Knowledge of tuberculosis among drug users. Relationship to return rates for tuberculosis screening at a syringe exchange.
Tuberculosis is an important health issue among drug users. We sought to evaluate active drug users' (DUs) knowledge of tuberculosis (TB) and to assess the relationship between TB knowledge and attitudes and tuberculin skin test (TST) return rates at a syringe exchange program. DUs were recruited at a syringe exchange program in New York City, were interviewed and offered TSTs, and received $15.00 upon returning for TST reading. The questionnaire evaluated knowledge of TB transmission, prevention, and treatment. From March 13, 1995 to January 31, 1996, 610 of 650 (94%) of DUs approached agreed to participate. Of these, 80% had previous TSTs within the past 2 years and 20% were known to be HIV infected. Almost all knew that TB is contagious and more than two thirds knew that TB is treatable and that TB preventive therapy existed. However, fewer than half knew that HIV-related TB could be treated, 30% thought TB could be treated without a medical doctor, and the majority (70%) thought a reactive TST implied infectivity. The rate of return for TST reading was 93%. In multivariate analysis, those who knew that HIV-related TB was curable were more likely to return for TST reading (odds ratio 2.0; 95% confidence interval 1.04 to 3.95; p = .03). The high acceptance and return rates suggest that TB services can be incorporated into syringe exchange programs. However, several important gaps in TB knowledge existed in this population at high risk of TB, which may impact on adherence and which support the need for TB education for drug users.


Effect of Zizyphus jujuba fruits on dyslipidemia in obese adolescents: a triple-masked randomized controlled clinical trial.
This study aimed to assess the effects of Ziziphus jujuba (ZJ) fruit on controlling dyslipidemia in obese adolescents. This triple-blind randomized placebo-controlled clinical trial comprised 86 obese adolescents aged 12-18 years with dyslipidemia, i.e. serum low density lipoprotein-cholesterol (LDL-C) or total cholesterol (TC) or triglycerides (TG) equal or more than the age- and gender-specific 95th percentile or high density lipoprotein- cholesterol (HDL-C) less than 5th percentile. They were randomly assigned into two groups of equal number Both groups received similar recommendations for dietary and physical activity habits. The case group received 5 grams of ZJ fruit powder three times a day for one month and controls took the same amount of a placebo powder. Fasting blood sugar, TC, LDL-C, HDL-C and TG were measured at the beginning and at the end of the trial. Data were analyzed using General linear method (multivariate) test. Overall, 70 participants (51% boys, mean age of 14 +/- 2) completed the trial. The two groups studied did not differ in terms of age, gender, weight and body mass index (BMI). After the trial, serum TC decreased significantly (19 +/- 37 mg/dl in controls vs. 170 +/- 29 mg/dl in cases, P = 0.007) reduction. The corresponding figure was also significant for LDL-C (114 +/- 38 mg/dl vs. 104 +/- 22 mg/dl, respectively, P = 0.004). The changes in BMI and other lipids were not significant. This study suggest that ZJ's fruits is generally well tolerated and may have potential favorable effects on serum lipid profile. While healthy lifestyle is the mainstay of controlling childhood obesity, this nutraceutical may be considered as a complementary treatment. Key words: Zizyphus, dyslipidemia, adolescence, obesity.


Nasogastric tube feeding in predicted severe acute pancreatitis. A systematic review of the literature to determine safety and tolerance.
Nasogastric tube feeding is safe and well tolerated in most critically ill patients. However, its safety and tolerance in the setting of severe acute pancreatitis is debatable. We aimed to review all available studies on nasogastric feeding in patients with severe acute pancreatitis to determine the safety and tolerance of this approach. A further aim was to perform a meta-analysis of the available randomized controlled trials regarding nasogastric versus nasojejunal feeding. Three electronic databases (Cochrane Central Register of Controlled Trials, EMBASE and MEDLINE) and the abstracts of major gastroenterological meetings were reviewed. Meta-analysis was performed using the random effects model. The summary estimates were reported as risk ratio (RR) with 95% confidence interval (95% CI). A total of four studies on nasogastric tube feeding in 92 patients with predicted severe acute pancreatitis were identified. Documented infected pancreatic necrosis developed in 11 patients (16.9%) and multiple organ failure in 10 (15.4%) out of 65 patients with available data. Overall, there were 15 deaths (16.3%). An exacerbation of pain after initiation of feeding occurred in 3 (4.3%) out of 69 patients with available data. Full tolerance was achieved in 73 (79.3%) patients who did not require temporary reduction, stoppage or withdrawal of nasogastric feeding. The results of nasogastric feeding as compared to nasojejunal feeding, were no worse in terms of mortality (RR=0.77; 95% CI: 0.37 to 1.62; P=0.50) or intolerance of feeding (RR=1.09; 95% CI: 0.46 to 2.59; P=0.84). Nasogastric feeding appears safe and well tolerated in patients with predicted severe acute pancreatitis. An adequately powered randomized trial on nasogastric versus nasojejunal feeding is required to support this approach as routine clinical management.


A new method for non-labeling attomolar detection of diseases based on an individual gold nanorod immunosensor.
Herein, we present the use of a single gold nanorod sensor for detection of diseases on an antibody-functionalized surface, based on antibody-antigen interaction and the localized surface plasmon resonance (LSPR) λ(max) shifts of the resonant Rayleigh light scattering spectra. By replacing the cetyltrimethylammonium bromide (CTAB), a tightly packed self-assembled monolayer of HS(CH(2))(11)(OCH(2)CH(2))(6)OCH(2)COOH(OEG(6)) has been successfully formed on the gold nanorod surface prior to the LSPR sensing, leading to the successful fabrication of individual gold nanorod immunosensors. Using prostate specific antigen (PSA) as a protein biomarker, the lowest concentration experimentally detected was as low as 111 aM, corresponding to a 2.79 nm LSPR λ(max) shift. These results indicate that the detection platform is very sensitive and outperforms detection limits of commercial tests for PSA so far. Correlatively, its detection limit can be equally compared to the assays based on DNA biobarcodes. This study shows that a gold nanorod has been used as a single nanobiosensor to detect antigens for the first time; and the detection method based on the resonant Rayleigh scattering spectrum of individual gold nanorods enables a simple, label-free detection with ultrahigh sensitivity.


Understanding the Interaction of Polyelectrolyte Architectures with Proteins and Biosystems.
The counterions neutralizing the charges on polyelectrolytes such as DNA or heparin may dissociate in water and greatly influence the interaction of such polyelectrolytes with biomolecules, particularly proteins. In this Review we give an overview of studies on the interaction of proteins with polyelectrolytes and how this knowledge can be used for medical applications. Counterion release was identified as the main driving force for the binding of proteins to polyelectrolytes: Patches of positive charge become multivalent counterions of the polyelectrolyte and lead to the release of counterions from the polyelectrolyte and a concomitant increase in entropy. This is shown from investigations on the interaction of proteins with natural and synthetic polyelectrolytes. Special emphasis is paid to sulfated dendritic polyglycerols (dPGS). The Review demonstrates that we are moving to a better understanding of charge-charge interactions in systems of biological relevance. Research along these lines will aid and promote the design of synthetic polyelectrolytes for medical applications.


Individual patient data meta-analysis of diagnostic studies: opportunities and challenges.
Individual patient data meta-analyses using the raw data from primary diagnostic accuracy studies are taking hold in systematic reviews evaluating tests. Conventional reviews and meta-analyses that summarise study-level data on test accuracy (sensitivity and specificity) have several disadvantages. The most fundamental limitation of this approach is that it estimates the rates of test result-given disease (sensitivity is probability of positive test result-given disease is present; and specificity is probability of negative test result-given disease is absent). This may be addressed by summarising predictive values, but estimating accuracy for individual tests without consideration of other tests in the test chains that make up everyday diagnostic work-ups remain a problem. To inform clinical practice it is essential that test evaluation generates information about probability of disease given test results, and that it does so in view of the preceding contribution to diagnosis of other tests, for example, symptoms and signs. A multivariable (logistic regression) framework generates disease probabilities taking into account the important factors that play a role in diagnosis. Most primary accuracy studies lack statistical power to do this, particularly because of the small absolute number of disease events per test included in the diagnostic work. Synthesis using their raw data can overcome this problem, but meta-analysts will have limited success if there are difficulties in obtaining the large majority of valid studies, without 'missing' data on the tests relevant in clinical decision-making. Successful individual patient data meta-analyses create the opportunity to calculate directly and reliably disease probabilities corresponding with realistic chains of tests, thereby making outputs of reviews of test accuracy clinically applicable.


Dietary Polyphenol Supplementation Prevents Alterations of Spatial Navigation in Middle-Aged Mice.
Spatial learning and memory deficits associated with hippocampal synaptic plasticity impairments are commonly observed during aging. Besides, the beneficial role of dietary polyphenols has been suggested as potential functional food candidates to prevent this memory decline. Indeed, polyphenols could potentiate the signaling pathways of synaptic plasticity underlying learning and memory. In this study, spatial learning deficits of middle-aged mice were first highlighted and characterized according to their navigation patterns in the Morris water maze task. An eight-week polyphenol-enriched diet, containing a polyphenol-rich extract from grape and blueberry (PEGB; from the Neurophenols Consortium) with high contents of flavonoids, stilbenes and phenolic acids, was then successful in reversing these age-induced effects. The use of spatial strategies was indeed delayed with aging whereas a polyphenol supplementation could promote the occurrence of spatial strategies. These behavioral results were associated with neurobiological changes: while the expression of hippocampal calmodulin kinase II (CaMKII) mRNA levels was reduced in middle-aged animals, the polyphenol-enriched diet could rescue them. Besides, an increased expression of nerve growth neurotrophic factor (NGF) mRNA levels was also observed in supplemented adult and middle-aged mice. Thus these data suggest that supplementation with polyphenols could be an efficient nutritional way to prevent age-induced cognitive decline.


