervised way is important. In this computational study we explore a DS map that is already latent in a simple artificial network. This latent selectivity arises purely from the cortical architecture without any explicit coding for DS and prior to any self-organising process facilitated by spontaneous activity or training. We find DS maps with local patchy regions that exhibit features similar to maps derived experimentally and from previous modeling studies. We explore the consequences of changes to the afferent and lateral connectivity to establish the key features of this proto-architecture that support DS.


Evaluation for Testosterone Deficiency.
There has been a recent increase in the number of Operators presenting to clinics for evaluation of possible low testosterone. In response, USASOC recently released an Androgen Deficiency Clinical Practice Guideline (CPG) to help guide providers through the initial evaluation and treatment of patients. The diagnosis of hypogonadism is based on consistent signs and symptoms of androgen deficiency and unequivocally low serum testosterone (below 300 ng/dL). Testosterone levels can change for a variety of reasons and an adequate evaluation requires multiple laboratory tests over a period of time. If a diagnosis of hypogonadism is confirmed, differentiating between primary and secondary hypogonadism can help guide further care. Testosterone replacement therapy options are available, but careful monitoring for side-effects is required. Controversy still exists surrounding the safety of testosterone replacement therapy, and referral to endocrinology should strongly be considered before initiating treatment.


High perceived social support and hospital readmissions in an older multi-ethnic, limited English proficiency, safety-net population.
Early readmission amongst older safety-net hospitalized adults is costly. Interventions to prevent early readmission have had mixed success. The role of perceived social support is unclear. We examined the association of perceived social support in 30-day readmission or death in older adults admitted to a safety-net hospital. This is an observational cohort study derived from the Support From Hospital to Home for Elders (SHHE) trial. Participants were community-dwelling English, Spanish and Chinese speaking older adults admitted to medicine wards at an urban safety-net hospital in San Francisco. We assessed perceived social support using the Multidimensional Scale of Perceived Social Support (MSPSS). We defined high social support as the highest quartile of MSPSS. We ascertained 30-day readmission and mortality based on a combination of participant self-report, hospital and death records. We used multiple/multivariable logistic regression to adjust for patient demographics, health status, and health behaviors. We tested for whether race/ethnicity modified the effect high social support had on 30-day readmission or death by including a race-social support interaction term. Participants (n = 674) had mean age of 66.2 (SD 9.0), with 18.8% White, 24.8% Black, 31.9% Asian, and 19.3% Latino. The 30-day readmission or death rate was 15.0%. Those with high social support had half the odds of readmission or death than those with low social support (OR = 0.47, 95% CI 0.26-0.88). Interaction analyses revealed race modified this association; higher social support was protective against readmission or death among minorities (AOR = 0.35, 95% CI 0.16-0.76) but increased likelihood of readmission or death among Whites (AOR = 3.7, 95% CI 1.07-12.9). In older safety-net patients nearing discharge, high perceived social support may protect against 30-day readmission or death among minorities. Assessing patients' social support may aid targeting of transitional care resources and intervention design. How perceived social support functions across racial/ethnic groups in health outcomes warrants further study. NIH trials registry number ClinicalTrials.gov: NCT01221532 .


Zika virus infection induces endoplasmic reticulum stress and apoptosis in placental trophoblasts.
Zika virus (ZIKV) infection to a pregnant woman can be vertically transmitted to the fetus via the placenta leading to Congenital Zika syndrome. This is characterized by microcephaly, retinal defects, and intrauterine growth retardation. ZIKV induces placental trophoblast apoptosis leading to severe abnormalities in the growth and development of the fetus. However, the molecular mechanism behind ZIKV-induced apoptosis in placental trophoblasts remains unclear. We hypothesize that ZIKV infection induces endoplasmic reticulum (ER) stress in the trophoblasts, and sustained ER stress results in apoptosis. HTR-8 (HTR-8/SVneo), a human normal immortalized trophoblast cell and human choriocarcinoma-derived cell lines (JEG-3 and JAR) were infected with ZIKV. Biochemical and structural markers of apoptosis like caspase 3/7 activity and percent apoptotic nuclear morphological changes, respectively were assessed. ZIKV infection in placental trophoblasts showed an increase in the levels of CHOP mRNA and protein expression, which is an inducer of apoptosis. Next, we also observed increased levels of ER stress markers such as phosphorylated forms of inositol-requiring transmembrane kinase/endoribonuclease 1α (P-IRE1α), and its downstream target, the spliced form of XBP1 mRNA, phosphorylated eukaryotic initiation factor 2α (P-eIF2α), and activation of cJun N-terminal Kinase (JNK) and p38 mitogen activated protein kinase (MAPK) after 16-24 h of ZIKV infection in trophoblasts. Inhibition of JNK or pan-caspases using small molecule inhibitors significantly prevented ZIKV-induced apoptosis in trophoblasts. Further, JNK inhibition also reduced XBP1 mRNA splicing and viral E protein staining in ZIKV infected cells. In conclusion, the mechanism of ZIKV-induced placental trophoblast apoptosis involves the activation of ER stress and JNK activation, and the inhibition of JNK dramatically prevents ZIKV-induced trophoblast apoptosis.


Cloning and expression analysis of a wood-associated xylosidase gene (PtaBXL1) in poplar tension wood.
In stems of woody angiosperms responding to mechanical stress, imposed for instance by tilting the stem or formation of a branch, tension wood (TW) forms above the affected part, while anatomically distinct opposite wood (OW) forms below it. In poplar TW the S3 layer of the secondary walls is substituted by a "gelatinous layer" that is almost entirely composed of cellulose and has much lower hemicellulose contents than unstressed wood. However, changes in xylan contents (the predominant hemicelluloses), their interactions with other wall components and the mechanisms involved in TW formation have been little studied. Therefore, in the study reported here we determined the structure and distribution of xylans, cloned the genes encoding the xylan remodeling enzymes beta-xylosidases (PtaBXLi), and examined their expression patterns during tension wood, normal wood and opposite wood xylogenesis in poplar. We confirm that poplar wood xylans are substituted solely by 4-O-methylglucuronic acid in both TW and OW. However, although glucuronoxylans are strongly represented in both primary and secondary layers of OW, no 4-O-methylGlcA xylan was found in G-layers of TW. Four full-length BXL cDNAs encoding putative beta-xylosidases were cloned. One, PtaBXL1, for which xylosidase activity was confirmed by heterologous expression in Escherichia coli, exhibited a wood-specific expression pattern in TW. In conclusion, xylan as PtaBXL1, encoding beta4-xylosidase activity, are down-regulated in TW.


