Probabilistic Approach for Determining the Material Properties of Meniscal Attachments In Vivo Using Magnetic Resonance Imaging and a Finite Element Model.
The material properties of in vivo meniscal attachments were evaluated using a probabilistic finite element (FE) model and magnetic resonance imaging (MRI). MRI scans of five subjects were collected at full extension and 30°, 60°, and 90° flexion. One subject with radiographic evidence of no knee injury and four subjects with Kellgren-Lawrence score of 1 or 2 (two each) were recruited. Isovoxel sagittal three-dimensional cube sequences of the knee were acquired in extension and flexion. Menisci movement in flexion was investigated using sensitivity analysis based on the Monte Carlo method in order to generate a subject-specific FE model to evaluate significant factors. The material properties of horn attachment in the five-subject FE model were optimized to minimize the differences between meniscal movements in the FE model and MR images in flexion. We found no significant difference between normal and patient knees in flexion with regard to movement of anterior, posterior, medial, and lateral menisci or changes in height morphology. At 90° flexion, menisci movement was primarily influenced by posterior horn stiffness, followed by anterior horn stiffness, the transverse ligament, and posterior cruciate ligament. The optimized material properties model predictions for menisci motion were more accurate than the initial material properties model. The results of this approach suggest that the material properties of horn attachment, which affects the mobile characteristics of menisci, could be determined in vivo. Thus, this study establishes a basis for a future design method of attachment for tissue-engineered replacement menisci.


C-C bond migration in the cycloisomerization of oxygen-tethered 1,6-enynes.
A C-C bond migration event during the cycloisomerization of 1,6-enynes is described. Two different catalytic systems, iridium- or platinum-based, are able to induce this process. Alkyl migrations of larger rings and acyclic groups indicate that the reaction is not fully driven by the release of ring strain.


Are government incentives effective for avoided deforestation in the tropical Andean forest?
In order to ensure the provision of goods and services from forests, many governments have promoted less-traditional conservation initiatives such as programs of payments for ecosystem services called, more broadly, direct payments for conservation. The Socio Bosque Program (SBP) is a governmental program in Ecuador that directly provides economic incentives to rural families and local and indigenous communities who have voluntarily agreed to comply with some conservation activities. An impact evaluation method (matching) was used to assess the impact of the SBP between 2008 and 2014. This study revealed that on average, the SBP reduced deforestation by 1.5% in those forests that received the SBP's direct payment. These forests would have been deforested if the SBP had not been implemented. Assessment of the impact of the SBP on individual and collective contracts, using the matching method, revealed that 3.4% and roughly 1% of the forest would have been deforested in the absence of the program, respectively. In other words, the protected area in the collective SBP was 1,247,500 ha and, if the SBP had not been implemented, an area of 11,227 ha would have been lost between 2008 and 2014. The 165,700 ha protected by the individual SBP, it was estimated that 5,733 ha were not deforested due to the implementation of the conservation program. Conventional estimates of the impact of the SBP tend to overestimate avoided deforestation because they do not control for observable covariates that correlate with or affect both SBP participation and deforestation. The conclusions are robust, even given potential hidden biases. The present study demonstrated that the SBP serves to mitigate the effects of climate change, especially with those contracts that are intended for individual owners.


Economic evaluations of lymphatic filariasis interventions: a systematic review and research needs.
In 2000, the World Health Organization established the Global Programme to Eliminate Lymphatic Filariasis (GPELF), with the goal of eliminating the disease as a public health problem by 2020. Since the start of the programme, a cumulative total of 6.2 billion treatments have been delivered to affected populations - with more than 556 million people treated in 2015 alone. In this paper, we perform a rigorous systematic review of the economic evaluations of lymphatic filariasis interventions have been conducted. We demonstrate that the standard interventions to control lymphatic filariasis are consistently found to be highly cost-effective. This finding has important implications for advocacy groups and potential funders. However, there are several important inconsistencies and research gaps that need to be addressed as we move forward towards the 2020 elimination goals. One of the most important identified research gaps was a lack of evaluation of new interventions specifically targeting areas co-endemic with onchocerciasis and Loa loa - which could become a major barrier to achieving elimination.


Jets in extragalactic radio sources.
Observations now require that there be a continuous supply of energy to the giant extragalactic radio sources. These observations also suggest that this energy input may be in the form of streams or jets of gas emanating from the centers of galaxies and quasi-stellar objects. Current data indicate that the large-scale jet structures are not moving with relativistic speeds, as previously proposed. Slow-moving jets, which possess turbulent interiors and are dominated by relatively cool gas, can account for the observed jet properties at optical and radio wavelengths. Extremely small-scale jets observed adjacent to the central energy source may or may not be in relativistic motion.


Generation and analysis of a 29,745 unique Expressed Sequence Tags from the Pacific oyster (Crassostrea gigas) assembled into a publicly accessible database: the GigasDatabase.
Although bivalves are among the most-studied marine organisms because of their ecological role and economic importance, very little information is available on the genome sequences of oyster species. This report documents three large-scale cDNA sequencing projects for the Pacific oyster Crassostrea gigas initiated to provide a large number of expressed sequence tags that were subsequently compiled in a publicly accessible database. This resource allowed for the identification of a large number of transcripts and provides valuable information for ongoing investigations of tissue-specific and stimulus-dependant gene expression patterns. These data are crucial for constructing comprehensive DNA microarrays, identifying single nucleotide polymorphisms and microsatellites in coding regions, and for identifying genes when the entire genome sequence of C. gigas becomes available. In the present paper, we report the production of 40,845 high-quality ESTs that identify 29,745 unique transcribed sequences consisting of 7,940 contigs and 21,805 singletons. All of these new sequences, together with existing public sequence data, have been compiled into a publicly-available Website http://public-contigbrowser.sigenae.org:9090/Crassostrea_gigas/index.html. Approximately 43% of the unique ESTs had significant matches against the SwissProt database and 27% were annotated using Gene Ontology terms. In addition, we identified a total of 208 in silico microsatellites from the ESTs, with 173 having sufficient flanking sequence for primer design. We also identified a total of 7,530 putative in silico, single-nucleotide polymorphisms using existing and newly-generated EST resources for the Pacific oyster. A publicly-available database has been populated with 29,745 unique sequences for the Pacific oyster Crassostrea gigas. The database provides many tools to search cleaned and assembled ESTs. The user may input and submit several filters, such as protein or nucleotide hits, to select and download relevant elements. This database constitutes one of the most developed genomic resources accessible among Lophotrochozoans, an orphan clade of bilateral animals. These data will accelerate the development of both genomics and genetics in a commercially-important species with the highest annual, commercial production of any aquatic organism.


Transient low back pain development during standing predicts future clinical low back pain in previously asymptomatic individuals.
Longitudinal, observational. To determine if development of transient low back pain (LBP) during prolonged standing in individuals without prior history of LBP predicts future clinical LBP development at higher rates than in individuals who do not develop LBP during prolonged standing. Prolonged standing has been found to induce transient LBP in 40% to 70% of previously asymptomatic individuals. Individuals who develop pain during standing have been found to have altered neuromuscular profiles prior to the standing exposure compared with their pain free counterparts; therefore, it has been hypothesized that these individuals may have higher risk for LBP disorders. Previously asymptomatic participants who had completed a biomechanical study investigating LBP development during standing and response to exercise intervention completed annual surveys regarding LBP status for a period of 3 years. χ2 analyses were performed to determine group differences in LBP incidence rates. Accuracy statistics were calculated for ability of LBP development during standing to predict future LBP. Participants who developed transient LBP during standing had significantly higher rates of clinical LBP during the 3-year follow-up period (35.3% vs. 23.1%) and were 3 times more likely to experience an episode of clinical LBP during the first 24 months than their non-pain developing counterparts. Transient LBP development during prolonged standing is a positive predictive factor for future clinical LBP in previously asymptomatic individuals. Individuals who experience transient LBP during standing may be considered a "preclinical" group who are at increased risk for future LBP disorders.


Azathioprine for prevention of postoperative recurrence in Crohn's disease.
The clinical relapse rate after surgery for Crohn's disease in prospective studies is about 40% at 2 years in people who receive no postoperative prophylaxis. Thiopurines (azathioprine and 6-mercaptopurine) are likely to be the most effective pharmacotherapy for preventing postoperative relapse: about four patients need to be treated for 2 years to prevent one clinical relapse. The factors that help to identify patients at highest risk of relapse are discussed, along with the reasons for the choice of thiopurine, dose and duration of therapy. Other measures to reduce the relapse rate are addressed.


A 56-Day Oral Toxicity Study of the Aqueous Extract of Rapanea melanophloeos (L.) Mez in Rats.
Rapanea melanophloeos is a tropical tree that is extensively utilized in African traditional medicine to treat helminthiases, tuberculosis, and heart-water. As with many other medicinal plants, there is insufficient information regarding the safety of therapeutic R. melanophloeos extracts. An aqueous extract of R. melanophloeos stem bark was administered to Sprague Dawley rats at doses of 100 mg/kg, 300 mg/kg, and 1000 mg/kg for 56 days to characterize its potential toxicity after prolonged dosing. Blood samples were obtained fortnightly for serum chemistry and hematology, while organs were collected at the end of the study. The extract caused an increase in organ weight indices of the kidneys and testis at 300 mg/kg and 1000 mg/kg. Hematological and biochemical examination revealed a drop in leukocyte counts and the hematocrit at 1000 mg/kg dose level, while there was a general but nondose-related elevation in alkaline phosphatase activity. There were time-associated variations in the hematological and clinical chemistry parameters at days 28, 42, and 56 in all dose levels, but most values remained within physiological limits. No pathological lesions were evident at histopathology after treatment with the extract. Our data shows that the aqueous extract of R. melanophloeos is not likely to be toxic at the doses tested and provides support to its medicinal use.


