[Dilemmas in discontinuation of antipsychotic drug use in people with intellectual disabilities].
The prevalence of antipsychotic drug use in people with intellectual disability (id) is high and largely off-label for challenging behaviour (cb), while evidence for their efficacy lacks. Side-effects frequently occur. Guidelines recommend appropriate psychotropic drug use by monitoring of effects and side-effects and discontinuing off-label use for cb. However, they are insufficiently adhered to. Discontinuation often fails due to behavioural worsening by largely unknown causes.
 AIM: To offer an overview of results of off-label antipsychotic drug discontinuation and determinants for success or failure.
 METHOD: Literature search in Medline, embase and Psycinfo.
 RESULTS: Prospective open-label studies show that discontinuation in selected populations is possible in 33-40% and in placebo-controlled studies in 55-82%. Challenging behaviours, as measured with a standardized scale, mostly remained similar in those who succeeded as well as in those who failed to discontinue. Health problems, extrapyramidal symptoms, higher antipsychotic drug dosage, more severe cb, autism and male gender in participants, negative emotions towards cb, less knowledge on psychotropic drugs and male gender of support professional were related to less chance of successful discontinuation.
 CONCLUSION: To improve results of antipsychotic drug discontinuation, proper diagnostics of underlying causes for cb, involvement of all stakeholders and enhancement of treatment opportunities for psychopathology in people with id are needed. Integrative care and knowledge development of id- and mental health care may be helpful.


Protection of humans by plant glucosinolates: efficiency of conversion of glucosinolates to isothiocyanates by the gastrointestinal microflora.
Plant-based diets rich in crucifers are effective in preventing cancer and other chronic diseases. Crucifers contain very high concentrations of glucosinolates (GS; β-thioglucoside-N-hydroxysulfates). Although not themselves protective, GS are converted by coexisting myrosinases to bitter isothiocyanates (ITC) which defend plants against predators. Coincidentally, ITC also induce mammalian genes that regulate defenses against oxidative stress, inflammation, and DNA-damaging electrophiles. Consequently, the efficiency of conversion of GS to ITC may be critical in controlling the health-promoting benefits of crucifers. If myrosinase is heat-inactivated by cooking, the gastrointestinal microflora converts GS to ITC, a process abolished by enteric antibiotics and bowel cleansing. When single oral doses of GS were administered as broccoli sprout extracts (BSE) to two dissimilar populations (rural Han Chinese and racially mixed Baltimoreans) patterns of excretions of urinary dithiocarbamates (DTC) were very similar. Individual conversions in both populations varied enormously, from about 1% to more than 40% of dose. In contrast, administration of ITC (largely sulforaphane)-containing BSE resulted in uniformly high (70%-90%) conversions to urinary DTC. Despite the remarkably large range of conversion efficiencies between individuals, repeated determinations within individuals were much more consistent. The rates of urinary excretion (slow or fast) were unrelated to the ultimate magnitudes (low or high) of these conversions. Although no demographic factors affecting conversion efficiency have been identified, there are clearly diurnal variations: conversion of GS to DTC was greater during the day, but conversion of ITC to DTC was more efficient at night.


Exercise therapy may postpone total hip replacement surgery in patients with hip osteoarthritis: a long-term follow-up of a randomised trial.
Exercise treatment is recommended for all patients with hip osteoarthritis (OA), but its effect on the long-term need for total hip replacement (THR) is unknown. We conducted a long-term follow-up of a randomised trial investigating the efficacy of exercise therapy and patient education versus patient education only on the 6-year cumulative survival of the native hip to THR in 109 patients with symptomatic and radiographic hip OA. Results regarding the primary outcome measure of the trial, self-reported pain at 16 months follow-up, have been reported previously. There were no group differences at baseline. The response rate at follow-up was 94%. 22 patients in the group receiving both exercise therapy and patient education and 31 patients in the group receiving patient education only underwent THR during the follow-up period, giving a 6-year cumulative survival of the native hip of 41% and 25%, respectively (p=0.034). The HR for survival of the native hip was 0.56 (CI 0.32 to 0.96) for the exercise therapy group compared with the control group. Median time to THR was 5.4 and 3.5 years, respectively. The exercise therapy group had better self-reported hip function prior to THR or end of study, but no significant differences were found for pain and stiffness. Our findings in this explanatory study suggest that exercise therapy in addition to patient education can reduce the need for THR by 44% in patients with hip OA. ClinicalTrials.gov number NCT00319423 (original project protocol) and NCT01338532 (additional protocol for long-term follow-up).


Purification and characterization of mouse interferon with novel affinity sorbents.
Several novel selective sorbents for mouse interferon are described that exploit the hydrophobic property and glycoprotein nature of this molecule. Low-molecular-weight ligands (hydrocarbons) and high-molecular-weight ligands (bovine serum albumin) immobilized on agarose bind selectively mouse L-cell interferon. The high selectivity of binding is due primarily to a hydrophobic effect, although electrostatic forces are also apparently involved. Mouse L-cell interferon binds to immobilized serum albumin and can be completely recovered by raising the ionic strength of the eluant. The specific activity of interferon preparations can be increased 2,000-fold to a value of 3 x 10(8) reference units per mg of protein in a single step with full recovery of the antiviral activity. A selective adsorption, although to a lesser degree, can be also obtained on hydrocarbon-coated agarose (Affi-Gel 202), resulting in 300-fold purification on desorption. The existence of two major components of mouse interferon was revealed upon its chromatography on the following sorbents: (i) bovine serum albumin-agarose, (ii) omega-carboxypentyl-agarose; and (iii) Bandeiraea simplicifolia lectin-agarose. This report thus provides for the first time a means for efficient and clear-cut separation of interferon components, thus enabling their further characterization.


Contribution by polymorphonucleate granulocytes to elevated gamma-glutamyltransferase in cystic fibrosis sputum.
Cystic fibrosis (CF) is an autosomal recessive disorder characterized by a chronic neutrophilic airways inflammation, increasing levels of oxidative stress and reduced levels of antioxidants such as glutathione (GSH). Gamma-glutamyltransferase (GGT), an enzyme induced by oxidative stress and involved in the catabolism of GSH and its derivatives, is increased in the airways of CF patients with inflammation, but the possible implications of its increase have not yet been investigated in detail. The present study was aimed to evaluate the origin and the biochemical characteristics of the GGT detectable in CF sputum. We found GGT activity both in neutrophils and in the fluid, the latter significantly correlating with myeloperoxidase expression. In neutrophils, GGT was associated with intracellular granules. In the fluid, gel-filtration chromatography showed the presence of two distinct GGT fractions, the first corresponding to the human plasma b-GGT fraction, the other to the free enzyme. The same fractions were also observed in the supernatant of ionomycin and fMLP-activated neutrophils. Western blot analysis confirmed the presence of a single band of GGT immunoreactive peptide in the CF sputum samples and in isolated neutrophils. In conclusion, our data indicate that neutrophils are able to transport and release GGT, thus increasing GGT activity in CF sputum. The prompt release of GGT may have consequences on all GGT substrates, including major inflammatory mediators such as S-nitrosoglutathione and leukotrienes, and could participate in early modulation of inflammatory response.


[An experimental study on the pathology and role of intervertebral discs in the progression and correction of scoliotic deformity].
This experimental study was designed to clarify the role of the intervertebral disc in the progression and correction of scoliosis. A total of 186 Wistar strain rats were used. Progressive scoliosis-like deformity was produced in tails by fixation of a given strain for a certain period. Changes in the intervertebral disc and epiphysis of one group with removal of the nucleus pulposus, and the other without removal were examined radiologically and pathohistologically. The results are as follows: 1) deformity originated from deviation of the nucleus pulposus toward the convex side and was followed by changes of the concave side, and led to deformities of the epiphysis and vertebral body; 2) on correction of the deformity, deviated nucleus pulposus and contracture of the concave side served as correction-inhibiting factors. The author's results indicate that intervertebral disc affecting the progression and correction of scoliosis are of great clinical significance.


Expression pattern of the JAB1/CSN5 gene during murine embryogenesis: colocalization with NEDD8.
The COP9 signalosome (CSN) is a conserved multiprotein complex, with an important developmental role in several organisms, ranging from plants to mammalians. The influence of the CSN on several signaling and developmental processes has been ascribed to its ability to regulate degradation of a number of signaling proteins by the ubiquitin-proteasome system. The CSN controls the function of the SCF ubiquitin-ligase complex through an enzymatic activity that removes the small ubiquitin-like molecule NEDD8 from the cullin component of the SCF and that requires subunit 5 of the CSN (JAB1/CSN5). Mutants of the CSN display early embryonic lethality, a feature that has hindered further characterization of the role of the CSN at later stages of mammalian development. Here we report the analysis of JAB1/CSN5 expression pattern in the mouse embryo. At early stages of development, JAB1/CSN5 transcripts were present with low expression levels in all tissues. Preferential expression in selected tissues was detected starting at E11.5, with higher levels in dorsal root ganglia; at later stages, prominent expression of JAB1/CSN5 transcripts was observed in cranial nerve, spinal and sympathetic ganglia, as well as in selected epithelia, such as the oral and the olfactory epithelium. In the adult brain, additional areas of JAB1/CSN5 expression were the hippocampus and the Purkinjie layer of the cerebellum. We also analyzed the temporal and spatial expression pattern of NEDD8, and found that it substantially overlapped JAB1/CSN5 expression at all stages analyzed, supporting the model of a functional interaction between the two proteins during developmental processes.


Methamphetamine-related deaths in San Francisco: demographic, pathologic, and toxicologic profiles.
A study was undertaken to develop demographic, toxicologic, and pathological profiles of methamphetamine-related deaths. Anatomic and toxicologic findings in 413 deaths where methamphetamine was detected were compared with findings in a control group of 114 drug-free trauma victims. The number of cases per year did not change significantly over the course of the study. Mean age was 36.8 years, but 11% were over the age of 50. Decedents were overwhelmingly male (85.2%) and Caucasian (75%). Blood concentrations of methamphetamine and amphetamine were indistinguishable in cases where methamphetamine was related to the cause of death (MR) and cases where it was not (non-MR) (2.08 vs. 1.78 mg/L, p = 0.65, and 0.217 vs. 0.19 mg/L, p = 0.82). Coronary artery disease, ranging from minimal to severe multivessel, was identified in 79 of the 413 drug users, but in only six of the 114 drug-free controls (p = 0.0004), and MR decedents had enlarged hearts compared with controls. There were also ten cases of subarachnoid and intracranial hemorrhage in the MR group. Abnormalities of the liver (34%) and lungs (24.7%) were frequent. In 65% of these cases, death was due to accidental methamphetamine toxicity. In the remaining cases, methamphetamine was an incidental finding. We conclude that, in our jurisdiction, neither the rate of detection nor the number of methamphetamine deaths has increased significantly in the past 13 years. Decedents are almost all Caucasian males, and many were approaching middle-age. Methamphetamine use is strongly associated with coronary artery disease and with subarachnoid hemorrhage.


