Effects of stress on the functional properties of pre- and postsynaptic 5-HT1B receptors in the rat brain.
Numerous studies have clearly shown that the turnover and release of serotonin (5-hydroxytryptamine, 5-HT) are increased under acute stressful conditions. Inasmuch as this latter process is under the control of a feedback mechanism involving the stimulation of presynaptic 5-HT1B autoreceptors, we have investigated the possible effects of acute restraint (40 min) on the functional properties of 5-HT1B receptors. The efficacy of the selective 5-HT1B receptor agonist 3-[1,2,5,6-tetrahydropyrid-4-yl]pyrrolo-[3,2-b]pyrid-5-one (CP-93,129) in inhibiting in vitro the K+-evoked release of [3H]5-HT, was significantly reduced in stressed rats as compared to naive animals. Similarly, the responsiveness of 5-HT1B receptors inhibiting the release of [3H]acetylcholine (presynaptic 5-HT1B heteroreceptors), was reduced by restraint. These effects were observed in the hippocampus, but using the inhibitory effect of CP-93,129 on forskolin-stimulated adenylyl cyclase activity as an index of 5-HT1B receptor function, it could be shown that the 5-HT1B receptors located in the substantia nigra are also desensitized by stress. The number as well as the apparent affinity constant of 5-HT1B binding sites labelled by [125I]iodocyanopindolol, as measured by quantitative autoradiography and membrane binding, were similar in naive and restraint-stressed rats suggesting that the stress-induced desensitization of 5-HT1B receptors is not due to a reduced number of 5-HT1B binding sites. As stress is thought to be a causal factor for the etiology of anxiety and depression, these results support the potential involvement of 5-HT1B receptor dysfunction in the development of these neurological disorders.


Expression of distinct RNAs from 3' untranslated regions.
The 3' untranslated regions (3'UTRs) of eukaryotic genes regulate mRNA stability, localization and translation. Here, we present evidence that large numbers of 3'UTRs in human, mouse and fly are also expressed separately from the associated protein-coding sequences to which they are normally linked, likely by post-transcriptional cleavage. Analysis of CAGE (capped analysis of gene expression), SAGE (serial analysis of gene expression) and cDNA libraries, as well as microarray expression profiles, demonstrate that the independent expression of 3'UTRs is a regulated and conserved genome-wide phenomenon. We characterize the expression of several 3'UTR-derived RNAs (uaRNAs) in detail in mouse embryos, showing by in situ hybridization that these transcripts are expressed in a cell- and subcellular-specific manner. Our results suggest that 3'UTR sequences can function not only in cis to regulate protein expression, but also intrinsically and independently in trans, likely as noncoding RNAs, a conclusion supported by a number of previous genetic studies. Our findings suggest novel functions for 3'UTRs, as well as caution in the use of 3'UTR sequence probes to analyze gene expression.


Scaffold-free culture of mesenchymal stem cell spheroids in suspension preserves multilineage potential.
While traditional cell culture methods have relied on growing cells as monolayers, three-dimensional (3D) culture systems can provide a convenient in vitro model for the study of complex cell-cell and cell-matrix interactions in the absence of exogenous substrates and may benefit the development of regenerative medicine strategies. In this study, mesenchymal stem cell (MSC) spheroids, or "mesenspheres", of different sizes, were formed using a forced aggregation technique and maintained in suspension culture for extended periods of time thereafter. Cell proliferation and differentiation potential within mesenspheres and dissociated cells retrieved from spheroids were compared to conventional adherent monolayer cultures. Mesenspheres maintained in growth medium exhibited no evidence of cell necrosis or differentiation, while mesenspheres in differentiation media exhibited differentiation similar to conventional 2D culture methods based on histological markers of osteogenic and adipogenic commitment. Furthermore, when plated onto tissue culture plates, cells that had been cultured within mesenspheres in growth medium recovered morphology typical of cells cultured continuously in adherent monolayers and retained their capacity for multi-lineage differentiation potential. In fact, more robust matrix mineralization and lipid vacuole content were evident in recovered MSCs when compared to monolayers, suggesting enhanced differentiation by cells cultured as 3D spheroids. Thus, this study demonstrates the development of a 3D culture system for mesenchymal stem cells that may circumvent limitations associated with conventional monolayer cultures and enhance the differentiation potential of multipotent cells.


Demographic genetics of brown trout (Salmo trutta) and estimation of effective population size from temporal change of allele frequencies.
We studied temporal allele frequency shifts over 15 years and estimated the genetically effective size of four natural populations of brown trout (Salmo trutta L.) on the basis of the variation at 14 polymorphic allozyme loci. The allele frequency differences between consecutive cohorts were significant in all four populations. There were no indications of natural selection, and we conclude that random genetic drift is the most likely cause of temporal allele frequency shifts at the loci examined. Effective population sizes were estimated from observed allele frequency shifts among cohorts, taking into consideration the demographic characteristics of each population. The estimated effective sizes of the four populations range from 52 to 480 individuals, and we conclude that the effective size of natural brown trout populations may differ considerably among lakes that are similar in size and other apparent characteristics. In spite of their different effective sizes all four populations have similar levels of genetic variation (average heterozygosity) indicating that excessive loss of genetic variability has been retarded, most likely because of gene flow among neighboring populations.


Metabolism of vasopressin.
The clearance of vasopressin (VP) by the kidneys and splanchnic viscera was studied in the anesthetized dog. VP is bound to plasma protein, 10% at basal plasma VP levels and 40% at plasma VP concentrations greater than 20 microU/ml. The urinary clearance of VP is 70-100% of the glomerular filtration rate; the renal organ clearance of the hormone is 20-30% greater than its urinary clearance. There is evidence that the renal organ clearance of VP is affected by changes in both glomerular filtration rate and renal blood flow. The renal clearance of VP is a result of glomerular filtration, degradation, or reabsorption in the proximal nephron, and secretion into the distal nephron. In the short term, the renal clearance of VP is unaffected either by changes in the plasma VP concentration over a broad range or by moderate hemorrhage. The splanchnic clearance of VP is accomplished almost equally by the intestine and the liver. Because the sum of the splanchnic and renal clearances of VP is less than estimates of its metabolic clearance rate, there may be a physiologically significant clearance of VP by organs in addition to the kidneys and splanchnic viscera.


A randomized, placebo-controlled, double-blind study to evaluate the efficacy of a citrus bioflavanoid blend in the treatment of senile purpura.
Senile purpura is a common, chronic skin condition affecting more than 10 percent of individuals over the age of 50. Despite being a benign condition, the continual development of purpura lesions in afflicted patients is frequently a source of significant visual and social concern. To date, there are no known effective treatments for this condition. To evaluate the efficacy of a novel nutraceutical citrus bioflavonoid blend in improving the skin's appearance in patients with senile purpura. A six-week, randomized, multicenter, placebo-controlled, double-blind study was conducted to determine whether a uniquely formulated, oral citrus bioflavonoid supplement could treat active lesions of senile purpura while preventing new lesions from arising. Seventy patients with senile purpura were enrolled and 67 completed the study. Subjects were randomized into two groups receiving either a citrus bioflavonoid blend or placebo medication, which was taken orally twice daily for six weeks. Clinical evaluations were performed by blinded investigators at two locations. A statistically significant reduction in the number of new purpura lesions in the skin area undergoing clinical study was documented. At the end of six weeks, the citrus bioflavonoid blend treated group showed a 50 percent reduction in purpura lesions from baseline. Patient self-assessment of the effectiveness of the medication echoed the results of an investigator global assessment with a statistically significant improvement in the skin's appearance noted by the patients receiving the active medication. No adverse effects were noted by either the patients or investigators. This new treatment appears to both safely and effectively diminish skin bruising in patients with senile purpura.


Optimization of Data-Independent Acquisition Mass Spectrometry for Deep and Highly Sensitive Proteomic Analysis.
Data-independent acquisition (DIA)-mass spectrometry (MS)-based proteomic analysis overtop the existing data-dependent acquisition (DDA)-MS-based proteomic analysis to enable deep proteome coverage and precise relative quantitative analysis in single-shot liquid chromatography (LC)-MS/MS. However, DIA-MS-based proteomic analysis has not yet been optimized in terms of system robustness and throughput, particularly for its practical applications. We established a single-shot LC-MS/MS system with an MS measurement time of 90 min for a highly sensitive and deep proteomic analysis by optimizing the conditions of DIA and nanoLC. We identified 7020 and 4068 proteins from 200 ng and 10 ng, respectively, of tryptic floating human embryonic kidney cells 293 (HEK293F) cell digest by performing the constructed LC-MS method with a protein sequence database search. The numbers of identified proteins from 200 ng and 10 ng of tryptic HEK293F increased to 8509 and 5706, respectively, by searching the chromatogram library created by gas-phase fractionated DIA. Moreover, DIA protein quantification was highly reproducible, with median coefficients of variation of 4.3% in eight replicate analyses. We could demonstrate the power of this system by applying the proteomic analysis to detect subtle changes in protein profiles between cerebrums in germ-free and specific pathogen-free mice, which successfully showed that >40 proteins were differentially produced between the cerebrums in the presence or absence of bacteria.


The gut microbiota of siblings offers insights into microbial pathogenesis of inflammatory bowel disease.
Siblings of patients with Crohn's disease (CD) have elevated risk of developing CD and display aspects of disease phenotype, including faecal dysbiosis. In our recent article we have used 16S rRNA gene targeted high-throughput sequencing to comprehensively characterize the mucosal microbiota in healthy siblings of CD patients, and determine the influence of genotypic and phenotypic factors on the gut microbiota (dysbiosis). We have demonstrated that the core microbiota of both patients with CD and healthy siblings is significantly less diverse than controls. Faecalibacterium prausnitzii contributed most to core metacommunity dissimilarity between both patients and controls and between siblings and controls. Phenotype/genotype markers of CD risk significantly influenced microbiota variation between and within groups, of which genotype had the largest effect. Individuals with elevated CD-risk display mucosal dysbiosis characterized by reduced diversity of core microbiota and lower abundance of F. prausnitzii. The presence of this dysbiosis in healthy people at-risk of CD implicates microbiological processes in CD pathogenesis.