Prediction of Human Pharmacokinetics of Phosphorodiamidate Morpholino Oligonucleotides in Duchenne Muscular Dystrophy Patients Using Viltolarsen.
Several modified antisense oligonucleotides (ASOs) have recently been approved for clinical use. Some are phosphorodiamidate morpholino oligomers (PMOs), which, unlike other nucleic acids, are not negatively charged. Thus, PMOs differ from other ASOs in their pharmacokinetic (PK) properties. Drugs with a PMO backbone have been administered to Duchenne muscular dystrophy pediatric patients; however, appropriate methodologies are not currently available to predict their human PK from nonclinical data. In this study, we used viltolarsen as a representative PMO to investigate the applicability of the allometric scaling approach to human PK prediction. We first summarized the nonclinical and clinical PK data for viltolarsen as showing high total clearance, low serum protein binding, metabolic resistance, and urinary excretion as the unchanged drug in both animals and humans. We then investigate the PK of viltolarsen in mice, rats, cynomolgus monkeys, and dogs and used the results, with body weight, to extrapolate to humans by several methods. The estimate of human total clearance obtained from cynomolgus monkeys was the best, and body weight may be the key factor in accurately predicting human total clearance. In contrast, all of the well-known prediction methods for the volume of distribution at steady state gave underestimates. However, the human PK profiles predicted from the PK parameters in cynomolgus monkeys fit the observed human plasma concentrations well. These results are expected to contribute to the further development of PMOs. SIGNIFICANCE STATEMENT: We investigated how to predict the human PK of phosphorodiamidate morpholino oligomers from nonclinical data. The estimates of human PK parameters and profiles determined from cynomolgus monkeys by an allometric scaling approach were the most suitable, and the cynomolgus monkey body weight may be the key factor in accurately predicting human total clearance.


The ecological stoichiometry of toxins produced by harmful cyanobacteria: an experimental test of the carbon-nutrient balance hypothesis.
The elemental composition of primary producers reflects the availability of light, carbon and nutrients in their environment. According to the carbon-nutrient balance hypothesis, this has implications for the production of secondary metabolites. To test this hypothesis, we investigated a family of toxins, known as microcystins, produced by harmful cyanobacteria. The strain Microcystis aeruginosa HUB 5-2-4, which produces several microcystin variants of different N:C stoichiometry, was cultured in chemostats supplied with various combinations of nitrate and CO(2). Excess supply of both nitrogen and carbon yielded high cellular N:C ratios accompanied by high cellular contents of total microcystin and the nitrogen-rich variant microcystin-RR. Comparable patterns were found in Microcystis-dominated lakes, where the relative microcystin-RR content increased with the seston N:C ratio. In total, our results are largely consistent with the carbon-nutrient balance hypothesis, and warn that a combination of rising CO(2) and nitrogen enrichment will affect the microcystin composition of harmful cyanobacteria.


Hydrogen-bond-supported dimeric boron complexes of potentially tetradentate β-diketiminate ligands.
Two dimeric boron complexes of potentially tetradentate and trianionic β-diketiminate ligands bearing phenol substituents were prepared and characterized. The synthetic routes employed were designed to circumvent the undesirable formation of β-ketimines and 2-methylbenzoxazoles observed when traditional synthetic routes toward the target β-diketiminate ligands were attempted. The title complexes were isolated via demethylation of β-diketimine ligands and boron difluoride complexes bearing 2-anisole N-aryl substituents using boron tribromide. The resulting complexes were found to contain a unique hydrogen-bond-supported boron-oxygen-boron bridge, as confirmed by X-ray crystallography. The stability of the resulting dimeric structures relative to the corresponding monomeric, tetradentate boron complexes was studied computationally, and theory confirmed that the dimeric structures were strongly favored. The absorption spectra of the dimers were red-shifted relative to the parent β-diketimine ligands. The complexes were irreversibly oxidized and reduced electrochemically and were weakly emissive at low concentrations (Stokes shifts between 23 and 31 nm), showing little solvent dependence.


Nurse prescribers: who are they and how do they perceive their role?
This paper reports a study to elicit background data from recently qualified nurse prescribers and explore aspects of their work. Nurse prescribing has been introduced quite recently in the United Kingdom. Although a certain amount of information is available about the characteristics of nurse prescribers, relatively little is known about their professional backgrounds, their reasons for choosing to become nurse prescribers and their perceptions of their emerging role. More information is needed to inform the selection, education and support of nurse prescribers. All nurses who undertook a nurse prescribing course in one university in the West Midlands during 2003-2004 were invited to participate in the study. A 40-item questionnaire was used to gather data on demographics, expectations of nurse prescribing, personal and professional development and perceived education needs. Respondents considered that, despite initial problems, the nurse prescribing initiative would ultimately prove to be a cornerstone of improved service delivery for service users. The majority of nurses were already heavily involved in prescribing 'by proxy' and the course merely formalized what they were currently doing. Potentially, prescribing could advance the professional development of nurses, improve communication between professionals and patients, and make the experience of patients more beneficial. However, some concerns were expressed about how supportive the current climate in health care could be, given the multiple demands on time and energy required by so many other innovations. Respondents appeared balanced in their perceptions of this innovation and what it could realistically achieve. They were not indifferent to the many short and long-term problems that need to be resolved before it can be claimed to have become embedded in practice. The success of non-medical prescribing may depend on organizational support, coupled with a robust continuing professional development strategy for all nurse prescribers.


Inhibitory effects of a phage-derived peptide on Au nanocrystal nucleation and growth.
Peptides have been shown to mediate the reduction and clustering of inorganic ions during biomineralization processes to build nanomaterials with well-defined shape, size, and composition. This precise control has been linked to specific amino acid sequence; however, there is a lack of information about the role of peptides during mineralization. Here, we investigate the nucleation and growth behavior of Au nanocrystals that are mediated by the engineered peptide AYSSGAPPMPPF. Unlike other nanocrystal synthesis schemes, this peptide produces Au nanocrystals from Au(III) ions at very low relative peptide concentrations, at ambient temperature, and in water at neutral pH. Our data show that (i) the peptide AYSSGAPPMPPF actually inhibits nucleation and growth of nanocrystals, (ii) HEPES plays an active chemical role as the reducing agent, and (iii) HAuCl4 accelerates the kinetics of nanoparticle nucleation and growth. Herein, we propose empirical rate laws for nucleation and growth of Au nanocrystals and compare kinetic rate laws for this peptide, citrate, and various other polymer ligands. We find that the peptide belongs to a unique class of nonreducing inhibitor ligands regulating the surface-reaction-limited growth of nanocrystals.


Characterization of municipal waste in Kampala, Uganda.
In Kampala, Uganda, about 28,000 tons of waste is collected and delivered to a landfill every month. Kampala Capital City Authority (KCCA) records show that this represents approximately 40% of the waste generated in the city. The remaining uncollected waste is normally dumped in unauthorized sites, causing health and environmental problems. However, the organic fraction of domestic waste can provide an opportunity to improve livelihoods and incomes through fertilizer and energy production. This study characterized the municipal waste generated in Kampala and delivered to Kiteezi landfill between July 2011 and June 2012, that is, covering the dry and wet months. On each sampling day, waste was randomly selected from five trucks, sorted and weighed into different physical fractions. Samples of the organic waste from each truck were analyzed for total solids, major nutrients, and energy content. During the wet months, the waste consisted of 88.5% organics, 3.8% soft plastics, 2.8% hard plastics, 2.2% paper, 0.9% glass, 0.7% textiles and leather 0.2% metals, and 1.0% others. During the dry months, the waste consisted of 94.8% organics, 2.4% soft plastics, 1.0% hard plastics, 0.7% papers, 0.3% glass, 0.3% textile and leather, 0.1% metals, and 0.3% others. The organic waste on average had a moisture content of 71.1% and contained 1.89% nitrogen, 0.27% phosphorus, and 1.95% potassium. The waste had an average gross energy content of 17.3 MJ/kg. It was concluded that the organic waste generated can be a suitable source of some plant nutrients that are useful especially in urban agriculture. The result of the waste characterization in Kampala was found to be significantly different from that obtained for other Sub-Saharan African (SSA) cities, showing that studies assuming average values for the waste fractions are likely to result in erroneous results. Furthermore, no reduction in organic fraction of the waste was noticed when compared with a study done two decades ago in spite of greatly improved economic status of Kampala city, a finding that is not in agreement with several other similar studies done for other SSA cities.


Chemical Species, Micromorphology, and XRD Fingerprint Analysis of Tibetan Medicine Zuotai Containing Mercury.
Zuotai (gTso thal) is one of the famous drugs containing mercury in Tibetan medicine. However, little is known about the chemical substance basis of its pharmacodynamics and the intrinsic link of different samples sources so far. Given this, energy dispersive spectrometry of X-ray (EDX), scanning electron microscopy (SEM), atomic force microscopy (AFM), and powder X-ray diffraction (XRD) were used to assay the elements, micromorphology, and phase composition of nine Zuotai samples from different regions, respectively; the XRD fingerprint features of Zuotai were analyzed by multivariate statistical analysis. EDX result shows that Zuotai contains Hg, S, O, Fe, Al, Cu, and other elements. SEM and AFM observations suggest that Zuotai is a kind of ancient nanodrug. Its particles are mainly in the range of 100-800 nm, which commonly further aggregate into 1-30 μm loosely amorphous particles. XRD test shows that β-HgS, S8, and α-HgS are its main phase compositions. XRD fingerprint analysis indicates that the similarity degrees of nine samples are very high, and the results of multivariate statistical analysis are broadly consistent with sample sources. The present research has revealed the physicochemical characteristics of Zuotai, and it would play a positive role in interpreting this mysterious Tibetan drug.


A phase 1b trial of the CXCR4 inhibitor mavorixafor and nivolumab in advanced renal cell carcinoma patients with no prior response to nivolumab monotherapy.
Background The CXCR4 chemokine receptor promotes tumor survival through mechanisms that include suppressing antitumor immune responses. Mavorixafor (X4P-001) is an oral, selective, allosteric CXCR4 inhibitor that decreases the recruitment of immunosuppressive cells into the tumor microenvironment and increases activated cytotoxic Tcell infiltration. Methods Patients with metastatic clear cell renal cell carcinoma (ccRCC) unresponsive to nivolumab monotherapy received oral mavorixafor 400 mg daily plus 240 mg intravenous nivolumab every 2 weeks. Results Nine patients were enrolled, median age 65 years. At baseline 4 had progressive disease (PD) and 5 had stable disease (SD). One of 5 patients with SD at study entry on prior nivolumab monotherapy had a partial response (PR) on combination treatment; all 4 patients with PD at study entry had a best response of SD with the combination treatment (median duration: 6.7 months; range: 3.7-14.7). Four patients discontinued therapy due to treatment-related adverse events (AEs). Grade ≥ 3 drug-related AEs were elevated alanine and aspartate aminotransferase (2 patients each); and autoimmune hepatitis, chronic kidney disease, increased lipase, maculopapular rash, and mucosal inflammation (1 patient each). A robust increase in levels of chemokine (C-X-C motif) ligand 9 CXCL9 on mavorixafor appeared to correlate with clinical benefit. Conclusions The CXCR4 inhibition mediated by mavorixafor, in combination with PD-1 blockade to enhance antitumor immune responses in patients unresponsive to checkpoint inhibitor monotherapy, is worthy of further study. Mavorixafor and nivolumab combination therapy in patients with advanced ccRCC demonstrated potential antitumor activity and a manageable safety profile.Trial registration: ClinicalTrials.gov identifier: NCT02923531. Date of registration: October 04, 2016.