Characterization of the human homologue of RAD54: a gene located on chromosome 1p32 at a region of high loss of heterozygosity in breast tumors.
A search of the Human Genome Sciences database of expressed sequence-tagged DNA fragments, for sequences containing homology to known yeast DNA recombination and repair genes, yielded a cDNA fragment with high homology to RAD54. Here we describe the complete cDNA sequence and the characterization of the genomic locus coding for the human homologue of the yeast RAD54 gene (hRAD54). The yeast RAD54 belongs to the RAD52 epistasis group and appears to be involved in both DNA recombination and repair. The hRAD54 gene maps to chromosome 1p32 in a region of frequent loss of heterozygosity in breast tumors and encodes a protein of M(r) 93,000 that displays 52% identity to the yeast RAD54 protein. The hRAD54 protein sequence additionally contains all seven of the consensus segments of a superfamily of proteins with presumed or proven DNA helicase activity. Mutations in genes with consensus helicase homology have been found in cancer-prone syndromes such as xeroderma pigmentosum and Bloom syndrome as well as Werner's syndrome, in which patients age prematurely, and the X-linked mental retardation with alpha-thalassemia syndrome, ATR-X. We have examined the hRAD54 gene in several breast tumors and breast tumor cell lines and, although the gene region appears to be deleted in several tumors, at present we have found no coding sequence mutations.


Fano resonance formula for lossy two-port systems.
We provide a modified Fano resonance formula applicable to dissipative two-port resonance systems. Based on a generic coupled-resonator model, the formula embodies loss-related correction terms and fundamental resonance parameters that can be determined by an analytic method or experimentally as opposed to finding phenomenological parameters by fitting to numerical results. The theory applies physically meaningful resonance parameters including resonance frequency, total decay rates, and partial radiation probabilities. For example, it shows that the classic Fano shape parameter q is given directly in terms of the phase difference between the resonant and non-resonant transmission pathways. Our new resonance formula quantitatively expresses the resonance spectra pertaining to modal nanophotonic and surface-plasmonic thin-film structures as verified by comparing with exact numerical models.


Progranulin as a candidate biomarker for therapeutic trial in patients with ALS and FTLD.
The loss-of-function mechanism in progranulin (PGRN) mutation carriers makes PGRN an interesting target for upregulation as a therapeutic approach in neurodegenerative diseases like frontotemporal lobar degeneration. This gives rise to several questions: (1) how stable are PGRN levels in blood and cerebrospinal fluid (CSF) in follow-up? (2) Is it necessary to measure PGRN levels in CSF to monitor a therapeutic effect? Therefore, concentrations of PGRN were measured in paired CSF and serum samples of 22 patients with behavioural variant frontotemporal dementia, including one GRN mutation carrier (c.349+1G>C), 16 patients with amyotrophic lateral sclerosis and 17 non-neurodegenerative patients, which included 22 follow-up levels. PGRN levels of 14 patients with isolated dysfunction of the blood-CSF barrier were measured and PGRN was correlated with albumin quotients as a marker for blood-CSF barrier function. The intrathecal fraction of PGRN was calculated on the basis of CSF-to-serum ratios and hydrodynamic properties. Follow-up measurements of CSF and serum PGRN levels did not show any significant change in diagnostic groups. Mean PGRN levels are 35 times higher in blood than in CSF. However, the CSF-to-serum PGRN ratio does not correlate with the albumin quotient even in patients with severe impairment of the blood-CSF barrier. The calculated intrathecal fraction of CSF PGRN levels ranged between 80 and 90 %. Assuming that CSF PGRN is either brain-derived or transported from the vascular compartment via receptor mediated mechanisms, we propose that monitoring CNS specific effects of PGRN modulating drugs should be done in CSF.


The origins of the vocal brain in humans.
The evolution of vocal communication in humans required the emergence of not only voluntary control of the vocal apparatus and a flexible vocal repertoire, but the capacity for vocal learning. All of these capacities are lacking in non-human primates, suggesting that the vocal brain underwent significant modifications during human evolution. We review research spanning from early neurophysiological descriptions of great apes to the state of the art in human neuroimaging on the neural organization of the larynx motor cortex, the major regulator of vocalization for both speech and song in humans. We describe changes to the location, structure, function, and connectivity of the larynx motor cortex in humans compared with non-human primates, including critical gaps in the current understanding of the brain systems mediating vocal control and vocal learning. We explore a number of models of the origins of the vocal brain that incorporate findings from comparative neuroscience, and conclude by presenting a summary of contemporary hypotheses that can guide future research.


Differences in collagen architecture between keloid, hypertrophic scar, normotrophic scar, and normal skin: An objective histopathological analysis.
Normotrophic, hypertrophic, and keloidal scars are different types of scar formation, which all need a different approach in treatment. Therefore, it is important to differentiate between these types of scar, not only clinically but also histopathologically. Differences were explored for collagen orientation and bundle thickness in 25 normal skin, 57 normotrophic scar, 56 hypertrophic scar, and 56 keloid biopsies, which were selected on clinical diagnosis. Image analysis was performed by fast fourier transformation. The calculated collagen orientation index ranged from 0 (random orientation) to 1 (parallel orientation). The bundle distance was calculated by the average distance between the centers of the collagen bundles. The results showed that compared with all three types of scars, the collagen orientation index was significantly lower in normal skin, which indicates that scars are organized in a more parallel manner. No differences were found between the different scars. Secondly, compared with normal skin, normotrophic scar, and hypertrophic scar, the bundle distance was significantly larger in keloidal scar, which suggests that thicker collagen bundles are present in keloidal scar. This first extensive histological study showed objective differences between normal skin, normotrophic, hypertrophic, and keloidal scar.


The Value of Unstructured Electronic Health Record Data in Geriatric Syndrome Case Identification.
To examine the value of unstructured electronic health record (EHR) data (free-text notes) in identifying a set of geriatric syndromes. Retrospective analysis of unstructured EHR notes using a natural language processing (NLP) algorithm. Large multispecialty group. Older adults (N=18,341; average age 75.9, 58.9% female). We compared the number of geriatric syndrome cases identified using structured claims and structured and unstructured EHR data. We also calculated these rates using a population-level claims database as a reference and identified comparable epidemiological rates in peer-reviewed literature as a benchmark. Using insurance claims data resulted in a geriatric syndrome prevalence ranging from 0.03% for lack of social support to 8.3% for walking difficulty. Using structured EHR data resulted in similar prevalence rates, ranging from 0.03% for malnutrition to 7.85% for walking difficulty. Incorporating unstructured EHR notes, enabled by applying the NLP algorithm, identified considerably higher rates of geriatric syndromes: absence of fecal control (2.1%, 2.3 times as much as structured claims and EHR data combined), decubitus ulcer (1.4%, 1.7 times as much), dementia (6.7%, 1.5 times as much), falls (23.6%, 3.2 times as much), malnutrition (2.5%, 18.0 times as much), lack of social support (29.8%, 455.9 times as much), urinary retention (4.2%, 3.9 times as much), vision impairment (6.2%, 7.4 times as much), weight loss (19.2%, 2.9 as much), and walking difficulty (36.34%, 3.4 as much). The geriatric syndrome rates extracted from structured data were substantially lower than published epidemiological rates, although adding the NLP results considerably closed this gap. Claims and structured EHR data give an incomplete picture of burden related to geriatric syndromes. Geriatric syndromes are likely to be missed if unstructured data are not analyzed. Pragmatic NLP algorithms can assist with identifying individuals at high risk of experiencing geriatric syndromes and improving coordination of care for older adults.


Evidence against C-type natriuretic peptide as an arterial 'EDHF'.
C-type natriuretic peptide (CNP) is found in and released from vascular endothelial cells. Recently, a novel role has been suggested for this peptide, that of an endothelium-derived hyperpolarizing factor or EDHF. Implicit in this proposal is a widespread role for CNP as a key mediator of vascular dilatation. In this issue of the British Journal of Pharmacology, Leuranguer et al. compare the profile of membrane potential changes evoked with this putative EDHF or with endogenous EDHF (activated with ACh) in small carotid arteries. Marked differences between the two profiles lead them to discount a possible role for CNP as an EDHF.


Brachial-ankle pulse wave velocity as an early indicator of left ventricular diastolic function among hypertensive subjects.
While increased arterial stiffness is a known risk of cardiovascular disease, pulse wave velocity (PWV) is a conventionally adopted index of arterial stiffness. However, the relationship between PWV and left ventricular functions are not thoroughly evaluated. This cross-sectional study investigated whether PWV measurement is an early indicator of left ventricular (LV) dysfunction. A noninvasive, volume-plethysmographic apparatus was used to determine blood pressure, electrocardiogram, heart sounds, and PWV in 42 consecutively diagnosed subjects with hypertension, and 42 sex- and age-matched nonhypertension subjects were studied. Arterial stiffness and aortic stiffness were evaluated by brachial-ankle (b-a) PWV, heart-carotid (h-c) PWV, heart-femoral (h-f) PWV, carotid-femoral (c-f) PWV, and femoral-ankle (f-a) PWV. Function of LV was estimated by tissue Doppler imaging (TDI) echocardiography. Hypertension subjects exhibited higher b-a PWV and late diastolic mitral flow velocity values than those of nonhypertensive subjects. Pearson correlation analysis revealed that LV diastolic function (Em(av)) negatively correlated with c-f PWV and b-a PWV. Multiple linear regression analysis indicated that b-a PWV was independently and negatively associated with LV diastolic function (Em(av)). Further analysis by stratified hypertensive status, the b-a PWV were independently and negatively associated with Em(av) in hypertensive subjects (p = 0.004) only. In conclusion, the b-a PWV, but not c-f PWV, h-c PWV, h-f PWV, or f-a PWV, is significantly correlated with LV diastolic function in hypertensive subjects, indicating that b-a PWV involving both central and peripheral components of arterial stiffness may be an early indicator of LV dysfunction.