Biogenesis pathways of piRNAs loaded onto AGO3 in the Drosophila testis.
PIWI-interacting RNAs (piRNAs) silence transposable elements in animal germ cells. In Drosophila ovaries, piRNAs are produced by two distinct pathways: the "ping-pong" amplification cycle that operates in germ cells and a ping-pong-independent pathway termed the primary pathway that mainly operates in somatic cells. AGO3, one of three PIWI proteins in flies, is involved in the ping-pong cycle in ovaries. We characterized AGO3-associated piRNAs in fly testes and found that like in ovaries, AGO3 functions in the ping-pong cycle with Aubergine (Aub) for piRNA production from transposon transcripts. In contrast, most AGO3-associated piRNAs corresponding to Suppressor of Stellate [Su(Ste)] genes are antisense-oriented and bound to Aub. In addition, the vast majority of AGO3-bound piRNAs derived from the AT-chX locus on chromosome X are antisense-oriented and are also found among Aub-associated piRNAs. The presence of very few sense Su(Ste) and AT-chX piRNAs suggests that biogenesis of both Su(Ste) and AT-chX piRNAs by a ping-pong mechanism only is highly unlikely. Nevertheless, the mutual interdependence of AGO3 and Aub for the accumulation of these piRNAs shows that their production relies on both AGO3 and Aub. Analysis of piRNA pathway mutants revealed that although the requirements for piRNA factors for Su(Ste)- and AT-chX-piRNA levels mostly overlap and resemble those for the ping-pong mechanism in the ovaries, Armitage (armi) is not required for the accumulation of AT-chX-1 piRNA. These findings suggest that the impacts of armi mutants on the operation of the piRNA pathway are variable in germ cells of fly testes.


Impact of cross-enterprise data sharing on portable media with decentralised upload of DICOM data into PACS.
To evaluate portable media utilisation for image data sharing between enterprises. To predict the costs required to keep up with the trend. To identify related problems. A software package was developed to include patient image data from CD into our normal workflow. The trend in the workload of CDs that were uploaded into a Picture Archiving and Communication System (PACS) over 89 months was analysed. The average number of images per month (and per investigation) was calculated to provide the estimation of storage and cost required in the whole process. All Digital Imaging and Communications in Medicine (DICOM) files can be read from compact disc (CD) on any workstation in the hospital, processed quickly to the central server and checked after storage using the software tool. A total of 33,982,404 images from 88,952 CDs have been stored into the PACS system. In recent years, the stored images have reached an average of 4.2 terabytes (TB) uncompressed annually. Integrated information about patients is clearly needed to provide easy and timely access to these data. The steadily growing storage can be solved by a more automated approach to portable media handling or the installation and acceptance of network-based transfer using cross-enterprise document sharing (XDS). • Rapid assimilation of external imaging into a PACS system is essential. • But data distribution using portable media also carries some disadvantages. • A DICOM data uploader incorporates studies from portable media to hospital workflow. • Automated media handling or XDS should solve the steadily growing storage problem. • Software improvements will facilitate the steady increase in the amount of CDs processed.


11C-acetate PET/CT before radical prostatectomy: nodal staging and treatment failure prediction.
Despite early detection programs, many patients with prostate cancer present with intermediate- or high-risk disease. We prospectively investigated whether (11)C-acetate PET/CT predicts lymph node (LN) metastasis and treatment failure in men for whom radical prostatectomy is planned. 107 men with intermediate- or high-risk localized prostate cancer and negative conventional imaging findings underwent PET/CT with (11)C-acetate. Five underwent LN staging only, and 102 underwent LN staging and prostatectomy. PET/CT findings were correlated with pathologic nodal status. Treatment-failure-free survival was estimated by the Kaplan-Meier method. The ability of PET/CT to predict outcomes was evaluated by multivariate Cox proportional hazards analysis. PET/CT was positive for pelvic LN or distant metastasis in 36 of 107 patients (33.6%). LN metastasis was present histopathologically in 25 (23.4%). The sensitivity, specificity, and positive and negative predictive values of PET/CT for detecting LN metastasis were 68.0%, 78.1%, 48.6%, and 88.9%, respectively. Treatment failed in 64 patients: 25 with metastasis, 17 with a persistent postprostatectomy prostate-specific antigen level greater than 0.20 ng/mL, and 22 with biochemical recurrence (prostate-specific antigen level > 0.20 ng/mL after nadir) during follow-up for a median of 44.0 mo. Treatment-failure-free survival was worse in PET-positive than in PET-negative patients (P < 0.0001) and in those with false-positive than in those with true-negative scan results (P < 0.01), suggesting that PET may have demonstrated nodal disease not removed surgically or identified pathologically. PET positivity independently predicted failure in preoperative (hazard ratio, 3.26; P < 0.0001) and postoperative (hazard ratio, 3.07; P = 0.0001) multivariate models. In patients planned for or completing prostatectomy, (11)C-acetate PET/CT detects LN metastasis not identified by conventional imaging and independently predicts treatment-failure-free survival.


Haemodynamic effects of noise exposure before and after beta 1-selective and non-selective beta-adrenoceptor blockade in patients with essential hypertension.
1. Noise stimulation (100 dBA) for 10 min caused a significant increase in diastolic (7.0%, P less than 0.001) and mean arterial blood pressure (4.3%, P less than 0.01) in patients with essential hypertension. 2. The blood pressure response to noise was due to an increase in total peripheral resistance (4.8%, P less than 0.02); heart rate, stroke volume and cardiac output were unchanged. 3. beta 1-selective adrenoceptor blockade (metoprolol) did not change the haemodynamic reaction pattern induced by noise. 4. Noise exposure during non-selective beta-adrenoceptor blockade (propranolol) caused an accentuated blood pressure response with increments of both systolic and diastolic blood pressure as well as a more pronounced rise in total peripheral resistance. 5. The haemodynamic changes induced by noise stimulation at 100 dBA totally disappeared after 5 min of quiet rest at 40 dBA.


Synchronized drumming enhances activity in the caudate and facilitates prosocial commitment--if the rhythm comes easily.
Why does chanting, drumming or dancing together make people feel united? Here we investigate the neural mechanisms underlying interpersonal synchrony and its subsequent effects on prosocial behavior among synchronized individuals. We hypothesized that areas of the brain associated with the processing of reward would be active when individuals experience synchrony during drumming, and that these reward signals would increase prosocial behavior toward this synchronous drum partner. 18 female non-musicians were scanned with functional magnetic resonance imaging while they drummed a rhythm, in alternating blocks, with two different experimenters: one drumming in-synchrony and the other out-of-synchrony relative to the participant. In the last scanning part, which served as the experimental manipulation for the following prosocial behavioral test, one of the experimenters drummed with one half of the participants in-synchrony and with the other out-of-synchrony. After scanning, this experimenter "accidentally" dropped eight pencils, and the number of pencils collected by the participants was used as a measure of prosocial commitment. Results revealed that participants who mastered the novel rhythm easily before scanning showed increased activity in the caudate during synchronous drumming. The same area also responded to monetary reward in a localizer task with the same participants. The activity in the caudate during experiencing synchronous drumming also predicted the number of pencils the participants later collected to help the synchronous experimenter of the manipulation run. In addition, participants collected more pencils to help the experimenter when she had drummed in-synchrony than out-of-synchrony during the manipulation run. By showing an overlap in activated areas during synchronized drumming and monetary reward, our findings suggest that interpersonal synchrony is related to the brain's reward system.


Developments in Gastrointestinal Electrical Stimulation.
Electrical stimulation of the gastrointestinal (GI) tract, analogous to pacing the human heart, is an attractive idea. This is because these organs, like the heart, have their own natural pacemakers, and the electrical signals they generate can be altered by externally delivering certain types of electric currents via intraluminal or serosal electrodes to certain areas of the GI tract. A number of studies on animals have been accomplished successfully to treat a variety of disease models, including gastroparesis, dumping, and short bowel syndrome. Over the past 10 years or so, electrical stimulation of the GI tract has received increasing attention among researchers and clinicians because of new techniques, such as implantable devices, and promising results achieved in treatment of gastroparesis and morbid obesity. The objective of this article is to review the advances in electrical stimulation of the gastrointestinal tract. First the electrophysiology of the GI tract and history of GI electrical stimulation are introduced. Then various methods of electrical stimulation of the stomach and small bowel in healthy animals and models of GI diseases are reviewed. Finally clinical applications of electrical stimulation to GI disorders and their possible mechanisms are discussed.


Single-axon tracing study of corticostriatal projections arising from primary motor cortex in primates.
The axonal projections arising from the forelimb area of the primary motor cortex (M1) in cynomolgus monkeys (Macaca fascicularis) were studied following microiontophoretic injections of biotinylated dextran amine under electrophysiological guidance. The microinjections were centered on layer V, and 42 anterogradely labeled corticofugal axons were reconstructed from serial frontal or sagittal sections with a camera lucida. Our investigation shows that the primate striatum receives both direct and indirect projections from M1. The direct corticostriatal projection is formed by axons that remain uniformly thin and unbranched throughout their sinuous trajectory to the ipsilateral striatum. They divide as they enter the dorsolateral sector of the post-commissural putamen, the so-called sensorimotor striatal territory. The indirect corticostriatal projection derives from a thin collateral emitted within the corona radiata by thick, long-range fibers that descend toward the brainstem. The collateral enters the putamen dorsomedially and remains unbranched until it reaches the dorsolateral sector of the putamen, where it breaks out into two to four axonal branches displaying small and equally spaced varicosities. Both direct and indirect corticostriatal axons branch moderately but occupy vast rostrocaudal striatal territories, where they appear to contact en passant several widely distributed striatal neurons. These findings reveal that, in contrast to current beliefs, the primate motor corticostriatal system is not exclusively formed by axons dedicated solely to the striatum. It also comprises collaterals from long-range corticofugal axons, which can thus provide to the striatum a copy of the neural information that is being conveyed to the brainstem and/or spinal cord.