Self-Care for Common Colds by Primary Care Patients: A European Multicenter Survey on the Prevalence and Patterns of Practices-The COCO Study.
Background. Patients use self-care to relieve symptoms of common colds, yet little is known about the prevalence and patterns across Europe. Methods/Design. In a cross-sectional study 27 primary care practices from 14 countries distributed 120 questionnaires to consecutive patients (≥18 years, any reason for consultation). A 27-item questionnaire asked for patients' self-care for their last common cold. Results. 3,074 patients from 27 European sites participated. Their mean age was 46.7 years, and 62.5% were females. 99% of the participants used ≥1 self-care practice. In total, 527 different practices were reported; the age-standardized mean was 11.5 (±SD 6.0) per participant. The most frequent self-care categories were foodstuffs (95%), extras at home (81%), preparations for intestinal absorption (81%), and intranasal applications (53%). Patterns were similar across all sites, while the number of practices varied between and within countries. The most frequent single practices were water (43%), honey (42%), paracetamol (38%), oranges/orange juice (38%), and staying in bed (38%). Participants used 9 times more nonpharmaceutical items than pharmaceutical items. The majority (69%) combined self-care with and without proof of evidence, while ≤1% used only evidence-based items. Discussion. This first cross-national study on self-care for common colds showed a similar pattern across sites but quantitative differences.


Ion channels in microbes.
Studies of ion channels have for long been dominated by the animalcentric, if not anthropocentric, view of physiology. The structures and activities of ion channels had, however, evolved long before the appearance of complex multicellular organisms on earth. The diversity of ion channels existing in cellular membranes of prokaryotes is a good example. Although at first it may appear as a paradox that most of what we know about the structure of eukaryotic ion channels is based on the structure of bacterial channels, this should not be surprising given the evolutionary relatedness of all living organisms and suitability of microbial cells for structural studies of biological macromolecules in a laboratory environment. Genome sequences of the human as well as various microbial, plant, and animal organisms unambiguously established the evolutionary links, whereas crystallographic studies of the structures of major types of ion channels published over the last decade clearly demonstrated the advantage of using microbes as experimental organisms. The purpose of this review is not only to provide an account of acquired knowledge on microbial ion channels but also to show that the study of microbes and their ion channels may also hold a key to solving unresolved molecular mysteries in the future.


Emerging pathogens and deliberate attacks on European water supplies: a scenario planning workshop.
Microbiological contamination of drinking water supplies is an ever-present concern for water utility managers. Most such threats are routine, well-recognised and described. Therefore, they can usually be prevented using standard protection measures. Incidents involving emerging pathogens and malicious attacks are inherently less predictable. In a multi-stage process over one day, participants with backgrounds in microbiology, medicine, infrastructure, data analysis, environmental or public health and facility management developed qualitative scenarios on potential threats posed by either an emergent pathogen in or a microbiological attack on drinking water supplies in a European country. Participants were guided via structured activities to identify key factors that would impact the magnitude and severity of such an emergency. Plausible variant states for each key factor were determined, and participants constructed sequences of events to create scenario outlines. Five scenarios in outline form are reported which incorporate genuine possible future events as well as pathogens of international concern. Common features that would exacerbate all scenarios were under-investment in public services, inadequate water quality testing, and monitoring and lack of resources to keep water supplies safe. Participant evaluation of their scenario planning experience was broadly very positive and the scenario planning process was received as credible and relevant.


N-acetyl cysteine versus allopurinol in the prevention of contrast nephropathy in patients with chronic kidney disease: A randomized controlled trial.
Contrast media administration can lead to acute deterioration in renal function particularly in patients with pre-existing chronic kidney disease. This prospective, randomized controlled open-label parallel group study was undertaken at Nizam's Institute of Medical Sciences, Hyderabad, from June to December 2015. A total of 95 patients were included, of which 35 received n-acetylcysteine (NAC) + normal saline (NS), 30 patients received allopurinol (ALL) + NS, and 30 patients received placebo. In our study, the overall incidence of CIN was 24%. Incidence of CIN in NAC + NS, ALL + NS, and placebo group were 20%, 16%, and 36%, respectively. The major finding of this study was there was no significant difference between NAC and allopurinol in the prevention of contrast nephropathy. However, only allopurinol was superior to placebo. In our study, hyperuricemia and baseline serum creatinine were the only risk factors associated with CIN.


A restricted subset of var genes mediates adherence of Plasmodium falciparum-infected erythrocytes to brain endothelial cells.
Cerebral malaria (CM) is a deadly complication of Plasmodium falciparum infection, but specific interactions involved in cerebral homing of infected erythrocytes (IEs) are poorly understood. In this study, P. falciparum-IEs were characterized for binding to primary human brain microvascular endothelial cells (HBMECs). Before selection, CD36 or ICAM-1-binding parasites exhibited punctate binding to a subpopulation of HBMECs and binding was CD36 dependent. Panning of IEs on HBMECs led to a more dispersed binding phenotype and the selection of three var genes, including two that encode the tandem domain cassette 8 (DC8) and were non-CD36 binders. Multiple domains in the DC8 cassette bound to brain endothelium and the cysteine-rich interdomain region 1 inhibited binding of P. falciparum-IEs by 50%, highlighting a key role for the DC8 cassette in cerebral binding. It is mysterious how deadly binding variants are maintained in the parasite population. Clonal parasite lines expressing the two brain-adherent DC8-var genes did not bind to any of the known microvascular receptors, indicating unique receptors are involved in cerebral binding. They could also adhere to brain, lung, dermis, and heart endothelial cells, suggesting cerebral binding variants may have alternative sequestration sites. Furthermore, young African children with CM or nonsevere control cases had antibodies to HBMEC-selected parasites, indicating they had been exposed to related variants during childhood infections. This analysis shows that specific P. falciparum erythrocyte membrane protein 1 types are linked to cerebral binding and suggests a potential mechanism by which individuals may build up immunity to severe disease, in the absence of CM.


Optimal foraging and fitness in Columbian ground squirrels.
Optimal diets were determined for each of 109 individual Columbian ground squirrels (Spermophilus columbianus) at two sites in northwestern Montana. Body mass, daily activity time, and vegetation consumption rates for individuals were measured in the field, along with the average water content of vegetation at each ground squirrel colony. I also measured stomach and caecal capacity and turnover rate of plant food through the digestive tract for individuals in the laboratory to construct regressions of digestive capacity as a function of individual body mass. Finally, I obtained literature estimates of average daily energy requirements as a function of body mass and digestible energy content of vegetation. These data were used to construct a linear programming diet model for each individual. The model for each individual was used to predict the proportion of two food types (monocots and dicots) that maximized daily energy intake, given time and digestive constraints on foraging. Individuals were classified as "optimal" or "deviating", depending on whether their observed diet was significantly different from their predicted optimal diet. I determined the consequences of selecting an optimal diet for energy intake and fitness. As expected, daily energy intake calculated for deviators (based on their observed diet proportion) was less than that for optimal foragers. Deviating foragers do not appear to compensate for their lower calculated energy intake through other factors such as body size or physiological efficiency of processing food. Growth rate, yearly survivorship, and litter size increase with calculated energy intake, and optimal foragers have six times the reproductive success of deviators by age three. Optimal foraging behavior, therefore, appears to confer a considerable fitness advantage.


The REVOLUTA gene is necessary for apical meristem development and for limiting cell divisions in the leaves and stems of Arabidopsis thaliana.
The form of seed plants is determined by the growth of a number of meristems including apical meristems, leaf meristems and cambium layers. We investigated five recessive mutant alleles of a gene REVOLUTA that is required to promote the growth of apical meristems and to limit cell division in leaves and stems of Arabidopsis thaliana. REVOLUTA maps to the bottom of the fifth chromosome. Apical meristems of both paraclades (axillary shoots) and flowers of revoluta mutants frequently fail to complete normal development and form incomplete or abortive structures. The primary shoot apical meristem sometimes also arrests development early. Leaves, stems and floral organs, in contrast, grow abnormally large. We show that in the leaf epidermis this extra growth is due to extra cell divisions in the leaf basal meristem. The extent of leaf growth is negatively correlated with the development of a paraclade in the leaf axil. The thickened stems contain extra cell layers, arranged in rings, indicating that they may result from a cambium-like meristem. These results suggest that the REVOLUTA gene has a role in regulating the relative growth of apical and non-apical meristems in Arabidopsis.


The "Hot-Solvent/Cold-Solute" Problem Revisited.
The temperature steers the equilibrium and nonequilibrium conformational dynamics of macromolecules in solution. Therefore, corresponding molecular dynamics simulations require a strategy for temperature control which should guarantee that the experimental statistical ensemble is also sampled in silico. Several algorithms for temperature control have been proposed. All these thermostats interfere with the macromolecule's "natural" dynamics as given by the Newtonian mechanics. Furthermore, using a single thermostat for an inhomogeneous solute-solvent system can lead to stationary temperature gradients. To avoid this "hot solvent/cold solute" problem, two separate thermostats are frequently applied, one to the solute and one to the solvent. However, such a separate temperature control will perturb the dynamics of the macromolecule much more strongly than a global one and, therefore, can introduce large artifacts into its conformational dynamics. Based on the concept that an explicit solvent environment represents an ideal thermostat concerning the magnitude and time correlation of temperature fluctuations of the solute, we propose a temperature control strategy that, on the one hand, provides a homogeneous temperature distribution throughout the system together with the correct statistical ensemble for the solute molecule while, on the other hand, minimally perturbing its dynamics.