An overview of stress response and hypometabolic strategies in Caenorhabditis elegans: conserved and contrasting signals with the mammalian system.
Studies of the molecular mechanisms that are involved in stress responses (environmental or physiological) have long been used to make links to disease states in humans. The nematode model organism, Caenorhabditis elegans, undergoes a state of hypometabolism called the 'dauer' stage. This period of developmental arrest is characterized by a significant reduction in metabolic rate, triggered by ambient temperature increase and restricted oxygen/ nutrients. C. elegans employs a number of signal transduction cascades in order to adapt to these unfavourable conditions and survive for long times with severely reduced energy production. The suppression of cellular metabolism, providing energetic homeostasis, is critical to the survival of nematodes through the dauer period. This transition displays molecular mechanisms that are fundamental to control of hypometabolism across the animal kingdom. In general, mammalian systems are highly inelastic to environmental stresses (such as extreme temperatures and low oxygen), however, there is a great deal of conservation between the signal transduction pathways of nematodes and mammals. Along with conserving many of the protein targets in the stress response, many of the critical regulatory mechanisms are maintained, and often differ only in their level of expression. Hence, the C. elegans model outlines a framework of critical molecular mechanisms that may be employed in the future as therapeutic targets for addressing disease states.


Trait mindfulness helps shield decision-making from translating into health-risk behavior.
The cognitive tendency toward mindfulness may influence the enactment of health and risk behaviors by its bringing increased attention to and awareness of decision-making processes underlying behavior. The present study examined the moderating effect of trait mindfulness on associations between intentions to smoke (ITS)/smoking refusal self-efficacy (SRSE) and smoking frequency. Self-reports from Chinese adolescents (N = 5,287; mean age = 16.2 years, standard deviation = .7; 48.8% female) were collected in 24 schools. Smoking frequency was regressed on latent factor interactions Mindful Attention Awareness Scale*ITS and Mindful Attention Awareness Scale*SRSE, adjusting for school clustering effects and covariates. Both interaction terms were significant in cross-sectional analyses and showed that high ITS predicted higher smoking frequency among those low, relative to high, in trait mindfulness, whereas low SRSE predicted higher smoking frequency among those low, relative to high, in trait mindfulness. Findings suggest trait mindfulness possibly shields against decision-making processes that place adolescents at risk for smoking.


Associations of Circulating MicroRNAs (miR-17, miR-21, and miR-150) and Chronic Kidney Disease in a Japanese Population.
MicroRNAs (miRNAs) play crucial roles in the development of various diseases, including chronic kidney disease (CKD). Although previous studies in clinically severe patients have investigated associations between CKD and miRNAs, with particular attention on renal fibrosis, relationships in a general population have yet to be established. The aim of this study was to examine the relationship between expression level of circulating miRNAs and CKD in a middle-aged Japanese population. A final total of 513 individuals (216 men and 297 women) who participated in the health check-up program in 2012 were included in our analysis. Quantitative real-time polymerase chain reaction was used to determine expression levels of 22 miRNAs. Estimated glomerular filtration rate (eGFR) was calculated based on serum creatinine level, sex, and age. Participants with eGFR <60 mL/min/1.73 m2 were defined as having CKD. Three different miRNAs (miR-17, miR-21, and miR-150) showed significant correlations with eGFR after Bonferroni correction and were selected for further analyses. Expression levels of miR-17, miR-21, and miR-150 miRNAs were positively associated with eGFR after adjusting for potential confounders (P = 0.004, 0.002, and 0.004, respectively). Logistic regression analyses showed significantly lower odds ratios for CKD (eGFR <60 mL/min/1.73 m2) in the highest tertile of all three miRNAs (miR-17, miR-21, and miR-150) compared with the lowest tertile (P = 0.003, 0.01, and 0.02, respectively). We found that three circulating miRNAs were significantly associated with CKD in a general Japanese population, which suggested that these miRNAs may be biomarkers for CKD among general adults.


What Is the Best Proximal Anastomosis for the Free Right Internal Thoracic Artery during Bilateral Internal Thoracic Artery Revascularization? A Prospective, Randomized Study.
Objective. Bilateral internal thoracic artery (BITA) grafting provides improved graft patency and potential survival advantage in selected patients as compared to single left internal thoracic artery (LITA) revascularization. The ideal functional BITA configuration remains controversial. Methods. Patients undergoing planned BITA revascularization with greater than 75% stenosis in both the left anterior descending artery (LAD) and in a circumflex branch were prospectively randomized to one of two proximal free right internal thoracic artery (RITA) connections directly off the aorta (Ao) (n = 12) or as a "t" graft off the LITA (t) (n = 12). The LITA was placed to the LAD in all cases, and the RITA was placed to a single lateral wall vessel. Intraoperative transit time flow measurements of all arterial grafts were performed, and RITA fractional flow parameters were compared between the 2 groups. Results. There were no differences in preoperative patient variables between the two groups. Cross-clamp times (91.5 + 15.3 versus 68.0 + 12.5 minutes, P < 0.01) and total cardiopulmonary bypass times (109.0 + 16.2 versus 85.0 + 15.1 minutes, P < 0.01) were shorter in the t group. The Ao group demonstrated significantly higher mean RITA flow (38.3 ± 13.5 versus 22.1 ± 9.5, P < 0.01), mean RITA conductance (flow/mean arterial pressure) (0.45 ± 0.16 versus 0.28 ± 0.11, P < 0.01), RITA fractional flow (0.52 ± 0.15 versus 0.36 ± 0.11, P < 0.01), and RITA fractional conductance (0.51 ± 0.15 versus 0.36 ± 0.11, P < 0.01) than the "t" grafted patients. Thirty-day mortality and wound infection were 0% for each group. Over an average of 42.8 + 6.6 months of followup there were no mortalities in either group. Repeat angiography were performed in 4 patients (33%) in the Ao group and 2 patients in the t group (16%). One occluded RITA graft and one ostial RITA stenosis were detected in the Ao group. Conclusions. Acute flow measurements indicate that the free RITA anastomosed to the aorta provides more acute fractional RITA flow than composite "t" grafting to the LITA. Longer-term angiographic and clinical followup are necessary to determine the consequences of these acute hemodynamic findings.


Surface functionalization of electrodes with molecular reagents.
The use of molecular reagents to manipulate the properties of electrode surfaces has broad application in areas such as electrochemical synthesis, energy conversion and storage, displays, sensors, and new kinds of microelectronic devices. Surface modification of electrodes has contributed to a revival of interest in basic and applied research in electrochemistry and electrochemical devices. This article is focused on specific examples of systems modified electrodes where basic developments provide promising opportunities for applications stemming from the properties of molecules attached to an electrode surface.


Review article: Patellar instability after total knee arthroplasty.
Patellar instability after total knee arthroplasty (TKA) is a serious complication that impairs functional outcome and may lead to revision surgery. Its aetiology can be related to the surgical technique and component positioning, extensor mechanism imbalance, and other causes. After TKA, the presence of anterior knee pain, especially during stressful activities, is indicative of patellar instability. Diagnosis can be made by radiological evaluation of the patella position, alignment, and component fixation. Main treatment options include revision of the TKA components (in case of malposition) and lateral retinacular release with or without a proximal or distal realignment (in case of soft-tissue imbalance).


Methods to validate Hsp90 inhibitor specificity, to identify off-target effects, and to rethink approaches for further clinical development.
The molecular chaperone Hsp90 is one component of a highly complex and interactive cellular proteostasis network (PN) that participates in protein folding, directs misfolded and damaged proteins for destruction, and participates in regulating cellular transcriptional responses to environmental stress, thus promoting cell and organismal survival. Over the last 20 years, it has become clear that various disease states, including cancer, neurodegeneration, metabolic disorders, and infection by diverse microbes, impact the PN. Among PN components, Hsp90 was among the first to be pharmacologically targeted with small molecules. While the number of Hsp90 inhibitors described in the literature has dramatically increased since the first such small molecule was described in 1994, it has become increasingly apparent that not all of these agents have been sufficiently validated for specificity, mechanism of action, and lack of off-target effects. Given the less than expected activity of Hsp90 inhibitors in cancer-related human clinical trials, a re-evaluation of potentially confounding off-target effects, as well as confidence in target specificity and mechanism of action, is warranted. In this commentary, we provide feasible approaches to achieve these goals and we discuss additional considerations to improve the clinical efficacy of Hsp90 inhibitors in treating cancer and other diseases.


The Role of e-NOS in Chronic Cholestasis-Induced Liver and Renal Injury in Rats: The Effect of N-Acetyl Cysteine.
Introduction. The role of chronic cholestasis (CC) in liver injury and fibrosis remains unclear. The aims of this study were to define the role of endothelial nitric oxide synthase (e-NOS) in CC and the protective effect of N-acetyl-L-cysteine (NAC) in liver and kidney injury. Materials and Methods. Group A (sham group); Group B (CBDL); and Group C (CBDL + NAC). Group C received daily dosage of NAC (100 mg/kg) intraperitoneally for up to 4 weeks. Results. The rate of bridging fibrosis was higher (100% versus 20%, P = .025), but the intensity of e-NOS in liver was lower in rats that received NAC (1.3 versus 2.7, P = .046). The necrotic area in the kidneys among rats that received NAC was lower at week 4 (48% versus 57%; P < .001). The numbers of e-NOS stained cells in kidney were similar in sham group and the two groups with CBDL. Discussion. NAC reduced the stimulus for liver fibrosis in this rat model of CC and attenuated liver and kidney injury. Our study showed that e-NOS expression increased in liver tissue of rats with CC and that this was reversed by NAC. Treatment with NAC might restore e-NOS protein expression and prevent liver injury in CC.