The impact of Chinese cultural values on Taiwan nursing leadership styles: comparing the self-assessments of staff nurses and head nurses.
The purpose of this study was to investigate the influence of Chinese culture on nursing leadership behavior in Taiwan nurses. A descriptive study compared staff nurses' assessment of Chinese value in the leadership behavior of their head nurses. Data analysis was made on a convenience sample in Taiwan of 214 head nurses and 2,127 staff nurses who had worked with their head nurse for at least one year. Six medical centers and regional hospitals in northern (Taipei), central (Taichung) and southern (Kaohsiung) Taiwan were recruited for this study. Instruments included the demographic questionnaire, Chinese Value Survey, and Kang's Chinese Leadership Behaviors Module Scale. Results indicated that head nurses scored significantly higher than staff nurses in terms of all cultural values and leadership behaviors. Both staff nurses and head nurses scored the highest mean scores in personal integrity (Yi) and human connectedness (Ren) and the lowest in moral discipline (Li). Staff nurse perceptions of leadership behavior indicated the role of parent to be higher than either the role of director or mentor. Head nurses perceptions of leadership behavior emphasized the role of the director more than either parent or mentor. There were no significant differences between the staff nurses and head nurses in terms of expectative leadership behavior, which gave the role of director higher mean scores than those of either the parent or mentor. Positive and significant associations (r = .266 to r = .334) were found between cultural values and perceptions of leadership behavior. Cultural values predicted 10.6% of leadership behavior variance. The three demographic characteristics of location in northern Taiwan (beta = .09), intention to leave (beta = -.14), and general unit (beta = .10) and the two cultural values of human connectedness (Ren) (beta = .16) and personal integrity (Yi) (beta = .16) together reported a cumulative R2 of 14.6% to explain variance in leadership behavior perceptions. Results of this study identified the important cultural values "Ren" and "Yi". Managers and administrators could add the consideration of such cultural values into nursing leadership to enhance the organization in which Taiwan nurses work.


A physical wiring diagram for the human immune system.
The human immune system is composed of a distributed network of cells circulating throughout the body, which must dynamically form physical associations and communicate using interactions between their cell-surface proteomes1. Despite their therapeutic potential2, our map of these surface interactions remains incomplete3,4. Here, using a high-throughput surface receptor screening method, we systematically mapped the direct protein interactions across a recombinant library that encompasses most of the surface proteins that are detectable on human leukocytes. We independently validated and determined the biophysical parameters of each novel interaction, resulting in a high-confidence and quantitative view of the receptor wiring that connects human immune cells. By integrating our interactome with expression data, we identified trends in the dynamics of immune interactions and constructed a reductionist mathematical model that predicts cellular connectivity from basic principles. We also developed an interactive multi-tissue single-cell atlas that infers immune interactions throughout the body, revealing potential functional contexts for new interactions and hubs in multicellular networks. Finally, we combined targeted protein stimulation of human leukocytes with multiplex high-content microscopy to link our receptor interactions to functional roles, in terms of both modulating immune responses and maintaining normal patterns of intercellular associations. Together, our work provides a systematic perspective on the intercellular wiring of the human immune system that extends from systems-level principles of immune cell connectivity down to mechanistic characterization of individual receptors, which could offer opportunities for therapeutic intervention.


Drooling, saliva production, and swallowing in cerebral palsy.
Fourteen participants (six females, eight males) ranging in age from 7 years 11 months to 18 years 2 months (mean 11y 7mo) with a confirmed diagnosis of spastic cerebral palsy (CP) were included in the study. Participants included those who drooled (CP+, n=14); age- and sex-matched children with spastic CP who were dry to mild and never to infrequent droolers (CP-, n=14) as well as typically developing peers (CTRL, n=14) served as controls. Frequency of swallowing was measured by using simultaneous cervical ausculation and videotaping of the head and neck. Saliva production was measured with the Saxon test, a simple gauze-chewing procedure. In addition, Pediatric Evaluation of Disability Inventory (PEDI), Test of Nonverbal Intelligence-3 (TONI-3), dysarthria severity scale, and Gross Motor Function Classification System (GMFCS) scores were obtained for each participant. Both groups of participants with CP tended to swallow less frequently than typically developing participants and tended to produce less saliva than typically developing controls; however, these differences were not statistically significant. No correlation was found between amount of saliva produced and amount drooled (r=0.245). An analysis of variance (ANOVA) conducted on the PEDI functional skills mean scores indicated significant differences between the three groups (F(2,39)=23.522,p<0.0001). Likewise, an ANOVA conducted on the TONI-3 scores revealed statistically significant differences between the three groups (F(2,39)=31.761, p<0.0001). A Spearman's rho correlation indicated that GMFCS scores were not significantly correlated with drooling severity (Spearman's rho correlation=0.3951,p=0.037). Drooling severity was found to be positively correlated with dysarthria severity (Spearman's rho correlation=0.82,p<0.0001). These findings suggest that drooling in patients with CP is related to swallowing difficulties rather than hypersalivation.


Efficacy and tolerability of atorvastatin/fenofibrate fixed-dose combination tablet compared with atorvastatin and fenofibrate monotherapies in patients with dyslipidemia: a 12-week, multicenter, double-blind, randomized, parallel-group study.
Coadministration of statin and fenofibrate monotherapies is frequently used to treat patients with dyslipidemia; however, a fixed-dose combination (FDC) tablet is not currently marketed. This study evaluates a new FDC tablet of atorvastatin 40 mg and fenofibrate 100 mg. This was a 12-week, multicenter, double-blind, randomized, parallel-group Phase IIb study. Adults with dyslipidemia (non-HDL-C >130 mg/dL and triglycerides [TG] > or =150 but < or =500 mg/dL) were randomly assigned in a 1:1:1 ratio to receive the FDC, atorvastatin 40 mg, or fenofibrate 145 mg for 12 weeks. Study medication was taken once daily in the evening, without regard to meals. Patients attended follow-up visits after 4, 8, and 12 weeks of the double-blind treatment. The primary efficacy end points were the mean percentage changes from baseline to the final visit (week 12) in non-HDL-C, HDL-C, and TG. Secondary variables were LDL-C, VLDL-C particle concentration, total cholesterol, apolipoprotein B, lipoprotein (a), high-sensitivity C-reactive protein, fibrinogen, homocysteine, creatinine, myeloperoxidase, and lipoprotein-associated phospholipase A2. Tolerability was assessed by adverse events, laboratory parameters, vital signs, physical examinations, and ECGs. Patients (n = 220) were aged 26 to 87 years; 115 (52.3%) were men and 105 (47.7%) were women; 189 (85.9%) were white, 17 (7.7%) were black, and 15 (6.8%) were Hispanic or Latino; and mean (SD) weight was 200.5 (40.85) lb (range, 103.5-367.4 lb). Previous treatments were statins (25.9% [57/220]), fibrates (1.8% [4/220]), and dietary supplements (25.5% [56/220]); 57.7% (127/220) of patients were treatment naive. Use of the FDC was associated with an improvement in non-HDL-C (-44.8%) that was significantly greater than with fenofibrate monotherapy (-16.1%; P < 0.001) but was not significantly different from that with atorvastatin monotherapy (-40.2%; P = NS). HDL-C increased significantly more in the FDC group (19.7%) than with atorvastatin (6.5%; P < 0.001) but was not significantly different from fenofibrate (18.2%; P = NS). TG lowering in the FDC group (-49.1%) was significantly greater than with both atorvastatin (-28.9%; P < 0.001) and fenofibrate (-27.8%; P = 0.001). LDL-C lowering in the FDC group (-42.3%) was significantly greater than with fenofibrate (-13.9%; P < 0.001) but not significantly different from atorvastatin (-43.1%; P = NS). The FDC had either comparable or significantly greater improvements in other lipid variables and multiple secondary variables. The FDC was generally well tolerated; the tolerability profile was consistent with those of atorvastatin and fenofibrate monotherapies. Treatment-emergent adverse events (ie, those occurring after the first dose of study medication) were recorded in 43 of 73 patients (58.9%) for the FDC, 49 of 74 (66.2%) for atorvastatin, and 48 of 73 (65.8%) for fenofibrate. In this 12-week study, patients with dyslipidemia treated with the 40/100-mg atorvastatin/ fenofibrate FDC had a significantly greater reduction in TG than those treated with atorvastatin 40 mg or higher-dose fenofibrate 145 mg. Treatment with the FDC was also associated with a significantly greater reduction in non-HDL-C compared with fenofibrate alone and a greater increase in HDL-C compared with atorvastatin alone. All treatments were generally well tolerated.


Improved estimates of upper-ocean warming and multi-decadal sea-level rise.
Changes in the climate system's energy budget are predominantly revealed in ocean temperatures and the associated thermal expansion contribution to sea-level rise. Climate models, however, do not reproduce the large decadal variability in globally averaged ocean heat content inferred from the sparse observational database, even when volcanic and other variable climate forcings are included. The sum of the observed contributions has also not adequately explained the overall multi-decadal rise. Here we report improved estimates of near-global ocean heat content and thermal expansion for the upper 300 m and 700 m of the ocean for 1950-2003, using statistical techniques that allow for sparse data coverage and applying recent corrections to reduce systematic biases in the most common ocean temperature observations. Our ocean warming and thermal expansion trends for 1961-2003 are about 50 per cent larger than earlier estimates but about 40 per cent smaller for 1993-2003, which is consistent with the recognition that previously estimated rates for the 1990s had a positive bias as a result of instrumental errors. On average, the decadal variability of the climate models with volcanic forcing now agrees approximately with the observations, but the modelled multi-decadal trends are smaller than observed. We add our observational estimate of upper-ocean thermal expansion to other contributions to sea-level rise and find that the sum of contributions from 1961 to 2003 is about 1.5 +/- 0.4 mm yr(-1), in good agreement with our updated estimate of near-global mean sea-level rise (using techniques established in earlier studies) of 1.6 +/- 0.2 mm yr(-1).


The use of Campath-1H as induction therapy in renal transplantation: preliminary results.
In an attempt to reduce both initial and long-term (nephrotoxic) calcineurin inhibitor maintenance dosage and totally eliminate maintenance corticosteroids, alemtuzumab (Campath-1H) was used as induction therapy in first cadaver and non-HLA-identical living donor renal transplantation. Forty-four de novo renal allograft recipients were treated with Campath-1H (0.3 mg/kg) on days 0 and 4 postoperatively, preceded by methylprednisolone boluses. Maintenance target 12-hr tacrolimus trough levels of 5 to 7 ng/mL were operational from the outset as well as (reduced) mycophenolate mofetil dosage of 500 mg twice daily. No corticosteroids were planned to be given after the first week postoperatively. With a median follow-up of 9 (range, 1-19) months, patient and graft survival rates are each at 100%. Biopsy-proven acute rejection was diagnosed in four patients. Infections requiring hospitalization developed in four patients. Thirty-eight recipients remain without the need for long-term corticosteroid therapy. In an early assessment, the combination of Campath-1H, low dosing of tacrolimus and mycophenolate mofetil, and avoidance of maintenance corticosteroid use seems to be safe and effective for kidney transplant recipients. Long-term outcomes will be reported in the future.