Stem photosynthesis in a desert ephemeral, Eriogonum inflatum : Morphology, stomatal conductance and water-use efficiency in field populations.
Seasonal patterns in plant morphology, phenology, and physiology were monitored in several populations of Eriogonum inflatum, a desert ephemeral which produces a large photosynthetic inflorescence above a basal leaf rosette. Green stems accounted for 66-77% of whole plant photosynthetic surface area when integrated over a developmental cycle, whereas only 40-67% of the yearly transpirational water loss could be attributed to stems. Stems were found to have lower nitrogen and chlorophyll contents than leaves, and lower stomatal conductance under all physiological conditions encountered. However, because stems occur later in the year than leaves, comparison of physiological patterns was complicated by the two structures being exposed to different climatic regimes during their developmental cycles. Stems exhibited higher δ13C values than leaves, indicating that stems operated at higher water-use efficiencies than leaves, at least during periods when both leaves and stems were present. Higher water-use efficiency in stems of E. inflatum is attributed to both more conservative water use patterns and to their vertical orientation, allowing stems to remain photosynthetically active longer into the dry season after senescence of the horizontal leaf rosette.


Localization of the alpha(1F) calcium channel subunit in the rat retina.
The molecular identity of the calcium channels that mediate glutamate release from photoreceptors is unknown. Mutations in the recently identified, retina-specific alpha(1F) calcium channel subunit cause incomplete X-linked congenital stationary night blindness (CSNB2), the phenotype of which is consistent with a defect in neurotransmission within the retina. The purpose of this study was to determine the cellular distribution of the alpha(1F) subunit in the retina. Antibodies were raised against a unique peptide from the human alpha(1F) sequence. Rat retina sections were labeled with affinity-purified alpha(1F) antibodies and the immunofluorescence analyzed by confocal microscopy. The alpha(1F) staining was compared with that obtained with a pan-alpha(1) antibody, used to reveal the distribution of known voltage-gated calcium channels in the retina. Some sections were double labeled for alpha(1F) and the photoreceptor synaptic ribbon marker, bassoon. Staining of retina sections with anti-alpha(1F) resulted in strong punctate labeling in the outer plexiform layer (OPL) and weak punctate labeling in the inner plexiform layer (IPL), consistent with a synaptic localization. Staining was also observed in the outer nuclear layer. Within the OPL, alpha(1F) immunoreactivity was clustered in discrete, horseshoe-shaped patches, the shape and dimensions of which are characteristic of rod active zones. Similar structures were labeled with the pan-alpha(1) antibody. Localization of alpha(1F) immunoreactivity to rod active zones was confirmed by double labeling for bassoon, a component of photoreceptor synaptic ribbons. The distribution of alpha(1F) immunoreactivity in the OPL suggests that calcium influx through alpha(1F) or alpha(1F)-like channels mediates glutamate release from rod photoreceptors.


Intravenous Arginine Administration Promotes Proangiogenic Cells Mobilization and Attenuates Lung Injury in Mice with Polymicrobial Sepsis.
This study investigated the influence of intravenous arginine (Arg) administration on alteration of circulating proangiogenic cells and remote lung injury in a model of polymicrobial sepsis. Mice were assigned to one normal control group (NC) and two sepsis groups that were induced by cecal ligation and puncture (CLP). One of the sepsis groups was injected with saline (SS), whereas the other (SA) was administered with a single bolus of 300 mg Arg/kg body weight via the tail vein 1 h after CLP. Septic mice were sacrificed at either 24 or 48 h after CLP, with their blood and lung tissues collected for analysis. Results showed that septic groups had higher proangiogenic cells releasing factors and proangiogenic cells percentage in blood. Also, concentration of inflammatory cytokines and expression of angiopoietin (Angpt)/Tie-2 genes in lung tissues were upregulated. Arg administration promoted mobilization of circulating proangiogenic cells while it downregulated the production of inflammatory cytokines and expression of Angpt/Tie-2 genes in the lung. The results of this investigation suggested that intravenous administration of Arg shortly after the onset of sepsis enhanced the mobilization of circulating proangiogenic cells, maintained the homeostasis of the Angpt/Tie-2 axis, and attenuated remote organ injury in polymicrobial sepsis.


Combined Office-based Vergence Therapy and Home Therapy System for Convergence Insufficiency in Egyptian Children.
Convergence Insufficiency (CI) is a common binocular vision disorder characterized by exophoria more at near than at far, a receded Near Point of Convergence (NPC), and decreased Positive Fusional Vergence (PFV) at near. This disorder is often associated with several symptoms that may disturb the person's quality of life. Therefore, diagnosis and treatment of CI is a vital issue. To compare therapeutic yield of Office Based Vision Therapy (OBVT) and combined OBVT with Home Therapy System (HTS) in patients with CI. The study included 102 patients with age range of 7-13 years. All patients underwent Convergence Insufficiency Symptom Survey (CISS) scoring, estimation of Near Point of Convergence (NPC) and determination of Positive Fusional Vergence at near (PFV) using Sheard's criterion. Patients were randomly allocated in two groups: Group I: received Office-based Vision Therapy (OBVT) and Group II: received OBVT with home reinforcement using the Home Therapy System (HTS). At the end of 12th week of therapy; outcome was determined as Successful (all the following: CISS score of <16, NPC <6 cm and PFV >15Δ), Improved (CISS score of <16 or a 10 points-decrease and one of the following: NPC <6cm or improved by >4 cm, PFV >15Δ or increased by > 10Δ), Insufficient response (NPC <6cm or improved by >4 cm, PFV >15Δ or increased by > 10Δ) and non-responders. At the end of the 12th week of therapy, the applied therapeutic polices were successful in 48 patients (47.1%), the symptoms were improved in 30 patients (29.4%), improvement was insufficient in 13 patients (12.7%) and 11 patients (10.8%) were considered as non-responders. There was significantly higher frequency of patients with improved outcome in group II (86%) compared to group I (69.2%). OBVT with home supplement using HTS provided a high success rate, and it seems to be superior to OBVT alone in treatment of children with convergence insufficiency after 12-week course of therapy.


The gestural origins of language.
The idea that language evolved from manual gestures rather than primate calls dates back at least to the 18th century, and was revived in modern form by the anthropologist, Gordon W. Hewes, in 1973. The main sources of current evidence are: (1) Signed languages invented by deaf communities share with speech the essential characteristics of language, including such properties as reference, generativity, grammar, and prosody; (2) Great apes in captivity are much better able to learn intentional communication systems based on manual gestures than to acquire speech; (3) The manual gestures of chimpanzees in the wild are more flexible and context-independent than their vocalizations; (4) The mirror system in the primate brain provides a natural platform for the evolution of language; it represents manual gestures and some nonvocal oral movements, but not vocalizations. Vocal gestures were probably incorporated into the mirror system late in hominin evolution, perhaps only with the emergence of our own species, Homo sapiens. Copyright © 2009 John Wiley & Sons, Ltd. For further resources related to this article, please visit the WIREs website.


North American Solitaire Stent Retriever Acute Stroke registry: post-marketing revascularization and clinical outcome results.
Limited post-marketing data exist on the use of the Solitaire FR device in clinical practice. The North American Solitaire Stent Retriever Acute Stroke (NASA) registry aimed to assess the real world performance of the Solitaire FR device in contrast with the results from the SWIFT (Solitaire with the Intention for Thrombectomy) and TREVO 2 (Trevo versus Merci retrievers for thrombectomy revascularization of large vessel occlusions in acute ischemic stroke) trials. The investigator initiated NASA registry recruited North American sites to submit retrospective angiographic and clinical outcome data on consecutive acute ischemic stroke (AIS) patients treated with the Solitaire FR between March 2012 and February 2013. The primary outcome was a Thrombolysis in Myocardial Ischemia (TIMI) score of ≥2 or a Treatment in Cerebral Infarction (TICI) score of ≥2a. Secondary outcomes were 90 day modified Rankin Scale (mRS) score, mortality, and symptomatic intracranial hemorrhage. 354 patients underwent treatment for AIS using the Solitaire FR device in 24 centers. Mean time from onset to groin puncture was 363.4±239 min, mean fluoroscopy time was 32.9±25.7 min, and mean procedure time was 100.9±57.8 min. Recanalization outcome: TIMI ≥2 rate of 83.3% (315/354) and TICI ≥2a rate of 87.5% (310/354) compared with the operator reported TIMI ≥2 rate of 83% in SWIFT and TICI ≥2a rate of 85% in TREVO 2. 42% (132/315) of NASA patients demonstrated a 90 day mRS ≤2 compared with 37% (SWIFT) and 40% (TREVO 2). 90 day mortality was 30.2% (95/315) versus 17.2% (SWIFT) and 29% (TREVO 2). The NASA registry demonstrated that the Solitaire FR device performance in clinical practice is comparable with the SWIFT and TREVO 2 trial results.


Behavioral profiles of three C57BL/6 substrains.
C57BL/6 inbred strains of mice are widely used in knockout and transgenic research. To evaluate the loss-of-function and gain-of-function effects of the gene of interest, animal behaviors are often examined. However, an issue of C57BL/6 substrains that is not always appreciated is that behaviors are known to be strongly influenced by genetic background. To investigate the behavioral characteristics of C57BL/6 substrains, we subjected C57BL/6J, C57BL/6N, and C57BL/6C mice to a behavior test battery. We performed both a regular scale analysis, in which experimental conditions were tightly controlled, and large-scale analysis from large number of behavioral data that we have collected so far through the comprehensive behavioral test battery applied to 700-2,200 mice in total. Significant differences among the substrains were found in the results of various behavioral tests, including the open field, rotarod, elevated plus maze, prepulse inhibition, Porsolt forced swim, and spatial working memory version of the eight-arm radial maze. Our results show a divergence of behavioral performance in C57BL/6 substrains, which suggest that small genetic differences may have a great influence on behavioral phenotypes. Thus, the genetic background of different substrains should be carefully chosen, equated, and considered in the interpretation of mutant behavioral phenotypes.