Evaluation of the systematic error in using 3D dose calculation in scanning beam proton therapy for lung cancer.
The objective of this study was to evaluate and understand the systematic error between the planned three-dimensional (3D) dose and the delivered dose to patient in scanning beam proton therapy for lung tumors. Single-field and multifield optimized scanning beam proton therapy plans were generated for ten patients with stage II-III lung cancer with a mix of tumor motion and size. 3D doses in CT datasets for different respiratory phases and the time-weighted average CT, as well as the four-dimensional (4D) doses were computed for both plans. The 3D and 4D dose differences for the targets and different organs at risk were compared using dose-volume histogram (DVH) and voxel-based techniques, and correlated with the extent of tumor motion. The gross tumor volume (GTV) dose was maintained in all 3D and 4D doses, using the internal GTV override technique. The DVH and voxel-based techniques are highly correlated. The mean dose error and the standard deviation of dose error for all target volumes were both less than 1.5% for all but one patient. However, the point dose difference between the 3D and 4D doses was up to 6% for the GTV and greater than 10% for the clinical and planning target volumes. Changes in the 4D and 3D doses were not correlated with tumor motion. The planning technique (single-field or multifield optimized) did not affect the observed systematic error. In conclusion, the dose error in 3D dose calculation varies from patient to patient and does not correlate with lung tumor motion. Therefore, patient-specific evaluation of the 4D dose is important for scanning beam proton therapy for lung tumors.


Video-gaming among high school students: health correlates, gender differences, and problematic gaming.
Video game playing may negatively impact youth. However, the existing literature on gaming is inconsistent and often has focused on aggression rather than the health correlates of gaming and the prevalence and correlates of problematic gaming. We anonymously surveyed 4028 adolescents about gaming and reported problems with gaming and other health behaviors. A total of 51.2% of the sample reported gaming (76.3% of boys and 29.2% of girls). There were no negative health correlates of gaming in boys and lower odds of smoking regularly; however, girls who reported gaming were less likely to report depression and more likely to report getting into serious fights and carrying a weapon to school. Among gamers, 4.9% reported problematic gaming, defined as reporting trying to cut back, experiencing an irresistible urge to play, and experiencing a growing tension that could only be relieved by playing. Boys were more likely to report these problems (5.8%) than girls (3.0%). Correlates of problematic gaming included regular cigarette smoking, drug use, depression, and serious fights. Results suggest that gaming is largely normative in boys and not associated with many health factors. In girls, however, gaming seems to be associated with more externalizing behaviors and fewer internalizing symptoms. The prevalence of problematic gaming is low but not insignificant, and problematic gaming may be contained within a larger spectrum of externalizing behaviors. More research is needed to define safe levels of gaming, refine the definition of problematic gaming, and evaluate effective prevention and intervention strategies.


Reversed selection responses in small populations of the housefly (Musca domestica L.).
We compared the efficacy of artificial and natural selection processes in purging the genetic load of perpetually small populations. We subjected replicate lines of the housefly (Musca domestica L.), recently derived from the wild, to artificial selection for increased mating propensity (i.e., the proportion of male-female pairs initiating copulation within 30 min) in efforts to cull out the inbreeding depression effects of long-term small population size (as determined by a selection protocol for increased assortative mating). We also maintained parallel non-selection lines for assessing the spontaneous purge of genetic load due to inbreeding alone. We thus evaluated the fitness of artificially and 'naturally' purging populations held at census sizes of 40 individuals over the course of 18 generations. We found that the artificially selected lines had significant increases in mating propensity (up to 46% higher from the beginning of the protocol) followed by reversed selection responses back to the initial levels, resulting in non-significant heritabilities. Nevertheless, the 'naturally' selected lines had significantly lower fitness overall (a 28% reduction from the beginning of the protocol), although lower effective population sizes could have contributed to this effect. We conclude that artificial selection bolstered fitness, but only in the short-term, because the inadvertent fixation of extant genetic load later resulted in pleiotropic fitness declines. Still, the short-term advantage of the selection protocol likely contributed to the success of the speciation experiment since our recently-derived housefly populations are particularly vulnerable to inbreeding depression effects on mating behavior.


Mental work demands, retirement, and longitudinal trajectories of cognitive functioning.
Age-related changes in cognitive abilities are well-documented, and a very important indicator of health, functioning, and decline in later life. However, less is known about the course of cognitive functioning before and after retirement and specifically whether job characteristics during one's time of employment (i.e., higher vs. lower levels of mental work demands) moderate how cognition changes both before and after the transition to retirement. We used data from n = 4,182 (50% women) individuals in the Health and Retirement Study, a nationally representative panel study in the United States, across an 18 year time span (1992-2010). Data were linked to the O*NET occupation codes to gather information about mental job demands to examine whether job characteristics during one's time of employment moderates level and rate of change in cognitive functioning (episodic memory and mental status) both before and after retirement. Results indicated that working in an occupation characterized by higher levels of mental demands was associated with higher levels of cognitive functioning before retirement, and a slower rate of cognitive decline after retirement. We controlled for a number of important covariates, including socioeconomic (education and income), demographic, and health variables. Our discussion focuses on pathways through which job characteristics may be associated with the course of cognitive functioning in relation to the important transition of retirement. Implications for job design as well as retirement are offered.


Thymidylate synthase genotype-directed chemotherapy for patients with gastric and gastroesophageal junction cancers.
Retrospective studies indicate associations between TSER (thymidylate synthase enhancer region) genotypes and clinical outcomes in patients receiving 5-FU based chemotherapy, but well-controlled prospective validation has been lacking. In this phase II study (NCT00515216 registered through ClinicalTrials.gov, http://clinicaltrials.gov/show/NCT00515216), patients with "good risk" TSER genotypes (at least one TSER*2 allele) were treated with FOLFOX chemotherapy to determine whether prospective patient selection can improve overall response rates (ORR) in patients with gastric and gastroesophageal junction (GEJ) cancers, compared with historical outcomes in unselected patients (estimated 43%). The ORR in genotype-selected patients was 39.1% (9 partial responses out of 23 evaluable patients, 95% CI, 22.2 to 59.2), not achieving the primary objective of improving ORR. An encouraging disease control rate (DCR, consisting of partial responses and stable diseases) of 95.7% was noted and patients with homozygous TSER*2 genotype showed better tumor response. In this first prospective, multi-institutional study in patients with gastric or GEJ cancers, selecting patients with at least one TSER*2 allele did not improve the ORR but led to an encouraging DCR. Further studies are needed to investigate the utility of selecting patients homozygous for the TSER*2 allele and additional genomic markers in improving clinical outcomes for patients with gastric and GEJ cancers. ClinicalTrials.gov NCT00515216.


Transverse Coherence Limited Coherent Diffraction Imaging using a Molybdenum Soft X-ray Laser Pumped at Moderate Pump Energies.
Coherent diffraction imaging (CDI) in the extreme ultraviolet has become an important tool for nanoscale investigations. Laser-driven high harmonic generation (HHG) sources allow for lab scale applications such as cancer cell classification and phase-resolved surface studies. HHG sources exhibit excellent coherence but limited photon flux due poor conversion efficiency. In contrast, table-top soft X-ray lasers (SXRL) feature excellent temporal coherence and extraordinary high flux at limited transverse coherence. Here, the performance of a SXRL pumped at moderate pump energies is evaluated for CDI and compared to a HHG source. For CDI, a lower bound for the required mutual coherence factor of |μ 12| ≥ 0.75 is found by comparing a reconstruction with fixed support to a conventional characterization using double slits. A comparison of the captured diffraction signals suggests that SXRLs have the potential for imaging micron scale objects with sub-20 nm resolution in orders of magnitude shorter integration time compared to a conventional HHG source. Here, the low transverse coherence diameter limits the resolution to approximately 180 nm. The extraordinary high photon flux per laser shot, scalability towards higher repetition rate and capability of seeding with a high harmonic source opens a route for higher performance nanoscale imaging systems based on SXRLs.


Correlation of symptoms with vitamin D deficiency and symptom response to cholecalciferol treatment: a randomized controlled trial.
To examine the association of symptoms with vitamin D deficiency and symptom response to cholecalciferol treatment in a randomized, double-blind, placebo-controlled trial. Adult primary care patients in Duluth, Minnesota, were screened for vitamin D deficiency in February 2007. Participants completed questionnaires pertaining to a variety of symptoms, vitamin D intake, and selected medical conditions. Patients with mild to moderate vitamin D deficiency (25-hydroxyvitamin D [25(OH)D], 10-25 ng/mL) participated in a randomized controlled trial (RCT) of vitamin D replacement and its effect on symptoms. Participants were randomly assigned to receive 50 000 units of cholecalciferol (vitamin D3) weekly or placebo for 8 weeks. Patients with severe vitamin D deficiency (25[OH]D <10 ng/mL) were treated in an unblinded fashion, and symptoms were reevaluated post treatment. A total of 610 patients underwent initial screening, and 100 patients with mild to moderate vitamin D deficiency participated in the RCT. Thirty-eight severely deficient patients were treated in an unblinded fashion. On initial screening, 46.2% of participants were deficient in vitamin D. Self-reported vitamin D supplementation, milk intake, celiac disease, gastric bypass, and chronic pancreatitis were predictive of vitamin D status. Severely deficient participants reported increased musculoskeletal symptoms, depression (including seasonal), and higher (worse) scores on a fibromyalgia assessment questionnaire. In the RCT, the treated group showed significant improvement in fibromyalgia assessment scores (P = 0.03), whereas the placebo-treated participants did not. Severely deficient patients did not show symptom improvement over the 8-week trial period or when followed up 1 year later. Compared with participants in the placebo group, patients in the treatment group showed mild short-term improvement in the overall fibromyalgia impact score, but did not show significant improvement in most musculoskeletal symptoms or in activities of daily living.


Two-dimensional temperature measurements in particle loaded technical flames by filtered Rayleigh scattering.
Filtered Rayleigh scattering (FRS) is applied to determine two-dimensional temperature distributions in a hexamethyldisiloxane loaded propane/air flame intended for combustion chemical vapor deposition processes. An iodine cell as a molecular filter suppresses background scattering, e.g., by particles, while the wings of the spectrally broadened Rayleigh scattering can pass this filter. A frequency-doubled Nd:YAG laser is tuned to a strong absorption line of iodine. The gas temperature is deduced from the transmitted Rayleigh scattering signal. Since FRS also depends on molecule-specific scattering cross sections, the local gas composition of majority species is measured using the Raman scattering technique. Limits and restrictions are discussed.


