Sevoflurane leads to learning and memory dysfunction via breaking the balance of tPA/PAI-1.
Exposure to general anesthesia in early childhood may lead to adverse effects on adolescent neurocognition. This study investigated the effects of multiple inhalations of sevoflurane on long-term learning and memory in developing rats, and explored the mechanistic role of the tissue plasminogen activator (tPA)/plasminogen activator inhibitor-1 (PAI-1) fibrinolysis system and its regulatory relationship with the brain derived neurotrophic factor (BDNF) by activation of tropomysin related kinase B (TrkB). After rats were inhaled with sevoflurane for 2 h/d for three days, the expression levels of tPA, PAI-1, BDNF, its precursor(proBDNF), TrkB and phosphorylation of TrkB (p-TrkB) were detected at different time points. After 28 d, Morris water maze was used to examine learning and memory function; Golgi staining was used to investigate synaptic plasticity and synaptic-related proteins, such as Synapsin I(SYN1), growth associated protein 43(GAP-43), and postsynaptic density protein 95(PSD-95). Rats were given exogenous tPA and an inhibitor of PAI-1, TM5275. The results showed multiple inhalation of sevoflurane led to learning and memory dysfunction, downregulated the expression of the synaptic-related proteins, decreased dendritic spine density in the hippocampus, increased the expression level of proBDNF and PAI-1, and reduced expression of BDNF, tPA, and p-TrkB. Interestingly, tPA or TM5275 partially reversed the learning and memory dysfunction and the reduction of synaptic plasticity induced by sevoflurane exposure. Furthermore, they blocked the upregulation of proBDNF and PAI-1 protein expression and increased the expression of BDNF, tPA, and p-TrkB. The protective effect of tPA or TM5275 on rats following multiple sevoflurane inhalation was blocked by a TrkB inhibitor. Multiple inhalation of sevoflurane in rats inhibited the cleavage of proBDNF by disrupting the balance of the tPA/PAI-1 fibrinolysis system. This blocked the activation of the downstream TrkB signaling pathway and reduced hippocampal synaptic plasticity, leading to long-term learning and memory dysfunction. Therefore, Sevoflurane exposure could lead to learning and memory dysfunction by inhibiting BDNF cleavage via breaking the balance of tPA/PAI-1.


Changes in temporomandibular joint anatomy, changes in condylar translation, and their relationship with disc displacement: magnetic resonance imaging study.
To assess changes in the articular surfaces of the temporomandibular joint (TMJ) and in condylar translation, as detected by magnetic resonance imaging (MRI), determining whether such changes correlate with disc displacement. We retrospectively analyzed the MRI scans of 2076 TMJs of 1038 patients with symptoms of temporomandibular disorder. We attempted to determine whether articular disc deformity and changes in condylar translation, as well as changes in the articular surfaces of the condyle, glenoid fossa, and articular eminence, correlated with disc displacement. Disc displacement with reduction was associated with changes in the shape of the articular eminence. Disc displacement without reduction was most strongly associated with disc deformity, condylar degeneration, glenoid fossa degeneration, and effusion. Neither decreases nor increases in condylar translation were associated with disc deformity, degenerative bone changes, or disc displacement. Changes in the shape of the articular eminence seem to predispose to progression of internal derangement of the TMJ.


Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine.
5-methylcytosine (5mC) in DNA plays an important role in gene expression, genomic imprinting, and suppression of transposable elements. 5mC can be converted to 5-hydroxymethylcytosine (5hmC) by the Tet (ten eleven translocation) proteins. Here, we show that, in addition to 5hmC, the Tet proteins can generate 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC) from 5mC in an enzymatic activity-dependent manner. Furthermore, we reveal the presence of 5fC and 5caC in genomic DNA of mouse embryonic stem cells and mouse organs. The genomic content of 5hmC, 5fC, and 5caC can be increased or reduced through overexpression or depletion of Tet proteins. Thus, we identify two previously unknown cytosine derivatives in genomic DNA as the products of Tet proteins. Our study raises the possibility that DNA demethylation may occur through Tet-catalyzed oxidation followed by decarboxylation.