Neural Networks for Prognostication of Patients With Heart Failure.
Background Prognostication of heart failure patients from cardiopulmonary exercise test (CPET) currently involves simplification of complex time-series data into summary indices. We hypothesized that prognostication could be improved by considering the totality of the data generated during a CPET, instead of using summary indices alone. Methods and Results Complete data from 1156 CPETs were used to predict clinical deterioration (characterized by initiation of mechanical circulatory support, listing for heart transplantation or mortality) 1 year post-CPET. We compared the prognostic value (area under the receiver operating characteristic curve) of (1) the most predictive summary indices, (2) staged data collected at discrete intervals using multivariable regression models, and (3) breath-by-breath data using a feedforward neural network. The top-performing models were compared with the commonly used CPET risk score, using absolute net reclassification index. All models were trained and assessed using a 100-iteration Monte Carlo cross-validation. A total of 190 (16.4%) patients experienced clinical deterioration. The summary indices demonstrated subpar discriminative value (area under the receiver operating characteristic curve ≤0.800). Each multivariable model outperformed the summary indices, with the neural network incorporating breath-by-breath data achieving the best performance (area under the receiver operating characteristic curve =0.842). When compared with the CPET risk score (area under the receiver operating characteristic curve =0.759), the top-performing model obtained a net reclassification index of 4.9%. Conclusions The current practice of considering summary indices in isolation fails to realize the full value of CPET data. This may lead to less accurate prognostication of patients and in consequence, inaccurate selection of patients for advanced therapy. Clinical practices, like CPET prognostication, must be continuously reevaluated to ensure optimal usage of valuable (and oft-underutilized) data sources.


A possible artefactual component in specific cause mortality gradients. Social class variations in the clinical accuracy of death certificates.
This paper investigates one possible avenue of artefactual influence on the production and/or concealment of social class gradients in specific cause mortality rates, namely, the possibility of social class biases in the accuracy of diagnosis of cause of death and the systematic misallocation of certain social groups to particular diagnoses. Information on this topic was obtained by matching occupational data gathered at death registration with data on the accuracy of diagnosis of cause of death (measured by diagnostic agreement between clinician and pathologist) collected in a prospective study of 1152 hospital necropsies. Extrapolation from these data to national mortality rates should be cautious, but it appears that in the majority of the most common causes of death grouped by ICD chapter (neoplasms, cerebrovascular and digestive) social class gradients would be steeper if mortality data were based on pathologists' rather than clinicians' diagnoses. Only in the respiratory chapter would the gradient be reduced, with the gradient in cardiovascular deaths unaffected.


Consistent paternity skew through ontogeny in Peron's tree frog (Litoria peronii).
A large number of studies in postcopulatory sexual selection use paternity success as a proxy for fertilization success. However, selective mortality during embryonic development can lead to skews in paternity in situations of polyandry and sperm competition. Thus, when assessment of paternity fails to incorporate mortality skews during early ontogeny, this may interfere with correct interpretation of results and subsequent evolutionary inference. In a previous series of in vitro sperm competition experiments with amphibians (Litoria peronii), we showed skewed paternity patterns towards males more genetically similar to the female. Here we use in vitro fertilizations and sperm competition trials to test if this pattern of paternity of fully developed tadpoles reflects patterns of paternity at fertilization and if paternity skews changes during embryonic development. We show that there is no selective mortality through ontogeny and that patterns of paternity of hatched tadpoles reflects success of competing males in sperm competition at fertilization. While this study shows that previous inferences of fertilization success from paternity data are valid for this species, rigorous testing of these assumptions is required to ensure that differential embryonic mortality does not confound estimations of true fertilization success.


Alterations in energy/redox metabolism induced by mitochondrial and environmental toxins: a specific role for glucose-6-phosphate-dehydrogenase and the pentose phosphate pathway in paraquat toxicity.
Parkinson's disease (PD) is a multifactorial disorder with a complex etiology including genetic risk factors, environmental exposures, and aging. While energy failure and oxidative stress have largely been associated with the loss of dopaminergic cells in PD and the toxicity induced by mitochondrial/environmental toxins, very little is known regarding the alterations in energy metabolism associated with mitochondrial dysfunction and their causative role in cell death progression. In this study, we investigated the alterations in the energy/redox-metabolome in dopaminergic cells exposed to environmental/mitochondrial toxins (paraquat, rotenone, 1-methyl-4-phenylpyridinium [MPP+], and 6-hydroxydopamine [6-OHDA]) in order to identify common and/or different mechanisms of toxicity. A combined metabolomics approach using nuclear magnetic resonance (NMR) and direct-infusion electrospray ionization mass spectrometry (DI-ESI-MS) was used to identify unique metabolic profile changes in response to these neurotoxins. Paraquat exposure induced the most profound alterations in the pentose phosphate pathway (PPP) metabolome. 13C-glucose flux analysis corroborated that PPP metabolites such as glucose-6-phosphate, fructose-6-phosphate, glucono-1,5-lactone, and erythrose-4-phosphate were increased by paraquat treatment, which was paralleled by inhibition of glycolysis and the TCA cycle. Proteomic analysis also found an increase in the expression of glucose-6-phosphate dehydrogenase (G6PD), which supplies reducing equivalents by regenerating nicotinamide adenine dinucleotide phosphate (NADPH) levels. Overexpression of G6PD selectively increased paraquat toxicity, while its inhibition with 6-aminonicotinamide inhibited paraquat-induced oxidative stress and cell death. These results suggest that paraquat "hijacks" the PPP to increase NADPH reducing equivalents and stimulate paraquat redox cycling, oxidative stress, and cell death. Our study clearly demonstrates that alterations in energy metabolism, which are specific for distinct mitochondiral/environmental toxins, are not bystanders to energy failure but also contribute significant to cell death progression.


The association between balance and free-living physical activity in an older community-dwelling adult population: a systematic review and meta-analysis.
Poor balance is associated with an increased risk of falling, disability and death in older populations. To better inform policies and help reduce the human and economic cost of falls, this novel review explores the effects of free-living physical activity on balance in older (50 years and over) healthy community-dwelling adults. Search methods: CENTRAL, Bone, Joint and Muscle Trauma Group Specialised register and CDSR in the Cochrane Library, MEDLINE, EMBASE, CINAHL, PsychINFO, and AMED were searched from inception to 7th June 2016. Intervention and observational studies investigating the effects of free-living PA on balance in healthy community-dwelling adults (50 years and older). Thirty studies were eligible for inclusion. Data extraction and risk of bias assessment were independently carried out by two review authors. Due to the variety of outcome measures used in studies, balance outcomes from observational studies were pooled as standardised mean differences or mean difference where appropriate and 95% confidence intervals, and outcomes from RCTs were synthesised using a best evidence approach. Limited evidence provided by a small number of RCTs, and evidence from observational studies of moderate methodological quality, suggest that free-living PA of between one and 21 years' duration improves measures of balance in older healthy community-dwelling adults. Statistical analysis of observational studies found significant effects in favour of more active groups for neuromuscular measures such as gait speed; functionality using Timed Up and Go, Single Leg Stance, and Activities of Balance Confidence Scale; flexibility using the forward reach test; and strength using the isometric knee extension test and ultrasound. A significant effect was also observed for less active groups on a single sensory measure of balance, the knee joint repositioning test. There is some evidence that free-living PA is effective in improving balance outcomes in older healthy adults, but future research should include higher quality studies that focus on a consensus of balance measures that are clinically relevant and explore the effects of free-living PA on balance over the longer-term.


Choice of psychological coping in laryngectomized, head and neck squamous cell carcinoma patients versus multiple sclerosis patients.
To be treated for cancer must be a frightening experience. Yet quality of life (QoL) of successfully treated cancer patients seems to be relatively similar in comparison with QoL of a general population, with psychological coping partly responsible for this finding. When measuring choice of coping, the nature of coping score levels constituting appropriate scores, and whether score levels rely on the context of the disease has not been settled. We have studied the COPE coping responses as related to disease in successfully treated head and neck squamous cell carcinoma (HNSCC) patient groups (general and laryngectomized), as well as compared to multiple sclerosis (MS) patients. The COPE response patterns have also been compared to the Beck depression inventory (BDI) scores. Age and gender of patients were not directly associated with choice of coping. Within the problem-focused coping indexes, the coping index "active coping" was reported to be most utilized among HNSCC patients, whereas "coping by suppression" and "coping by social support" were most utilized among MS patients. Emotional-focused coping was most prevalent among HNSCC patients and lowest among the MS patients. Level of avoidance coping was similar between the groups. The coping of the general HNSCC patients differed most from the MS patients. An association was shown between increased coping efforts and lowered mood. In particular, avoidance coping was associated with lowered mood. These associations were stronger among the MS patients than HNSCC patients. Drinking to cope was most prevalent among the laryngectomized group, and was correlated with BDI scores in all groups. Furthermore, adequate coping seems to be to limit avoidance coping and promote coping by acceptance. The response pattern of the COPE inventory seems to be valid among HNSCC and MS patients.


Estimating genetic effect sizes under joint disease-endophenotype models in presence of gene-environment interactions.
Effects of genetic variants on the risk of complex diseases estimated from association studies are typically small. Nonetheless, variants may have important effects in presence of specific levels of environmental exposures, and when a trait related to the disease (endophenotype) is either normal or impaired. We propose polytomous and transition models to represent the relationship between disease, endophenotype, genotype and environmental exposure in family studies. Model coefficients were estimated using generalized estimating equations and were used to derive gene-environment interaction effects and genotype effects at specific levels of exposure. In a simulation study, estimates of the effect of a genetic variant were substantially higher when both an endophenotype and an environmental exposure modifying the variant effect were taken into account, particularly under transition models, compared to the alternative of ignoring the endophenotype. Illustration of the proposed modeling with the metabolic syndrome, abdominal obesity, physical activity and polymorphisms in the NOX3 gene in the Quebec Family Study revealed that the positive association of the A allele of rs1375713 with the metabolic syndrome at high levels of physical activity was only detectable in subjects without abdominal obesity, illustrating the importance of taking into account the abdominal obesity endophenotype in this analysis.