Network reorganization during verbal fluency task in fronto-temporal epilepsy: A functional near-infrared spectroscopy study.
This is the first study to use functional near-infrared spectroscopy (fNIRS) to investigate how the lateralization of the epileptogenic zone affects the reconfiguration of task-related network patterns. Eleven left fronto-temporal epilepsy (L-FTE) and 11 right fronto-temporal epilepsy (R-FTE), as well as 22 age- and gender-matched controls, were enrolled. Signals from 52-channel fNIRS were recorded while the subject was undertaking verbal fluency tasks (VFTs), which included categorical (CFT) and letter (LFT) fluency tasks. Three analytic methods were used to study the network topology: network-based analysis, hub identification, and proportional threshold to select the top 20% strongest connections for both graph theory parameters and clinical correlation. Performance of CFT is accomplished primarily using the ventral pathway, and bilateral ventral pathways are augmented in fronto-temporal epilepsy patients by strengthening the inter-hemispheric connections, especially for R-FTE. LFT mainly employed the dorsal pathway, and further prioritized the left dorsal pathway in strengthening intra-hemispheric connections in fronto-temporal epilepsy, especially L-FTE. The top 20% of the strongest connections only present differences in CFT network compared with the controls. R-FTE increased inter-hemispheric network density, while L-FTE decreased inter-hemispheric average characteristic path length. Accumulative seizure burden only affects L-FTE network. Better LFT performance and longer educational years seem to promote left fronto-temporal networks, and decreased the demand from RR intra-hemispheric connectivity in L-FTE. LFT scores in R-FTE are maintained by preserved RR intra-hemispheric networks. However, CFT scores and educational years seem to have no effect on the CFT network topology in both FTE.


Seroprevalence and risk factors of syphilis infection in pregnant women delivering at Harare Maternity Hospital, Zimbabwe.
To evaluate risk factors and outcomes of syphilis during pregnancy. Hospital based, cross sectional study. Harare Maternity Hospital, Harare, Zimbabwe. A random sample of 2 969 pregnant women. Syphilis seroprevalence. Of the 2 969 women who provided blood samples, 4.8% were RPR positive. Approximately 2.2% of study subjects were RPR positive and TPHA negative. Notably, 2.5% of the population was RPR and TPHA positive at the time of giving birth. Older women had a higher risk of having positive syphilis status (p = 0.057). Increases in parity and gravidity were significantly associated with increased risk of syphilis infection. Prior stillbirths were associated with an increased risk of syphilis infection (odds ratio [OR], 3.4; 95% CI, 1.61 to 7.37; p = 0.001). Syphilis positive mothers were significantly more likely to give birth to syphilis positive newborns (p < 0.0001). Our results suggest that there should be more effective antenatal screening and treatment of syphilis in Harare. Syphilis affects many sub-Saharan countries where effective educational outreach, screening, and treatment should take place to prevent the transmission of this venereal disease, especially among reproductive age and pregnant women.


Hydrological and environmental assessment of urban growth in a sub-tropical town in India.
Roorkee, a sub-tropical urban town in India, has shown a rapid unplanned growth in the past. This paper presents the findings of a study of characteristics of urban soil, rainwater, and runoff emanating from different sources areas and the stormwater flows in the drains. Urban soil showed significant increase in the concentration of all constituents in comparison to the nearby rural soil. Soil metal pollution index suggested multi-element contamination. The traffic and transportation system emerged as the major source of metals and organics. Concentration of rainwater ions was observed to follow the pattern Ca²⁺ > HCO(3)(-) > Cl⁻ > NO(3)(-) > Na⁺ > Mg²⁺ > SO(4)(²⁻) > K⁺. Runoff results indicated a significant enhancement in the concentration of most measured constituents over their rainfall levels. The values of runoff coefficient varied between 0.05 and 0.58, with the high values displayed by the paved areas. Multiple regression equations were developed relating event mean concentration to various storm characteristics. The total load of all measured constituents was observed to vary considerably among the study sites, the direct runoff loads being much higher than the dry weather loads.


Canine vector-borne disease: mapping and the accuracy of forecasting using big data from the veterinary community.
Diagnosis, treatment, and prevention of vector-borne disease (VBD) in pets is one cornerstone of companion animal practices. Veterinarians are facing new challenges associated with the emergence, reemergence, and rising incidence of VBD, including heartworm disease, Lyme disease, anaplasmosis, and ehrlichiosis. Increases in the observed prevalence of these diseases have been attributed to a multitude of factors, including diagnostic tests with improved sensitivity, expanded annual testing practices, climatologic and ecological changes enhancing vector survival and expansion, emergence or recognition of novel pathogens, and increased movement of pets as travel companions. Veterinarians have the additional responsibility of providing information about zoonotic pathogen transmission from pets, especially to vulnerable human populations: the immunocompromised, children, and the elderly. Hindering efforts to protect pets and people is the dynamic and ever-changing nature of VBD prevalence and distribution. To address this deficit in understanding, the Companion Animal Parasite Council (CAPC) began efforts to annually forecast VBD prevalence in 2011. These forecasts provide veterinarians and pet owners with expected disease prevalence in advance of potential changes. This review summarizes the fidelity of VBD forecasts and illustrates the practical use of CAPC pathogen prevalence maps and forecast data in the practice of veterinary medicine and client education.


Depth cue reweighting requires altered correlations with haptic feedback.
Depth cue reweighting is a feedback-driven learning process that modifies the relative influences of different sources of three-dimensional shape information in perceptual judgments and or motor planning. In this study, we investigated the mechanism supporting reweighting of stereo and texture information by manipulating the haptic feedback obtained during a series of grasping movements. At the end of each grasp, the fingers closed down on a physical object that was consistent with one of the two cues, depending on the condition. Previous studies have shown that this style of visuomotor training leads to cue reweighting for perceptual judgments, but the time course has never been documented for a single training session, and many questions remain regarding the underlying mechanism, such as the pattern of feedback signals required to drive reweighting. We address these issues in two experiments, finding short-term changes in the motor response consistent with cue reweighting: the slope of the grip aperture with respect to the reliable cue increased, whereas the slope with respect to the unreliable cue decreased. Critically, Experiment 2 shows that slope changes do not occur when one of the cues is rendered with a constant bias; the grip aperture simply becomes uniformly larger or smaller. Our findings support a model of cue reweighting driven by altered correlations between haptic feedback and individual cues, rather than simple mismatches, which can be resolved by other mechanisms such as sensorimotor adaptation or cue recalibration.


Neuroanatomical organization of the brain gonadotropin-inhibitory hormone and gonadotropin-releasing hormone systems in the frog Pelophylax esculentus.
Growing evidence suggests that gonadotropin-inhibitory hormone (GnIH) may play a key role in mediating vertebrate reproduction. GnIH inhibits gonadotropin synthesis and release by decreasing the activity of gonadotropin-releasing hormone (GnRH) neurons as well as by directly regulating gonadotropin secretion from the pituitary. Whereas the presence of GnIH has been widely investigated in various classes of vertebrates, there are very few immunohistochemical reports focusing on GnIH in amphibians. The aim of this study was to assess the presence and neuroanatomical distribution of GnIH-like immunoreactivity in the brain of the anuran amphibian Pelophylax (Rana) esculentus (esculenta) and to explore any potential anatomical relationship with mammalian GnRH-immunoreactive (mGnRH-ir) elements. The GnIH-like immunoreactive (GnIH-ir) system constitutes two distinct subpopulations in the telencephalon and diencephalon, with the highest number of immunoreactive cells located in the preoptic and suprachiasmatic areas. GnIH-ir neurons were also observed in the medial septum, the anterior commissure, the dorsal hypothalamus, the periventricular nucleus of the hypothalamus, and the posterior tuberculum. Scattered GnIH-ir fibers were present in all major subdivisions of the brain but only occasionally in the median eminence. mGnRH-ir neurons were distributed in the mediobasal telencephalon, the medial septal area, and the anterior preoptic area. Double-label immunohistochemistry revealed that the GnRH and GnIH systems coexist and have overlapping distributions at the level of the anterior preoptic area. Some GnIH-ir fibers were in close proximity to mGnRH-ir cell bodies. Our results suggest that both the neuroanatomy and the functional regulation of GnRH release are conserved properties of the hypothalamic GnIH-ir system among vertebrate species.


Comparison of Interviewer-Administered and Automated Self-Administered 24-Hour Dietary Recalls in 3 Diverse Integrated Health Systems.
Twenty-four-hour dietary recalls provide high-quality intake data but have been prohibitively expensive for large epidemiologic studies. This study's goal was to assess whether the web-based Automated Self-Administered 24-Hour Recall (ASA24) performs similarly enough to the standard interviewer-administered, Automated Multiple-Pass Method (AMPM) 24-hour dietary recall to be considered a viable alternative. In 2010-2011, 1,081 adults from 3 integrated health systems in Detroit, Michigan; Marshfield, Wisconsin; and Kaiser-Permanente Northern California participated in a field trial. A quota design ensured a diverse sample by sex, age, and race/ethnicity. Each participant was asked to complete 2 recalls and was randomly assigned to 1 of 4 protocols differing by type of recall and administration order. For energy, the mean intakes were 2,425 versus 2,374 kcal for men and 1,876 versus 1,906 kcal for women by AMPM and ASA24, respectively. Of 20 nutrients/food groups analyzed and controlling for false discovery rate, 87% were judged equivalent at the 20% bound. ASA24 was preferred over AMPM by 70% of the respondents. Attrition was lower in the ASA24/AMPM study group than in the AMPM/ASA24 group, and it was lower in the ASA24/ASA24 group than in the AMPM/AMPM group. ASA24 offers the potential to collect high-quality dietary intake information at low cost with less attrition.


The mixed serotonin receptor agonist psilocybin reduces threat-induced modulation of amygdala connectivity.
Stimulation of serotonergic neurotransmission by psilocybin has been shown to shift emotional biases away from negative towards positive stimuli. We have recently shown that reduced amygdala activity during threat processing might underlie psilocybin's effect on emotional processing. However, it is still not known whether psilocybin modulates bottom-up or top-down connectivity within the visual-limbic-prefrontal network underlying threat processing. We therefore analyzed our previous fMRI data using dynamic causal modeling and used Bayesian model selection to infer how psilocybin modulated effective connectivity within the visual-limbic-prefrontal network during threat processing. First, both placebo and psilocybin data were best explained by a model in which threat affect modulated bidirectional connections between the primary visual cortex, amygdala, and lateral prefrontal cortex. Second, psilocybin decreased the threat-induced modulation of top-down connectivity from the amygdala to primary visual cortex, speaking to a neural mechanism that might underlie putative shifts towards positive affect states after psilocybin administration. These findings may have important implications for the treatment of mood and anxiety disorders.