Canine intestinal parasitic infections and soil contamination by Toxocara spp. in selected areas of Sri Lanka.
Contaminated environment with canine parasitic eggs is the main source for toxocariasis and other geohelminth infections of humans. This study aimed to determine the prevalence and associated risk factors for intestinal parasitic infections in dogs and the degree of soil contamination with Toxocara eggs in Kandy and Gampaha districts in Sri Lanka. A total of 188 fecal samples from both stray and domestic owned dogs from Gampaha district and Kandy district were collected. In addition, soil samples were collected from home gardens and public places. Hypochlorite recovery technique and zinc sulfate floatation method were used to concentrate eggs in soil samples. The prevalence of intestinal parasitic infections of domestic and stray dogs in Gampaha district was 38.2% and 42.9%, respectively, while in Kandy district, it was 41.1% and 50%, respectively. Hookworms were the most common parasitic infection among domestic dogs (18.5%), while Toxocara spp. were the most common among stray dogs (17.2%). Intestinal parasitic infections were significantly more prevalent among female dogs than males. Age, deworming, immunization, immunization time, and living in rural areas were not significantly associated with intestinal parasitic infections in domestic dogs. A total of 4% and 4.5% soil samples were contaminated with Toxocara spp. eggs in Gampaha and Kandy districts, respectively. The higher prevalence of intestinal parasitic infections in dogs could be a major public health issue. Implementations of programs to improve the awareness of parasitic infections among pet owners and control strategies need to decrease the risk of infections to both animal and human health.


Human milk vitamin content after pasteurisation, storage, or tube feeding.
We investigated the effect of the composition of the storage container, Holder pasteurisation, and conditions during tube feeding on the concentration of selected vitamins in human milk. Though the fat soluble vitamins A, D, and E were not affected, the concentration of several water soluble vitamins decreased. The lower vitamin C concentration of milk stored in polypropylene containers compared with milk stored in glass containers (29%) was not significant. Holder pasteurisation significantly lowered the concentrations of vitamins C (36%), folacin (31%), and B6 (15%). Tube feeding significantly lowered the concentrations of vitamins C (44%) and B6 (19%), and exposure to phototherapy seemed to lower the vitamin C concentration (53%) further. Low birthweight infants have increased vitamin requirements. Vitamin losses in expressed human milk before or during feeding may increase the incidence of vitamin deficiencies in these babies.


Childhood temporary separation: long-term effects of the British evacuation of children during World War 2 on older adults' attachment styles.
This study investigates long-term effects on adult attachment due to temporary childhood separation as a result of the British evacuation of children during World War 2. A total of 859 respondents, aged 62-72 years, were recruited who had childhood homes in the county of Kent during the war. Of these, 770 had been evacuated and 89 remained at home and formed a non-evacuated control group. They participated in this retrospective survey of possible associations between childhood experiences of the evacuation, early upbringing, and later life-course variables, with adult attachment style assessed by the Relationship Questionnaire (Bartholomew & Horowitz, 1991). Reflecting the wartime concerns of Bowlby, male and female respondents evacuated between the ages of 4 and 6 years showed low incidences in secure attachment style of 38% and 27%, compared to those not evacuated at 64% and 44%, respectively, with a corresponding increase in the fearful category. The quality of care received during evacuation and the frequency of parental visits were also found to be significantly associated with attachment style for female respondents. Irrespective of experience of evacuation, both male and female respondents who reported poor home nurture showed a similar low incidence of secure attachment of 23% compared to those from homes with good quality care of 45% and 43%, respectively, with concomitant increases in proportions in the dismissing category for males and the fearful category for females. The clinical implications of the study are briefly discussed.


Reproductive innovation and the recognition of a new genus within the Polystomatidae (Monogenea) infecting chelonian vertebrates.
Polystomatid monogeneans have a wide diversity of life cycles correlated with the varied ecology and behaviour of their aquatic vertebrate hosts. Typically, transmission involves a swimming infective larva but most hosts are amphibious and invasion is interrupted when hosts leave water. A key life cycle adaptation involves a uterus that, in the most specialised cases, may contain several hundred fully-developed larvae prepared for instant host-to-host transmission. By contrast, one subfamily of the Polystomatidae - the Polystomoidinae, specific to chelonians (freshwater turtles) - has a simplified reproductive system without a uterus. Recently, Polystomoides nelsoni Du Preez et Van Rooyen, 2015 has been described with a uterus containing multiple eggs. The present study explores the exceptional interest of this parasite - for the functional biology of egg production, for the evolution of a reproductive system unique amongst ca 60 species in the subfamily, and for systematic relationships. A new genus is proposed, Uteropolystomoides gen. n., separate from the four currently-recognised genera Polystomoides Ward, 1917, Uropolystomoides Tinsley et Tinsley, 2016, Neopolystoma Price, 1939 and Polystomoidella Price, 1939 which lack a uterus. In addition, U. nelsoni (Du Preez et Van Rooyen, 2015) comb. n. has a suite of distinctive copulatory stuctures: a massive genital bulb with an exceptionally large number of very long genital spines and hyper-development of the vaginal openings. These characters set U. nelsoni apart from all other polystomoidines worldwide except Polystomoides multifalx Stunkard, 1924 and P. stunkardi Harwood, 1931. Missing data for these latter species preclude definitive assessment of inter-relationships but the distinguishing characters of U. nelsoni, especially the unique occurrence of the uterus, suggest a novel evolutionary pathway isolated from other lineages of polystomatids infecting chelonians.


Role of post-translational modifications in modulating the structure, function and toxicity of alpha-synuclein: implications for Parkinson's disease pathogenesis and therapies.
A better understanding of the molecular and cellular determinants that influence the pathology of Parkinson's disease (PD) is essential for developing effective diagnostic, preventative and therapeutic strategies to treat this devastating disease. A number of post-translational modifications to alpha-syn are present within the Lewy bodies in the brains of affected patients and transgenic models of PD and related disorders. However, whether disease-associated alpha-syn post-translational modifications promote or inhibit alpha-syn aggregation and neurotoxicity in vivo remains unknown. Herein, we summarize and discuss the major disease-associated post-translational modifications (phosphorylation, truncation and ubiquitination) and present our current understanding of the effect of these modifications on alpha-syn aggregation and toxicity. Elucidating the molecular mechanisms underlying post-translation modifications of alpha-syn and the consequences of such modifications on the biochemical, structural, aggregation and toxic properties of the protein is essential for unravelling the molecular basis of its function(s) in health and disease. Furthermore, the identification of the natural enzymes involved in regulating the post-translational modifications of alpha-synuclein will yield novel and more tractable therapeutic targets to treat PD and related synucleinopathies.


LSD: injection early in pregnancy produces abnormalities in offspring of rats.
One of five rats given a single subcutaneous injection of lysergic acid diethylamide (LSD) early in pregnancy appeared to abort early; two delivered stunted stillborn offspring at term, one delivered a littler of seven healthy and one underdeveloped young, and the last one delivered an apparently normal litter. All five matched controls, given saline injections, went to term and delivered healthy litters of 11 to 16 offspring; there were no abortions and no stillbirths. In a replicate experiment, one of five rats given LSD on the 4th day of gestation aborted, two delivered some stillborn offspring, one gave an abnormally small litter of four, and the last one produced an apparently normal litter of ten. All matched controls delivered healthy litters, totaling 66. Some surviving offspring treated with LSD failed to develop as well as control animals. Treatment of five additional rats with LSD late in pregnancy had no obvious effect on the offspring.


Effects of ouabain and potassium on rabbit arterial smooth muscle cells in culture.
The membrane-bound Na/K-ATPase system is an important energy regulating system for all primate cells and is suspected to be either primary or secondary affected in different but important metabolic disorders as essential hypertension, diabetes II (mature onset diabetes) or severe overweight. Rabbit smooth muscle cells grown in culture have been incubated with different concentrations of ouabain (10(-7)-10(-4) mol/l) and potassium (4 and 6 mmol/l). In controlled series, the incorporation of 3H-thymidine (and collagen secretion) during incubation with ouabain was found to be diminished by at maximum 73% (P less than 0.01) and this was found to be reversible by changing to ouabain-free medium or partly by the addition of extra potassium. The intracellular ATP level and lactate production was diminished together with the fall in 3H-thymidine incorporation. These effects were probably not due to a non-specific toxic effect of ouabain because no difference in leakage of prelabelled 3H-thymidine from cells compared to control series was seen. We suggest that an optimal function of the membrane-bound Na/K-ATPase system is of great importance not only for intracellular energy production but also for cell proliferation and protein synthesis.


Multimodal optical microscopy methods reveal polyp tissue morphology and structure in Caribbean reef building corals.
An integrated suite of imaging techniques has been applied to determine the three-dimensional (3D) morphology and cellular structure of polyp tissues comprising the Caribbean reef building corals Montastraeaannularis and M. faveolata. These approaches include fluorescence microscopy (FM), serial block face imaging (SBFI), and two-photon confocal laser scanning microscopy (TPLSM). SBFI provides deep tissue imaging after physical sectioning; it details the tissue surface texture and 3D visualization to tissue depths of more than 2 mm. Complementary FM and TPLSM yield ultra-high resolution images of tissue cellular structure. Results have: (1) identified previously unreported lobate tissue morphologies on the outer wall of individual coral polyps and (2) created the first surface maps of the 3D distribution and tissue density of chromatophores and algae-like dinoflagellate zooxanthellae endosymbionts. Spectral absorption peaks of 500 nm and 675 nm, respectively, suggest that M. annularis and M. faveolata contain similar types of chlorophyll and chromatophores. However, M. annularis and M. faveolata exhibit significant differences in the tissue density and 3D distribution of these key cellular components. This study focusing on imaging methods indicates that SBFI is extremely useful for analysis of large mm-scale samples of decalcified coral tissues. Complimentary FM and TPLSM reveal subtle submillimeter scale changes in cellular distribution and density in nondecalcified coral tissue samples. The TPLSM technique affords: (1) minimally invasive sample preparation, (2) superior optical sectioning ability, and (3) minimal light absorption and scattering, while still permitting deep tissue imaging.