Antireflux surgery.
Gastro-oesophageal reflux disease is extremely common throughout Europe and the United States. This review on antireflux surgery examines the best evidence for surgical treatment of gastro-esophageal reflux disease. Comparison is made with medical antireflux therapy including histamine H2 receptor antagonist and proton pump inhibitor therapy. The randomized trials and systematic reviews available on gastro-esophageal reflux disease are reviewed and where data are scarce, the largest cohort studies available are discussed. Overall, laparoscopic antireflux surgery is safe and has a similar efficacy to open antireflux surgery and best medical therapy with proton pump inhibitors. There is a failure rate, which in some series is greater than 50% at 5 years. Due to the cost of a proportion of patients still taking antireflux medications, it cannot be recommended on cost-effectiveness grounds over best medical therapy. The choice of procedure lies between complete wrap with Nissen's fundoplication and partial fundoplication (most frequently Toupet). Division of the short gastric vessels is not usually necessary and is associated with increased wind-related complications. Total fundoplication tends to produce superior reflux control, but at the cost of increased risk of dysphagia. There is a trend for antireflux surgery to be superior to best medical therapy in cancer prevention in Barrett's oesophagus, but this has not reached statistical significance.


SAME-GENDER SEX AMONG U.S. ADULTS: TRENDS ACROSS THE TWENTIETH CENTURY AND DURING THE 1990s.
Trends in reporting of same-gender sex are assessed using data from the 1988-2002 General Social Surveys (Ns = 9,487 males and 12,336 females). Analyses indicate that the reported prevalence of female-female sexual contact increased substantially and monotonically across twentieth-century birth cohorts, rising from 1.6 percent (Standard error [SE] = 0.60) for the cohort of U.S. women born prior to 1920 to 6.9 percent (SE = 0.81) for women born in 1970 and afterward. Increases in the reported prevalence of female-female contacts also occurred within the 1990s. These trends persist when statistical controls are introduced for changes in attitudes toward same-gender sexual behavior. No parallel trend is observed in the reporting of male-male sexual contacts during adulthood, although the proportion of U.S. men reporting such contacts in the past year and in the past five years increased during the 1990s.


BMP-7 is an efficacious treatment of vascular calcification in a murine model of atherosclerosis and chronic renal failure.
Chronic renal failure is complicated by high cardiovascular mortality. One key contributor to this mortality is vascular calcification, for which no therapy currently exists. Bone morphogenetic protein 7 is an essential renal morphogen that maintains renal tubular differentiation in the adult and is downregulated in renal failure. Several studies have demonstrated its efficacy in treating various renal diseases in rodents, and it was hypothesized that it would also be an effective treatment of vascular calcification in this setting. Uremia was imposed on LDL receptor null mice (a model of atherosclerosis), which were then treated with bone morphogenetic protein 7 for 15 wk. Uremic animals had increased vascular calcification by histology and chemical analysis. Calcification in treated animals was similar to or less than non-uremic control animals. Cells exhibiting an osteoblast-like phenotype in the vessel wall may be important in the etiology of vascular calcification. Expression of osteocalcin was assessed as a marker of osteoblastic function, and it is shown that it is increased in untreated uremic animals but downregulated to levels similar to non-uremic control animals with treatment. The data are compatible with bone morphogenetic protein 7 deficiency as a pathophysiologic factor in chronic renal failure, and they demonstrate its efficacy as a potential treatment of vascular calcification.


The Visible Behaviour of Drowning Persons: A Pilot Observational Study Using Analytic Software and a Nominal Group Technique.
Although drowning is a common phenomenon, the behaviour of drowning persons is poorly understood. The purpose of this study is to provide a quantitative and qualitative analysis of this behaviour. This was an observational study of drowning videos observed by 20 international experts in the field of water safety. For quantitative analysis, each video was analysed with Lince observation software by four participants. A Nominal Group Technique generated input for the qualitative analysis and the two principal investigators conducted a post-hoc analysis. A total of 87.5% of the 23 videos showed drowning in swimming pools, 50% of the drowned persons were male, and 58.3% were children or teenagers. Nineteen persons were rescued before unconsciousness and showed just the beginning of downing behaviour. Another five were rescued after unconsciousness, which allowed the observation of their drowning behaviour from the beginning to the end. Significant differences were found comparing both groups regarding the length of disappearances underwater, number, and length of resurfacing (resp. p = 0.003, 0.016, 0.005) and the interval from the beginning of the incident to the rescue (p = 0.004). All persons drowned within 2 min. The qualitative analysis showed previously suggested behaviour patterns (immediate disappearance n = 5, distress n = 6, instinctive drowning response n = 6, climbing ladder motion n = 3) but also a striking new pattern (backward water milling n = 19). This study confirms previous assumptions of drowning behaviour and provides novel evidence-based information about the large variety of visible behaviours of drowning persons. New behaviours, which mainly include high-frequency resurfacing during a struggle for less than 2 min and backward water milling, have been recognised in this study.


Outcomes in Economic Evaluations of Public Health Interventions in Low- and Middle-Income Countries: Health, Capabilities and Subjective Wellbeing.
Public health programmes tend to be complex and may combine social strategies with aspects of empowerment, capacity building and knowledge across sectors. The nature of the programmes means that some effects are likely to occur outside the healthcare sector; this breadth impacts on the choice of health and non-health outcomes to measure and value in an economic evaluation. Employing conventional outcome measures in evaluations of public health has been questioned. There are concerns that such measures are too narrow, overlook important dimensions of programme effect and, thus, lead to such interventions being undervalued. This issue is of particular importance for low-income and middle-income countries, which face considerable budget constraints, yet deliver a large proportion of health activities within public health programmes. The need to develop outcome measures, which include broader measures of quality of life, has given impetus to the development of a variety of new, holistic approaches, including Sen's capability framework and measures of subjective wellbeing. Despite their promise, these approaches have not yet been widely applied, perhaps because they present significant methodological challenges. This paper outlines the methodological challenges for the identification and measurement of broader outcomes of public health interventions in economic evaluation in low-income and middle-income countries.


The Streptococcus pneumoniae capsule is required for full virulence in pneumococcal endophthalmitis.
To determine whether Streptococcus pneumoniae capsule was necessary for pathogenesis of pneumococcal endophthalmitis. An isogenic capsule-deficient strain was created using homologous recombination. New Zealand White rabbits were injected intravitreously with 10(2) colony-forming units (CFU) of the parent strain or the capsule mutant. Slit lamp examination (SLE), electroretinography, and myeloperoxidase activity were performed 24 and 48 hours postinfection (PI). Serial dilutions of vitreous were plated to quantitate CFU, eyes were extracted for histology, and host cytokine mRNA expression was determined. Eyes infected with the parent strain had significantly higher SLE scores than eyes infected with the capsule-deficient strain 24 and 48 hours PI (P < 0.001). CFU recovered from eyes infected with the capsule mutant were significantly fewer than CFU recovered from eyes infected with the parent strain 24 and 48 hours PI (P < 0.001). The parent strain caused a significantly greater decrease in retinal function and more retinal destruction than the mutant strain 48 hours PI (P = 0.026). Vitreal IL-1β, IL-6, and TNF-α were upregulated by both the parent and mutant strain 12 hours PI. By 48 hours PI, there was significantly more neutrophil infiltration in the vitreous infected with the parent strain. Endophthalmitis caused by the encapsulated strain is more damaging to retinal function and structural integrity. These findings indicate that capsule is an important virulence factor of S. pneumoniae endophthalmitis, in contrast to keratitis, suggesting that the anatomic host site in pneumococcal ocular infections is important.


Using on-line video clips to enhance self-efficacy toward dealing with difficult situations among nursing students.
The aim of the study was twofold. The first aim was to develop on-line video clip material that showed examples of nurses dealing with potentially difficult and delicate patient groups. The second aim was to evaluate the effectiveness of video clip materials for enhancing nursing student's self-efficacy to effectively communicate with the type of patients described above. The production of contextually relevant video clip material involved the identification of relevant material based on real experiences, writing appropriate scripts, recruiting actors, recording the performances and producing them in a form that could be accessed on-line. Self-report questionnaires were used to assess the effectiveness of video clip material. Level 1 (n = 145) nursing students completed a self-efficacy measure that assessed confidence to deal with situations such as breaking news of death, working with children, people with disability and aggressive behaviour at the start and the end of the module. Results indicated that student's self-efficacy increased noticeably over the course of the module. Differences between increases in self-efficacy attributed to watching videos or attending lectures were marginal. Findings suggest that using video clips that show students effectively coping with adverse situations provide an effective teaching approach for enhancing self-efficacy. Future research is needed to test the extent to which self-efficacy measures relate with nursing performance.


[Operative invasiveness of off-pump coronary artery bypass grafting].
In our institution, steroid is administrated intravenously during the anesthesia induction for conventional coronary artery bypass grafting( CABG) to prevent the inflammatory response due to cardiopulmonary bypass and reperfusion injury, however, steroid is not used for off-pump CABG (OPCAB) with expectation of less invasiveness of the procedure. We evaluated the early outcomes and postoperative inflammatory response of conventional CABG with preoperative steroid use and OPCAB. From May 2004 to April 2010, 120 patients underwent elective CABG requiring the ventricle elevation to expose the target vessels. Twenty eight patients(group C)treated with conventional CABG and 92 patients (group O) with OPCAB. Perioperative course was analyzed and compared between the 2 groups. OPCAB had several advantages such as shorter operative duration, decreased requirement of blood transfusion and myocardial protection compared with conventional CABG. However, frequency of postoperative paroxysmal atrial fibrillation was similar between these techniques and early postoperative C-reactive protein levels were shown to be significantly higher in OPCAB. OPCAB has advantage over conventional CABG in blood loss during surgery and myocardial protection. However the inflammatory response was significantly severe in OPCAB. OPCAB might become less invasive with the anti-inflammatory medication.