Feeding styles of caregivers of children 6-23 months of age in Derashe special district, Southern Ethiopia.
Apart from basic determinants, appropriate child care practices are important in prevention of growth faltering and undernutrition. Providing safe and appropriate quality complementary foods is crucial to child growth and development. However, some children in low-income communities grow normally mainly due to proper caregiver feeding behaviors. Hence, the objective of this study was to determine caregivers' feeding styles as well as to indentify predictors in Derashe special district, Southern Ethiopia. A community based cross-sectional study design was employed in the seven randomly selected Kebeles (smallest administrative unit) of Derashe special district. A total of 826 caregivers provided data pertaining to socio-demographic variables. However, 764 caregivers had complete data for the outcome variable (caregiver feeding style). A multistage stratified sampling technique was used to identify study subjects. An adapted Caregiver's Feeding Styles Questionnaire (CFSQ) was used to gather information about caregivers' feeding styles. Multivariate multinomial logistic regression was employed to identify predictors of caregivers' feeding style. The majority (80.6%) of caregivers were biological mothers. Nearly seventy-six percent of the caregivers practiced a responsive feeding style. Caregivers other than the biological mother favoured a laissez-faire feeding style, while caregivers residing in rural Kebeles were more responsive. Caregivers with a breastfeeding frequency of more than eight times predicted both laissez-faire (RRR = 1.88; 95% CI = 1.03-3.41) and controlling (RRR = 1.7; 95% CI = 1.02-2.85) feeding styles as compared to responsive feeding. Responsive feeding was the commonest style practiced by the caregivers. Many of the caregivers who were rural residents and birth parents have been responsive in child feeding. The instruments needed to be validated in the Ethiopian context and an additional prospective study based on direct observation of caregiver-child interactions is recommended.


Breastfeeding, PAM50 tumor subtype, and breast cancer prognosis and survival.
Breastfeeding is associated with decreased breast cancer risk, yet associations with prognosis and survival by tumor subtype are largely unknown. We conducted a cohort study of 1636 women from two prospective breast cancer cohorts. Intrinsic tumor subtype (luminal A, luminal B, human epidermal growth factor receptor 2 [HER2]-enriched, basal-like) was determined by the PAM50 gene expression assay. Breastfeeding history was obtained from participant questionnaires. Questionnaires and medical record reviews documented 383 recurrences and 290 breast cancer deaths during a median follow-up of nine years. Multinomial logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) between breastfeeding and tumor subtype. Cox regression was used to estimate hazard ratios (HRs) for breast cancer recurrence or death. Statistical significance tests were two-sided. Breast cancer patients with basal-like tumors were less likely to have previously breastfed than those with luminal A tumors (OR = 0.56, 95% CI = 0.39 to 0.80). Among all patients, ever breastfeeding was associated with decreased risk of recurrence (HR = 0.70, 95% CI = 0.53 to 0.93), especially breastfeeding for six months or more (HR = 0.63, 95% CI = 0.46 to 0.87, P trend = .01). Similar associations were observed for breast cancer death. Among women with luminal A subtype, ever breastfeeding was associated with decreased risks of recurrence (HR = 0.52, 95% CI = 0.31 to 0.89) and breast cancer death (HR = 0.52, 95% CI = 0.29 to 0.93), yet no statistically significant associations were observed among the other subtypes. Effects appeared to be limited to tumors with lower expression of proliferation genes. History of breastfeeding might affect prognosis and survival by establishing a luminal tumor environment with lower proliferative activity.


CyREST: Turbocharging Cytoscape Access for External Tools via a RESTful API.
As bioinformatic workflows become increasingly complex and involve multiple specialized tools, so does the difficulty of reliably reproducing those workflows. Cytoscape is a critical workflow component for executing network visualization, analysis, and publishing tasks, but it can be operated only manually via a point-and-click user interface. Consequently, Cytoscape-oriented tasks are laborious and often error prone, especially with multistep protocols involving many networks. In this paper, we present the new cyREST Cytoscape app and accompanying harmonization libraries. Together, they improve workflow reproducibility and researcher productivity by enabling popular languages (e.g., Python and R, JavaScript, and C#) and tools (e.g., IPython/Jupyter Notebook and RStudio) to directly define and query networks, and perform network analysis, layouts and renderings. We describe cyREST's API and overall construction, and present Python- and R-based examples that illustrate how Cytoscape can be integrated into large scale data analysis pipelines. cyREST is available in the Cytoscape app store (http://apps.cytoscape.org) where it has been downloaded over 1900 times since its release in late 2014.


The association between regular yoga and meditation practice and falls and injuries: Results of a national cross-sectional survey among Australian women.
Falls are the leading cause of injuries in women across all ages. While yoga has been shown to increase balance, it has also been associated with injuries due to falls during practice. This study aimed to analyse whether regular yoga or meditation practice is associated with the frequency of falls and fall-related injuries in upper middle-aged Australian women. Women aged 59-64 years from the Australian Longitudinal Study on Women's Health (ALSWH) were queried regarding falls and falls-related injuries; and whether they regularly practiced yoga or meditation. Associations of falls and falls-related injuries with yoga or meditation practice were analysed using chi-squared tests and multiple logistic regression modelling. Of 10,011 women, 4413 (44.1%) had slipped, tripped or stumbled, 2770 (27.7%) had fallen to the ground, 1398 (14.0%) had been injured as a result of falling, and 901 (9.0%) women had sought medical attention for a fall-related injury within the previous 12 months. Yoga or meditation was practiced regularly by 746 (7.5%) women. No associations of falls, fall-related injuries and treatment due to falls-related injury with yoga or meditation practice were found. No association between yoga or meditation practice and falls or fall-related injuries have been found. Further studies are warranted for conclusive judgement of benefits and safety of yoga and meditation in relation to balance, falls and fall-related injuries.


Hydrophobic confinement modulates thermal stability and assists knotting in the folding of tangled proteins.
There is growing support for the idea that the in vivo folding process of knotted proteins is assisted by chaperonins, but the mechanism of chaperonin assisted folding remains elusive. Here, we conduct extensive Monte Carlo simulations of lattice and off-lattice models to explore the effects of confinement and hydrophobic intermolecular interactions with the chaperonin cage in the folding and knotting processes. We find that moderate to high protein-cavity interactions (which are likely to be established in the beginning of the chaperonin working cycle) cause an energetic destabilization of the protein that overcomes the entropic stabilization driven by excluded volume, and leads to a decrease of the melting temperature relative to bulk conditions. Moreover, mild-to-moderate hydrophobic interactions with the cavity (which would be established later in the cycle) lead to a significant enhancement of knotting probability in relation to bulk conditions while simultaneously moderating the effect of steric confinement in the enhancement of thermal stability. Our results thus indicate that the chaperonin may be able to assist knotting without simultaneously thermally stabilizing potential misfolded states to a point that would hamper productive folding thus compromising its functional role.


Narrowband optical interactions in a plasmonic nanoparticle chain coupled to a metallic film.
We study the coupling of localized surface plasmon (LSP) and surface-plasmon polariton (SPP) modes in a system composed of a metallic nanoparticle chain separated from a thin metallic film by a dielectric spacer. The thickness of such a spacer influences the level of interaction between LSP and SPP modes and controls the electromagnetic enhancement in this system. An enhancement with narrow resonances can be observed for appropriate parameters. The high-resonance quality factor and tunability of this system make it a very promising candidate for biosensing and surface-enhanced spectroscopy applications.


Plant-derived human acetylcholinesterase-R provides protection from lethal organophosphate poisoning and its chronic aftermath.
Therapeutically valuable proteins are often rare and/or unstable in their natural context, calling for production solutions in heterologous systems. A relevant example is that of the stress-induced, normally rare, and naturally unstable "read-through" human acetylcholinesterase variant, AChE-R. AChE-R shares its active site with the synaptic AChE-S variant, which is the target of poisonous organophosphate anticholinesterase insecticides such as the parathion metabolite paraoxon. Inherent AChE-R overproduction under organophosphate intoxication confers both short-term protection (as a bioscavenger) and long-term neuromuscular damages (as a regulator). Here we report the purification, characterization, and testing of human, endoplasmic reticulum-retained AChE-R(ER) produced from plant-optimized cDNA in Nicotiana benthamiana plants. AChE-R(ER) purified to homogeneity showed indistinguishable biochemical properties, with IC50 = 10(-7) M for the organophosphate paraoxon, similar to mammalian cell culture-derived AChE. In vivo titration showed dose-dependent protection by intravenously injected AChE-R(ER) of FVB/N male mice challenged with a lethal dose of paraoxon, with complete elimination of short-term clinical symptoms at near molar equivalence. By 10 days postexposure, AChE-R prophylaxis markedly limited postexposure increases in plasma murine AChE-R levels while minimizing the organophosphate-induced neuromuscular junction dismorphology. Our findings present plant-produced AChE-R(ER) as a bimodal agent, conferring both short- and long-term protection from organophosphate intoxication.


Coronary angiography using the left distal radial approach - An alternative site to conventional radial coronary angiography.
To share our experience with the left distal radial approach for transradial coronary angiography and interventions. By performing the radial puncture in the fossa radialis or the so called anatomical "Snuffbox" we aimed to present the feasibility and complications of this new technique. Left distal radial artery was used as an access site in 54 patients admitted to our clinic for coronary angiography and intervention between May 25th and October 20th 2017. All of them had pulse in their left distal radial artery. In the laboratory, they had their left arm gently flexed at the shoulder so that the hand was placed over their right groin. The operator stood on the right side of the patient and performed coronary angiography and interventions. During the hospital stay, demographic features and complications were recorded. Mean age of patients was 59.3 years and 80% were male. We used Judkins 6 French catheters for the procedures. Seventeen patients admitted with acute coronary syndrome. They all underwent successful left distal transradial coronary angiography and intervention. Primary angioplasty was performed in 10 patients. In total, 20 patients had coronary intervention. Left anterior descending artery was the artery requiring most intervention (11 patients). Two patients experienced brachial spasm requiring crossover to right femoral artery. There were no cases of radial artery occlusion, hematoma, or hand numbness. The radial sheath was removed at procedure termination. Hemostasis was achieved with manual compression. Left distal radial approach is safe and feasible as a new technique for coronary angiography and interventions.