Predicted impact of barriers to migration on the Serengeti wildebeest population.
The Serengeti wildebeest migration is a rare and spectacular example of a once-common biological phenomenon. A proposed road project threatens to bisect the Serengeti ecosystem and its integrity. The precautionary principle dictates that we consider the possible consequences of a road completely disrupting the migration. We used an existing spatially-explicit simulation model of wildebeest movement and population dynamics to explore how placing a barrier to migration across the proposed route (thus creating two disjoint but mobile subpopulations) might affect the long-term size of the wildebeest population. Our simulation results suggest that a barrier to migration--even without causing habitat loss--could cause the wildebeest population to decline by about a third. The driver of this decline is the effect of habitat fragmentation (even without habitat loss) on the ability of wildebeest to effectively track temporal shifts in high-quality forage resources across the landscape. Given the important role of the wildebeest migration for a number of key ecological processes, these findings have potentially important ramifications for ecosystem biodiversity, structure, and function in the Serengeti.


Early life socioeconomic adversity is associated in adult life with chronic inflammation, carotid atherosclerosis, poorer lung function and decreased cognitive performance: a cross-sectional, population-based study.
Socioeconomic gradients in health persist despite public health campaigns and improvements in healthcare. The Psychosocial and Biological Determinants of Ill-health (pSoBid) study was designed to uncover novel biomarkers of chronic disease that may help explain pathways between socioeconomic adversity and poorer physical and mental health. We examined links between indicators of early life adversity, possible intermediary phenotypes, and markers of ill health in adult subjects (n = 666) recruited from affluent and deprived areas. Classical and novel risk factors for chronic disease (lung function and atherosclerosis) and for cognitive performance were assessed, and associations sought with early life variables including conditions in the parental home, family size and leg length. Associations were observed between father's occupation, childhood home status (owner-occupier; overcrowding) and biomarkers of chronic inflammation and endothelial activation in adults (C reactive protein, interleukin 6, intercellular adhesion molecule; P < 0.0001) but not number of siblings and leg length. Lung function (forced expiratory volume in 1 second) and cognition (Choice Reaction Time, the Stroop test, Auditory Verbal Learning Test) were likewise related to early life conditions (P < 0.001). In multivariate models inclusion of inflammatory variables reduced the impact and independence of early life conditions on lung function and measures of cognitive ability. Including variables of adult socioeconomic status attenuated the early life associations with disease biomarkers. Adverse levels of biomarkers of ill health in adults appear to be influenced by father's occupation and childhood home conditions. Chronic inflammation and endothelial activation may in part act as intermediary phenotypes in this complex relationship. Reducing the 'health divide' requires that these life course determinants are taken into account.


Application of WHO's guideline for the selection of sentinel sites for hospital-based influenza surveillance in Indonesia.
A sentinel hospital-based severe acute respiratory infection (SARI) surveillance system was established in Indonesia in 2013. Deciding on the number, geographic location and hospitals to be selected as sentinel sites was a challenge. Based on the recently published WHO guideline for influenza surveillance (2012), this study presents the process for hospital sentinel site selection. From the 2,165 hospitals in Indonesia, the first step was to shortlist to hospitals that had previously participated in respiratory disease surveillance systems and had acceptable surveillance performance history. The second step involved categorizing the shortlist according to five regions in Indonesia to maximize geographic representativeness. A checklist was developed based on the WHO recommended attributes for sentinel site selection including stability, feasibility, representativeness and the availability of data to enable disease burden estimation. Eight hospitals, a maximum of two per geographic region, were visited for checklist administration. Checklist findings from the eight hospitals were analyzed and sentinel sites selected in the third step. Six hospitals could be selected based on resources available to ensure system stability over a three-year period. For feasibility, all eight hospitals visited had mechanisms for specimen shipment and the capacity to report surveillance data, but two had limited motivation for system participation. For representativeness, the eight hospitals were geographically dispersed around Indonesia, and all could capture cases in all age and socio-economic groups. All eight hospitals had prerequisite population data to enable disease burden estimation. The two hospitals with low motivation were excluded and the remaining six were selected as sentinel sites. The multi-step process enabled sentinel site selection based on the WHO recommended attributes that emphasize right-sizing the surveillance system to ensure its stability and maximizing its geographic representativeness. This experience may guide other countries interested in adopting WHO's influenza surveillance standards for sentinel site selection.


Genome-Wide Association Study on Male Genital Shape and Size in Drosophila melanogaster.
Male genital morphology of animals with internal fertilization and promiscuous mating systems have been one of the most diverse and rapidly evolving morphological traits. The male genital morphology in general is known to have low phenotypic and genetic variations, but the genetic basis of the male genital variation remains unclear. Drosophila melanogaster and its closely related species are morphologically very similar, but the shapes of the posterior lobe, a cuticular projection on the male genital arch are distinct from each other, representing a model system for studying the genetic basis of male genital morphology. In this study, we used highly inbred whole genome sequenced strains of D. melanogaster to perform genome wide association analysis on posterior lobe morphology. We quantified the outline shape of posterior lobes with Fourier coefficients obtained from elliptic Fourier analysis and performed principal component analysis, and posterior lobe size. The first and second principal components (PC1 and PC2) explained approximately 88% of the total variation of the posterior lobe shape. We then examined the association between the principal component scores and posterior lobe size and 1902142 single nucleotide polymorphisms (SNPs). As a result, we obtained 15, 14 and 15 SNPs for PC1, PC2 and posterior lobe size with P-values smaller than 10(-5). Based on the location of the SNPs, 13, 13 and six protein coding genes were identified as potential candidates for PC1, PC2 and posterior lobe size, respectively. In addition to the previous findings showing that the intraspecific posterior shape variation are regulated by multiple QTL with strong effects, the present study suggests that the intraspecific variation may be under polygenic regulation with a number of loci with small effects. Further studies are required for investigating whether these candidate genes are responsible for the intraspecific posterior lobe shape variation.


Attentional modulation of auditory steady-state responses.
Auditory selective attention enables task-relevant auditory events to be enhanced and irrelevant ones suppressed. In the present study we used a frequency tagging paradigm to investigate the effects of attention on auditory steady state responses (ASSR). The ASSR was elicited by simultaneously presenting two different streams of white noise, amplitude modulated at either 16 and 23.5 Hz or 32.5 and 40 Hz. The two different frequencies were presented to each ear and participants were instructed to selectively attend to one ear or the other (confirmed by behavioral evidence). The results revealed that modulation of ASSR by selective attention depended on the modulation frequencies used and whether the activation was contralateral or ipsilateral. Attention enhanced the ASSR for contralateral activation from either ear for 16 Hz and suppressed the ASSR for ipsilateral activation for 16 Hz and 23.5 Hz. For modulation frequencies of 32.5 or 40 Hz attention did not affect the ASSR. We propose that the pattern of enhancement and inhibition may be due to binaural suppressive effects on ipsilateral stimulation and the dominance of contralateral hemisphere during dichotic listening. In addition to the influence of cortical processing asymmetries, these results may also reflect a bias towards inhibitory ipsilateral and excitatory contralateral activation present at the level of inferior colliculus. That the effect of attention was clearest for the lower modulation frequencies suggests that such effects are likely mediated by cortical brain structures or by those in close proximity to cortex.


A causal inference approach for estimating effects of non-pharmaceutical interventions during Covid-19 pandemic.
In response to the outbreak of the coronavirus disease 2019 (Covid-19), governments worldwide have introduced multiple restriction policies, known as non-pharmaceutical interventions (NPIs). However, the relative impact of control measures and the long-term causal contribution of each NPI are still a topic of debate. We present a method to rigorously study the effectiveness of interventions on the rate of the time-varying reproduction number Rt and on human mobility, considered here as a proxy measure of policy adherence and social distancing. We frame our model using a causal inference approach to quantify the impact of five governmental interventions introduced until June 2020 to control the outbreak in 113 countries: confinement, school closure, mask wearing, cultural closure, and work restrictions. Our results indicate that mobility changes are more accurately predicted when compared to reproduction number. All NPIs, except for mask wearing, significantly affected human mobility trends. From these, schools and cultural closure mandates showed the largest effect on social distancing. We also found that closing schools, issuing face mask usage, and work-from-home mandates also caused a persistent reduction on Rt after their initiation, which was not observed with the other social distancing measures. Our results are robust and consistent across different model specifications and can shed more light on the impact of individual NPIs.


Short sleep duration as a risk factor for hypertension: analyses of the first National Health and Nutrition Examination Survey.
Depriving healthy subjects of sleep has been shown to acutely increase blood pressure and sympathetic nervous system activity. Prolonged short sleep durations could lead to hypertension through extended exposure to raised 24-hour blood pressure and heart rate, elevated sympathetic nervous system activity, and increased salt retention. Such forces could lead to structural adaptations and the entrainment of the cardiovascular system to operate at an elevated pressure equilibrium. Sleep disorders are associated with cardiovascular disease, but we are not aware of any published prospective population studies that have shown a link between short sleep duration and the incidence of hypertension in subjects without apparent sleep disorders. We assessed whether short sleep duration would increase the risk for hypertension incidence by conducting longitudinal analyses of the first National Health and Nutrition Examination Survey (n=4810) using Cox proportional hazards models and controlling for covariates. Hypertension incidence (n=647) was determined by physician diagnosis, hospital record, or cause of death over the 8- to 10-year follow-up period between 1982 and 1992. Sleep durations of < or =5 hours per night were associated with a significantly increased risk of hypertension (hazard ratio, 2.10; 95% CI, 1.58 to 2.79) in subjects between the ages of 32 and 59 years, and controlling for the potential confounding variables only partially attenuated this relationship. The increased risk continued to be significant after controlling for obesity and diabetes, which was consistent with the hypothesis that these variables would act as partial mediators. Short sleep duration could, therefore, be a significant risk factor for hypertension.