Fine mapping of loci linked to autoimmune thyroid disease identifies novel susceptibility genes.
Genetic factors play a major role in the etiology of autoimmune thyroid disease (AITD) including Graves' disease (GD) and Hashimoto's thyroiditis (HT). We have previously identified three loci on chromosomes 10q, 12q, and 14q that showed strong linkage with AITD, HT, and GD, respectively. The objective of the study was to identify the AITD susceptibility genes at the 10q, 12q, and 14q loci. Three hundred forty North American Caucasian AITD patients and 183 healthy controls were studied. The 10q, 12q, and 14q loci were fine mapped by genotyping densely spaced single-nucleotide polymorphisms (SNPs) using the Illumina GoldenGate genotyping platform. Case control association analyses were performed using the UNPHASED computer package. Associated SNPs were reanalyzed in a replication set consisting of 238 AITD patients and 276 controls. Fine mapping of the AITD locus, 10q, showed replicated association of the AITD phenotype (both GD and HT) with SNP rs6479778. This SNP was located within the ARID5B gene recently reported to be associated with rheumatoid arthritis and GD in Japanese. Fine mapping of the GD locus, 14q, revealed replicated association of the GD phenotype with two markers, rs12147587 and rs2284720, located within the NRXN3 and TSHR genes, respectively. Fine mapping of three linked loci identified novel susceptibility genes for AITD. The discoveries of new AITD susceptibility genes will engender a new understanding of AITD etiology.


Muscle biopsies from the supraspinatus in retracted rotator cuff tears respond normally to passive mechanical testing: a pilot study.
The aim of the present study was to assess the function of the isolated muscle component in retracted rotator cuff tears. Muscle biopsies were harvested from the supraspinatus and the ipsilateral deltoid in seven patients undergoing surgery for a large, retracted rotator cuff tear. Single fibres and fibre bundles were subjected to passive stretching in vitro with subsequent recordings of tension and sarcomere lengths using the laser diffraction technique. Stress-strain curves were plotted, and the elastic modulus was calculated for all preparations. Morphology was evaluated with regard to collagen fraction, ratio between fast and slow fibres, fibre size and fibre size variability using standard staining techniques. Intra-individual comparisons of the stress-strain curves showed a high degree of conformity in terms of both shape and tangent values, and there were no statistically significant differences in the elastic modulus for single fibres and bundles in the deltoid and supraspinatus muscles, respectively, supported by the analysis of the observed confidence interval of the differences between the paired values of the elastic modulus. There were no differences in collagen content, fibre size and ratio between fast and slow fibres in the deltoid and supraspinatus muscles, respectively. We conclude that muscle biopsies from the supraspinatus in retracted rotator cuff tears respond normally to mechanical testing in vitro.


Bacteriophage lysin mediates the binding of streptococcus mitis to human platelets through interaction with fibrinogen.
The binding of bacteria to human platelets is a likely central mechanism in the pathogenesis of infective endocarditis. We have previously found that platelet binding by Streptococcus mitis SF100 is mediated by surface components encoded by a lysogenic bacteriophage, SM1. We now demonstrate that SM1-encoded lysin contributes to platelet binding via its direct interaction with fibrinogen. Far Western blotting of platelets revealed that fibrinogen was the major membrane-associated protein bound by lysin. Analysis of lysin binding with purified fibrinogen in vitro confirmed that these proteins could bind directly, and that this interaction was both saturable and inhibitable. Lysin bound both the Aalpha and Bbeta chains of fibrinogen, but not the gamma subunit. Binding of lysin to the Bbeta chain was further localized to a region within the fibrinogen D fragment. Disruption of the SF100 lysin gene resulted in an 83+/-3.1% reduction (mean +/- SD) in binding to immobilized fibrinogen by this mutant strain (PS1006). Preincubation of this isogenic mutant with purified lysin restored fibrinogen binding to wild type levels. When tested in a co-infection model of endocarditis, loss of lysin expression resulted in a significant reduction in virulence, as measured by achievable bacterial densities (CFU/g) within vegetations, kidneys, and spleens. These results indicate that bacteriophage-encoded lysin is a multifunctional protein, representing a new class of fibrinogen-binding proteins. Lysin appears to be cell wall-associated through its interaction with choline. Once on the bacterial surface, lysin can bind fibrinogen directly, which appears to be an important interaction for the pathogenesis of endocarditis.


An abnormal methylation ratio induces hypomethylation in vitro in the brain of pig and man, but not in rat.
1. The ratio of the methyl donor, S-adenosylmethionine, to the co-product, S-adenosylhomocysteine (the methylation ratio) is known to control the activity of methyltransferases in tissues. Inactivation of the vitamin B12-dependent enzyme, methionine synthase, reduces the methylation ratio in rats and pigs in vivo. 2. We have determined the effect that such alterations have on neural protein 'O' and 'N' methyltransferases using an in vitro assay in rats, pigs and humans in the presence of the normal methylation ratio and the abnormal methylation ratios found experimentally in vivo in rats and pigs. 3. The methylation ratio found in the neural tissues of vitamin B12-inactivated pigs significantly inhibits the protein methyltransferases of pigs and humans. 4. By contrast, the altered methylation ratio found in vitamin B12-inactivated rats only marginally inhibits the equivalent rat methyltransferases. 5. This is consistent with the induction of a myelopathy by such treatment in pigs and humans, but not in the rat. 6. Dietary supplements of methionine given to vitamin B12-inactivated pigs have been shown to prevent the myelopathy in vivo by both elevating the neural S-adenosylmethionine level and resetting the methylation ratio. We find in our in vitro assay that these events reinstate the methyltransferase activity to near normal levels, thus explaining its protective effect in vivo.


Rapid expression of vaccine proteins for B-cell lymphoma in a cell-free system.
The idiotype (Id)-granulocyte-macrophage colony-stimulating factor (GM-CSF) fusion proteins are potential vaccines for immunotherapy of B-cell lymphoma. In this study, four vaccine candidates were constructed by fusing murine GM-CSF to the amino- or carboxy-terminus of the 38C13 murine B-lymphocyte Id scFv with two different arrangements of the variable regions of the heavy chain and light chain (VL-VH and VH-VL). scFv (VH-VL) and GM-CSF/scFv fusion proteins were expressed in an Escherichia coli cell-free protein synthesis system. In order to promote disulfide bond formation during cell-free expression, cell extract was pretreated with iodoacetamide (IAM), and a sulfhydryl redox buffer composed of oxidized and reduced glutathione was added. The E. coli periplasmic disulfide isomerase, DsbC, was also added to rearrange incorrectly formed disulfide linkages. The 38C13 B-lymphocyte Id scFv was expressed with 30% of its soluble yield in active form (43 microg/ml) when tested with an anti-idiotypic mAb, S1C5, as the capture antibody in radioimmunoassay. It was found that the amino-terminal GM-CSF fusion proteins, GM-VL-VH and GM-VH-VL, showed much higher activity than the carboxy-terminal GM-CSF fusion proteins, VL-VH-GM and VH-VL-GM, in stimulating the cell proliferation of a GM-CSF-dependent cell line, NFS-60. Between the two amino-terminal GM-CSF fusion proteins, GM-VL-VH showed a higher total and soluble yield than GM-VH-VL.