Personalization of loco-regional care for primary breast cancer patients (part 1).
ABSTRACT Kyoto Breast Cancer Consensus Conference, Kyoto, Japan, 18-20 February 2014 The loco-regional management of breast cancer is increasingly complex with application of primary systemic therapies, oncoplastic techniques and genetic testing for breast cancer susceptibility. Personalization of loco-regional treatment is integral to optimization of breast cancer care. Clinical and pathological tumor stage, biological features and host factors influence loco-regional treatment strategies and extent of surgical procedures. Key issues including axillary staging, axillary treatment, radiation therapy, primary systemic therapy (PST), preoperative hormonal therapy and genetic predisposition were identified and discussed at the Kyoto Breast Cancer Consensus Conference (KBCCC2014). In the first of a two part conference scene, consensus recommendations for axillary management are presented and focus on the following topics: indications for completion axillary lymph node dissection in primary surgical patients with ≤2 macrometastases or any sentinel nodal deposits after PST; the timing of sentinel lymph node biopsy in the context of PST; use of axillary irradiation as a component of primary treatment plans and the role of intraoperative node assessment in the post-Z0011 era.


ORAL ADMINISTRATION OF PENICILLIN IN CORN OIL AND LANOLIN.
Oral administration of penicillin suspended in equal parts of corn oil and lanolin extends the maintenance of the penicillin level in the system (as determined by urine bio-assay). Measurable quantities were found 24 to 42 hours after ingestion. Recovery of the penicillin is about five times higher than under administration in saline solution. We wish to express our sincere appreciation to the various members of our staff who volunteered as subjects for these experiments.


An Extract of Chinpi, the Dried Peel of the Citrus Fruit Unshiu, Enhances Axonal Remyelination via Promoting the Proliferation of Oligodendrocyte Progenitor Cells.
The aging-induced decrease in axonal myelination/remyelination is due to impaired recruitment and differentiation of oligodendrocyte progenitor cells (OPCs). Our previous studies have shown that a monoclonal antibody to DEAD (Asp-Glu-Ala-Asp) box polypeptide 54 (Ddx54), a member of the DEAD box family of RNA helicases, (1) specifically labels oligodendrocyte lineages, (2) binds to mRNA and protein isoforms of myelin basic proteins (MBP), and (3) regulates migration of OPCs from ventricular zone to corpus callosum in mice. It has also been demonstrated that specific loss of a 21.5 kDa MBP isoform (MBP21.5) reflects demyelination status, and oral administration of an extract of Chinpi, citrus unshiu peel, reversed the aging-induced demyelination. Here, we report that Chinpi treatment induced a specific increase in the MBP21.5, led to the reappearance of Ddx54-expressing cells in ventricular-subventricular zone and corpus callosum of aged mice, and promoted remyelination. Treatment of in vitro OPC cultures with Chinpi constituents, hesperidin plus narirutin, led to an increase in 5-bromo-2'-deoxyuridine incorporation in Ddx54-expressing OPCs, but not in NG2- or Olig2-expressing cell populations. The present study suggests that Ddx54 plays crucial role in remyelination. Furthermore, Chinpi and Chinpi-containing herbal medicines may be a therapeutic option for the aging-induced demyelination diseases.


Analysis of Recent Interception Records Reveals Frequent Transport of Arboreal Ants and Potential Predictors for Ant Invasion in Taiwan.
We uncovered taxonomic diversity, country of origin and commodity type of intercepted ants at Taiwanese borders based on an 8 year database of 439 interception records. We found intercepted ants arrived predominantly via timber, a pattern likely reflecting the high domestic demand for foreign timber in Taiwan. The most frequently intercepted species were either arboreal or wood-dwelling ants, raising a concern of these ants constituting a next wave of ant invasion in Taiwan. Further analyses indicate that the taxonomic composition of intercepted ants does not match that of established non-native ant species, suggesting that interception data alone fails to provide adequate power to predict the establishment success of ants. Yet, interception frequency and selected life-history traits (i.e., flexible colony founding mode and general nesting habits) were shown to jointly serve as a practical predictor of the establishment risk of non-native ants. Consistent with other border interception databases, secondary introduction (i.e., species arriving from their introduced ranges instead of their native ranges) also represents a major pathway for transport of invasive ants into Taiwan, suggesting its role in shaping the global invasion of ants. Our findings offer baseline information for constructing a prediction framework for future ant invasions and assist in the decision-making process of quarantine authorities in Taiwan.


Closed loop tracked Doppler optical coherence tomography based heart monitor for the Drosophila melanogaster larvae.
This paper presents a novel instrument for biosciences, useful for studies of moving embryos. A dual sequential imaging/measurement channel is assembled via a closed-loop tracking architecture. The dual channel system can operate in two regimes: (i) single-point Doppler signal monitoring or (ii) fast 3-D swept source OCT imaging. The system is demonstrated for characterizing cardiac dynamics in Drosophila melanogaster larva. Closed loop tracking enables long term in vivo monitoring of the larvae heart without anesthetic or physical restraint. Such an instrument can be used to measure subtle variations in the cardiac behavior otherwise obscured by the larvae movements. A fruit fly larva (top) was continuously tracked for continuous remote monitoring. A heartbeat trace of freely moving larva (bottom) was obtained by a low coherence interferometry based doppler sensing technique.


Aerodynamics of the hovering hummingbird.
Despite profound musculoskeletal differences, hummingbirds (Trochilidae) are widely thought to employ aerodynamic mechanisms similar to those used by insects. The kinematic symmetry of the hummingbird upstroke and downstroke has led to the assumption that these halves of the wingbeat cycle contribute equally to weight support during hovering, as exhibited by insects of similar size. This assumption has been applied, either explicitly or implicitly, in widely used aerodynamic models and in a variety of empirical tests. Here we provide measurements of the wake of hovering rufous hummingbirds (Selasphorus rufus) obtained with digital particle image velocimetry that show force asymmetry: hummingbirds produce 75% of their weight support during the downstroke and only 25% during the upstroke. Some of this asymmetry is probably due to inversion of their cambered wings during upstroke. The wake of hummingbird wings also reveals evidence of leading-edge vortices created during the downstroke, indicating that they may operate at Reynolds numbers sufficiently low to exploit a key mechanism typical of insect hovering. Hummingbird hovering approaches that of insects, yet remains distinct because of effects resulting from an inherently dissimilar-avian-body plan.


Communication: Practical intramolecular symmetry adapted perturbation theory via Hartree-Fock embedding.
We develop a simple methodology for the computation of symmetry-adapted perturbation theory (SAPT) interaction energy contributions for intramolecular noncovalent interactions. In this approach, the local occupied orbitals of the total Hartree-Fock (HF) wavefunction are used to partition the fully interacting system into three chemically identifiable units: the noncovalent fragments A and B and a covalent linker C. Once these units are identified, the noninteracting HF wavefunctions of the fragments A and B are separately optimized while embedded in the HF wavefunction of C, providing the dressed zeroth order wavefunctions for A and B in the presence of C. Standard two-body SAPT (particularly SAPT0) is then applied between the relaxed wavefunctions for A and B. This intramolecular SAPT procedure is found to be remarkably straightforward and efficient, as evidenced by example applications ranging from diols to hexaphenyl-ethane derivatives.


A tri-site fluorescent probe for simultaneous sensing of hydrogen sulfide and glutathione and its bioimaging applications.
Hydrogen sulfide (H2S) and biothiol molecules, such as glutathione (GSH), cysteine (Cys), and homocysteine (Hcy), play an important role in biology. However, understanding the complicated relationship between H2S and biothiols remains an enormous challenge owing to the difficulty in sensing H2S and biothiols simultaneously. Therefore, the development of probes for detecting H2S and biothiols is of great importance in biological science. In this work, we reported a novel fluorescent probe for the sensitive and selective detection of H2S and glutathione (GSH) simultaneously in different buffer solutions. The key design principle is based on a coumarin as the fluorophore structuring a fluorescent probe with three potential sites which could react with H2S and biothiols. This probe displays a rapid response with highly sensitive and selective detection of H2S and GSH (the detection limit of 75 nM and 280 nM, respectively). Moreover, with the assistance of a confocal fluorescence microscope, we demonstrated that the probe can be successfully applied for imaging H2S and GSH in MCF-7 cells.


Autofluorescence of Skin Advanced Glycation End Products as a Risk Factor for Open Angle Glaucoma: The ALIENOR Study.
To analyze the association between skin autofluorescence (sAF), estimating tissue accumulation of advanced glycation end-products (AGEs), and open angle glaucoma (OAG) in an elderly population. The Antioxydants, Lipides Essentiels, Nutrition and maladies OculaiRes (ALIENOR) study is an on-going epidemiologic population-based study on age-related eye diseases. In 2009 to 2010, 624 subjects, aged 74 years or older, were recruited. All subjects underwent a complete eye examination, including optic disc color photography and spectral-domain optical coherence tomography (SD-OCT) examination. Sociodemographic and medical history data were collected using standardized questionnaires. Glaucoma diagnosis was made using optic nerve head retinophotography and International Society for Epidemiologic and Geographical Ophthalmology criteria. sAF was measured with a noninvasive autofluorescence reader in 467 subjects. Of subjects, 455 had complete data, 424 were classified as controls, and 31 classified as OAG. Mean age was 82.3 ± 4.3 years, mean and median sAF were 2.8 ± 0.7 and 2.7 arbitrary units (AU), respectively. In a multivariate analysis, higher sAF values (≥2.7 AU) were associated with OAG (odds ratio [OR] = 2.28, 95% Confidence Interval [CI]: 1.03; 5.04). Other variables significantly associated with OAG were age (OR = 1.10, 95%CI: 1.00; 1.21), glaucoma family history (OR = 2.83, 95%CI: 1.14; 7.01) and smoking (1-20 pack-years [OR = 3.31, 95%CI: 1.18; 9.26]; ≥20 pack-years [OR = 3.85, 95%CI: 1.42; 10.46]). Higher level of sAF, which may act as a long-term biomarker of metabolic memory, and smoking are independently associated with an increased risk of glaucoma. Long-term accumulation of AGEs, a marker of oxidative stress, could play a role in the pathogenesis of glaucomatous chronic optic neuropathy.