Recognition of viral and self-antigens by TH1 and TH1/TH17 central memory cells in patients with multiple sclerosis reveals distinct roles in immune surveillance and relapses.
Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) that is caused by autoreactive T cells and associated with viral infections. However, the phenotype of pathogenic T cells in peripheral blood remains to be defined, and how viruses promote MS is debated. We aimed to identify and characterize potentially pathogenic autoreactive T cells, as well as protective antiviral T cells, in patients with MS. We analyzed CD4+ helper T-cell subsets from peripheral blood or cerebrospinal fluid for cytokine production, gene expression, plasticity, homing potentials, and their reactivity to self-antigens and viral antigens in healthy subjects and patients with MS. Moreover, we monitored their frequencies in untreated and fingolimod- or natalizumab-treated patients with MS. TH1/TH17 central memory (TH1/TH17CM) cells were selectively increased in peripheral blood of patients with relapsing-remitting MS with a high disease score. TH1/TH17CM cells were closely related to conventional TH17 cells but had more pathogenic features. In particular, they could shuttle between lymph nodes and the CNS and produced encephalitogenic cytokines. The cerebrospinal fluid of patients with active MS was enriched for CXCL10 and contained mainly CXCR3-expressing TH1 and TH1/TH17 subsets. However, while TH1 cells responded consistently to viruses, TH1/TH17CM cells reacted strongly with John Cunningham virus in healthy subjects but responded instead to myelin-derived self-antigens in patients with MS. Fingolimod and natalizumab therapies efficiently targeted autoreactive TH1/TH17CM cells but also blocked virus-specific TH1 cells. We propose that autoreactive TH1/TH17CM cells expand in patients with MS and promote relapses after bystander recruitment to the CNS, whereas TH1 cells perform immune surveillance. Thus the selective targeting of TH1/TH17 cells could inhibit relapses without causing John Cunningham virus-dependent progressive multifocal encephalomyelitis.


Time Spent on School-Related Activities at Home During the Pandemic: A Longitudinal Analysis of Social Group Inequality Among Secondary School Students.
Substantial educational inequalities have been documented in Germany for decades. In this article, we examine whether educational inequalities among children have increased or remained the same since the school closures of spring 2020 due to the COVID-19 pandemic. Our perspective is longitudinal: We compare the amount of time children in secondary schools spent on school-related activities at home before the pandemic, during school closures, and immediately after returning to in-person learning. We operationalize family socio-economic status using the highest parental educational attainment. Based on the theoretical assumption that the pandemic affected everyone equally, we formulate a hypothesis of equalization during the first period of school closures. For the period thereafter, however, we assume that parents with a low level of education had more difficulties bearing the additional burden of supervising and supporting their children's learning activities. Thus, for that period, we postulate an increase in educational inequality. To study our hypotheses, we use data from the 2019 wave of the SOEP and the SOEP-CoV study, both of which are probability samples. The SOEP-CoV study provides a unique database, as it was conducted during the lockdown of spring 2020 and in the following month. For statistical analysis, we use probit regressions at three measurement points (in 2019, in 2020 during the school closures, and in the month after closures). The comparison of these three time points makes our analysis and findings unique in the research on education during the COVID-19 pandemic, in particular with regard to Germany-wide comparisons. Our results confirm the hypothesis of equalization during the first school closures and the hypothesis of an increase in educational in the subsequent period. Our findings have direct policy implications regarding the need to further expand support systems for children.


HLA-Cw6-positive patients with psoriasis show improved response to methotrexate treatment.
It is well documented that patients with human leucocyte antigen (HLA)-Cw6+ (type 1) psoriasis have increased severity and reduced age of onset of psoriasis. However, not much is known about any differential response of this genetic subgroup to various treatments. We set out to determine if there was any genetic association of the HLA-Cw6 allele with the first-line systemic treatment commonly used in psoriasis, methotrexate. A cohort of patients from Tayside in Scotland was recruited through a novel generic consenting process (GoShare); they were extensively phenotyped and analysed for an association of their HLA-Cw6 genotype status with treatment outcomes. HLA-Cw6+ patients showed notably improved response to methotrexate (P = 0.05), and further analysis demonstrated an even greater response in a subcohort of the HLA-Cw6+ patients, who did not have concomitant psoriatic arthritis (P = 0.01). HLA-Cw6+ patients also exhibited fewer treatment-limiting adverse events. In addition to these findings, the methodology and primary clinical outcome phenotype, which we validate here, will greatly facilitate replication of the present results in independent cohorts.


Multi-rate Poisson tree processes for single-locus species delimitation under maximum likelihood and Markov chain Monte Carlo.
In recent years, molecular species delimitation has become a routine approach for quantifying and classifying biodiversity. Barcoding methods are of particular importance in large-scale surveys as they promote fast species discovery and biodiversity estimates. Among those, distance-based methods are the most common choice as they scale well with large datasets; however, they are sensitive to similarity threshold parameters and they ignore evolutionary relationships. The recently introduced "Poisson Tree Processes" (PTP) method is a phylogeny-aware approach that does not rely on such thresholds. Yet, two weaknesses of PTP impact its accuracy and practicality when applied to large datasets; it does not account for divergent intraspecific variation and is slow for a large number of sequences. We introduce the multi-rate PTP (mPTP), an improved method that alleviates the theoretical and technical shortcomings of PTP. It incorporates different levels of intraspecific genetic diversity deriving from differences in either the evolutionary history or sampling of each species. Results on empirical data suggest that mPTP is superior to PTP and popular distance-based methods as it, consistently yields more accurate delimitations with respect to the taxonomy (i.e., identifies more taxonomic species, infers species numbers closer to the taxonomy). Moreover, mPTP does not require any similarity threshold as input. The novel dynamic programming algorithm attains a speedup of at least five orders of magnitude compared to PTP, allowing it to delimit species in large (meta-) barcoding data. In addition, Markov Chain Monte Carlo sampling provides a comprehensive evaluation of the inferred delimitation in just a few seconds for millions of steps, independently of tree size. mPTP is implemented in C and is available for download at http://github.com/Pas-Kapli/mptp under the GNU Affero 3 license. A web-service is available at http://mptp.h-its.org . : firstname.lastname@example.com or firstname.lastname@example.com or email@example.com. Supplementary data are available at Bioinformatics online.


MicroRNA expression analysis in triple-negative (ER, PR and Her2/neu) breast cancer.
miRNAs are small, regulatory molecules approximately 21-24 nucleotides in length. They function at the post-transcriptional level by controlling the expression of more than 50% of human protein-coding genes and play an essential role in cell signaling pathways. The objective of the present study was to explore the expression profile of oncomiRs and tumor-suppressor miRs, and to define their possible correlations in triple-negative (ER, PR and Her2/neu) primary breast cancers. Forty-nine primary triple-negative breast cancer cases, along with 34 matched tumor-associated normal samples were investigated for the expression of 9 miRNAs using qPCR. Relationships between the expression of miR-10b, miR-21, miR-122a, miR-145, miR-205, miR-210, miR-221, miR-222 and miR-296 and the pathologic features of the tumors were examined, as were the influences of miR expression on patient overall and cancer-specific survival. miR-21, miR-210 and miR-221 were significantly overexpressed, whereas miR-10b, miR-145, miR-205, miR-122a were significantly underexpressed in the triple-negative primary breast cancers. Significant correlations among all of the studied miRs were scored both in the breast cancer and control tissue. Expression of miR-222 and miR-296 did not exhibit any significant difference between the breast cancer and normal tissue. There was a non-significant trend for high expression levels of the microRNAs, miR-21, miR-210, miR-221 and miR-222, to be associated with worse patient disease-free and overall survival. miR-21, miR-210 and miR-221 expression plays a significant role in triple- negative primary breast cancers.


A 40-year-old man with testicular torsion and large bilateral spermatoceles.
Testicular torsion is a rare disease that mostly involves children. Peak incidence is in infancy and in adolescence. Testicular torsion is rarely seen in men over 40 years of age and has only once been accompanied with spermatocele. We report the case of a 40-year-old man with testicular pain one day prior to visiting our clinic. The patient's visit to the clinic was delayed due to history of occasional testicular pain related to his bilateral spermatoceles. On arrival, a color Doppler ultrasound test was performed, which revealed heterogeneous echo in the right testis with no vascular flow, suggestive of torsion, as well as two cystic lesions in the right and left scrotums indicating spermatoceles. The patient was immediately transferred to the operating room where the bilateral spermatoceles were resected and after detorting, the right testis was saved. After four months, a normal left testis along with partial right testicular atrophy was observed. It is highly recommended to educate patients with spermatocele who have no indication for surgical treatment to visit their physician in case any new testicular pain is experienced. Furthermore, testicular pain regardless of the co-existing pathology may always be treated as an indicator of suspected torsion.


RCLens: Interactive Rare Category Exploration and Identification.
Rare category identification is an important task in many application domains, ranging from network security, to financial fraud detection, to personalized medicine. These are all applications which require the discovery and characterization of sets of rare but structurally-similar data entities which are obscured within a larger but structurally different dataset. This paper introduces RCLens, a visual analytics system designed to support user-guided rare category exploration and identification. RCLens adopts a novel active learning-based algorithm to iteratively identify more accurate rare categories in response to user-provided feedback. The algorithm is tightly integrated with an interactive visualization-based interface which supports a novel and effective workflow for rare category identification. This paper (1) defines RCLens' underlying active-learning algorithm; (2) describes the visualization and interaction designs, including a discussion of how the designs support user-guided rare category identification; and (3) presents results from an evaluation demonstrating RCLens' ability to support the rare category identification process.


Use of the Internet by print medical journals in 2003 to 2009: a longitudinal observational study.
To determine how a sample of medical journals use the Internet to provide additional content and features to readers and how this has changed since 2003. In 2005, we surveyed 2003 and 2005 issues of 138 high-impact print medical journals to determine to what extent they were using the Internet to provide online-only articles and supplementary content to print articles (sampled 28 journals), and electronic space for the postpublication critique of their articles (sampled all 138 journals). We used the same methodology to determine what kinds of Web-only supplementary material were provided with each print article in March 2007 and 2009 issues of the same 28 journals used for the 2003 to 2005 study. As before, we also determined which of the 138 journals offered rapid response pages and how those pages were being used. The proportion of the 28 journals providing Web-only supplementary material increased from 32% (2003) to 50% (2005) to 61% (2007) to 64% (2009), and the percentage of articles that contained supplementary material increased from 7% to 14% to 20% to 25%, respectively. We observed a marked increase in the number of video supplements. In contrast, journals offering online postpublication review decreased from 17 of 138 (12%) to 12 of 138 (9%) to 11 of 138 (8%) from 2005 to 2007 to 2009, and the percentage of articles with no responses was unchanged at 82%. The use of online-only articles and online-only supplements by print journals continues to increase. Postpublication critique of articles in online pages provided by the journal does not seem to be taking hold.