A Swine Model of Selective Geographic Atrophy of Outer Retinal Layers Mimicking Atrophic AMD: A Phase I Escalating Dose of Subretinal Sodium Iodate.
To establish the dose of subretinal sodium iodate (NaIO3) in order to create a toxin-induced large animal model of selective circumscribed atrophy of outer retinal layers, the retinal pigment epithelium (RPE), and photoreceptors, by spectral-domain optical coherence tomography (SD-OCT) and immunocytochemistry. Fifteen male and female healthy Yorkshire pigs received unilateral subretinal escalating doses of NaIO3 under general anesthesia. In all the animals, volumes of 0.1 to 0.2 mL NaIO3 were injected into the subretinal space of the area centralis through a 23/38-gauge subretinal cannula. Control SD-OCTs were performed 1 and 2 months after the surgery, at which time pigs were euthanized and eyes enucleated. Globes were routinely processed for histologic and immunohistochemical evaluation. Spectral-domain OCT and immunohistochemistry revealed circumscribed and well-demarcated funduscopic lesions, limited to the outer retinal layers in pigs treated with 0.01 mg/mL subretinal sodium iodate. The swine model of a controlled area of circumscribed retinal damage, with well-delimited borders, and selectively of the outer layers of the retina presented herein shows several clinical and histologic features of geographic atrophy in AMD. Therefore, it may represent a valuable tool in the investigation of new emerging regenerative therapies that aim to restore visual function, such as stem cell transplantation or optogenetics.


Articular cartilage degeneration after frozen meniscus and Achilles tendon allograft transplantation: experimental study in sheep.
The purpose of this study was to analyze cartilage degeneration in knees after total medial meniscectomy, transplantation of fresh-frozen meniscus allograft, and Achilles tendon allograft. Experimental study. We have studied the articular cartilage in the medial compartment of the left knees in 32 sheep aged 5 to 6 months, with 8 animals in each group. The study was performed after meniscectomy (group I), transplantation of fresh-frozen meniscus allograft (group II), use of fresh-frozen Achilles tendon allograft (group III), and in a control group (group IV). For the histologic study, all samples were stained with Masson's trichrome and Safranine-O. Mankin's score was applied to grade the histologic damage to the articular cartilage. The group with the greatest number of degenerative changes was group III, followed by groups I and II. The percentage of thickness of cartilage detected by Safranine-O stain was found to be significantly different in both tibia and femur between the control group and the other 3 groups, but not among groups I, II, and III. The immunoreactivity of the articular surfaces in tibia and femur showed notable differences in all the groups. Collagen X was present in the degenerative hypertrophic chondrocytes in the damaged articular surfaces. Meniscal replacement with meniscal and Achilles tendon allografts provides partial protection against articular damage after a meniscectomy.


Internet use and health: Connecting secondary data through spatial microsimulation.
Internet use may affect health and health service use, and is seen as a potential lever for empowering patients, levelling inequalities and managing costs in the health system. However, supporting evidence is scant, partially due to a lack of data to investigate the relationship on a larger scale. This paper presents an approach for connecting existing datasets to generate new insights. Spatial microsimulation offers a way to combine a random sample survey on Internet use with aggregate census data and other routine data from the health system based on small geographic areas to examine the relationship between Internet use, perceived health and health service use. While health research has primarily used spatial microsimulation to estimate the geographic distribution of a certain phenomenon, this research highlights this simulation technique as a way to link datasets for joint analysis, with location as the connecting element. Internet use is associated with higher perceived health and lower health service use independently of whether Internet use was conceptualised in terms of access, support or usage, and controlling for sociodemographic covariates. Internal validation confirms that differences between actual and simulated data are small; external validation shows that the simulated dataset is a good reflection of the real world. Spatial microsimulation helps to generate new insights through linking secondary data in a privacy-preserving and cost-effective way. This allows for better understanding the relationship between Internet use and health, enabling theoretical insights and practical implications for policy with insights down to the local level.


Population based ascertainment of twins and their siblings, born in Western Australia 1980 to 1992, through the construction and validation of a maternally linked database of siblings.
This paper describes the creation of a unique maternal identifier for use in the investigation of perinatal, postneonatal and child outcomes in relation to maternal characteristics. All Midwives' records of Western Australian (WA) births were routinely linked to registrations of births and deaths for infants born from 1980 to 1992 inclusive, then linked to WA hospital discharge data and to registries of birth defects and cerebral palsy to create a longitudinal health record for each infant. However, since each birth to a woman was recorded as a separate event, there was no way to identify siblings. Probabilistic record linkage, based on information about the mother, was used for this task. Logical inconsistencies within the data were used to test the validity of the linkages between birth records attributed to each mother. Information about the mother from other epidemiological studies and data abstracted from hospital case notes was also used to validate sibships. Linkage of the records of 310,255 births in WA during that period resulted in the formation of 181,133 sibships of one or more children. Pooling the results of all of the validation methods gave an error of 0.9%. Linkage identified 3678 sibships containing multiple births, and 305 sets of maternal twins. Ascertainment of twins and their siblings for an ongoing twin register, the WA Twin Child Health (WATCH) study, was a natural consequence of this process.


[Updated inventory of mosquitoes (Dipbra: Culkidae) from the French islets of Europa, Juan-de-Nova and Grande-Glorieuse (Mozambique channel, Indian Ocean)].
The islets of Europa, Juan-de-Nova and Grande-Glorieuse are French territories isolated in the Mozambique Channel (Indian Ocean) which have remained relatively preserved from anthropization all along their history These three islets have been classified entire nature reserves from 1975 and are today inhabited only by a permanent military detachment of about fifteen men even if they occasionally greet technical and scientific staff. Sanitary and environmental issues brought about assessment of the present culicid fauna. The authors propose a synthesis of the culicid knowledge from the islets and make an inventory of new species. The role played by humans in importation of culicids is discussed as well as sanitary consequences of their adaptation to environment


Long-term population dynamics of phototrophic sulfur bacteria in the chemocline of Lake Cadagno, Switzerland.
Population analyses in water samples obtained from the chemocline of crenogenic, meromictic Lake Cadagno, Switzerland, in October for the years 1994 to 2003 were studied using in situ hybridization with specific probes. During this 10-year period, large shifts in abundance between purple and green sulfur bacteria and among different populations were obtained. Purple sulfur bacteria were the numerically most prominent phototrophic sulfur bacteria in samples obtained from 1994 to 2001, when they represented between 70 and 95% of the phototrophic sulfur bacteria. All populations of purple sulfur bacteria showed large fluctuations in time with populations belonging to the genus Lamprocystis being numerically much more important than those of the genera Chromatium and Thiocystis. Green sulfur bacteria were initially represented by Chlorobium phaeobacteroides but were replaced by Chlorobium clathratiforme by the end of the study. C. clathratiforme was the only green sulfur bacterium detected during the last 2 years of the analysis, when a shift in dominance from purple sulfur bacteria to green sulfur bacteria was observed in the chemocline. At this time, numbers of purple sulfur bacteria had decreased and those of green sulfur bacteria increased by about 1 order of magnitude and C. clathratiforme represented about 95% of the phototrophic sulfur bacteria. This major change in community structure in the chemocline was accompanied by changes in profiles of turbidity and photosynthetically available radiation, as well as for sulfide concentrations and light intensity. Overall, these findings suggest that a disruption of the chemocline in 2000 may have altered environmental niches and populations in subsequent years.