Select tissue mineral concentrations and chronic wasting disease status in mule deer from North-central Colorado.
Trace mineral imbalances have been suggested as having a causative or contributory role in chronic wasting disease (CWD), a prion disease of several North American cervid species. To begin exploring relationships between tissue mineral concentrations and CWD in natural systems, we measured liver tissue concentrations of copper, manganese, and molybdenum in samples from 447 apparently healthy, adult (> or = 2 yr old) mule deer (Odocoileus hemionus) culled or vehicle killed from free-ranging populations in north-central Colorado, United States, where CWD occurs naturally; we also measured copper concentrations in brain-stem (medulla oblongata at the obex) tissue from 181 of these deer. Analyses revealed a wide range of concentrations of all three minerals among sampled deer (copper: 5.6-331 ppm in liver, 1.5-31.9 ppm in obex; manganese: 0.1-21.4 ppm in liver; molybdenum: 0.5-4.0 ppm in liver). Bayesian multiple regression analysis revealed a negative association between obex copper (-0.097; 95% credible interval -0.192 to -0.006) and the probability of sampled deer also being infected with CWD, as well as a positive association between liver manganese (0.158; 95% credible interval 0.066 to 0.253) and probability of infection. We could not discern whether the tendencies toward lower brain-stem copper concentrations or higher systemic manganese concentrations in infected deer preceded prion infection or rather were the result of infection and its subsequent effects, although the distribution of trace mineral concentrations in infected deer seemed more suggestive of the latter.


High-space resolution imaging plate analysis of extreme ultraviolet (EUV) light from tin laser-produced plasmas.
With the advent of high volume manufacturing capabilities by extreme ultraviolet lithography, constant improvements in light source design and cost-efficiency are required. Currently, light intensity and conversion efficiency (CE) measurments are obtained by charged couple devices, faraday cups etc, but also phoshpor imaging plates (IPs) (BaFBr:Eu). IPs are sensitive to light and high-energy species, which is ideal for studying extreme ultraviolet (EUV) light from laser produced plasmas (LPPs). In this work, we used IPs to observe a large angular distribution (10°-90°). We ablated a tin target by high-energy lasers (1064 nm Nd:YAG, 1010 and 1011 W/cm2) to generate the EUV light. The europium ions in the IP were trapped in a higher energy state from exposure to EUV light and high-energy species. The light intensity was angular dependent; therefore excitation of the IP depends on the angle, and so highly informative about the LPP. We obtained high-space resolution (345 μm, 0.2°) angular distribution and grazing spectrometer (5-20 nm grate) data simultaneously at different target to IP distances (103 mm and 200 mm). Two laser systems and IP types (BAS-TR and BAS-SR) were also compared. The cosine fitting values from the IP data were used to calculate the CE to be 1.6% (SD ± 0.2) at 13.5 nm 2% bandwidth. Finally, a practical assessment of IPs and a damage issue are disclosed.


Epidemiological characteristics and molecular basis of fluoroquinolone-resistant Neisseria gonorrhoeae strains isolated in Korea and nearby countries.
This study was performed to examine the cause of the increase in quinolone-resistant Neisseria gonorrhoeae (QRNG) observed in Korea. The antimicrobial susceptibilities of 190 isolates of gonococci from Korea in 2000 were examined by NCCLS methods, and subsets of these isolates underwent mutation analysis of the quinolone resistance-determining regions (QRDRs) of gyrA and parC. Molecular epidemiological characterization of 25 Korean isolates and 54 isolates from overseas was performed by pulsed-field gel electrophoresis (PFGE) and the results compared. Most (172, 90.5%) of the 190 gonococci tested displayed reduced susceptibility to ciprofloxacin. All strains with high-level ciprofloxacin resistance (ciprofloxacin MIC >/= 4 mg/L) contained a double amino acid alteration at the 91 and 95 positions in the QRDR of GyrA and a single alteration in ParC. PFGE types of high-level QRNG in Korea were mostly different from those of other nearby countries. These results suggest that the observed increase in ciprofloxacin-resistant isolates is due to the mutation and spread of Korean multiclonal isolates rather than importation from overseas.


[N]pT ensemble and finite-size-scaling study of the critical isostructural transition in the generalized exponential model of index 4.
First-order transitions of system where both lattice site occupancy and lattice spacing fluctuate, such as cluster crystals, cannot be efficiently studied by traditional simulation methods, which necessarily fix one of these two degrees of freedom. The difficulty, however, can be surmounted by the generalized [N]pT ensemble [J. Chem. Phys. 136, 214106 (2012)]. Here we show that histogram reweighting and the [N]pT ensemble can be used to study an isostructural transition between cluster crystals of different occupancy in the generalized exponential model of index 4 (GEM-4). Extending this scheme to finite-size scaling studies also allows us to accurately determine the critical point parameters and to verify that it belongs to the Ising universality class.


Disentangling global and local ring currents.
Magnetic field-induced ring currents in aromatic and antiaromatic molecules cause characteristic shielding and deshielding effects in the molecules' NMR spectra. However, it is difficult to analyze (anti)aromaticity directly from experimental NMR data if a molecule has multiple ring current pathways. Here we present a method for using the Biot-Savart law to deconvolute the contributions of different ring currents to the experimental NMR spectra of polycyclic compounds. This method accurately quantifies local and global ring current susceptibilities in porphyrin nanorings, as well as in a bicyclic dithienothiophene-bridged [34]octaphyrin. There is excellent agreement between ring current susceptibilities derived from both experimental and computationally-predicted chemical shifts, and with ring currents calculated by the GIMIC method. Our method can be applied to any polycyclic system, with any number of ring currents, provided that appropriate NMR data are available.


Genetic depletion of Polo-like kinase 1 leads to embryonic lethality due to mitotic aberrancies.
Polo-like kinase 1 (PLK1) is a serine/threonine kinase that plays multiple and essential roles during the cell division cycle. Its inhibition in cultured cells leads to severe mitotic aberrancies and cell death. Whereas previous reports suggested that Plk1 depletion in mice leads to a non-mitotic arrest in early embryos, we show here that the bi-allelic Plk1 depletion in mice certainly results in embryonic lethality due to extensive mitotic aberrations at the morula stage, including multi- and mono-polar spindles, impaired chromosome segregation and cytokinesis failure. In addition, the conditional depletion of Plk1 during mid-gestation leads also to severe mitotic aberrancies. Our data also confirms that Plk1 is completely dispensable for mitotic entry in vivo. On the other hand, Plk1 haploinsufficient mice are viable, and Plk1-heterozygous fibroblasts do not harbor any cell cycle alterations. Plk1 is overexpressed in many human tumors, suggesting a therapeutic benefit of inhibiting Plk1, and specific small-molecule inhibitors for this kinase are now being evaluated in clinical trials. Therefore, the different Plk1 mouse models here presented are a valuable tool to reexamine the relevance of the mitotic kinase Plk1 during mammalian development and animal physiology.


Auxotypes of Neisseria gonorrhoeae in Toronto: relationship to penicillin resistance and to sex of patient.
The relationship of auxotype to penicillinase production, penicillin susceptibility, and sex of the patient, has been studied in 8446 non-penicillinase-producing and 153 penicillinase-producing Neisseria gonorrhoeae (PPNG) strains isolated during 1980-1983 in Toronto. Proline-requiring types constituted 51% of the PPNG and 13% of the non-PPNG strains; ornithine-requiring types constituted only 4% of the PPNG compared with 12% of the non-PPNG isolates. The various auxotypes of the non-PPNG isolates showed marked differences in their degree of resistance to penicillin; and the proportions of each auxotype from male and female patients were dissimilar.


SETD2 Haploinsufficiency for Microtubule Methylation Is an Early Driver of Genomic Instability in Renal Cell Carcinoma.
Loss of the short arm of chromosome 3 (3p) occurs early in >95% of clear cell renal cell carcinoma (ccRCC). Nearly ubiquitous 3p loss in ccRCC suggests haploinsufficiency for 3p tumor suppressors as early drivers of tumorigenesis. We previously reported methyltransferase SETD2, which trimethylates H3 histones on lysine 36 (H3K36me3) and is located in the 3p deletion, to also trimethylate microtubules on lysine 40 (αTubK40me3) during mitosis, with αTubK40me3 required for genomic stability. We now show that monoallelic, Setd2-deficient cells retaining H3K36me3, but not αTubK40me3, exhibit a dramatic increase in mitotic defects and micronuclei count, with increased viability compared with biallelic loss. In SETD2-inactivated human kidney cells, rescue with a pathogenic SETD2 mutant deficient for microtubule (αTubK40me3), but not histone (H3K36me3) methylation, replicated this phenotype. Genomic instability (micronuclei) was also a hallmark of patient-derived cells from ccRCC. These data show that the SETD2 tumor suppressor displays a haploinsufficiency phenotype disproportionately impacting microtubule methylation and serves as an early driver of genomic instability.Significance: Loss of a single allele of a chromatin modifier plays a role in promoting oncogenesis, underscoring the growing relevance of tumor suppressor haploinsufficiency in tumorigenesis. Cancer Res; 78(12); 3135-46. ©2018 AACR.


Mismatch between perceived and objectively assessed neighborhood walkability attributes: prospective relationships with walking and weight gain.
We examined prospectively whether persons who perceive their objectively measured high walkable environment as low walkable decrease their walking more and gain more weight than those with matched perceptions. Walkability was measured objectively using GIS. Corresponding perceptions were collected using the Neighborhood Environment Walkability Scale from 1027 urban Australian adults. Objective and perceived measures were dichotomized and categories of match and mismatch were created. Overall, walking levels decreased and BMI increased significantly over the four year follow-up period. Those who perceived high walkability, dwelling density or land use mix as low decreased their walking for transport significantly more than those with matched perceptions. Those who perceived high walkability, land use mix or retail density as low increased their BMI significantly more than those with concordant perceptions. These prospective findings corroborate recommendations from previous cross-sectional studies. Interventions to improve negative perceptions of walkability among those living in high walkable areas may be a relevant public health intervention to increase physical activity and support weight maintenance.