Left atrial appendage obliteration: mechanisms of healing and intracardiac integration.
The objectives of this study were: 1) to delineate the temporal course of histopathologic healing as the left atrial appendage (LAA) is obliterated by a mechanical device; and 2) to compare this process with other intravascular and intracardiac implanted technologies. Intracardiac device healing is incompletely understood. We thus studied the histopathology of device-based LAA obliteration. Nine dog hearts were examined over time after LAA device placement and results were compared with human hearts with prior LAA obliteration using the same device. At 3 days in dogs, atrial surfaces were covered by fibrin, which sealed gaps between the LA wall and the device and filled the LA appendage cavity. At 45 days, endothelial cells covered the endocardial surface with underlying smooth muscle cells that sealed the device-LA interface. Regions with prior thrombus were replaced by endocardium surrounding the device membrane. Disorganized thrombus remained in the LAA body and at the periphery near the appendage walls. Mild inflammation was observed as thrombus resorbed. By 90 days, a complete endocardial lining covered the former LAA ostium. Organizing thrombus had become connective tissue, with no residual inflammation. The human necropsy hearts had similar findings. In these 4 hearts (139, 200, 480, and 852 days after implant), the ostial fabric membrane was covered with endocardium. The appendage surface contained organizing thrombus with minimal inflammation. Organizing fibrous tissue was inside the LAA cavity, prominent near the atrial wall. The LAA interior contained organizing thrombus. This intracardiac device integration study delineated healing stages of early thrombus deposition, thrombus organization, inflammation and granulation tissue, final healing by connective tissue, and endocardialization without inflammation. These observations may yield insight into cellular healing processes in other cardiac devices.


Cancer and noncancer mortality among aluminum smelting workers in Badin, North Carolina.
Badin, North Carolina, hosted an aluminum smelting plant from 1917 to 2007. The Concerned Citizens of West Badin reported suspected excess cancer mortality among former employees. This study aimed to investigate these concerns. The study cohort was enumerated from United Steel Workers' records of workers employed from 1980 to 2007. Cause-specific mortality rates in the cohort were compared with North Carolina population mortality rates using standardized mortality ratios (SMRs), standardized by age, sex, race, and calendar period. We estimated cause-specific adjusted standardized mortality ratios (aSMRs) using negative controls to mitigate healthy worker survivor bias (HWSB). Standardized rate ratios (SRRs) were calculated to compare mortality rates between workers ever employed vs never employed in the pot room. All-cause mortality among Badin workers was lower than in the general population (SMR: 0.81, 95% confidence interval [CI]: 0.71-0.92). After adjusting for HWSB, excesses for all cancers (aSMR: 1.55, 95% CI: 1.10-2.21), bladder cancer (3.47, 95% CI: 1.25-9.62), mesothelioma (17.33, 95% CI: 5.40-55.59), and respiratory cancer (1.24, 95% CI: 0.77-1.99) were observed. Black males worked the highest proportion of their employed years in the pot room. Potroom workers experienced higher respiratory cancer (SRR: 2.99, 95% CI: 1.23-7.26), bladder cancer (SRR: 1.58, 95% CI: 0.15-15.28), and mesothelioma (SRR: 3.36, 95% CI: 0.21-53.78) mortality rates than never workers in the pot room. This study responds to concerns of a group of former aluminum workers. The results, while imprecise, suggest excess respiratory and bladder cancers among pot room workers in a contemporary cohort of union employees at a US smelter.


Generic path for droplet relaxation in microfluidic channels.
In two-phase microfluidics, droplets often undergo deformations that drive them away from their circular equilibrium shape. Herein we concentrate on the relaxation of symmetrical deformations to a circle driven by surface tension effects, which are predominant at the micrometer scales. Working in a Hele-Shaw cell, we report a generic pathway for these types of relaxations. We simulate numerically the interface shape evolution and investigate it using linear stability analysis. Finally, we characterize this universal aspect of relaxation using a purely geometrical model that is tested in experiments.


Unresectable hepatocellular carcinoma treated with radiotherapy and/or chemoembolization.
The purpose of our study was to evaluate the outcome, patterns of failure, and toxicity for patients with unresectable hepatocellular carcinoma (HCC) treated with radiotherapy, transcatheter arterial chemoembolization (TACE), or combined TACE and radiotherapy. Forty-two patients with unresectable HCC were treated with combined radiotherapy and TACE (TACE+RT group, 17 patients), radiotherapy alone (RT group, 9 patients), or with TACE alone (TACE group, 16 patients). Mean dose of radiation was 46.9 +/- 5.8 Gy in a daily fraction of 1.8 to 2 Gy, directed only to the cancer-involved areas of the liver. TACE was performed with a combination of Lipiodol, doxorubicin, cisplatin, and mitomycin C, followed by Gelfoam or Ivalon embolization. Tumor size was smaller in the TACE group (mean: 5.4 cm) compared with the TACE+RT group (8.6 cm) and the RT group (13.1 cm) (P = 0.0003). The median follow-up was 24 months in the TACE+RT group, 28 months in the RT group, and 23 months in the TACE group. Survival was significantly worse for patients treated with radiotherapy alone due to the selection bias of patients with more advanced disease and compromised condition in this group. In contrast, the TACE+RT and TACE groups had comparable survival (two-year rates: TACE+RT 58%, TACE 56%, P = 0.69). The local control rate for the treated tumors was similar in the TACE+RT and TACE groups (P = 0.11). The intrahepatic recurrence outside the treated tumors was common and similar between these two groups (P = 0.48). The extrahepatic progression-free survival was significantly shorter for patients in the TACE+RT group than in the TACE group (two-year rates: TACE+RT 36%, TACE 100%, P = 0.002). Seven patients died from complications of treatment. Local radiotherapy may be added to treat patients with unresectable HCC, and the control of progression of the treated tumors was promising even in patients with large hepatic tumors. Survival of patients with combined TACE and radiotherapy was similar to that with TACE as the only treatment, while a significant portion of the patients treated with radiotherapy developed extrahepatic metastasis.


Tbx2b is required for ultraviolet photoreceptor cell specification during zebrafish retinal development.
The vertebrate rod and cone photoreceptors are highly specialized sensory neurons that transduce light into the chemical and electrical signals of the nervous system. Although the physiological properties of cones and rods are well known, only a handful of genes have been identified that regulate the specification of photoreceptor subtypes. Taking advantage of the mosaic organization of photoreceptors in zebrafish, we report the isolation of a mutation resulting in a unique change in photoreceptor cell fate. Mutation of the lots-of-rods (lor) locus results in a near one-for-one transformation of UV-cone precursors into rods. The transformed cells exhibit morphological characteristics and a gene-expression pattern typical of rods, but differentiate in a temporal and spatial pattern consistent with UV-cone development. In mutant larvae and adults, the highly ordered photoreceptor mosaic is maintained and degeneration is not observed, suggesting that lor functions after the specification of the other photoreceptor subtypes. In genetic chimeras, lor functions cell-autonomously in the specification of photoreceptor cell fate. Linkage analysis and genetic-complementation testing indicate that lor is an allele of tbx2b/fby (from beyond). fby was identified by a pineal complex phenotype, and carries a nonsense mutation in the T-box domain of the tbx2b transcription factor. Homozygous fby mutant larvae and lor/fby transheterozygotes also display the lots-of-rods phenotype. Based upon these data, we propose a previously undescribed function for tbx2b in photoreceptor cell precursors, to promote the UV cone fate by repressing the rod differentiation pathway.


Sex Differences in the Personality and Cognitive Characteristics of First-Time DWI Offenders.
Driving while impaired by alcohol (DWI) is a significant yet preventable public health problem. The overrepresentation of males among DWI offenders has been attributed in part to greater sensation seeking and impulsivity features in males, although recent evidence points to increasing female DWI events. Studies exploring sex differences in DWI to better understand and intervene in these trends are rare and often methodologically lacking. This study examined sex differences among first-time DWI offenders by testing the hypotheses that, compared with non-DWI drivers, male offending is primarily associated with greater impulsive and sensation-seeking personality features and response disinhibition, whereas female offending is primarily associated with greater alcohol misuse. Male and female drivers ages 18-44 years convicted of a first DWI offense (n = 217) and non-DWI driver controls (n = 79) were recruited and compared on measures of psychosocial characteristics, substance use, personality, and response inhibition. In partial support of our hypotheses, greater alcohol misuse severity was found in female DWI offenders compared with female non-DWI drivers but an equivalent effect was not detected in males. Counter to hypothesis, greater impulsivity, sensation seeking, and response disinhibition were not found in male non-DWI drivers compared with male non-DWI drivers. Unexpectedly, greater impulsivity was found in female DWI offenders compared with female DWI drivers. Little evidence was found for impulsivity, sensation seeking, and response disinhibition being factors that directly explain higher rates of DWI offending in males. In contrast, more marked alcohol misuse and trait impulsivity in female DWI drivers suggest a greater vulnerability to uncontrolled drinking leading to dangerous driving. These findings represent a basis for examining sex-related responsivity to distinct approaches to DWI prevention.