Visual field progression in glaucoma: estimating the overall significance of deterioration with permutation analyses of pointwise linear regression (PoPLR).
To establish a method for estimating the overall statistical significance of visual field deterioration from an individual patient's data, and to compare its performance to pointwise linear regression. The Truncated Product Method was used to calculate a statistic S that combines evidence of deterioration from individual test locations in the visual field. The overall statistical significance (P value) of visual field deterioration was inferred by comparing S with its permutation distribution, derived from repeated reordering of the visual field series. Permutation of pointwise linear regression (PoPLR) and pointwise linear regression were evaluated in data from patients with glaucoma (944 eyes, median mean deviation -2.9 dB, interquartile range: -6.3, -1.2 dB) followed for more than 4 years (median 10 examinations over 8 years). False-positive rates were estimated from randomly reordered series of this dataset, and hit rates (proportion of eyes with significant deterioration) were estimated from the original series. The false-positive rates of PoPLR were indistinguishable from the corresponding nominal significance levels and were independent of baseline visual field damage and length of follow-up. At P < 0.05, the hit rates of PoPLR were 12, 29, and 42%, at the fifth, eighth, and final examinations, respectively, and at matching specificities they were consistently higher than those of pointwise linear regression. In contrast to population-based progression analyses, PoPLR provides a continuous estimate of statistical significance for visual field deterioration individualized to a particular patient's data. This allows close control over specificity, essential for monitoring patients in clinical practice and in clinical trials.


A multifunctional micro-fluidic system for dielectrophoretic concentration coupled with immuno-capture of low numbers of Listeria monocytogenes.
In this study, we demonstrated a micro-fluidic system with multiple functions, including concentration of bacteria using dielectrophoresis (DEP) and selective capture using antibody recognition, resulting in a high capture efficiency of bacterial cells. The device consisted of an array of oxide covered interdigitated electrodes on a flat silicon substrate and a approximately 16 microm high and approximately 260 microm wide micro-channel within a PDMS cover. For selective capture of Listeria monocytogenes from the samples, the channel surface was functionalized with a biotinylated BSA-streptavidin-biotinylated monoclonal antibody sandwich structure. Positive DEP (at 20 V(pp) and 1 MHz) was used to concentrate bacterial cells from the fluid flow. DEP could collect approximately 90% of the cells in a continuous flow at a flow rate of 0.2 microl min(-1) into the micro-channel with concentration factors between 10(2)-10(3), in sample volumes of 5-20 microl. A high flow rate of 0.6 microl min(-1) reduced the DEP capture efficiency to approximately 65%. Positive DEP attracts cells to the edges of the electrodes where the field gradient is the highest. Cells concentrated by DEP were captured by the antibodies immobilized on the channel surface with efficiencies of 18 to 27% with bacterial cell numbers ranging from 10(1) to 10(3) cells. It was found that DEP operation in our experiments did not cause any irreversible damage to bacterial cells in terms of cell viability. In addition, increased antigen expression (antigens to C11E9 monoclonal antibody) on cell membranes was observed following the exposure to DEP.


Validation of the questionnaire for impulsive-compulsive disorders in Parkinson's disease.
As no comprehensive assessment instrument for impulse control disorders (ICDs) in Parkinson's disease (PD) exists, the aim of this study was to design and assess the psychometric properties of a self-administered screening questionnaire for ICDs and other compulsive behaviors in PD. The Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease (QUIP) has 3 sections: Section 1 assesses four ICDs (involving gambling, sexual, buying, and eating behaviors), Section 2 other compulsive behaviors (punding, hobbyism, and walkabout), and Section 3 compulsive medication use. For validation, a convenience sample of 157 PD patients at 4 movement disorders centers first completed the QUIP, and then was administered a diagnostic interview by a trained rater blinded to the QUIP results. A shortened instrument (QUIP-S) was then explored. The discriminant validity of the QUIP was high for each disorder or behavior (receiver operating characteristic area under the curve [ROC AUC]: gambling = 0.95, sexual behavior = 0.97, buying = 0.87, eating = 0.88, punding = 0.78, hobbyism = 0.93, walkabout = 0.79). On post hoc analysis, the QUIP-S ICD section had similar properties (ROC AUC: gambling = 0.95, sexual behavior = 0.96, buying = 0.87, eating = 0.88). When disorders/behaviors were combined, the sensitivity of the QUIP and QUIP-S to detect an individual with any disorder was 96 and 94%, respectively. Scores on the QUIP appear to be valid as a self-assessment screening instrument for a range of ICDs and other compulsive behaviors that occur in PD, and a shortened version may perform as well as the full version. A positive screen should be followed by a comprehensive, clinical interview to determine the range and severity of symptoms, as well as need for clinical management.


Human papillomavirus oncogenic mRNA testing for cervical cancer screening: baseline and longitudinal results from the CLEAR study.
This study determined the longitudinal clinical performance of a high-risk human papillomavirus (HR-HPV) E6/E7 RNA assay (Aptima HPV [AHPV]; Hologic, San Diego, CA) compared with an HR-HPV DNA assay (Hybrid Capture 2 [HC2]; Qiagen, Gaithersburg, MD) as an adjunctive method for cervical cancer screening. Women 30 years or older with a negative result for intraepithelial lesions or malignancy cytology (n = 10,860) positive by AHPV and/or HC2 assays and randomly selected women negative by both assays were referred to colposcopy at baseline. Women without baseline cervical intraepithelial neoplasia (CIN) grade 2 or higher (CIN2+) continued into the 3-year follow-up. The specificity of AHPV for CIN2 or lower was significantly greater at 96.3% compared with HC2 specificity of 94.8% (P < .001). Estimated sensitivities and risks for detection of CIN2+ were similar between the two assays. After 3 years of follow-up, women negative by either human papillomavirus test had a very low risk of CIN2+ (<0.3%) compared with CIN2+ risk in women with positive AHPV results (6.3%) or positive HC2 results (5.1%). These results support the use of AHPV as a safe and effective adjunctive cervical cancer screening method.


Optimal timing of influenza vaccine during pregnancy: A systematic review and meta-analysis.
Pregnant women have an elevated risk of illness and hospitalisation from influenza. Pregnant women are recommended to be prioritised for influenza vaccination during any stage of pregnancy. The risk of seasonal influenza varies substantially throughout the year in temperate climates; however, there is limited knowledge of how vaccination timing during pregnancy impacts the benefits received by the mother and foetus. To compare antenatal vaccination timing with regard to influenza vaccine immunogenicity during pregnancy and transplacental transfer to their newborns. Studies were eligible for inclusion if immunogenicity to influenza vaccine was evaluated in women stratified by trimester of pregnancy. Haemagglutination inhibition (HI) titres, stratified by trimester of vaccination, had to be measured at either pre-vaccination and within one month post-vaccination, post-vaccination and at delivery in the mother, or in cord/newborn blood. Authors searched PubMed, Scopus, Web of Science and EMBASE databases from inception until June 2016 and authors of identified studies were contacted for additional data. Extracted data were tabulated and summarised via random-effect meta-analyses and qualitative methods. Sixteen studies met the inclusion criteria. Meta-analyses found that compared with women vaccinated in an earlier trimester, those vaccinated in a later trimester had a greater fold increase in HI titres (1.33- to 1.96-fold) and higher HI titres in cord/newborn blood (1.21- to 1.64-fold). This review provides comparative analysis of the effect of vaccination timing on maternal immunogenicity and protection of the infant that is informative and relevant to current vaccine scheduling for pregnant women.


Does home oxygen therapy (HOT) in addition to standard care reduce disease severity and improve symptoms in people with chronic heart failure? A randomised trial of home oxygen therapy for patients with chronic heart failure.
Home oxygen therapy (HOT) is commonly used for patients with severe chronic heart failure (CHF) who have intractable breathlessness. There is no trial evidence to support its use. To detect whether or not there was a quality-of-life benefit from HOT given as long-term oxygen therapy (LTOT) for at least 15 hours per day in the home, including overnight hours, compared with best medical therapy (BMT) in patients with severely symptomatic CHF. A pragmatic, two-arm, randomised controlled trial recruiting patients with severe CHF. It included a linked qualitative substudy to assess the views of patients using home oxygen, and a free-standing substudy to assess the haemodynamic effects of acute oxygen administration. Heart failure outpatient clinics in hospital or the community, in a range of urban and rural settings. Patients had to have heart failure from any aetiology, New York Heart Association (NYHA) class III/IV symptoms, at least moderate left ventricular systolic dysfunction, and be receiving maximally tolerated medical management. Patients were excluded if they had had a cardiac resynchronisation therapy device implanted within the past 3 months, chronic obstructive pulmonary disease fulfilling the criteria for LTOT or malignant disease that would impair survival or were using a device or medication that would impede their ability to use LTOT. Patients received BMT and were randomised (unblinded) to open-label LTOT, prescribed for 15 hours per day including overnight hours, or no oxygen therapy. The primary end point was quality of life as measured by the Minnesota Living with Heart Failure (MLwHF) questionnaire score at 6 months. Secondary outcomes included assessing the effect of LTOT on patient symptoms and disease severity, and assessing its acceptability to patients and carers. Between April 2012 and February 2014, 114 patients were randomised to receive either LTOT or BMT. The mean age was 72.3 years [standard deviation (SD) 11.3 years] and 70% were male. Ischaemic heart disease was the cause of heart failure in 84%; 95% were in NYHA class III; the mean left ventricular ejection fraction was 27.8%; and the median N-terminal pro-B-type natriuretic hormone was 2203 ng/l. The primary analysis used a covariance pattern mixed model which included patients only if they provided data for all baseline covariates adjusted for in the model and outcome data for at least one post-randomisation time point (n = 102: intervention, n = 51; control, n = 51). There was no difference in the MLwHF questionnaire score at 6 months between the two arms [at baseline the mean score was 54.0 (SD 18.4) for LTOT and 54.0 (SD 17.9) for BMT; at 6 months the mean score was 48.1 (SD 18.5) for LTOT and 49.0 (SD 20.2) for BMT; adjusted mean difference -0.10, 95% confidence interval (CI) -6.88 to 6.69; p = 0.98]. At 3 months, the adjusted mean MLwHF questionnaire score was lower in the LTOT group (-5.47, 95% CI -10.54 to -0.41; p = 0.03) and breathlessness scores improved, although the effect did not persist to 6 months. There was no effect of LTOT on any secondary measure. There was a greater number of deaths in the BMT arm (n = 12 vs. n = 6). Adherence was poor, with only 11% of patients reporting using the oxygen as prescribed. Although the study was significantly underpowered, HOT prescribed for 15 hours per day and subsequently used for a mean of 5.4 hours per day has no impact on quality of life as measured by the MLwHF questionnaire score at 6 months. Suggestions for future research include (1) a trial of patients with severe heart failure randomised to have emergency oxygen supply in the house, supplied by cylinders rather than an oxygen concentrator, powered to detect a reduction in admissions to hospital, and (2) a study of bed-bound patients with heart failure who are in the last few weeks of life, powered to detect changes in symptom severity. Current Controlled Trials ISRCTN60260702. This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 19, No. 75. See the NIHR Journals Library website for further project information.