Caregiving reduces mortality risk for most caregivers: a census-based record linkage study.
Countries with advanced welfare systems are increasingly relying on the input of informal caregivers, and there are growing concerns for their mental and physical wellbeing. However, the evidence about the relationship between caregiving and mortality risk is less clear. A census-based record linkage study with mortality follow-up of 33 months: participants totalled 1 122 779 individuals including 183 842 caregivers, of whom 28.2% (51 927) were providing 50 or more hours caregiving per week. Over 33 months of follow-up a total of 29 335 deaths occurred, 2443 of these among caregivers. Mortality risk for caregivers was lower than for non-caregivers [hazard ratio (HR) = 0.72: 95% confidence interval (CI) = 0.69, 0.75 in the fully adjusted model], and the lower risk was evident even for those providing 50 or more h of caregiving per week (adjusted HR = 0.77: 95% CI = 0.71, 0.83 and 0.76: 95% CI = 0.69, 0.83 for men and women, respectively). There was no evidence that this relationship varied by either age or marital status. Even among people with chronic health problems such as poor mental health, caregivers had lower mortality risk than non-caregivers. Caregiving is associated with reduced mortality risk for most causes—for example, the risk of death from ischaemic heart disease for caregivers providing 50 or more h was 27% and 31% lower for men and for women, respectively, compared with non-caregivers (HR = 0.73: 95% CI = 0.60, 0.88 and HR = 0.69: 95% CI = 0.51, 0.92). This large population-based study confirms that for the majority of caregivers the beneficial effects of caregiving in terms of short-term mortality risk appear to outweigh any negative effects, even among people with significant health problems. These results underscore the need for a reappraisal of how caregiving is perceived.


Prospective Relationships Between Physical Activity and Optimism in Young and Mid-aged Women.
There is growing evidence that regular physical activity (PA) reduces the risk of poor mental health. Less research has focused on the relationship between PA and positive wellbeing. The study aims were to assess the prospective associations between PA and optimism, in both young and mid-aged women. 9688 young women (born 1973-1978) completed self-report surveys in 2000 (age 22 to 27), 2003, 2006, and 2009; and 11,226 mid-aged women (born 1946-1951) completed surveys in 2001 (age 50-55) 2004, 2007, and 2010, as part of the Australian Longitudinal Study on Women's Health. Generalized estimating equation models (with 3-year time lag) were used to examine the relationship between PA and optimism in both cohorts. In both cohorts, women reporting higher levels of PA had greater odds of reporting higher optimism over the 9-year period, (young, OR = 5.04, 95% CI: 3.85-6.59; mid-age, OR = 5.77, 95% CI: 4.76-7.00) than women who reported no PA. Odds were attenuated in adjusted models, with depression accounting for a large amount of this attenuation (young, OR = 2.00, 95% CI: 1.57-2.55; mid-age, OR = 1.64 95% CI: 1.38-1.94). Physical activity can promote optimism in young and mid-aged women over time, even after accounting for the negative effects of other psychosocial indicators such as depression.


Experiential peer support and its effects on desistance from delinquent behavior: protocol paper for a systematic realist literature review.
Experiential peers are increasingly involved in the development and delivery of interventions for individuals who are engaged in delinquent behavior. Experiential peer support, which is the provision of support to an individual engaged in delinquent behavior by someone who has previously also practiced such behavior, is one such application. Little is known, however, about its effects on desistance, or the mechanisms that explain these effects. On the basis of theoretical papers, program descriptions, and interviews with experts, we developed an initial program theory. We propose seven mechanisms that might play a role in the (potential) effects of support by experiential peers: (1) empathy and acceptance, (2) social learning, (3) social bonding, (4) social control, (5) narrative and identity formation, (6) hope and perspective, and (7) translation and connection. In addition, in this protocol paper, we describe the methods of a systematic realist literature review that will be conducted in order to investigate the evidence base for this program theory. The study described in this protocol paper is a realist review, which is a suitable approach to study complex interventions and fits the explanatory purpose of the study. We outline the steps to be taken for the systematic realist review, including the selection and assessment of studies and the methods for synthesizing the findings. Investigating the effects and the underlying mechanisms of support by experiential peers for individuals with delinquent behavior is relevant because the forensic setting has some unique features, and the involvement of service users might create even more tension than in other settings due to stigma and perceived risks. The findings that will be reported in the realist review will contribute to the knowledge of the effects of support by experiential peers and will provide insight into which aspects remain to be studied. It might also provide formal care institutions with guidance on whether to involve experiential peers in the delivery of their services and the conditions under which these interventions are likely to lead to positive results.


Interacting cortical and basal ganglia networks underlying finding and tapping to the musical beat.
Humans are able to find and tap to the beat of musical rhythms varying in complexity from children's songs to modern jazz. Musical beat has no one-to-one relationship with auditory features-it is an abstract perceptual representation that emerges from the interaction between sensory cues and higher-level cognitive organization. Previous investigations have examined the neural basis of beat processing but have not tested the core phenomenon of finding and tapping to the musical beat. To test this, we used fMRI and had musicians find and tap to the beat of rhythms that varied from metrically simple to metrically complex-thus from a strong to a weak beat. Unlike most previous studies, we measured beat tapping performance during scanning and controlled for possible effects of scanner noise on beat perception. Results showed that beat finding and tapping recruited largely overlapping brain regions, including the superior temporal gyrus (STG), premotor cortex, and ventrolateral PFC (VLPFC). Beat tapping activity in STG and VLPFC was correlated with both perception and performance, suggesting that they are important for retrieving, selecting, and maintaining the musical beat. In contrast BG activity was similar in all conditions and was not correlated with either perception or production, suggesting that it may be involved in detecting auditory temporal regularity or in associating auditory stimuli with a motor response. Importantly, functional connectivity analyses showed that these systems interact, indicating that more basic sensorimotor mechanisms instantiated in the BG work in tandem with higher-order cognitive mechanisms in PFC.


Live simian immunodeficiency virus vaccine correlate of protection: immune complex-inhibitory Fc receptor interactions that reduce target cell availability.
Principles to guide design of an effective vaccine against HIV are greatly needed, particularly to protect women in the pandemic's epicenter in Africa. We have been seeking these principles by identifying correlates of the robust protection associated with SIVmac239Δnef vaccination in the SIV-rhesus macaque animal model of HIV-1 transmission to women. We identified one correlate of SIVmac239Δnef protection against vaginal challenge as a resident mucosal system for SIV-gp41 trimer Ab production and neonatal FcR-mediated concentration of these Abs on the path of virus entry to inhibit establishment of infected founder populations at the portal of entry. In this study, we identify blocking CD4(+) T cell recruitment to thereby inhibit local expansion of infected founder populations as a second correlate of protection. Virus-specific immune complex interactions with the inhibitory FcγRIIb receptor in the epithelium lining the cervix initiate expression of genes that block recruitment of target cells to fuel local expansion. Immune complex-FcγRIIb receptor interactions at mucosal frontlines to dampen the innate immune response to vaginal challenge could be a potentially general mechanism for the mucosal immune system to sense and modulate the response to a previously encountered pathogen. Designing vaccines to provide protection without eliciting these transmission-promoting innate responses could contribute to developing an effective HIV-1 vaccine.


Origins of anteroposterior patterning and Hox gene regulation during chordate evolution.
All chordates share a basic body plan and many common features of early development. Anteroposterior (AP) regions of the vertebrate neural tube are specified by a combinatorial pattern of Hox gene expression that is conserved in urochordates and cephalochordates. Another primitive feature of Hox gene regulation in all chordates is a sensitivity to retinoic acid during embryogenesis, and recent developmental genetic studies have demonstrated the essential role for retinoid signalling in vertebrates. Two AP regions develop within the chordate neural tube during gastrulation: an anterior 'forebrain-midbrain' region specified by Otx genes and a posterior 'hindbrain-spinal cord' region specified by Hox genes. A third, intermediate region corresponding to the midbrain or midbrain-hindbrain boundary develops at around the same time in vertebrates, and comparative data suggest that this was also present in the chordate ancestor. Within the anterior part of the Hox-expressing domain, however, vertebrates appear to have evolved unique roles for segmentation genes, such as Krox-20, in patterning the hindbrain. Genetic approaches in mammals and zebrafish, coupled with molecular phylogenetic studies in ascidians, amphioxus and lampreys, promise to reveal how the complex mechanisms that specify the vertebrate body plan may have arisen from a relatively simple set of ancestral developmental components.


Associations Between Community-Level LGBTQ-Supportive Factors and Substance Use Among Sexual Minority Adolescents.
Purpose: Using representative school-based data and community-level primary data, we investigated how environmental factors (e.g., school and community climate) might be protective against substance use behaviors among a vulnerable population of adolescents. Methods: We analyzed a sample of 2678 sexual minority adolescents using a combination of student-level data (British Columbia Adolescent Health Survey) and primary community-level data (assessing lesbian, gay, bisexual, transgender, and queer [LGBTQ]-specific community and school environments). Using multilevel logistic regression models, we examined associations between lifetime substance use (alcohol, illegal drugs, marijuana, nonmedical use of prescription drugs, and smoking) and community-level predictors (community and school LGBTQ supportiveness). Results: Above and beyond student characteristics (e.g., age and years living in Canada), sexual minority adolescents residing in communities with more LGBTQ supports (i.e., more supportive climates) had lower odds of lifetime illegal drug use (for boys and girls), marijuana use (for girls), and smoking (for girls). Specifically, in communities with more frequent LGBTQ events (such as Pride events), the odds of substance use among sexual minority adolescents living in those communities was lower compared with their counterparts living in communities with fewer LGBTQ supports. Conclusions: The availability of LGBTQ community-level organizations, events, and programs may serve as protective factors for substance use among sexual minority adolescents. In particular, LGBTQ-supportive community factors were negatively associated with substance use, which has important implications for our investment in community programs, laws, and organizations that advance the visibility and rights of LGBTQ people.


Photoacoustic guided ultrasound wavefront shaping for targeted acousto-optic imaging.
To overcome speed of sound aberrations that negatively impact the acoustic focus in acousto-optic imaging, received photoacoustic signals are used to guide the formation of ultrasound wavefronts to compensate for acoustic inhomogeneities. Photoacoustic point sources composed of gold and superparamagnetic iron oxide nanoparticles are used to generate acoustic waves that acoustically probe the medium as they propagate to the detector. By utilizing cross-correlation techniques with the received photoacoustic signal, transmitted ultrasound wavefronts compensate for the aberration, allowing for optimized and configurable ultrasound transmission to targeted locations. It is demonstrated that utilizing a portable commercially available ultrasound system using customized software, photoacoustic guided ultrasound wavefront shaping for targeted acousto-optic imaging is robust in the presence of large, highly attenuating acoustic aberration.