Mammalian brain morphogenesis and midline axon guidance require heparan sulfate.
Heparan sulfate (HS) is required for morphogen signaling during Drosophila pattern formation, but little is known about its physiological importance in mammalian development. To define the developmental role of HS in mammalian species, we conditionally disrupted the HS-polymerizing enzyme EXT1 in the embryonic mouse brain. The EXT1-null brain exhibited patterning defects that are composites of those caused by mutations of multiple HS-binding morphogens. Furthermore, the EXT1-null brain displayed severe guidance errors in major commissural tracts, revealing a pivotal role of HS in midline axon guidance. These findings demonstrate that HS is essential for mammalian brain development.


Association between Iron Deficiency Anemia and Febrile Convulsion in 3- to 60-Month-Old Children: A Systematic Review and Meta-Analysis.
Controversy exists regarding the association between Iron Deficiency Anemia (IDA), iron status, and Febrile Convulsion (FC) during childhood. In this article, a systematic review and meta-analysis is conducted in order to determine possible association and the degree of association between these statuses and FC. To identify all studies related to IDA and FC, various references such as MEDLINE (PubMed), Embase (OVID), Web of sciences (Thomson Reuters) and Google scholar were searched (up until 15 January 2013). Heterogeneity was assessed using the Q statistic, Tau(2), and I(2). Additionally, subgroup analyses were performed. The outcome of primary interest was the overall Odds Ratio (OR) of FC for IDA and standard mean differences (SMD) of ferritin level. In total, 21 articles were considered to assess the association between IDA and FC. Anemia was more prevalent among the FC patients compared with the controls and the overall OR was 1.52 (95% CI=1.03 to 2.25). In addition, the pooled OR for 17 studies performed in the populations with low and moderate prevalence of anemia was 2.04 (95% CI=1.46 to 2.85). Furthermore, 12 studies assessed the association between the ferritin level and FC. The overall SMD was -0.02 with a 95% CI of -0.09 to 0.06. Besides, the pooled SMD of ferritin was -0.57 (95% CI=-0.7 to -0.46) in 6 studies reporting no difference between the FC and the control group with respect to temperature. IDA was associated with a moderate increased risk of FC in children, particularly in the areas with low and moderate prevalence of anemia.


Acute cardiovascular response to resistance training during cardiac rehabilitation: effect of repetition speed and rest periods.
Resistance training has been introduced into rehabilitation to improve the efficiency of the 1980s traditional training. Among the modalities, the choice of recovery period length or repetition speed is hardly explained in term of functional benefit but not in terms of cardiovascular (CV) response. To our knowledge, no investigation has been made on the acute CV effect of repetition speed and rest periods between sets of such training during rehabilitation. Our population included 17 male coronary patients. The experiment was performed on a leg extension device. A task force monitor noninvasive measurement system was used for continuous monitoring of the heart rate, systolic blood pressure and cardiac output. To evaluate the impact of the speed of contraction, individuals performed randomly, 3 x 10 repetitions (75% resistance maximum) at slow, moderate or fast pace. To evaluate the effect of the recovery period, individuals performed randomly, 3 x 10 repetitions separated by 30, 60, 90 or 120 s. We observed a progressive drift of heart rate, systolic blood pressure and cardiac output between each rest period and sets for all the modalities. These drifts were more pronounced when the rhythm of contraction was slow or when the recovery period was short (30 or 60 s). This work confirms the results of an earlier study showing that the main factor affecting the CV response is the length of the set. The 'ideal modality' should be three sets of 10 repetitions, at 75% resistance maximum, fast executed, with a 90 s recovery period between successive sets.


Structure and dynamics of interfacial water in an Lalpha phase lipid bilayer from molecular dynamics simulations.
Based on molecular dynamics simulations, an analysis of structure and dynamics is performed on interfacial water at a liquid crystalline dipalmitoylphosphatidycholine/water system. Water properties relevant for understanding NMR relaxation are emphasized. The first and second rank orientational order parameters of the water O-H bonds were calculated, where the second rank order parameter is in agreement with experimental determined quadrupolar splittings. Also, two different interfacial water regions (bound water regions) are revealed with respect to different signs of the second rank order parameter. The water reorientation correlation function reveals a mixture of fast and slow decaying parts. The fast (ps) part of the correlation function is due to local anisotropic water reorientation whereas the much slower part is due to more complicated processes including lateral diffusion along the interface and chemical exchange between free and bound water molecules. The 100-ns-long molecular dynamics simulation at constant pressure (1 atm) and at a temperature of 50 degrees C of 64 lipid molecules and 64 x 23 water molecules lack a slow water reorientation correlation component in the ns time scale. The (2)H(2)O powder spectrum of the dipalmitoylphosphatidycholine/water system is narrow and consequently, the NMR relaxation time T(2) is too short compared to experimental results.


Flow cytometric chromosome sorting in plants: the next generation.
Genome analysis in many plant species is hampered by large genome size and by sequence redundancy due to the presence of repetitive DNA and polyploidy. One solution is to reduce the sample complexity by dissecting the genomes to single chromosomes. This can be realized by flow cytometric sorting, which enables purification of chromosomes in large numbers. Coupling the chromosome sorting technology with next generation sequencing provides a targeted and cost effective way to tackle complex genomes. The methods outlined in this article describe a procedure for preparation of chromosomal DNA suitable for next-generation sequencing.