Curricular and pedagogic questions raised by recent medical education efforts on bioterrorism.
This article outlines the development of learning materials to educate osteopathic medical students about biological terrorism at the American Association of Colleges of Osteopathic Medicine (AACOM). The author then poses two questions that arose from this and concurrent AACOM projects and new technologic developments in medical education, regarding what colleges of osteopathic medicine teach and how they teach it.


VLA-4 mediates CD3-dependent CD4+ T cell activation via the CS1 alternatively spliced domain of fibronectin.
We previously showed that fibronectin (FN) synergized with anti-CD3 in induction of CD4+ T cell proliferation, and that VLA-5 acted as a functional FN receptor in a serum-free culture system. In the present study, we showed that VLA-4 is also involved in this CD3-dependent CD4 cell activation through its interaction with the alternatively spliced CS1 domain of FN. When highly purified CD4 cells were cultured on plates coated with anti-CD3 plus synthetic CS1 peptide-IgG conjugate, significant proliferation could be observed. Neither CS1 alone nor anti-CD3 alone induced this activation. This proliferation was completely blocked by anti-VLA beta 1 (4B4) and anti-VLA-4 (8F2), while anti-VLA-5 (monoclonal antibody [mAb] 16 and 2H6) had no effect. These data indicate that VLA-4 mediates CD3-dependent CD4 cell proliferation via the CS1 domain of FN. Anti-VLA-4 also partially (10-40%) inhibited CD4 cell proliferation induced by native FN plus anti-CD3, implying that the CS1 domain is active in the native plasma FN. However, this native FN-dependent proliferation was entirely abolished by addition of anti-VLA-5 alone. Moreover, when native FN-coated plates were pretreated with anti-FN (mAb 333), which blocks RGDS sites but not CS1 sites, no CD4 cell activation could be observed. These results strongly suggest that CD4 cell activation induced by plasma FN/anti-CD3 may be dependent on both VLA4/CS1 and VLA5/RGDS interactions, although the latter interaction may be required for function of the former.


Identification and preliminary characterization of a protein motif related to the zinc finger.
We have identified a protein motif, related to the zinc finger, which defines a newly discovered family of proteins. The motif was found in the sequence of the human RING1 gene, which is proximal to the major histocompatibility complex region on chromosome six. We propose naming this motif the "RING finger" and it is found in 27 proteins, all of which have putative DNA binding functions. We have synthesized a peptide corresponding to the RING1 motif and examined a number of properties, including metal and DNA binding. We provide evidence to support the suggestion that the RING finger motif is the DNA binding domain of this newly defined family of proteins.


Increasing resistance to beta-lactam antibiotics among clinical isolates of Enterococcus faecium: a 22-year review at one institution.
To identify any change in the antibiotic resistance of Enterococcus faecium, we examined the antibiotic susceptibilities of clinical strains (n = 84) isolated at one institution during the 22 years since 1968. A significant increase in resistance to penicillin was observed during the study period: the MICs of penicillin for 50 and 90% of isolates tested were 16 and 64 micrograms/ml, respectively, from 1969 to 1988 (n = 48; geometric mean MIC, 14 micrograms/ml) , whereas they were 256 and 512 micrograms/ml, respectively, from 1989 to 1990 (n = 36; geometric mean MIC, 123 micrograms/ml) (P less than 0.001). A comparable increase in resistance to ampicillin was also noted (P less than 0.001). No strains produced detectable beta-lactamase. In contrast, susceptibilities to vancomycin, teicoplanin, and ciprofloxacin remained stable. High-level resistance to gentamicin was observed in none of 48 isolates from 1969 to 1988, but was present in 22 of 36 strains (61%) from 1989 to 1990 (P less than 0.001) and was significantly associated with resistance (MIC, greater than or equal to 128 micrograms/ml) to penicillin (P less than 0.001). To assess the potential evolution of antibiotic resistance in this species, clinical isolates (n = 24) were compared with strains isolated in 1968 from a human population in the Solomon Islands that was never exposed to antibiotics. Solomon Island isolates were significantly more susceptible than all clinical strains to penicillin, ampicillin, and vancomycin (P less than 0.001 for each), but they exhibited no differences in susceptibility to teicoplanin or ciprofloxacin. The penicillin-binding affinity of penicillin-binding protein 5 (PBP 5) in penicillin-resistant clinical strains (MIC, 512 micrograms/ml) was notably lower than that in strains with more typical susceptibilities, suggesting an alteration in this PBP as a possible mechanism for increased penicillin resistance. Solomon Island strains most susceptible to penicillin demonstrated a prominent PBP 5* and the absence of PBP 5. These changes in the antibiotic resistance of E. faecium emphasize the importance of identifying this species in patients with serious enterococcal infections and the necessity of assessing its susceptibility to both beta-lactams and aminoglycosides if effective therapy is to be identified.


Efficacy of methylphenidate for attention-deficit hyperactivity disorder in children with tic disorder.
The findings from case reports and patient questionnaire surveys have been interpreted as indicating that administration of stimulants is ill-advised for the treatment of attention-deficit hyperactivity disorder in children with tic disorder. Thirty-four prepubertal children with attention-deficit hyperactivity disorder and tic disorder received placebo and three dosages of methylphenidate hydrochloride (0.1, 0.3, and 0.5 mg/kg) twice daily for 2 weeks each, under double-blind conditions. Treatment effects were assessed using direct observations of child behavior in a simulated (clinic-based) classroom and using rating scales completed by the parents, teachers, and physician. Methylphenidate effectively suppressed hyperactive, disruptive, and aggressive behavior. There was no evidence that methylphenidate altered the severity of tic disorder, but it may have a weak effect on the frequency of motor (increase) and vocal (decrease) tics. Methylphenidate appears to be a safe and effective treatment for attention-deficit hyperactivity disorder in the majority of children with comorbid tic disorder.


SIGLEC12, a human-specific segregating (pseudo)gene, encodes a signaling molecule expressed in prostate carcinomas.
The primate SIGLEC12 gene encodes one of the CD33-related Siglec family of signaling molecules in immune cells. We had previously reported that this gene harbors a human-specific missense mutation of the codon for an Arg residue required for sialic acid recognition. Here we show that this R122C mutation of the Siglec-XII protein is fixed in the human population, i.e. it occurred prior to the origin of modern humans. Additional mutations have since completely inactivated the SIGLEC12 gene in some but not all humans. The most common inactivating mutation with a global allele frequency of 58% is a single nucleotide frameshift that markedly shortens the open reading frame. Unlike other CD33-related Siglecs that are primarily found on immune cells, we found that Siglec-XII protein is expressed not only on some macrophages but also on various epithelial cell surfaces in humans and chimpanzees. We also found expression on certain human prostate epithelial carcinomas and carcinoma cell lines. This expression correlates with the presence of the nonframeshifted, intact SIGLEC12 allele. Although SIGLEC12 allele status did not predict prostate carcinoma incidence, restoration of expression in a prostate carcinoma cell line homozygous for the frameshift mutation induced altered regulation of several genes associated with carcinoma progression. These stably transfected Siglec-XII-expressing prostate cancer cells also showed enhanced growth in nude mice. Finally, monoclonal antibodies against the protein were internalized by Siglec-XII-expressing prostate carcinoma cells, allowing targeting of a toxin to such cells. Polymorphic expression of Siglec-XII in humans thus has implications for prostate cancer biology and therapeutics.


Conversion efficiency of broad-band rectennas for solar energy harvesting applications.
Optical antennas have been proposed as an alternative option for solar energy harvesting. In this work the power conversion efficiency of broadband antennas, log-periodic, square-spiral, and archimedian-spiral antennas, coupled to Metal-Insulator-Metal and Esaki rectifying diodes has been obtained from both theoretical and numerical simulation perspectives. The results show efficiencies in the order of 10(-6) to 10(-9) for these rectifying mechanisms, which is very low for practical solar energy harvesting applications. This is mainly caused by the poor performance of diodes at the given frequencies and also due to the antenna-diode impedance mismatch. If only losses due to antenna-diode impedance mismatch are considered an efficiency of about 10(-3) would be obtained. In order to make optical antennas useful for solar energy harvesting new rectification devices or a different harvesting mechanism should be used.


Outreach and support in south London (OASIS): implementation of a clinical service for prodromal psychosis and the at risk mental state.
While recent research points to the potential benefits of clinical intervention before the first episode of psychosis, the logistical feasibility of this is unclear. To assess the feasibility of providing a clinical service for people with prodromal symptoms in an inner city area where engagement with mental health services is generally poor. Following a period of liaison with local agencies to promote the service, referrals were assessed and managed in a primary care setting. Activity of the service was audited over 30 months. People with prodromal symptoms were referred by a range of community agencies and seen at their local primary care physician practice. Over 30 months, 180 clients were referred; 58 (32.2%) met criteria for an at risk mental state, most of whom (67.2%) had attenuated psychotic symptoms. Almost 30% were excluded due to current or previous psychotic illness, of which two-thirds were in the first episode of psychosis. The socio-demographic composition of the 'at risk' group reflected that of the local population, with an over-representation of clients from an ethnic minority. Over 90% of suitable clients remained engaged with the service after 1 year. It is feasible to provide a clinical service for people with prodromal symptoms in a deprived inner city area with a large ethnic minority population.


Recent advances in human flavivirus vaccines.
Dengue (DENV), West Nile (WNV) and Zika (ZIKV) viruses are mosquito-transmitted flaviviruses that cause thousands of human deaths and millions of illnesses each year. In the last decades, epidemic outbreaks of all three flaviviruses emerged and caused a major health and economical problem in many parts of the world. The increasing and expanding burden of flaviviruses has highlighted the need for effective human vaccines against all three viruses. This review provides an overview of the recent progress in DENV, WNV and ZIKV vaccines development with specific focus on candidates in human clinical development.