Systematic review of the survival rate and the incidence of biological, technical, and aesthetic complications of single crowns on implants reported in longitudinal studies with a mean follow-up of 5 years.
To assess the 5-year survival of implant-supported single crowns (SCs) and to describe the incidence of biological, technical, and aesthetic complications. The focused question was: What is the survival rate of implants supporting single crowns and implant-supported crowns with a mean follow-up of 5 years and to which extent do biological, technical, and aesthetic complications occur? A Medline search (2006-2011) was performed for clinical studies focusing on implant-supported SCs with a mean follow-up of at least 5 years. The search was complemented by an additional hand search and the inclusion of 24 studies from a previous systematic review (Jung et al. 2008a). Survival and complication rates were analyzed using random-effects Poisson's regression models to obtain summary estimates of 5- and 10-year proportions. Forty-six studies derived from an initial search count of 1083 titles and the complementary publications from the previous systematic review (Jung et al. 2008a) were selected and the data were extracted. Based on the meta-analysis, survival of implants supporting SCs at 5 years amounted to 97.2% (95% CI: 96.3-97.9%), and at 10 years amounted to 95.2% (95% CI: 91.8-97.2%). The survival of implant-supported SCs was 96.3% (95% CI: 94.2-97.6%) after 5 years and 89.4% (95% CI: 82.8-93.6%) after 10 years. For biological complications, a 5-year cumulative soft tissue complication rate of 7.1% (95% CI: 4.4-11.3%) and a cumulative complication rate for implants with bone loss >2 mm of 5.2% (95% CI: 3.1-8.6%) were calculated. Technical complications reached a cumulative incidence of 8.8% (95% CI: 5.1-15.0%) for screw-loosening, 4.1% (95% CI: 2.2-7.5%) for loss of retention, and 3.5% (95% CI: 2.4-5.2%) for fracture of the veneering material after 5 years. The cumulative 5-year aesthetic complication rate amounted to 7.1% (95% CI: 3.6-13.6%). The outcomes of the meta-analysis demonstrated high implant survival rates for both the single tooth implants and the respective single crowns after 5 and 10 years. However, technical, biological, and aesthetic complications were frequent.


The Arabidopsis Pleiotropic Drug Resistance Transporters PEN3 and PDR12 Mediate Camalexin Secretion for Resistance to Botrytis cinerea.
Plant defense often depends on the synthesis and targeted delivery of antimicrobial metabolites at pathogen contact sites. The pleiotropic drug resistance (PDR) transporter PENETRATION3 (PEN3)/PDR8 in Arabidopsis (Arabidopsis thaliana) has been implicated in resistance to a variety of fungal pathogens. However, the antimicrobial metabolite(s) transported by PEN3 for extracellular defense remains unidentified. Here, we report that PEN3 functions redundantly with another PDR transporter (PDR12) to mediate the secretion of camalexin, the major phytoalexin in Arabidopsis. Consistent with this, the pen3 pdr12 double mutants exhibit dramatically enhanced susceptibility to the necrotrophic fungus Botrytis cinerea as well as severe hypersensitivity to exogenous camalexin. PEN3 and PDR12 are transcriptionally activated upon B. cinerea infection, and their expression is regulated by the mitogen-activated protein kinase 3 (MPK3) and MPK6, and their downstream WRKY33 transcription factor. Further genetic analysis indicated that PEN3 and PDR12 contribute to B. cinerea resistance through exporting not only camalexin but also other unidentified metabolite(s) derived from Trp metabolism, suggesting that PEN3 and PDR12 have multiple functions in Arabidopsis immunity via transport of distinct Trp metabolic products.


Phosphorylation of the translational repressor PHAS-I by the mammalian target of rapamycin.
The immunosuppressant rapamycin interferes with G1-phase progression in lymphoid and other cell types by inhibiting the function of the mammalian target of rapamycin (mTOR). mTOR was determined to be a terminal kinase in a signaling pathway that couples mitogenic stimulation to the phosphorylation of the eukaryotic initiation factor (eIF)-4E-binding protein, PHAS-I. The rapamycin-sensitive protein kinase activity of mTOR was required for phosphorylation of PHAS-I in insulin-stimulated human embryonic kidney cells. mTOR phosphorylated PHAS-I on serine and threonine residues in vitro, and these modifications inhibited the binding of PHAS-I to eIF-4E. These studies define a role for mTOR in translational control and offer further insights into the mechanism whereby rapamycin inhibits G1-phase progression in mammalian cells.


Systematic review of robotic surgery in gynecology: robotic techniques compared with laparoscopy and laparotomy.
The Society of Gynecologic Surgeons Systematic Review Group performed a systematic review of both randomized and observational studies to compare robotic vs nonrobotic surgical approaches (laparoscopic, abdominal, and vaginal) for treatment of both benign and malignant gynecologic indications to compare surgical and patient-centered outcomes, costs, and adverse events associated with the various surgical approaches. MEDLINE and the Cochrane Central Register of Controlled Trials were searched from inception to May 15, 2012, for English-language studies with terms related to robotic surgery and gynecology. Studies of any design that included at least 30 women who had undergone robotic-assisted laparoscopic gynecologic surgery were included for review. The literature yielded 1213 citations, of which 97 full-text articles were reviewed. Forty-four studies (30 comparative and 14 noncomparative) met eligibility criteria. Study data were extracted into structured electronic forms and reconciled by a second, independent reviewer. Our analysis revealed that, compared with open surgery, robotic surgery consistently confers shorter hospital stay. The proficiency plateau seems to be lower for robotic surgery than for conventional laparoscopy. Of the various gynecologic applications, there seems to be evidence that renders robotic techniques advantageous over traditional open surgery for management of endometrial cancer. However, insofar as superiority, conflicting data are obtained when comparing robotics vs laparoscopic techniques. Therefore, the specific method of minimally invasive surgery, whether conventional laparoscopy or robotic surgery, should be tailored to patient selection, surgeon ability, and equipment availability.


Varicose vein surgery and endovenous laser therapy.
Varicose veins are a widespread problem, and are encountered by various medical specialists. Symptoms can appear from mild, such as tiredness of the legs, to severe chronic ulcers. Varicose veins are generally caused by the reflux of an incompetent saphenofemoral junction and long saphenous vein. In the presence of reflux, the treatment should be directed at the ablation of the hydrostatic forces of the reflux. Conventional surgical treatment consists of a high ligation of the saphenofemoral junction and stripping of the saphenous vein. In the era of minimally invasive surgery, various endovenous techniques have been developed, including endovenous laser therapy. This technique is relatively cheap and can be performed under only local anesthesia. During endovenous laser therapy, energy is delivered to the vein wall, causing it to shrink and eventually occlude. Currently, the mechanisms of action involved in laser treatment are not fully understood. Clinical studies have shown occlusion rates to be very competitive to conventional high ligation and stripping and superior cosmetics. Complications may include mild to moderate pain, ecchymosis, induration, hematoma, and phlebitis. All of these are generally self-limiting. In the challenge of finding the correct balance between a low incidence of varicose vein recurrence and complications and optimal cosmetic results, endovenous laser therapy is a promising modality. However, controlled studies that assess the effectiveness of endovenous laser therapy in comparison to saphenofemoral ligation with saphenous vein stripping are crucial before considering endovenous laser therapy as the new standard treatment.


Precisely full length, circularizable, complementary RNA: an infectious form of potato spindle tuber viroid.
The replication of many viral and subviral pathogens as well as the amplification of certain cellular genes proceeds via a rolling circle mechanism. For potato spindle tuber (PSTVd) and related viroids, the possible role of a circular (-)strand RNA as a template for synthesis of (+)strand progeny is unclear. Infected plants appear to contain only multimeric linear (-)strand RNAs, and attempts to initiate infection with multimeric (-)PSTVd RNAs generally have failed. To examine critically the infectivity of monomeric (-)strand viroid RNAs, we have developed a ribozyme-based expression system for the production of precisely full length (-)strand RNAs whose termini are capable of undergoing facile circularization in vitro. Mechanical inoculation of tomato seedlings with electrophoretically purified (-)PSTVd RNA led to a small fraction of plants becoming infected whereas parallel assays with an analogous tomato planta macho viroid (-)RNA resulted in a much larger fraction of infected plants. Ribozyme-mediated production of (-)PSTVd RNA in transgenic plants led to the appearance of monomeric circular (-)PSTVd RNA and large amounts of (+)PSTVd progeny. No monomeric circular (-)PSTVd RNA could be detected in naturally infected plants by using either ribonuclease protection or electrophoresis under partially denaturing conditions. Although not a component of the normal replicative pathway, precisely full length (-)PSTVd RNA appears to contain all of the structural and regulatory elements necessary for initiation of viroid replication.


Prevalence of HIV infection in New York call girls.
In order to evaluate the frequency of sexual transmission of human immunodeficiency virus (HIV) among promiscuous heterosexuals, we studied the prevalence of HIV infection among a group of predominantly Caucasian call girls and women working for escort services and massage parlors in New York City. In the 78 subjects studied, the mean age was 31.6 years and the mean duration of prostitution was 5.1 years. Study participants each had a median of 200 different sexual partners in the preceding year. Six women had a history of intravenous drug abuse and none had a history of any other recognized risk factor for HIV infection. Ninety percent of the women studied used condoms during intercourse with at least some of their partners. One of the six women with a history of drug abuse and none of the 72 non-drug-abusers were seropositive for HIV. This study indicates that despite their promiscuity, HIV infection is still uncommon in call girls in New York City.


Tumors at the aortoiliac/inferior vena cava bifurcation: preoperative, anesthetic, and intraoperative considerations.
Primary and recurrent retroperitoneal tumors can involve the aortoiliac vasculature. They are often considered inoperable or incurable because of the locally advanced nature of the disease or the technical aspects involved in safely resecting the lesion. Safe resection of these lesions requires experience and extensive preoperative planning for success. A retrospective database review of 76 patients with retroperitoneal tumors identified tumors involving major vascular structures in the abdomen and pelvis undergoing resection of tumor en bloc with the aortoiliac vasculature. Preoperative planning and intraoperative technical maneuvers are reviewed. Patients were followed until time of this report. Four patients with retroperitoneal tumors involving the aortoiliac vessels underwent surgery: two patients with sarcoma (one primary and one recurrent), one with metastatic renal cell carcinoma, and one with a paraganglioma. All patients had resection of the aorta and vena cava or the iliac artery and vein. Arterial reconstruction (anatomic or extra-anatomic) was performed in all cases. The patient with renal cell carcinoma also required venous reconstruction to support a renal autotransplant. Veno-venous bypass was required in one patient. Local control was achieved in 3 of 4 cases. Surgery for retroperitoneal tumors involving major vascular structures is technically feasible with appropriate planning and technique. Multiple disciplines are required, including general surgical oncology, vascular surgery, and possibly, cardiothoracic surgery.