Molecular epidemiology of acute hepatitis B in the Netherlands in 2004: nationwide survey.
To gain insight into hepatitis B virus (HBV) transmission in the Netherlands, epidemiological data and sera were collected from reported cases of acute HBV infections in the Netherlands in 2004. Cases were classified according to mode of transmission. A fragment of the S-gene of HBV (648 bp) was amplified, sequenced, and subjected to phylogenetic analysis. Of the 291 acute HBV cases reported in 2004, 158 (54%) were available for genotyping. Phylogenetic analysis identified 6 genotypes: A (64%), B (3%), C (3%), D (21%), E (5%) and F (5%). Of HBV infected men having sex with men, 86% were infected with genotype A, accounting for 43% of all patients infected with this genotype. There were only three reported cases of injecting drug use of which one was available for sequencing (genotype A). Unlike the genotype A cluster, sequences within the genotype B-E clusters were heterogenic. Within genotype F, several isolates had identical sequences, but patients could not be epidemiologically linked. Sexual transmission, particularly by men having sex with men was the most important transmission route for HBV. Injecting drug use plays a minor role. Genotype A is predominant in the Netherlands, especially among men having sex with men. In addition to imported strains, there seems to be a pool of related but non-identical strains circulating among chronic carriers in the migrant population, from which occasionally new patients are infected, primarily by heterosexual transmission.


In vivo 2H2O administration reveals impaired triglyceride storage in adipose tissue of insulin-resistant humans.
Indirect evidence suggests that impaired triglyceride storage in the subcutaneous fat depot contributes to the development of insulin resistance via lipotoxicity. We directly tested this hypothesis by measuring, in vivo, TG synthesis, de novo lipogenesis (DNL), adipocyte proliferation, and insulin suppression of lipolysis in subcutaneous adipose tissue of BMI-matched individuals classified as insulin resistant (IR) or insulin sensitive (IS). Nondiabetic, moderately obese subjects with BMI 25-35 kg/m(2), classified as IR or IS by the modified insulin suppression test, consumed deuterated water ((2)H2O) for 4 weeks. Deuterium incorporation into glycerol, palmitate, and DNA indicated TG synthesis, DNL, and adipocyte proliferation, respectively. Net TG synthesis and DNL in adipose cells were significantly lower in IR as compared with IS subjects, whereas adipocyte proliferation did not differ significantly. Plasma FFAs measured during an insulin suppression test were 2.5-fold higher in IR subjects, indicating resistance to insulin suppression of lipolysis. Adipose TG synthesis correlated directly with DNL but not with proliferation. These results provide direct in vivo evidence for impaired TG storage in subcutaneous adipose tissue of IR as compared with IS. Relative inability to store TG in the subcutaneous depot may represent a mechanism contributing to the development of insulin resistance in the setting of obesity.


Results of a double-blind, placebo-controlled study to assess the safety of intramuscular injection of hepatocyte growth factor plasmid to improve limb perfusion in patients with critical limb ischemia.
The Study to Assess the Safety of Intramuscular Injection of Hepatocyte Growth Factor Plasmid to Improve Limb Perfusion in Patients With Critical Limb Ischemia (HGF-STAT trial) determined the effect of hepatocyte growth factor (HGF) plasmid on safety and limb tissue perfusion as measured by transcutaneous oxygen tension (TcPo(2)) in patients with critical limb ischemia (CLI). Randomized patients with rest pain or ischemic ulcers and TcPo(2) <40 mm Hg and/or toe pressure <50 mm Hg received placebo or HGF-plasmid intramuscular injection as follows: 0.4 mg at days 0, 14, and 28 (low dose); 4.0 mg at days 0 and 28 (middle dose); or 4.0 mg at days 0, 14, and 28 (high dose). Patients were evaluated for safety, changes in TcPo(2) and ankle and toe pressure, amputation, and wound healing. Ninety-three of 104 treated patients were evaluated for safety (mean age 70 years, 63% male, 53% diabetic, 64% with tissue loss, mean ankle-brachial index 0.41, and mean toe pressure 26 mm Hg). Adverse events occurred in 86% of the patients, most of which were related to CLI or comorbid conditions and were not different between groups. TcPo(2) (mean+/-SE) increased at 6 months in the high-dose group (24.0+/-4.2 mm Hg, 95% CI 15.5 to 32.4 mm Hg) compared with the placebo (9.4+/-4.2 mm Hg, 95% CI 0.9 to 17.8), low-dose (11.1+/-3.7 mm Hg, CI 3.7 to 18.7 mm Hg), and middle-dose (7.3+/-4.8 mm Hg, CI -2.2 to 17.0 mm Hg) groups (ANCOVA P=0.0015). There was no difference between groups in secondary end points, including ankle-brachial index, toe-brachial index, pain relief, wound healing, or major amputation. Intramuscular injection of HGF plasmid was safe and well tolerated. Larger studies to determine whether HGF plasmid can improve wound healing and limb salvage in patients with CLI are warranted.


Selection by Anion-Exchange Chromatography of Exopolysaccharide Mutants of the Cyanobacterium Synechocystis Strain PCC 6803.
The degree of retention of whole cells of Synechocystis strain PCC 6803 on DEAE-cellulose columns was shown to depend on their content of exopolysaccharides, which are at least in part responsible for the external negative charge of the cells. This feature was used for the isolation of mutants modified in the apparent viscosity caused by these macromolecular constituents. When a wild-type suspension was loaded onto a DE52 column, the cells eluting in the two extreme fractions of a 0 to 5 M NaCl step gradient represented 10 to 10 of the total eluted population. The accuracy of the procedure was established through the analysis of four clones: Suc(0)32 and Suc(0)65 (0 M) and Suc(5)64A and Suc(5)61 (5 M). The decreased viscosity of the exopolymers of the two 0 M clones, which appeared identical, could be related to the production of molecules less charged in uronic acids and more readily liberated from the cells. The two 5 M clones exhibited a lower sedimentation velocity, correlating with either a 60% increase in uronic acid and a doubling of the specific viscosity of the exopolysaccharides [clone Suc(5)64A] or a doubling of the per-cell production of polymers otherwise identical to those from wild-type cells [clone Suc(5)61].


Endovascular grafts and other catheter-directed techniques in the management of ruptured abdominal aortic aneurysms.
Abdominal aortoiliac aneurysms that are ruptured and treated with open surgical repair have high morbidity and mortality rates. We have employed endovascular approaches to treat this entity since 1994. Patients with presumed ruptured aortoiliac aneurysms were treated with restricted fluid resuscitation (hypotensive hemostasis), transport to the operating room, placement under local anesthesia of a brachial or femoral guidewire into the supraceliac aorta and arteriography. If aortoiliac anatomy was suitable, an endovascular graft repair was performed. If the anatomy was unfavorable, the aneurysm was repaired in a standard open fashion. Only if circulatory collapse occurred was a supraceliac balloon placed and inflated using the previously positioned guidewire. Of 36 patients so managed, 30 underwent endovascular graft repair and six required open repair. Four patients died within 30 days (operative mortality = 11%). Only 10 patients required supraceliac balloon control. Endovascular grafts, when combined with hypotensive hemostasis and other endovascular techniques, including proximal balloon control, may improve treatment outcomes with ruptured abdominal aortoiliac aneurysms. These techniques should become widely used for the treatment of ruptured aneurysms.