Essence Core: Fluid Management in Acute Kidney Injury.
Acute kidney injury (AKI) is a heterogeneous disorder characterized by sudden decrease in kidney functioning, with increased serum creatinine levels and impairment of vital kidney functions such as fluid, electrolyte, and acid-base homeostasis. The key to perioperative AKI management is accomplishing optimal intravenous fluid therapy, involving guided fluid resuscitation and fluid balance management including proper fluid removal. In the present review, we highlighted the importance of fluid-based management of AKI, which is a critical process, as both reduced and increased levels of body fluids can have detrimental effects on the patient. While fluid depletion is commonly the targeted approach for fluid management, fluid overload is also largely recognized as a major contributor to worsening the outcomes. With the wide range of available fluid types, such as colloids and crystalloids, detailed knowledge and role of each are necessary before making the choice of a treatment strategy to be employed. While each of these has associated pros and cons, crystalloids are largely accepted as the treatment of choice due to better outcomes and affordability. Nevertheless, the dose and choice of fluid therapy must be goal irected and customized based on the patient's condition, ruling out the confounding factors.


Evaluation of suspected tuberculous pleurisy: clinical and diagnostic findings in HIV-1-positive and HIV-negative adults in Uganda.
National Tuberculosis Treatment Centre, Mulago Hospital, Kampala, Uganda. To compare clinical and radiographic presentation, and diagnostic methods, in adults with tuberculous pleurisy who are negative and positive for the human immunodeficiency virus (HIV). Adults with suspected pleural tuberculosis were screened by clinical examination, thoracocentesis and closed pleural biopsy. Biopsy material was cultured on Middlebrook 7H-10 solid medium and in BACTEC 12B radiometric vials. Pleural fluid was cultured using Löwenstein-Jensen slants, BACTEC and Kirchner liquid medium. Of 156 individuals enrolled, 142 had tuberculosis, of whom 80% were HIV-positive. Among those with tuberculosis, HIV-positive patients bad a more severe and longer illness. The size of effusions was similar in HIV-positive and HIV-negative patients. A higher proportion of HIV-positive patients had parenchymal infiltrates but this difference was not statistically significant. Pleural fluid lymphocytosis was present in all HIV-negative and 97% of the HIV-positive patients. HIV-positive patients had lower pleural fluid lymphocyte counts. Pleural fluid cultures were more often positive in HIV-positive patients. BACTEC and Kirchner liquid media gave higher yields than solid media. HIV-positive patients with tuberculous pleurisy had a more severe illness than HIV-negative patients. Mycobacterial cultures from HIV-positive patients were more often positive, suggesting more mycobacterial extension from the lungs into the pleural space. Liquid culture media were superior to solid media with regard to diagnostic yield and time until diagnosis.


Reduction of the CD16(-)CD56bright NK cell subset precedes NK cell dysfunction in prostate cancer.
Natural cytotoxicity, mediated by natural killer (NK) cells plays an important role in the inhibition and elimination of malignant tumor cells. To investigate the immunoregulatory role of NK cells and their potential as diagnostic markers, NK cell activity (NKA) was analyzed in prostate cancer (PCa) patients with particular focus on NK cell subset distribution. Prospective data of NKA and NK cell subset distribution patterns were measured from 51 patients initially diagnosed with PCa and 54 healthy controls. NKA was represented by IFN-γ levels after stimulation of the peripheral blood with Promoca®. To determine the distribution of NK cell subsets, PBMCs were stained with fluorochrome-conjugated monoclonal antibodies. Then, CD16(+)CD56(dim) and CD16(-)CD56(bright) cells gated on CD56(+)CD3(-) cells were analyzed using a flow-cytometer. NKA and the proportion of CD56(bright) cells were significantly lower in PCa patients compared to controls (430.9 pg/ml vs. 975.2 pg/ml and 2.3% vs. 3.8%, respectively; p<0.001). Both tended to gradually decrease according to cancer stage progression (p for trend = 0.001). A significantly higher CD56(dim)-to-CD56(bright) cell ratio was observed in PCa patients (41.8 vs. 30.3; p<0.001) along with a gradual increase according to cancer stage progression (p for trend = 0.001), implying a significant reduction of CD56(bright) cells in relation to the alteration of CD56(dim) cells. The sensitivity and the specificity of NKA regarding PCa detection were 72% and 74%, respectively (best cut-off value at 530.9 pg/ml, AUC = 0.786). Reduction of CD56(bright) cells may precede NK cell dysfunction, leading to impaired cytotoxicity against PCa cells. These observations may explain one of the mechanisms behind NK cell dysfunction observed in PCa microenvironment and lend support to the development of future cancer immunotherapeutic strategies.