Mutations in transmembrane domains 1, 4 and 9 of the Plasmodium falciparum chloroquine resistance transporter alter susceptibility to chloroquine, quinine and quinidine.
Mutations in the Plasmodium falciparum chloroquine (CQ) resistance transporter (PfCRT) can result in verapamil-reversible CQ resistance and altered susceptibility to other antimalarials. PfCRT contains 10 membrane-spanning domains and is found in the digestive vacuole (DV) membrane of intraerythrocytic parasites. The mechanism by which PfCRT mediates CQ resistance is unclear although it is associated with decreased accumulation of drug within the DV. On the permissive background of the P. falciparum 106/1(K76) parasite line, we used single-step drug selection to generate isogenic clones containing unique pfcrt point mutations that resulted in amino acid changes in PfCRT transmembrane domains 1 (C72R, K76N, K76I and K76T) and 9 (Q352K, Q352R). The resulting changes of charge and hydropathy affected quantitative CQ susceptibility and accumulation as well as the stereospecific responses to quinine and quinidine. These results, together with a previously described S163R mutation in transmembrane domain 4, indicate that transmembrane segments 1, 4 and 9 of PfCRT provide important structural components of a substrate recognition and translocation domain. Charge-affecting mutations within these segments may affect the ability of PfCRT to bind different quinoline drugs and determine their net accumulation in the DV.


Penile rehabilitation for postprostatectomy erectile dysfunction.
Despite efforts to preserve the neurovascular bundles with nerve-sparing surgery, erectile dysfunction remains common following radical prostatectomy. Postoperative penile rehabilitation seeks to restore erectile function but results have been conflicting. To evaluate the effects of penile rehabilitation strategies in restoring erectile function following radical prostatectomy for prostate cancer. We performed a comprehensive search of multiple databases (CENTRAL, MEDLINE, Embase), the Cochrane Library, Web of Science, clinical trial registries (ClinicalTrials.gov, International Clinical Trials Registry Platform) and a grey literature repository (Grey Literature Report) from their inception through to 3 January 2018. We also searched the reference lists of other relevant publications and abstract proceedings. We applied no language restrictions. We included randomised or quasi-randomised trials with a parallel or cross-over design. We used standard Cochrane methodological procedures. Two review authors independently screened the literature, extracted data, assessed risk of bias and rated quality of evidence according to GRADE on a per-outcome basis. Primary outcomes were self-reported potency, erectile function measured by validated questionnaires (with potency defined as an International Index of Erectile Function (IIEF-EF) score of 19 or greater and or an IIEF-5 of score of 17 or greater) and serious adverse events. For all quality of life assessments on a continuous scale, higher values indicated better quality of life. We included eight randomised controlled trials with 1699 participants across three comparisons. This abstract focuses on the primary outcomes of this review only.Scheduled phosphodiesterase type 5 inhibitors (PDE5I) versus placebo or no treatmentScheduled PDE5I may have little or no effect on short-term (up to 12 months) self-reported potency (risk ratio (RR) 1.13, 95% confidence interval (CI) 0.91 to1.41; very low quality evidence), which corresponds to 47 more men with self-reported potency per 1000 (95% CI 33 fewer to 149 more) and short-term erectile function as assessed by a validated instrument (RR 1.11, 95% CI 0.80 to 1.55; very low quality evidence), which corresponds to 28 more men per 1000 (95% CI 50 fewer to 138 more), but we are very uncertain of both of these findings. Scheduled PDE5I may result in fewer serious adverse events compared to placebo (RR 0.32, 95% CI 0.11 to 0.94; low quality evidence), though this does not appear biologically plausible and may represent a chance finding. We are also very uncertain of this finding. We found no long-term (longer than 12 months) data for any of the three primary outcomes.Scheduled PDE5I versus on-demand PDE5I Daily PDE5I appears to result in little to no difference in both short-term and long-term (greater than 12 months) self-reported potency (short term: RR 0.97, 95% CI 0.62 to 1.53; long term: RR 1.00, 95% CI 0.60 to 1.67; both very low quality evidence); this corresponds to nine fewer men with self-reported short-term potency per 1000 (95% CI 119 fewer to 166 more) and zero fewer men with self-reported long-term potency per 1000 (95% CI 153 fewer to 257 more). We are very uncertain of these findings. Daily PDE5I appears to result in little to no difference in short-term and long-term erectile function (short term: RR 1.00, 95% CI 0.65 to 1.55; long term; RR 0.74, 95% CI 0.48 to 1.14; both very-low quality evidence), which corresponds to zero men with short-term erectile dysfunction per 1000 (95% CI 80 fewer to 125 more) and 119 fewer men with long-term erectile dysfunction per 1000 (95% CI 239 fewer to 64 more). We are very uncertain of these findings. Scheduled PDE5I may result in little or no effects on short-term adverse events (RR 0.69 95% CI 0.12 to 4.04; very low quality evidence), which corresponds to seven fewer men with short-term serious adverse events (95% CI 18 fewer to 64 more), but we are very uncertain of these findings. We found no long-term data for serious adverse events.Scheduled PDE5I versus scheduled intraurethral prostaglandin E1At short-term follow-up, daily PDE5I may result in little or no effect on self-reported potency (RR 1.10, 95% CI 0.79, to 1.52; very low quality evidence), which corresponds to 46 more men per 1000 (95% CI 97 fewer to 241 more). Daily PDE5I may result in a small improvement of erectile function (RR 1.64, 95% CI 0.84 to 3.20; very low quality evidence), which corresponds to 92 more men per 1000 (95% CI 23 fewer to 318 more) but we are very uncertain of both these findings. We found no long-term (longer than 12 months) data for any of the three primary outcomes.We found no evidence for any other comparisons and were unable to perform any of the preplanned subgroup analyses based on nerve-sparing approach, age or baseline erectile function. Based on mostly very-low and some low-quality evidence, penile rehabilitation strategies consisting of scheduled PDE5I use following radical prostatectomy may not promote self-reported potency and erectile function any more than on demand use.


Injuries in team sport tournaments during the 2004 Olympic Games.
Several authors have analyzed the incidence of injuries in a given sport, but only a few have examined the exposure-related incidence of injuries in different types of sports using the same methodology. Analysis of the incidence, circumstances, and characteristics of injuries in different team sports during the 2004 Olympic Games. Cohort study; Level of evidence, 2. During the 2004 Olympic Games, injuries in 14 team sport tournaments (men's and women's soccer, men's and women's handball, men's and women's basketball, men's and women's field hockey, baseball, softball, men's and women's water polo, and men's and women's volleyball) were analyzed. After each match, the physician of the participating teams or the official medical representative of the sport completed a standardized injury report form. The mean response rate was 93%. A total of 377 injuries were reported from 456 matches, an incidence of 0.8 injuries per match (95% confidence interval, 0.75-0.91) or 54 injuries per 1000 player matches (95% confidence interval, 49-60). Half of all injuries affected the lower extremity; 24% involved the head or neck. The most prevalent diagnoses were head contusion and ankle sprain. On average, 78% of injuries were caused by contact with another player. However, a significantly higher percentage of noncontact (57%) versus contact injuries (37%) was expected to prevent the player from participating in his or her sport. Significantly more injuries in male players (46%) versus female players (35%) were expected to result in absence from match or training. The incidence, diagnosis, and causes of injuries differed substantially between the team sports. The risk of injury in different team sports can be compared using standardized methodology. Even if the incidence and characteristics of injuries are not identical in all sports, prevention of injury and promotion of fair play are relevant topics for almost all team sports.


Outcomes in registered, ongoing randomized controlled trials of patient education.
With the increasing prevalence of chronic noncommunicable diseases, patient education is becoming important to strengthen disease prevention and control. We aimed to systematically determine the extent to which registered, ongoing randomized controlled trials (RCTs) evaluated an educational intervention focus on patient-important outcomes (i.e., outcomes measuring patient health status and quality of life). On May 6, 2009, we searched for all ongoing RCTs registered in the World Health Organization International Clinical Trials Registry platform. We used a standardized data extraction form to collect data and determined whether the outcomes assessed were 1) patient-important outcomes such as clinical events, functional status, pain, or quality of life or 2) surrogate outcomes, such as biological outcome, treatment adherence, or patient knowledge. We selected 268 of the 642 potentially eligible studies and assessed a random sample of 150. Patient-important outcomes represented 54% (178 of 333) of all primary outcomes and 46% (286 of 623) of all secondary outcomes. Overall, 69% of trials (104 of 150) used at least one patient-important outcome as a primary outcome and 66% (99 of 150) as a secondary outcome. Finally, for 31% of trials (46 of 150), primary outcomes were only surrogate outcomes. The results varied by medical area. In neuropsychiatric disorders, patient important outcomes represented 84% (51 of 61) of primary outcomes, as compared with 54% (32 of 59) in malignant neoplasm and 18% (4 of 22) in diabetes mellitus trials. In addition, only 35% assessed the long-term impact of interventions (i.e., >6 months). There is a need to improve the relevance of outcomes and to assess the long term impact of educational interventions in RCTs.


Attitudes towards suicide following an undergraduate suicide prevention module: experience of medical students in Hong Kong.
To explore qualitative and quantitative changes in attitudes and experiences of medical students following a special study suicide prevention module. Pilot study. The University of Hong Kong, Hong Kong. A 2-week intensive special studies module was delivered to third- and fourth-year medical students in June 2011. The module was elective and involved several modes of teaching. All students filled the Chinese Attitude toward Suicide Questionnaire before and after the course. They also provided written feedback about the module experience. Three students participated in in-depth interviews. In all, 22 students aged 20 to 23 years enrolled in the special studies module; 15 (68%) of whom were male and only one was married. Positive trends were noted in attitudes towards suicide following the participation in the special studies module, namely, reduced negative appraisal of suicide, reduced stigmatisation of the phenomena, and increased sensitivity to suicide-related facts. Feedback of the students suggested inclusion of this module into the main medical curriculum, increased confidence in dealing with issues related to suicide, and appreciation of skills focusing on interviewing in patients. Overall the module was well received by medical students. A suicide prevention training module seems to have been valued by students and lead to positive attitudes towards understanding suicide. Adopting this initiative as a suicide prevention strategy warrants further exploration.