Performance of detecting IgM antibodies against enterovirus 71 for early diagnosis.
Enterovirus 71 (EV71) infection is more likely to induce severe complications and mortality than other enteroviruses. Methods for detection of IgM antibody against EV71 had been established for years, however, the performance of the methods in the very early diagnosis of EV71 infection had not been fully evaluated, which is especially meaningful because of the short incubation period of EV71 infection. In this report, the performance of an IgM anti-EV71 assay was evaluated using acute sera collected from 165 EV71 infected patients, 165 patients infected with other enteroviruses, and more than 2,000 sera from healthy children or children with other infected diseases. The results showed a 90% sensitivity in 20 patients who were in their first illness day, and similar sensitivity remained till 4 days after onset. After then the sensitivity increased to 95% to 100% for more than one month. The specificity of the assay in non-HFMD children is 99.1% (95% CI: 98.6-99.4), similar as the 99.9% specificity in healthy adults. The cross-reaction rate in patients infected with other non-EV71 enteroviruses was 11.4%. In conclusion, the data here presented show that the detection of IgM anti-EV71 by ELISA affords a reliable, convenient, and prompt diagnosis of EV71 infection.


The impact of variation in the number of CD8(+) T-cell precursors on the outcome of virus infection.
We investigated the role of varying the initial number of naive antiviral CTL precursors on the dynamics of LCMV-DOCILE infection. C57BL/6 mice, exhibiting LCMV-specific CTLp frequencies of about 50, are protected against virus persistence over a range of infectious doses up to 10(4) pfu. With 10-fold higher doses, a 100-fold increase in CTLp is required to restore virus control. With doses above 10(6) pfu, elevation of the initial CTLp number leads only to lethal immunopathology. Similarly, a 1000-fold increase in the number of initial naïve CTLp enhances the overall kinetics of virus elimination, but cannot limit early virus spread within the first 48 h after low-dose infection (500 pfu). Increases in initial naïve virus-specific CTLp numbers are of limited benefit in antiviral control. In addition to the number of virus-specific T cells, the time period needed to reach cytolytic effector function is a limiting parameter.


Design-Based Comparison of Spine Surgery Simulators: Optimizing Educational Features of Surgical Simulators.
Simulation-based education has made its entry into surgical residency training, particularly as an adjunct to hands-on clinical experience. However, one of the ongoing challenges to wide adoption is the capacity of simulators to incorporate educational features required for effective learning. The aim of this study was to identify strengths and limitations of spine simulators to characterize design elements that are essential in enhancing resident education. We performed a mixed qualitative and quantitative cohort study with a focused survey and interviews of stakeholders in spine surgery pertaining to their experiences on 3 spine simulators. Ten participants were recruited spanning all levels of training and expertise until qualitative analysis reached saturation of themes. Participants were asked to perform lumbar pedicle screw insertion on 3 simulators. Afterward, a 10-item survey was administrated and a focused interview was conducted to explore topics pertaining to the design features of the simulators. Overall impressions of the simulators were positive with regards to their educational benefit, but our qualitative analysis revealed differing strengths and limitations. Main design strengths of the computer-based simulators were incorporation of procedural guidance and provision of performance feedback. The synthetic model excelled in achieving more realistic haptic feedback and incorporating use of actual surgical tools. Stakeholders from trainees to experts acknowledge the growing role of simulation-based education in spine surgery. However, different simulation modalities have varying design elements that augment learning in distinct ways. Characterization of these design characteristics will allow for standardization of simulation curricula in spinal surgery, optimizing educational benefit.


Comparison of the response to endovascular reperfusion in relation to site of arterial occlusion.
We explored the relationship between the site of vascular occlusion and the response to endovascular treatment in patients with acute ischemic stroke and also considered the impact of mismatch profile. DEFUSE-2 was a prospective cohort study of patients treated with endovascular therapy. Patients with internal carotid artery (ICA) and middle cerebral artery (MCA) involvement were included in this substudy. Mismatch and reperfusion status was assessed on MRI. Favorable clinical response was defined as an improvement of at least 8 points on the NIH Stroke Scale. Reperfusion rates were comparable in both groups (61% for ICA and 59% for MCA). In the setting of reperfusion, percentages of favorable clinical response were similar between patients with stroke due to ICA (65%) and MCA (63%) occlusions. When reperfusion was not achieved, favorable outcomes were less frequent with obstructions of the ICA (9%) than the MCA (52%). Among target mismatch patients, the adjusted odds ratio for favorable clinical response associated with reperfusion was 39.7 (95% confidence interval 1.4-1,132.8) for ICA occlusions vs 5.1 (95% confidence interval 1.4-19.3) for MCA occlusions. Endovascular reperfusion is associated with favorable clinical response regardless of the location of the arterial occlusion. This association is strongest for target mismatch patients with ICA occlusions. Target mismatch patients with either ICA or MCA occlusions appear to be good candidates for endovascular reperfusion therapy.


Semen Quality and Sperm DNA Integrity in Patients With Severe Active Inflammatory Bowel Disease and Effects of Tumour Necrosis Factor-alpha Inhibitors.
The impact of severe inflammation on semen quality, including sperm DNA integrity, in men with inflammatory bowel disease [IBD] is unknown, as are the potential effects of anti-tumour necrosis factor-alpha [TNF-alpha] therapy. We investigated the influence of severe active IBD and anti-TNF-alpha treatment on semen quality. We prospectively included 20 patients admitted with severe active IBD. Further, 19 patients who initiated and 17 who stopped anti-TNF-alpha therapy were included. Semen samples were obtained during active disease, and on/off treatment. For paired comparisons, samples were collected not less than 3 months after achieving remission, after treatment initiation, or after treatment cessation. Sperm DNA Fragmentation Index [DFI], concentration, morphology, and motility were evaluated. Sex hormones and seminal plasma anti-TNF-alpha drug levels were measured. In patients with severe disease, progressive sperm motility was impaired and increased significantly [from 28.4% to 37.4%, p = 0.045] during remission. There was no difference in DFI [12.5% versus 12.0%, p = 0.55], concentration [55.0 mill/ml versus 70.0 mill/ml, p = 0.39], or normal morphology [4.7% versus 5.1%, p = 0.51] in these patients. During active disease, testosterone was decreased, and normalised after obtaining remission. Patients who started anti-TNF-alpha therapy had a statistically significant, but clinically irrelevant, reduction in DFI after treatment initiation [12.8% versus 10.0%, p = 0.02]. All other semen parameters were unaffected by therapy. Anti-TNF-alpha drugs were excreted in negligible amounts in semen. Severe active IBD reduces progressive sperm motility and testosterone levels, but sperm DNA integrity is unaffected by active disease. Anti-TNF-alpha therapy does not impair sperm quality.