Summarizing Patient Preferences for the Competitive Landscape of Multiple Sclerosis Treatment Options.
Objective. Quantitatively summarize patient preferences for European licensed relapsing-remitting multiple sclerosis (RRMS) disease-modifying treatment (DMT) options. Methods. To identify and summarize the most important RRMS DMT characteristics, a literature review, exploratory physician interviews, patient focus groups, and confirmatory physician interviews were conducted in Germany, the United Kingdom, and the Netherlands. A discrete choice experiment (DCE) was developed and executed to measure patient preferences for the most important DMT characteristics. The resulting DCE data (n=799 and n=363 respondents in the United Kingdom and Germany, respectively) were analyzed using Bayesian mixed logit models. The estimated individual-level patient preferences were subsequently summarized using 3 additional analyses: the quality of the choice data was assessed using individual-level R2 estimates, individual-level preferences for the available DMTs were aggregated into DMT-specific preference shares, and a principal component analysis was performed to explain the patients' choice process. Results. DMT usage differed between RRMS patients in Germany and the United Kingdom but aggregate patient preferences were similar. Across countries, 42% of all patients preferred oral medications, 38% infusions, 16% injections, and 4% no DMT. The most often preferred DMT was natalizumab (26%) and oral DMT cladribine tablets (22%). The least often preferred were mitoxantrone and the beta-interferon injections (1%-3%). Patient preferences were strongly correlated with patients' MS disease duration and DMT experience, and differences in patient preferences could be summarized using 8 principle components that together explain 99% of the variation in patients' DMT preferences. Conclusion. This study summarizes patient preferences for the included DMTs, facilitates shared decision making along the dimensions that are relevant to RRMS patients, and introduces methods in the medical DCE literature that are ideally suited to summarize the impact of DMT introductions in preexisting treatment landscapes.


Dynamic Changes of Brain Cilia Transcriptomes across the Human Lifespan.
Almost all brain cells contain primary cilia, antennae-like microtubule sensory organelles, on their surface, which play critical roles in brain functions. During neurodevelopmental stages, cilia are essential for brain formation and maturation. In the adult brain, cilia play vital roles as signaling hubs that receive and transduce various signals and regulate cell-to-cell communications. These distinct roles suggest that cilia functions, and probably structures, change throughout the human lifespan. To further understand the age-dependent changes in cilia roles, we identified and analyzed age-dependent patterns of expression of cilia's structural and functional components across the human lifespan. We acquired cilia transcriptomic data for 16 brain regions from the BrainSpan Atlas and analyzed the age-dependent expression patterns using a linear regression model by calculating the regression coefficient. We found that 67% of cilia transcripts were differentially expressed genes with age (DEGAs) in at least one brain region. The age-dependent expression was region-specific, with the highest and lowest numbers of DEGAs expressed in the ventrolateral prefrontal cortex and hippocampus, respectively. The majority of cilia DEGAs displayed upregulation with age in most of the brain regions. The transcripts encoding cilia basal body components formed the majority of cilia DEGAs, and adjacent cerebral cortices exhibited large overlapping pairs of cilia DEGAs. Most remarkably, specific α/β-tubulin subunits (TUBA1A, TUBB2A, and TUBB2B) and SNAP-25 exhibited the highest rates of downregulation and upregulation, respectively, across age in almost all brain regions. α/β-tubulins and SNAP-25 expressions are known to be dysregulated in age-related neurodevelopmental and neurodegenerative disorders. Our results support a role for the high dynamics of cilia structural and functional components across the lifespan in the normal physiology of brain circuits. Furthermore, they suggest a crucial role for cilia signaling in the pathophysiological mechanisms of age-related psychiatric/neurological disorders.


Brain reorganization as a function of walking experience in 12-month-old infants: implications for the development of manual laterality.
Hand preference in infancy is marked by many developmental shifts in hand use and arm coupling as infants reach for and manipulate objects. Research has linked these early shifts in hand use to the emergence of fundamental postural-locomotor milestones. Specifically, it was found that bimanual reaching declines when infants learn to sit; increases if infants begin to scoot in a sitting posture; declines when infants begin to crawl on hands and knees; and increases again when infants start walking upright. Why such pattern fluctuations during periods of postural-locomotor learning? One proposed hypothesis is that arm use practiced for the specific purpose of controlling posture and achieving locomotion transfers to reaching via brain functional reorganization. There has been scientific support for functional cortical reorganization and change in neural connectivity in response to motor practice in adults and animals, and as a function of crawling experience in human infants. In this research, we examined whether changes in neural connectivity also occurred as infants coupled their arms when learning to walk and whether such coupling mapped onto reaching laterality. Electroencephalogram (EEG) coherence data were collected from 43 12-month-old infants with varied levels of walking experience. EEG was recorded during quiet, attentive baseline. Walking proficiency was laboratory assessed and reaching responses were captured using small toys presented at mid-line while infants were sitting. Results revealed greater EEG coherence at homologous prefrontal/central scalp locations for the novice walkers compared to the prewalkers or more experienced walkers. In addition, reaching laterality was low in prewalkers and early walkers but high in experienced walkers. These results are consistent with the interpretation that arm coupling practiced during early walking transferred to reaching via brain functional reorganization, leading to the observed developmental changes in manual laterality.


Whole-exome sequence analysis of anthropometric traits illustrates challenges in identifying effects of rare genetic variants.
Anthropometric traits, measuring body size and shape, are highly heritable and significant clinical risk factors for cardiometabolic disorders. These traits have been extensively studied in genome-wide association studies (GWASs), with hundreds of genome-wide significant loci identified. We performed a whole-exome sequence analysis of the genetics of height, body mass index (BMI) and waist/hip ratio (WHR). We meta-analyzed single-variant and gene-based associations of whole-exome sequence variation with height, BMI, and WHR in up to 22,004 individuals, and we assessed replication of our findings in up to 16,418 individuals from 10 independent cohorts from Trans-Omics for Precision Medicine (TOPMed). We identified four trait associations with single-nucleotide variants (SNVs; two for height and two for BMI) and replicated the LECT2 gene association with height. Our expression quantitative trait locus (eQTL) analysis within previously reported GWAS loci implicated CEP63 and RFT1 as potential functional genes for known height loci. We further assessed enrichment of SNVs, which were monogenic or syndromic variants within loci associated with our three traits. This led to the significant enrichment results for height, whereas we observed no Bonferroni-corrected significance for all SNVs. With a sample size of ∼20,000 whole-exome sequences in our discovery dataset, our findings demonstrate the importance of genomic sequencing in genetic association studies, yet they also illustrate the challenges in identifying effects of rare genetic variants.


A comparison of error detection rates between the reading aloud method and the double data entry method.
Data entry and its verification are important steps in the process of data management in clinical studies. In Japan, a kind of visual comparison called the reading aloud (RA) method is often used as an alternative to or in addition to the double data entry (DDE) method. In a typical RA method, one operator reads previously keyed data aloud while looking at a printed sheet or computer screen, and another operator compares the voice with the corresponding data recorded on case report forms (CRFs) to confirm whether the data are the same. We compared the efficiency of the RA method with that of the DDE method in the data management system of the Japanese Registry of Renal Transplantation. Efficiency was evaluated in terms of error detection rate and expended time. Five hundred sixty CRFs were randomly allocated to two operators for single data entry. Two types of DDE and RA methods were performed. Single data entry errors were detected in 358 of 104,720 fields (per-field error rate=0.34%). Error detection rates were 88.3% for the DDE method performed by a different operator, 69.0% for the DDE method performed by the same operator, 59.5% for the RA method performed by a different operator, and 39.9% for the RA method performed by the same operator. The differences in these rates were significant (p<0.001) between the two verification methods as well as between the types of operator (same or different). The total expended times were 74.8 hours for the DDE method and 57.9 hours for the RA method. These results suggest that in detecting errors of single data entry, the RA method is inferior to the DDE method, while its time cost is lower.


DRD2 promoter region variation predicts antipsychotic-induced weight gain in first episode schizophrenia.
Many antipsychotic medications carry a substantial liability for weight gain, and one mechanism common to all antipsychotics is binding to the dopamine D2 receptor. We therefore examined the relationship between -141C Ins/Del (rs1799732), a functional promoter region polymorphism in DRD2, and antipsychotic-induced weight gain in 58 first episode schizophrenia patients enrolled in a randomized trial of risperidone versus olanzapine. Carriers of the deletion allele (n=29) were compared with Ins/Ins homozygotes (noncarriers, n=29) in a mixed model encompassing 10 weight measurements over 16 weeks. Deletion allele carriers showed significantly more weight gain after 6 weeks of treatment regardless of assigned medication. Although deletion carriers were prescribed higher doses of olanzapine (but not risperidone), dose did not seem to account for the genotype effects on weight gain. Given earlier evidence that deletion carriers show reduced symptom response to medication, additional study of appropriate treatment options for these patients seems warranted.


Morphometric evaluation of the cardiac ventricular capacity of anencephalic fetuses.
Anencephaly occurs in 1:1,000 to 1:20,000 infants who are potential donors in pediatric heart transplantation, so it is important to define any morphologic differences between the anencephalic and normal heart in newborns. The dimensions of the heart in anencephalics, however, may differ. For example, the absence of cerebral tissue in anencephalic fetuses may decrease the heart load resulting in a smaller heart. The position of the heart in the thoracic cavity of an anencephalic fetus may affect the size and shape of the heart. This study compares the ventricular volumes and the inlet and outlet lengths of right and left ventricles in 11 normal and 11 anencephalic fetuses of gestational ages between 27 and 35 weeks. There was no statistically significant difference between the right ventricular volumes of normal and anencephalic fetuses, however, the difference between the left ventricular volumes was found to be almost statistically significant (P = 0.07). No statistically significant difference was found between the right and left ventricular volumes of normal fetuses; in anencephalic fetuses left ventricular volumes were found to be significantly smaller than right ventricular volumes (P = 0.05). The outlet length of the right ventricle and the inlet and outlet lengths of left ventricle in anencephalic fetuses were found to be short in comparison with those of normal fetuses (P = 0.01, P = 0.008, P = 0.01). It is proposed that anencephalics, because of these morphologic differences, should be reconsidered as possible donors for heart transplantation.