Animal models of androgen-dependent disorders of the pilosebaceous apparatus. 1. The androchronogenetic alopecia (AGA) mouse as a model for male-pattern baldness.
The androchronogenetic alopecia (AGA) mouse if a mutant strain which expresses androgen-dependent baldness. Daily s.c. injection of testosterone (T) induced thinning of the hair coat along the upper dorsum after 4 weeks of treatment. After 12 to 14 weeks this diffuse alopecia eventually eveloped into a bald area which extended to the middorsum. Dihydrotestosterone was more effective than T in stimulating the onset of AGA. In this model, T produced the alopecia by decreasing the rate of hair growth, decreasing the duration of anagen, and markedly prolonging the duration of telogen. When applied topically at a concentration of 5%, cyproterone acetate delayed the progression of the T-mediated hair loss. However, this inhibitory effect occurred through systemic means as evidenced by decrease in the size of the submaxillary gland. Chronic feeding of androgen-treated female AGA mice with a diet containing 0.01% minoxidil also inhibited the development of alopecia. Skin and core temperatures were found to be higher in minoxidil-treated animals than in the placebo-treated controls. Minoxidil at a topical dose of 1% did not produce any effect. Increasing the dose to 2% caused a slight retardation of the development of alopecia. However, a 60% inhibition was observed at a topical dose of 5% minoxidil after 12 weeks of treatment (p less than 0.03). The data demonstrate that hair loss in the AGA mouse is androgen dependent and that this mutant strain can serve as a suitable model for the screening of compounds, such as antiandrogens and vasodilators, which may influence the balding process.


Contraindications to metformin therapy in patients with Type 2 diabetes--a population-based study of adherence to prescribing guidelines.
To define the number of people in Tayside, Scotland (population 349 303) with Type 2 diabetes who use metformin, the incidence of contraindications to its continued use in these people and the proportion that discontinued metformin treatment following the development of a contraindication. Retrospective cohort study of the incidence of contraindications to metformin in all patients with Type 2 diabetes using metformin from January 1993 to June 1995. The contraindications of acute myocardial infarction, cardiac failure, renal impairment and chronic liver disease were identified by: the regional diabetes information system, biochemistry database and hospital admissions database and a database of all encashed community prescriptions. One thousand eight hundred and forty seven subjects (26.3% of those with Type 2 diabetes) redeemed prescriptions for metformin. Of these, 3.5% were admitted with an acute myocardial infarction (71 episodes); 4.2% were admitted with cardiac failure (114 episodes); 21.0% received metformin and loop diuretics for cardiac failure concurrently; 4.8% developed renal impairment; and 2.8% developed chronic liver disease. The development of contraindications rarely resulted in discontinuation of metformin, for example only 17.5% and 25% stopped metformin after admission with acute myocardial infarction and development of renal impairment, respectively. In total, 24.5% of subjects receiving metformin, 6.4% of all people with Type 2 diabetes, had contraindications to its use. There was one episode of lactic acidosis in 4600 patient years. This population-based study shows that 24.5% of patients prescribed metformin have contraindications to its use. Development of contraindications rarely results in discontinuation of metformin therapy. Despite this, lactic acidosis remains rare. Diabet. Med. 18, 483-488 (2001)


Initial clonogenic potential of human endothelial progenitor cells is predictive of their further properties and establishes a functional hierarchy related to immaturity.
Endothelial progenitor cells (EPCs) generate in vitro Endothelial Colony Forming Cells (ECFCs) combining features of endothelial and stem/progenitor cells. Their angiogenic properties confer them a therapeutic potential for treating ischemic lesions. They may be isolated from umbilical cord blood (CB-ECFCs) or peripheral adult blood (AB-ECFCs). It is generally accepted that CB-ECFCs are more clonogenic, proliferative and angiogenic than AB-ECFCs. Nevertheless, only a few studies have focused on the functional heterogeneity of CB-ECFCs from different individuals. Moreover, AB-ECFC loss of function is yet to be precisely described. We have focused on these two issues that are critical for clinical perspectives. The detailed clonogenic profile of CB-ECFCs and AB-ECFCs was obtained and revealed a high inter individual heterogeneity and the absence of correlation with age. Most CB-ECFCs yielded initial colonies and had functional properties similar to those of AB-ECFCs. Conversely, a high clonogenicity was associated with an enhanced proliferative and angiogenic potential and stemness gene overexpression, confirming that immaturity, lost by AB-ECFCs, was a prerequisite to functionality. We thus demonstrated the importance of selecting CB-ECFCs according to specific criteria, and we propose using the initial clonogenicity as a relevant marker of their potential efficacy on vascular repair.


Concepts of the Distal Medial Patellar Restraints: Medial Patellotibial Ligament and Medial Patellomeniscal Ligament.
The important medial patellar ligamentous restraints to lateral dislocation are the proximal group (the medial quadriceps tendon femoral ligament and the medial patellofemoral ligament) and the distal group [medial patellotibial ligament (MPTL) and medial patellomeniscal ligament (MPML)]. The MPTL patellar insertion is at inferomedial border of patella and tibial insertion is in the anteromedial tibia. The MPML originates in the inferomedial patella, right proximal to the MPTL, inserting in the medial meniscus. On the basis of anatomy and biomechanical studies, the MPTL and MPML are more important in 2 moments during knee range of motion: terminal extension, when it directly counteracts quadriceps contraction. In a systematic review on MPTL reconstructions 19 articles were included detailing the clinical outcomes of 403 knees. All were case series. Overall, good and excellent outcomes were achieved in >75% of cohorts in most studies and redislocations were <10%, with or without the association of the medial patellofemoral ligament. The MPTL is a relevant additional tool to proximal restraint reconstruction in select patient profiles; however, more definitive clinical studies are necessary to better define surgical indications.


N6-methyladenosine (m6A) modification in Natural immune cell-mediated inflammatory diseases.
The post-transcriptional N6-methyladenosine (m6A) modification of RNA influences stability, transport and translation with implications for various physiological and pathological processes. Immune cell development, differentiation and activation are also thought to be regulated by m6A and affect host defense against pathogens and inflammatory response with impacts on infectious, neoplastic, autoimmune, cardiovascular, hepatic and osteal diseases. The current review summarizes recent research on m6A in monocyte/macrophages, neutrophils, dendritic cells, natural killer cells and microglia and gives insights into epigenetic modifications of the immune system and novel therapeutic strategies for immune-related diseases.


A Comparison of Network-Based Methods for Drug Repurposing along with an Application to Human Complex Diseases.
Drug repurposing strategy, proposing a therapeutic switching of already approved drugs with known medical indications to new therapeutic purposes, has been considered as an efficient approach to unveil novel drug candidates with new pharmacological activities, significantly reducing the cost and shortening the time of de novo drug discovery. Meaningful computational approaches for drug repurposing exploit the principles of the emerging field of Network Medicine, according to which human diseases can be interpreted as local perturbations of the human interactome network, where the molecular determinants of each disease (disease genes) are not randomly scattered, but co-localized in highly interconnected subnetworks (disease modules), whose perturbation is linked to the pathophenotype manifestation. By interpreting drug effects as local perturbations of the interactome, for a drug to be on-target effective against a specific disease or to cause off-target adverse effects, its targets should be in the nearby of disease-associated genes. Here, we used the network-based proximity measure to compute the distance between the drug module and the disease module in the human interactome by exploiting five different metrics (minimum, maximum, mean, median, mode), with the aim to compare different frameworks for highlighting putative repurposable drugs to treat complex human diseases, including malignant breast and prostate neoplasms, schizophrenia, and liver cirrhosis. Whilst the standard metric (that is the minimum) for the network-based proximity remained a valid tool for efficiently screening off-label drugs, we observed that the other implemented metrics specifically predicted further interesting drug candidates worthy of investigation for yielding a potentially significant clinical benefit.


Association between hospital process performance and outcomes among patients with acute coronary syndromes.
Selected care processes are increasingly being used to measure hospital quality; however, data regarding the association between hospital process performance and outcomes are limited. To evaluate contemporary care practices consistent with the American College of Cardiology/American Heart Association (ACC/AHA) guideline recommendations, to examine how hospital performance varied among centers, to identify characteristics predictive of higher guideline adherence, and to assess whether hospitals' overall composite guideline adherence was associated with observed and risk-adjusted in-hospital mortality rates. An observational analysis of hospital care in 350 academic and nonacademic US centers of 64,775 patients enrolled in the CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the ACC/AHA Guidelines) National Quality Improvement Initiative between January 1, 2001, and September 30, 2003, presenting with chest pain and positive electrocardiographic changes or cardiac biomarkers consistent with non-ST-segment elevation acute coronary syndrome (ACS). Use of 9 ACC/AHA class I guideline-recommended treatments and the correlation among hospitals' use of individual care processes as well as overall composite adherence rates. Overall, the 9 ACC/AHA guideline-recommended treatments were adhered to in 74% of eligible instances. There was modest correlation in hospital performance among the individual ACS process metrics. However, composite adherence performance varied widely (median [interquartile range] composite adherence scores from lowest to highest hospital quartiles, 63% [59%-66%] vs 82% [80%-84%]). Composite guideline adherence rate was significantly associated with in-hospital mortality, with observed mortality rates decreasing from 6.31% for the lowest adherence quartile to 4.15% for the highest adherence quartile (P<.001). After risk adjustment, every 10% increase in composite adherence at a hospital was associated with an analogous 10% decrease in its patients' likelihood of in-hospital mortality (adjusted odds ratio, 0.90; 95% confidence interval, 0.84-0.97; P<.001). A significant association between care process and outcomes was found, supporting the use of broad, guideline-based performance metrics as a means of assessing and helping improve hospital quality.