Hematopoietic cell activation in the subventricular zone after Theiler's virus infection.
The periventricular subventricular zone (SVZ) contains stem cells and is an area of active neurogenesis and migration. Since inflammation can reduce neurogenesis, we tested whether Theiler's murine encephalomyelitis virus (TMEV) induces inflammation and reduces neurogenesis in the SVZ. We performed immmunohistochemistry for the hematopoietic cell marker CD45 throughout the central nervous system and then examined neuroblasts in the SVZ. CD45+ activation (inflammation) occurred early in the forebrain and preceded cerebellar and spinal cord inflammation. Inflammation in the brain was regionally stochastic except for the SVZ and surrounding periventricular regions where it was remarkably pronounced and consistent. In preclinical mice, SVZ neuroblasts emigrated into inflamed periventricular regions. The number of proliferating phoshpohistone3+ cells and Doublecortin+ (Dcx) SVZ neuroblasts was overall unaffected during the periods of greatest inflammation. However the number of Dcx+ and polysialylated neural cell adhesion molecule (PSA-NCAM+) SVZ neuroblasts decreased only after periventricular inflammation abated. Our results suggest that after TMEV infection, the SVZ may mount an attempt at neuronal repair via emigration, a process dampened by decreases in neuroblast numbers.


Role of features and second-order spatial relations in face discrimination, face recognition, and individual face skills: behavioral and functional magnetic resonance imaging data.
We compared the contribution of featural information and second-order spatial relations (spacing between features) in face processing. A fully factorial design has the same or different "features" (eyes, mouth, and nose) across two successive displays, whereas, orthogonally, the second-order spatial relations between those features were the same or different. The range of such changes matched the possibilities within the population of natural face images. Behaviorally, we found that judging whether two successive faces depicted the same person was dominated by features, although second-order spatial relations also contributed. This influence of spatial relations correlated, for individual subjects, with their skill at recognition of faces (as famous, or as previously exposed) in separate behavioral tests. Using the same repetition design in functional magnetic resonance imaging, we found feature-dependent effects in the lateral occipital and right fusiform regions. In addition, there were spatial relation effects in the bilateral inferior occipital gyrus and right fusiform that correlated with individual differences in (separately measured) behavioral sensitivity to those changes. The results suggest that featural and second-order spatial relation aspects of faces make distinct contributions to behavioral discrimination and recognition, with features contributing most to face discrimination and second-order spatial relational aspects correlating best with recognition skills. Distinct neural responses to these aspects were found with functional magnetic resonance imaging, particularly when individual skills were taken into account for the impact of second-order spatial relations.


Creation of a gated antibody as a conditionally functional synthetic protein.
The ability to conditionally direct antibodies is a potentially powerful application for Synthetic Biology in Medicine. Here we show that control of antibody binding through site-specific, chemical phosphorylation of a recognition domain creates a 'gated' antibody (Ab). This displays a crude Boolean logic where binding is induced in an enzyme-AND-antigen dependent manner. This 'AND-Ab' is therefore active only in the presence of two biomarker inputs: the simultaneous expression of a (cell surface) antigen and secreted enzyme to generate function in vitro, on cells and in mammalian tissue. Such gated Abs, either alone or in combination, could allow the application of logic strategies to enhance precision in biological interrogation, modulation and in therapy.


Biased Intensity Judgements of Visceral Sensations After Learning to Fear Visceral Stimuli: A Drift Diffusion Approach.
A growing body of research has identified fear of visceral sensations as a potential mechanism in the development and maintenance of visceral pain disorders. However, the extent to which such learned fear affects visceroception remains unclear. To address this question, we used a differential fear conditioning paradigm with nonpainful esophageal balloon distensions of 2 different intensities as conditioning stimuli (CSs). The experiment comprised of preacquisition, acquisition, and postacquisition phases during which participants categorized the CSs with respect to their intensity. The CS+ was always followed by a painful electrical stimulus (unconditioned stimulus) during the acquisition phase and in 60% of the trials during postacquisition. The second stimulus (CS-) was never associated with pain. Analyses of galvanic skin and startle eyeblink responses as physiological markers of successful conditioning showed increased fear responses to the CS+ compared with the CS-, but only in the group with the low-intensity stimulus as CS+. Computational modeling of response times and response accuracies revealed that differential fear learning affected perceptual decision-making about the intensities of visceral sensations such that sensations were more likely to be categorized as more intense. These results suggest that associative learning might indeed contribute to visceral hypersensitivity in functional gastrointestinal disorders. This study shows that associative fear learning biases intensity judgements of visceral sensations toward perceiving such sensations as more intense. Learning-induced alterations in visceroception might therefore contribute to the development or maintenance of visceral pain.


New therapies for optic neuropathies: development in experimental models.
Experimental models of human diseases have affected the design and direction of both basic and clinical research into understanding the pathogenesis and treatments of demyelinating disease, stroke, and hereditary disorders of the central nervous system. However, in spite of major advances in molecular research that have linked Leber Hereditary Optic Neuropathy to mutations in mitochondrial DNA, there has been relatively little focus in applying basic scientific methodologies to optic neuropathies other than glaucoma. The relative absence of detailed scientific knowledge about the basic mechanisms involved in the pathogenesis of optic nerve injury has contributed to the use of empiric therapies for neuro-ophthalmic optic neuropathies. Over the past decade major clinical trials, such as the Optic Neuritis Treatment Trial and Ischemic Optic Neuropathy Decompression Trial, have proven that currently available treatment options for demyelinating and ischemic optic neuropathies are ineffective and can even be harmful. Although the pathogenesis of visual failure in demyelinating, ischemic, and hereditary optic neuropathies appears diverse, a final common pathway for irreparable optic nerve injury may exist. This article reviews several models of experimental optic neuropathies that may aid in the development of novel treatments for neuro-ophthalmic disorders of the optic nerve during the 21st century.


A multiway analysis for identifying high integrity bovine BACs.
In large genomics projects involving many different types of analyses of bacterial artificial chromosomes (BACs), such as fingerprinting, end sequencing (BES) and full BAC sequencing there are many opportunities for the identities of BACs to become confused. However, by comparing the results from the different analyses, inconsistencies can be identified and a set of high integrity BACs preferred for future research can be defined. The location of each bovine BAC in the BAC fingerprint-based genome map and in the genome assembly were compared based on the reported BESs, and for a smaller number of BACs the full sequence. BACs with consistent positions in all three datasets, or if the full sequence was not available, for both the fingerprint map and BES-based alignments, were deemed to be correctly positioned. BACs with consistent BES-based and fingerprint-based locations, but with conflicting locations based on the fully sequenced BAC, appeared to have been misidentified during sequencing, and included a number of apparently swapped BACs. Inconsistencies between BES-based and fingerprint map positions identified thirty one plates from the CHORI-240 library that appear to have suffered substantial systematic problems during the end-sequencing of the BACs. No systematic problems were identified in the fingerprinting of the BACs. Analysis of BACs overlapping in the assembly identified a small overrepresentation of clones with substantial overlap in the library and a substantial enrichment of highly overlapping BACs on the same plate in the CHORI-240 library. More than half of these BACs appear to have been present as duplicates on the original BAC-library plates and thus should be avoided in subsequent projects. Our analysis shows that approximately 95% of the bovine CHORI-240 library clones with both a BAC fingerprint and two BESs mapping to the genome in the expected orientations (approximately 27% of all BACs) have consistent locations in the BAC fingerprint map and the genome assembly. We have developed a broadly applicable methodology for checking the integrity of BAC-based datasets even where only incomplete and partially assembled genomic sequence is available.