An Intracardiac Soft Robotic Device for Augmentation of Blood Ejection from the Failing Right Ventricle.
We introduce an implantable intracardiac soft robotic right ventricular ejection device (RVED) for dynamic approximation of the right ventricular (RV) free wall and the interventricular septum (IVS) in synchrony with the cardiac cycle to augment blood ejection in right heart failure (RHF). The RVED is designed for safe and effective intracardiac operation and consists of an anchoring system deployed across the IVS, an RV free wall anchor, and a pneumatic artificial muscle linear actuator that spans the RV chamber between the two anchors. Using a ventricular simulator and a custom controller, we characterized ventricular volume ejection, linear approximation against different loads and the effect of varying device actuation periods on volume ejection. The RVED was then tested in vivo in adult pigs (n = 5). First, we successfully deployed the device into the beating heart under 3D echocardiography guidance (n = 4). Next, we performed a feasibility study to evaluate the device's ability to augment RV ejection in an experimental model of RHF (n = 1). RVED actuation augmented RV ejection during RHF; while further chronic animal studies will provide details about the efficacy of this support device. These results demonstrate successful design and implementation of the RVED and its deployment into the beating heart. This soft robotic ejection device has potential to serve as a rapidly deployable system for mechanical circulatory assistance in RHF.


Mixture effect of arsenic and fluoride at environmentally relevant concentrations in zebrafish (Danio rerio) liver: Expression pattern of Nrf2 and related xenobiotic metabolizing enzymes.
Nrf2 is a crucial transcription factor that regulates the expression of cytoprotective enzymes and controls cellular redox homeostasis. Both arsenic and fluoride are potent toxicants that are known to induce Nrf2. They are reported to coexist in many areas of the world leading to complex mixture effects in exposed organisms. The present study investigated the expression of Nrf2 and related xenobiotic metabolizing enzymes along with other stress markers such as histopathological alterations, catalase activity, reduced glutathione content and lipid peroxidation in zebrafish liver as a function of combined exposure to environmentally relevant concentrations of arsenic (37.87 μgL-1 or 5.05 × 10-7 M) and fluoride (6.8 mg L-1 or 3.57 × 10-4 M) for 60 days. The decrease in the total reduced glutathione level was evident in all treatment conditions. Hyperactivity of catalase along with conspicuous elevation in reactive oxygen species, malondialdehyde content and histo-architectural anomalies signified the presence of oxidative stress in the treatment groups. Nrf2 was seen to be induced at both transcriptional and translational levels in case of both individual and co-exposure. The same pattern was observed in case of its nuclear translocation also. From the results of qRT-PCR it was evident that at each time point co-exposure to arsenic and fluoride seemed to alter the gene expression of Cu/Zn Sod, Mn Sod, Gpx and Nqo1 just like their individual exposure but at a very low magnitude. In conclusion, this study demonstrates for the first time the differential expression and activity of Nrf2 and other stress response genes in the zebrafish liver following individual and combined exposure to arsenic and fluoride.


Age-related collagen turnover of the interstitial matrix and basement membrane: Implications of age- and sex-dependent remodeling of the extracellular matrix.
The extracellular matrix (ECM) plays a vital role in maintaining normal tissue function. Collagens are major components of the ECM and there is a tight equilibrium between degradation and formation of these proteins ensuring tissue health and homeostasis. As a consequence of tissue turnover, small collagen fragments are released into the circulation, which act as important biomarkers in the study of certain tissue-related remodeling factors in health and disease. The aim of this study was to establish an age-related collagen turnover profile of the main collagens of the interstitial matrix (type I and III collagen) and basement membrane (type IV collagen) in healthy men and women. By using well-characterized competitive ELISA-assays, we assessed specific fragments of degraded (C1M, C3M, C4M) and formed (PINP, Pro-C3, P4NP7S) type I, III and IV collagen in serum from 617 healthy men and women ranging in ages from 22 to 86. Subjects were divided into 5-year age groups according to their sex and age. Groups were compared using Kruskal-Wallis adjusted for Dunn's multiple comparisons test and Mann-Whitney t-test. Age-specific changes in collagen turnover was most profound for type I collagen. PINP levels decreased in men with advancing age, whereas in women, the level decreased in early adulthood followed by an increase around the age of menopause (age 40-60). Sex-specific changes in type I, III and IV collagen turnover was present at the age around menopause (age 40-60) with women having an increased turnover. In summary, collagen turnover is affected by age and sex with the interstitial matrix and the basement membrane being differently regulated. The observed changes needs to be accounted for when measuring ECM related biomarkers in clinical studies.


Classical dimers with aligning interactions on the square lattice.
We present a detailed study of a model of close-packed dimers on the square lattice with an interaction between nearest-neighbor dimers. The interaction favors parallel alignment of dimers, resulting in a low-temperature crystalline phase. With large-scale Monte Carlo and transfer matrix calculations, we show that the crystal melts through a Kosterlitz-Thouless phase transition to give rise to a high-temperature critical phase, with algebraic decays of correlations functions with exponents that vary continuously with the temperature. We give a theoretical interpretation of these results by mapping the model to a Coulomb gas, whose coupling constant and associated exponents are calculated numerically with high precision. Introducing monomers is a marginal perturbation at the Kosterlitz-Thouless transition and gives rise to another critical line. We study this line numerically, showing that it is in the Ashkin-Teller universality class, and terminates in a tricritical point at finite temperature and monomer fugacity. In the course of this work, we also derive analytic results relevant to the noninteracting case of dimer coverings, including a Bethe ansatz (at the free fermion point) analysis, a detailed discussion of the effective height model, and a free field analysis of height fluctuations.


Towards condom skills: a cross-sectional study of the association between condom proficiency, condom problems and STI risk amongst MSM.
Condom use problems are common amongst Scotland's men who have sex with men (MSM). To date condom errors have been associated with the likelihood of sexually transmitted infections in heterosexual sexually transmitted infection (STI) clinic attendees but not in MSM and direct evidence of a link between condom problems and STI acquisition in MSM have been lacking. This study investigated the possibility of an independent association between condom proficiency, condom problems and STI acquisition in MSM in Scotland. An exploratory observational design employed cross-sectional surveys in both STI clinic and community settings. Respondents completed self-report measures of socio-demographic variables, scales of condom proficiency and condom problems and numbers of different partners with whom men have had unprotected anal intercourse (UAI partners) in the preceding year. Self-report data was corroborated with clinical STI diagnosis where possible. Analysis included chi-squared and Mann-Whitney tests and multiple logistic regression. 792 respondents provided data with an overall response rate of 70% (n = 459 clinic sample, n = 333 community sample). Number of UAI partners was the strongest predictor of self-reported STI acquisition over the previous 12 months (p < 0.001 in both clinic and community samples). Demographic characteristics were not associated with self-reported STI diagnosis. However, condom proficiency score was associated with self-reported STI acquisition (p < 0.05 in both samples). Condom problem score was also associated with self-reported STI diagnosis in the clinic (p = 0.001) but not the community sample. Condom problem score remained associated with self-reported STI diagnosis in the clinic sample after adjusting for number of UAI partners with logistic regression. This exploratory study highlights the potential importance of targeted condom use skills interventions amongst MSM. It demands further research examining the utility of condom problem measures in wider populations, across prospective and experimental research designs, and a programme of research exploring their feasibility as a tool determining candidacy for brief interventions.


Influence of severe potassium depletion and subsequent repletion with potassium on muscle electrolytes, metabolites and amino acids in man.
1. Two women with severe hypokalaemic alkalosis were investigated by means of muscle biopsy before and at the end of 2 and 3 weeks respectively of intense therapy with potassium chloride. 2. The muscle biopsy material was analysed for water, electrolytes, adenine nucleotides, phosphocreatine, free creatine, pyruvate, lactate, glycogen and free amino acids. The extra- and intra-cellular distribution of water, electrolytes and amino acids was calculated by the chloride method. 3. Both patients showed a marked loss of intracellular potassium and an increase in intracellular sodium concentration. The muscle magnesium content was also slightly decreased. After repletion with potassium chloride, muscle sodium and potassium became normal. 4. The contents of creatine phosphate, ATP, ADP, AMP, lactate and pyruvate were within normal limits, but the phosphocreatine/total creatine ratio was reduced. After repletion, a small change in the apparent creatine-phosphokinase equilibrium had occurred, suggesting a minor increase in intracellular pH. 5. The concentrations of the basic amino acids, lysine, arginine and ornithine were increased far above normal. The intracellular accumulation of arginine was much higher than the increase in lysine concentration and histidine concentration was normal. This differs from findings in potassium-depleted rats, where the intracellular lysine concentration is much higher than arginine concentration and histidine is high as well. After potassium repletion the intracellular concentration of ornithine, lysine and arginine became normal in one case and decreased considerable in the other. An increased intracellular concentration of glutamate and glutamine was also observed after potassium repletion.


Telephone follow-up after the emergency department visit: experience with acute asthma.
This study explored how a variety of demographic and illness-related factors were associated with telephone follow-up among patients visiting the emergency department for acute asthma. We performed a prospective cohort study as part of the Multicenter Airway Research Collaboration (MARC). The study was performed at 77 EDs in 22 US states and 4 Canadian provinces. ED patients, ages 2 to 54 years, who presented with acute asthma underwent a structured interview during their visit. Two weeks later, research personnel attempted to contact participants by telephone, using numbers obtained during the ED interview. A total of 1,847 adult and 1,184 pediatric patients were interviewed in the ED. Of these, 1,308 (71%) adult patients and 1,026 (87%) pediatric patients were successfully reached for 2-week telephone follow-up. Multivariate analyses revealed the factor most strongly related to contact was age, with pediatric patients being 2.5 times more likely to be reached than adults (95% confidence interval 2.0 to 3.2). Also, participants who were black, low in socioeconomic status, lacking a primary care provider, and exposed to tobacco smoke were significantly less likely to have been reached (all P <.001). In contrast to some reports in the literature, telephone contact rates were high. However, successful contact was not equally likely among all patient groups. Although the high contact rates support the feasibility of telephone follow-up of asthmatic patients visiting the ED, the results also act as a reminder of the potential biases that may arise when using telephone contact for clinical, quality assurance, and research reasons. [Boudreaux ED, Clark S, Camargo CA Jr, on behalf of the MARC Investigators. Telephone follow-up after the emergency department visit: experience with acute asthma. Ann Emerg Med. June 2000;35:555-563.].