[Adolescent substance use and family problems].
This study aimed to evaluate the association between substance use (alcohol, tobacco, and illicit drugs) and family problems among 965 adolescents from 50 public schools in two cities in São Paulo State, Brazil, in 2007. The Drug Use Screening Inventory (DUSI) was used for data collection. Use of alcohol, tobacco, and illicit drugs was associated with a negative assessment of the family relationship, lack of monitoring/support, and psychoactive substance use by family members (p < 0.05). Adolescents that reported having used alcohol, tobacco, and illicit drugs had more family problems than those who did not consume any substance (p < 0.001). Adolescents that used alcohol and tobacco (p = 0.028) and illicit drugs (p < 0.001) reported having more family problems than those who used only alcohol. The results highlight the importance of awareness of alcohol and tobacco use by adolescents, since such use was associated with significant family impairments, similar to illicit drug use.


Acculturation and colorectal cancer screening among older Latino adults: differential associations by national origin.
Although modest improvements in colorectal cancer (CRC) screening utilization have occurred, rates remain low among Latinos. It is unclear whether acculturation plays a role in the utilization of CRC screening. This study aimed to examine the relationships between acculturation and CRC screening among older Mexican, Puerto-Rican and Cuban adults. Cross-sectional observational study. Latinos 50 years and older, never diagnosed with CRC, and who were surveyed in the 2000, 2003 and 2005 National Health Interview Survey (NHIS). We measured acculturation with US nativity and language of interview, and examined three different CRC screening outcomes: fecal occult blood test (FOBT) in the past year, up-to-date endoscopy and any up-to-date CRC screening. Logistic regression models were adjusted for predisposing, enabling and health-care need factors consistent with the behavioral model of health-care utilization. In adjusted analyses, US nativity was positively associated with up-to-date endoscopy among Mexicans (OR: 1.5; 95% CI: 1.1, 2.2), but negatively associated with FOBT in the past year among Puerto Ricans (OR: 0.3; 95% CI: 0.2, 0.7). In contrast to this latter finding among Puerto Ricans, English language interview was positively associated with FOBT in the past year (OR: 2.5; 95% CI: 1.1, 5.4). Results underscore the importance of stratification by national origin in studies of acculturation and cancer screening and of targeting less acculturated adults to promote CRC screening. Clinicians, however, should consider the complexity of acculturation and treat US nativity and language preference as independent dimensions among their Latino patients.


The pattern-pulse multifocal visual evoked potential.
To define the pattern-pulse multifocal visual evoked potential (PPMVEP) and determine its characteristics in a sample of normal subjects in terms of amplitude of response attainable, the variation in waveform across visual field, and distribution of potential over the scalp and to compare pattern-pulse with contrast-reversal multifocal stimuli. VEPs were obtained by concurrently stimulating 60 regions of a cortically scaled dartboard with pulses of pattern contrast. Responses were recorded from normal subjects, by using a 32-channel electroencephalogram recording system, and elementary responses to each region were estimated by multiple regression of each of the response channel signals on stimulus signals. Left-eye, right-eye, and binocular viewing conditions were concurrently tested by dichoptic stimulation. A direct comparison was then made with contrast-reversal stimulation. Response waveform sets for 12 subjects varied in maximum amplitude from 1.8 to 6.8 micro V. A stereotypical distribution of waveforms held in most subjects, depending primarily on the polar angle location of the stimulus within the visual field. In a direct comparison with a contrast-reversal multifocal analysis, the pattern-pulse responses had similar waveforms and scalp topography, but were 15 times larger in amplitude. Root mean square (RMS) signal-to-noise ratio (SNR) was 1.9 times higher with pattern-pulse stimulation, corresponding to a reduction of 73% in recording time to achieve the same SNR. The PPMVEP can simultaneously characterize 60 regions of the visual field for both eyes in less than 7 minutes. A general methodology is illustrated that allows multifocal analysis with flexible choice of stimulus conditions.


Revealing chlorinated ethene transformation hotspots in a nitrate-impacted hyporheic zone.
Hyporheic zones are increasingly thought of as natural bioreactors, capable of transforming and attenuating groundwater pollutants present in diffuse baseflow. An underappreciated scenario in the understanding of contaminant fate in hyporheic zones is the interaction between point-source trichloroethene (TCE) plumes and ubiquitous, non-point source pollutants such as nitrate. This study aims to conceptualise critical biogeochemical gradients in the hyporheic zone which govern the export potential of these redox-sensitive pollutants from carbon-poor, oxic aquifers. Within the TCE plume discharge zone, discrete vertical profiling of the upper 100 cm of sediment pore water chemistry revealed an 80% increase in dissolved organic carbon (DOC) concentrations and 20-60 cm thick hypoxic zones (<2 mg O2 L-1) within which most reactive transport was observed. A 33% reduction of nitrate concentrations coincided with elevated pore water nitrous oxide concentrations as well as the appearance of manganese and the TCE metabolite cis-1,2-dichloroethene (cDCE). Elevated groundwater nitrate concentrations (>50 mg L-1) create a large stoichiometric demand for bioavailable DOC in discharging groundwater. With the benefit of a high-resolution grid of pore water samplers investigating the shallowest 30 cm of hypoxic groundwater flow paths, we identified DOC-rich hotspots associated with submerged vegetation (Ranunculus spp.), where low-energy metabolic processes such as mineral dissolution/reduction, methanogenesis and ammonification dominate. Using a chlorine index metric, we show that enhanced TCE to cDCE transformation takes place within these biogeochemical hotspots, highlighting their relevance for natural plume attenuation.


Crystal Structure of Human Myotubularin-Related Protein 1 Provides Insight into the Structural Basis of Substrate Specificity.
Myotubularin-related protein 1 (MTMR1) is a phosphatase that belongs to the tyrosine/dual-specificity phosphatase superfamily. MTMR1 has been shown to use phosphatidylinositol 3-monophosphate (PI(3)P) and/or phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2) as substrates. Here, we determined the crystal structure of human MTMR1. The refined model consists of the Pleckstrin homology (PH)-GRAM and phosphatase (PTP) domains. The overall structure was highly similar to the previously reported MTMR2 structure. Interestingly, two phosphate molecules were coordinated by strictly conserved residues located in the C(X)5R motif of the active site. Additionally, our biochemical studies confirmed the substrate specificity of MTMR1 for PI(3)P and PI(3,5)P2 over other phosphatidylinositol phosphates. Our structural and enzymatic analyses provide insight into the catalytic mechanism and biochemical properties of MTMR1.


Tolerance to ethanol hypothermia in inbred mice: genotypic correlations with behavioral responses.
Hypothermia was studied 5 min before, and 30 and 60 min after intraperitoneal administration of ethanol (3 g/kg) in 20 inbred strains of mice. Ethanol was given daily for 8 days, and temperatures were taken on Days 1, 3, 5, and 8. Tolerance was indexed by the reduction in hypothermia over days. There were large strain differences in baseline temperature, the hypothermic effect of ethanol, and in development of tolerance to hypothermia. Some strains of mice (DBA/1J, DBA/2N, MA/MyJ, and PL/J) did not develop tolerance to the hypothermic effect of ethanol. Initial sensitivity to the hypothermic effect of ethanol was significantly genetically correlated with tolerance development, indicating control of these responses by common genes. Ethanol-induced changes in activity and ataxia, as well as blood ethanol concentrations, were also assessed. Although there were significant strain differences in activity reduction, ataxia, blood-ethanol concentrations, and changes in these parameters during the course of chronic treatment, none of these variables could explain the genetic differences in hypothermic sensitivity and tolerance.


Brk is coamplified with ErbB2 to promote proliferation in breast cancer.
Amplification of the receptor tyrosine kinase ErbB2 is frequently observed in breast cancer. Amplification of erbB2 is also associated with multiple genomic gains and losses; however, the importance of these associated changes is largely unknown. We demonstrate that Brk, a cytoplasmic tyrosine kinase, is coamplified and coexpressed with ErbB2 in human breast cancers. ErbB2 interacts with Brk and increases its intrinsic kinase activity. Expression of Brk enhances the ErbB2-induced activation of Ras/MAPK signaling and cyclin E/cdk2 activity to induce cell proliferation of mammary 3-dimensional acini in culture. In a murine model of breast cancer, expression of Brk was found to shorten the latency of ErbB2-induced tumors by promoting cell proliferation, with no effect on protection from apoptosis. Furthermore, overexpression of Brk conferred resistance to the ability of Lapatinib, an ErbB2 kinase inhibitor, to inhibit ErbB2-induced proliferation. Thus, we identified Brk as a drug target for ErbB2-positive cancers.


Protective effect of green tea polyphenols on bone loss in middle-aged female rats.
Recent studies have suggested that green tea polyphenols (GTP) are promising agents for preventing bone loss in women. Findings that GTP supplementation resulted in increased urinary GTP concentrations and bone mass via an increase of antioxidant capacity and/or a decrease of oxidative stress damage suggest a significant role of GTP in bone health of women. Recent studies suggested that green tea polyphenols (GTP) are promising agents for preventing bone loss in women. However, the mechanism related to the possible protective role of GTP in bone loss is not well understood. This study evaluated bioavailability, mechanisms, bone mass, and safety of GTP in preventing bone loss in middle-aged rats without (sham, SH) and with ovariectomy (OVX). A 16-week study of 2 (SH vs. OVX) x 3 (no GTP, 0.1% GTP, and 0.5% GTP in drinking water) factorial design using 14-month-old female rats (n = 10/group) was performed. An additional 10 rats in baseline group were euthanized at the beginning of study to provide baseline parameters. There was no difference in femur bone mineral density between baseline and the SH+0.5% GTP group. Ovariectomy resulted in lower values for liver glutathione peroxidase activity, serum estradiol, and bone mineral density. GTP supplementation resulted in increased urinary epigallocatechin and epicatechin concentrations, liver glutathione peroxidase activity and femur bone mineral density, decreased urinary 8-hydroxy-2'-deoxyguanosine and urinary calcium levels, but no effect on serum estradiol and blood chemistry levels. We conclude that a bone-protective role of GTP may contribute to an increase of antioxidant capacity and/or a decrease of oxidative stress damage.