Leveraging partnerships among community pharmacists, pharmacies, and health departments to improve pandemic influenza response.
Response to public health emergencies requires coordination across multiple sectors and effective use of existing resources in communities. With the expanded role of community pharmacists in public health during the past decade, their participation in response to emergencies has become increasingly important. Local health departments play a lead role in local public health emergency responses, and their ability to develop and leverage partnerships has become increasingly vital given their funding and personnel shortages. This article offers insight and recommendations on how local health departments can most effectively develop and maintain relationships with community pharmacies and pharmacists that will allow for a more coordinated and resourceful public health response to emergencies, and specifically to pandemic influenza outbreaks. Additionally, state and local health departments should reach out to pharmacies in a synchronized way to incorporate them into their pandemic influenza planning and response efforts. As pharmacists continue to expand their role as part of the public health system, pharmacy staff can be active participants with public health agencies to improve community public health emergency response.


Regulatory T cells in transplantation.
T Regulatory cells (Treg) play an important role in the induction and maintenance of immunological tolerance to self and alloantigens. Recent findings in experimental transplant models have demonstrated that Treg can control acute and delayed allograft rejection. Preclinical attempts to use Treg as a cellular therapy have been successfully undertaken demonstrating the safety and feasibility of such treatment, suggesting that they have therapeutic potential.


Bacterial flagellin is a dominant antigen in Crohn disease.
Chronic intestinal inflammation, as seen in inflammatory bowel disease (IBD), results from an aberrant and poorly understood mucosal immune response to the microbiota of the gastrointestinal tract in genetically susceptible individuals. Here we used serological expression cloning to identify commensal bacterial proteins that could contribute to the pathogenesis of IBD. The dominant antigens identified were flagellins, molecules known to activate innate immunity via Toll-like receptor 5 (TLR5), and critical targets of the acquired immune system in host defense. Multiple strains of colitic mice had elevated serum anti-flagellin IgG2a responses and Th1 T cell responses to flagellin. In addition, flagellin-specific CD4(+) T cells induced severe colitis when adoptively transferred into naive SCID mice. Serum IgG to these flagellins, but not to the dissimilar Salmonella muenchen flagellin, was elevated in patients with Crohn disease, but not in patients with ulcerative colitis or in controls. These results identify flagellins as a class of immunodominant antigens that stimulate pathogenic intestinal immune reactions in genetically diverse hosts and suggest new avenues for the diagnosis and antigen-directed therapy of patients with IBD.


Safety and immunogenicity of the quadrivalent human papillomavirus vaccine in HIV-1-infected men.
Human immunodeficiency virus type 1 (HIV-1)-infected men are at increased risk for anal cancer. Human papillomavirus (HPV) vaccination may prevent anal cancer caused by vaccine types. AIDS Malignancy Consortium Protocol 052 is a single-arm, open-label, multicenter clinical trial to assess the safety and immunogenicity of the quadrivalent HPV (types 6, 11, 16, and 18) vaccine in HIV-1-infected men. Men with high-grade anal intraepithelial neoplasia or anal cancer by history or by screening cytology or histology were excluded. Men received 0.5 mL intramuscularly at entry, week 8, and week 24. The primary end points were seroconversion to vaccine types at week 28, in men who were seronegative and without anal infection with the relevant HPV type at entry, and grade 3 or higher adverse events related to vaccination. There were no grade 3 or greater adverse events attributable to vaccination among the 109 men who received at least 1 vaccine dose. Seroconversion was observed for all 4 types: type 6 (59 [98%] of 60), type 11 (67 [99%] of 68), type 16 (62 [100%] of 62), and type 18 (74 [95%] of 78). No adverse effects on CD4 counts and plasma HIV-1 RNA levels were observed. The quadrivalent HPV vaccine appears safe and highly immunogenic in HIV-1-infected men. Efficacy studies in HIV-1-infected men are warranted. Clinical trials registration. NCT 00513526.


Inactivation of feline calicivirus and adenovirus type 40 by UV radiation.
Little information regarding the effectiveness of UV radiation on the inactivation of caliciviruses and enteric adenoviruses is available. Analysis of human calicivirus resistance to disinfectants is hampered by the lack of animal or cell culture methods that can determine the viruses' infectivity. The inactivation kinetics of enteric adenovirus type 40 (AD40), coliphage MS-2, and feline calicivirus (FCV), closely related to the human caliciviruses based on nucleic acid organization and capsid architecture, were determined after exposure to low-pressure UV radiation in buffered demand-free (BDF) water at room temperature. In addition, UV disinfection experiments were also carried out in treated groundwater with FCV and AD40. AD40 was more resistant than either FCV or coliphage MS-2 in both BDF water and groundwater. The doses of UV required to achieve 99% inactivation of AD40, coliphage MS-2, and FCV in BDF water were 109, 55, and 16 mJ/cm(2), respectively. The doses of UV required to achieve 99% inactivation of AD40, coliphage MS-2, and FCV in groundwater were slightly lower than those in BDF water. FCV was inactivated by 99% by 13 mJ/cm(2) in treated groundwater. A dose of 103 mJ/cm(2) was required for 99% inactivation of AD40 in treated groundwater. The results of this study indicate that if FCV is an adequate surrogate for human caliciviruses, then their inactivation by UV radiation is similar to those of other single-stranded RNA enteric viruses, such as poliovirus. In addition, AD40 appears to be more resistant to UV disinfection than previously reported.


Improving Gabor noise.
We have recently proposed a new procedural noise function, Gabor noise, which offers a combination of properties not found in the existing noise functions. In this paper, we present three significant improvements to Gabor noise: 1) an isotropic kernel for Gabor noise, which speeds up isotropic Gabor noise with a factor of roughly two, 2) an error analysis of Gabor noise, which relates the kernel truncation radius to the relative error of the noise, and 3) spatially varying Gabor noise, which enables spatial variation of all noise parameters. These improvements make Gabor noise an even more attractive alternative for the existing noise functions.