Sustainable bioenergy for climate mitigation: developing drought-tolerant trees and grasses.
Bioenergy crops are central to climate mitigation strategies that utilize biogenic carbon, such as BECCS (bioenergy with carbon capture and storage), alongside the use of biomass for heat, power, liquid fuels and, in the future, biorefining to chemicals. Several promising lignocellulosic crops are emerging that have no food role - fast-growing trees and grasses - but are well suited as bioenergy feedstocks, including Populus, Salix, Arundo, Miscanthus, Panicum and Sorghum. These promising crops remain largely undomesticated and, until recently, have had limited germplasm resources. In order to avoid competition with food crops for land and nature conservation, it is likely that future bioenergy crops will be grown on marginal land that is not needed for food production and is of poor quality and subject to drought stress. Thus, here we define an ideotype for drought tolerance that will enable biomass production to be maintained in the face of moderate drought stress. This includes traits that can readily be measured in wide populations of several hundred unique genotypes for genome-wide association studies, alongside traits that are informative but can only easily be assessed in limited numbers or training populations that may be more suitable for genomic selection. Phenotyping, not genotyping, is now the major bottleneck for progress, since in all lignocellulosic crops studied extensive use has been made of next-generation sequencing such that several thousand markers are now available and populations are emerging that will enable rapid progress for drought-tolerance breeding. The emergence of novel technologies for targeted genotyping by sequencing are particularly welcome. Genome editing has already been demonstrated for Populus and offers significant potential for rapid deployment of drought-tolerant crops through manipulation of ABA receptors, as demonstrated in Arabidopsis, with other gene targets yet to be tested. Bioenergy is predicted to be the fastest-developing renewable energy over the coming decade and significant investment over the past decade has been made in developing genomic resources and in collecting wild germplasm from within the natural ranges of several tree and grass crops. Harnessing these resources for climate-resilient crops for the future remains a challenge but one that is likely to be successful.


Levels of perfluorinated compounds (PFCs) in groundwater around improper municipal and industrial waste disposal sites in Thailand and health risk assessment.
The aims of this study were to examine the levels of perfluorinated compounds (PFCs) in groundwater around improperly developed municipal and industrial waste disposal sites, including estimating non-cancer risk and cancer risk from ingestion of the groundwater. A total of 27 groundwater samples were collected from two cities in Thailand, Ayutthaya and Chonburi. Seven target compounds were extracted by solid phase extraction (SPE) and analyzed by high-performance liquid chromatography-tandem mass spectrometer (HPLC-MS/MS). The results showed that the total PFCs in groundwater around municipal waste disposal sites (MWDSs) varied from 1.68 to 7.75 ng/L. In groundwater around the industrial waste disposal site (IWDS), total PFCs varied from 2.64 to 42.01 ng/L, which were significantly different from those found in groundwater around the MWDSs at p < 0.01. PFOS and PFOA were ubiquitous in both areas, while perfluorohexane sulfonate (PFHxS) was frequently found in the samples around IWDS. The findings possibly suggest that PFHxS has been introduced for use as an alternative substance for most current C8 and higher due to it having shorter chain length and shorter half-lives. The results for both non-cancer risk and cancer risk in all samples were acceptable.


The use of semen parameters to identify the subfertile male in the general population.
To present a structured review of the literature published on semen parameters and in vivo fertility potential and to establish fertility/subfertility thresholds for sperm morphology using Tygerberg strict criteria, sperm concentration, and sperm motility. The published literature comparing fertile and subfertile populations between 1983 and 2002 was reviewed. A total of 265 articles were identified by the sourcing methodology, but only four articles provided data that could be tabulated and analyzed. Using receiver-operating characteristics curves, morphology proved to be the best predictor of subfertility in 2 of the 4 articles, with concentration and motility also showing good predictive power. The thresholds calculated ranged between 4 and 10% for morphology, between 13.5 x 10(6)/ml and 34 x 10(6)/ml for concentration, and between 32 and 52% for motility. A second set of much lower thresholds was calculated in three of the articles using either a 15 or 50% prevalence of subfertility in the population or the tenth percentile of the fertile population. The adjusted thresholds were between 3 and 5% for morphology, between 9 x 10(6)/ml and 20 x 10(6)/ml for concentration, and between 20 and 30% for motility. Because these lower thresholds have a much higher positive predictive value, we suggest that thresholds of <5% normal sperm morphology, a concentration <15 x 10(6)/ml, and a motility <30% should be used to identify the subfertile male. The lower threshold for morphology also fits in vitro fertilization and intrauterine insemination data calculated previously. Using the parameters in combination increases the clinical value of semen analysis.


Cattle demographic history modelled from autosomal sequence variation.
The phylogeography of cattle genetic variants has been extensively described and has informed the history of domestication. However, there remains a dearth of demographic models inferred from such data. Here, we describe sequence diversity at 37 000 bp sampled from 17 genes in cattle from Africa, Europe and India. Clearly distinct population histories are suggested between Bos indicus and Bos taurus, with the former displaying higher diversity statistics. We compare the unfolded site frequency spectra in each to those simulated using a diffusion approximation method and build a best-fitting model of past demography. This implies an earlier, possibly glaciation-induced population bottleneck in B. taurus ancestry with a later, possibly domestication-associated demographic constriction in B. indicus. Strikingly, the modelled indicine history also requires a majority secondary admixture from the South Asian aurochs, indicating a complex, more diffuse domestication process. This perhaps involved multiple domestications and/or introgression from wild oxen to domestic herds; the latter is plausible from archaeological evidence of contemporaneous wild and domestic remains across different regions of South Asia.


Compound screening platform using human induced pluripotent stem cells to identify small molecules that promote chondrogenesis.
Articular cartilage, which is mainly composed of collagen II, enables smooth skeletal movement. Degeneration of collagen II can be caused by various events, such as injury, but degeneration especially increases over the course of normal aging. Unfortunately, the body does not fully repair itself from this type of degeneration, resulting in impaired movement. Microfracture, an articular cartilage repair surgical technique, has been commonly used in the clinic to induce the repair of tissue at damage sites. Mesenchymal stem cells (MSC) have also been used as cell therapy to repair degenerated cartilage. However, the therapeutic outcomes of all these techniques vary in different patients depending on their age, health, lesion size and the extent of damage to the cartilage. The repairing tissues either form fibrocartilage or go into a hypertrophic stage, both of which do not reproduce the equivalent functionality of endogenous hyaline cartilage. One of the reasons for this is inefficient chondrogenesis by endogenous and exogenous MSC. Drugs that promote chondrogenesis could be used to induce self-repair of damaged cartilage as a non-invasive approach alone, or combined with other techniques to greatly assist the therapeutic outcomes. The recent development of human induced pluripotent stem cell (iPSCs), which are able to self-renew and differentiate into multiple cell types, provides a potentially valuable cell resource for drug screening in a "more relevant" cell type. Here we report a screening platform using human iPSCs in a multi-well plate format to identify compounds that could promote chondrogenesis.


Response of Bone Turnover Markers and Cytokines to High-Intensity Low-Impact Exercise.
Low-impact, high-intensity interval exercise (HIE) was used to investigate the postexercise response in bone turnover markers and cytokines. Twenty-three recreationally active males (21.8 ± 2.4 yr) performed one HIE bout on a cycle ergometer at 90% maximum workload. The total duration of the exercise was 12 min and included six 1-min high-intensity exercise intervals separated by 1-min rest intervals. Blood samples were collected before exercise, 5 min, 1 h, and 24 h after exercise and were analyzed for serum levels of anti- and pro-inflammatory cytokines (interleukin 10 [IL-10], interleukin 6 [IL-6], interleukin 1-alpha [IL-1α], interleukin 1-beta [IL-1β], and tumor necrosis factor alpha [TNF-α]) and markers of bone formation (bone alkaline phosphatase [BAP], osteoprotegerin [OPG]) and resorption (amino-terminal cross-linking propeptide [NTX], receptor activator of NF-κB ligand [RANKL]). There was a significant (P < 0.05) time effect for all bone turnover markers. Post hoc analysis showed that BAP, OPG, and RANKL significantly increased from baseline to 5 min after exercise (10.9%, 13.5%, and 34.2%, P < 0.05). At 1 h after exercise, only BAP was significantly higher than baseline (9.5%, P = 0.010) and remained higher than baseline at 24 h (10.9%, P = 0.001). NTX was significantly lower than baseline 24 h after exercise (-14.6%, P = 0.046). Significant (P < 0.05) time effects were also observed for IL-1α, IL-1β, IL-6, and TNF-α, with all four significantly increasing 5 min after exercise and returning to baseline levels 1 h after exercise. The postexercise changes in bone formation markers correlated positively with the anti-inflammatory cytokine (IL-10) and negatively with the pro-inflammatory cytokines while NTX correlated positively with a pro-inflammatory cytokine, TNF-α (P < 0.05). These results suggest that HIE stimulates a response in bone turnover markers and cytokines and that a correlation exists between immune and skeletal responses to this form of exercise. This type of exercise may benefit individuals for whom high-impact exercise might be contraindicated.


The Uniform Data System for Medical Rehabilitation: report of follow-up information on patients discharged from inpatient rehabilitation programs in 2002-2010.
The aim of this study was to present yearly aggregated summaries of rehabilitation outcomes at admission, discharge, and follow-up from a national sample of patients receiving inpatient medical rehabilitation for stroke, traumatic brain injury, lower extremity fracture, lower extremity joint replacement, traumatic spinal cord injury, or debility. This is an analysis of secondary data from more than 300 inpatient rehabilitation facilities in the United States that contributed inpatient and follow-up data to the Uniform Data System for Medical Rehabilitation during the period January 2002 through December 2010. Aggregate variables reported include demographic information, social situation, and functional status (Functional Independence Measure instrument ratings at admission, discharge, and follow-up). Follow-up data were obtained 80-180 days after discharge through telephone interviews by trained clinical staff. The final sample included 287,104 patients with follow-up information. The median time to follow-up was 95 days. Overall, more than 90% of the patients within each impairment group were living in the community at follow-up. Follow-up Functional Independence Measure total ratings were stable to slightly increased over time. Change scores (discharge to follow-up) increased in all six groups. The mean Functional Independence Measure gains from discharge to follow-up, as a percentage of mean gains from admission to discharge, varied by impairment category: 46% for spinal cord injury to 71% for lower extremity fracture. Locomotion yielded the lowest ratings at all three assessments within each of the six impairment groups. The follow-up data from the national sample of patients discharged from inpatient rehabilitation indicate that gains in mean functional independence scores from both admission to discharge and discharge to follow-up gradually increased from 2002 to 2010. At follow-up, more than nine of ten patients in all six groups are living in the community.