Development of an outcome measurement system for service planning for children and youth with special needs.
This study described the process used in developing an outcome measurement framework for system planning to improve services for children and youth with special needs and their families in a Canadian province. The study reports the results of several parent-completed measures, which would be useful in service planning as well as the acceptability and utility of these measures for use by families and service centres. Development of a theoretical framework, consultation with key stakeholders, testing the utility of selected outcome measures and initial dissemination of results were critical elements in the successful development of an outcome system. Consultation with stakeholders confirmed use of the International Classification of Functioning, Disability and Health and the child-within-family-within community model as theoretical frameworks while building valuable partnerships and identifying potential barriers to implementation. Pilot testing showed three outcome measures were feasible for families to complete and the measures provided information about services for children that was valuable to families as well as service providers. Gaps in service delivery were identified and the need for better communication between service providers and communities to facilitate integrated services was highlighted. The findings from this study can be used to implement an outcome measurement system for children with special needs and may serve as a resource for international researchers who are working to develop valid tools as well as outcome systems that are useful for system planning.


T cell activation induces human osteoclast formation via receptor activator of nuclear factor kappaB ligand-dependent and -independent mechanisms.
In unstimulated conditions, osteoclast (OC) formation is regulated by stromal cell production of the key osteoclastogenic factors receptor activator of nuclear factor kappaB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF). However, the mechanisms of accelerated osteoclastogenesis and bone loss characteristic of inflammatory conditions are poorly understood but appear to involve T cells. In addition, the mechanism by which OCs arise spontaneously in cultures of peripheral blood mononuclear cells in the absence of stromal cells or added cytokines remains unclear. Using a stromal cell free human osteoclast generating system, we investigated the ability of activated T cells to support osteoclastogenesis. We show that when activated by phytohemagglutinin-P (PHA), T cells (both CD4+ and CD8+) stimulate human OC formation in vitro. Although both soluble M-CSF and RANKL were detected in activated T cell supernatants, the presence of M-CSF was not essential for macrophage survival or RANKL-dependent osteoclast formation, suggesting that other soluble T cell-derived factors were capable of substituting for this cytokine. We also found that saturating concentrations of osteoprotegerin (OPG) failed to neutralize 30% of the observed OC formation and that T cell conditioned medium (CM) could superinduce osteoclastogenesis in cultures of purified monocytes maximally stimulated by RANKL and M-CSF. Together, these data suggest that activated T cells support osteoclastogenesis via RANKL-dependent and -independent mechanisms. Although not relevant for T cell-induced osteoclastogenesis, secretion of soluble M-CSF is a previously undescribed property of activated T cells.


Dipeptidyl peptidase-4 inhibitors and risk of heart failure in type 2 diabetes: systematic review and meta-analysis of randomised and observational studies.
To examine the association between dipeptidyl peptidase-4 (DPP-4) inhibitors and the risk of heart failure or hospital admission for heart failure in patients with type 2 diabetes. Systematic review and meta-analysis of randomised and observational studies. Medline, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov searched up to 25 June 2015, and communication with experts. Randomised controlled trials, non-randomised controlled trials, cohort studies, and case-control studies that compared DPP-4 inhibitors against placebo, lifestyle modification, or active antidiabetic drugs in adults with type 2 diabetes, and explicitly reported the outcome of heart failure or hospital admission for heart failure. Teams of paired reviewers independently screened for eligible studies, assessed risk of bias, and extracted data using standardised, pilot tested forms. Data from trials and observational studies were pooled separately; quality of evidence was assessed by the GRADE approach. Eligible studies included 43 trials (n=68,775) and 12 observational studies (nine cohort studies, three nested case-control studies; n=1,777,358). Pooling of 38 trials reporting heart failure provided low quality evidence for a possible similar risk of heart failure between DPP-4 inhibitor use versus control (42/15,701 v 33/12,591; odds ratio 0.97 (95% confidence interval 0.61 to 1.56); risk difference 2 fewer (19 fewer to 28 more) events per 1000 patients with type 2 diabetes over five years). The observational studies provided effect estimates generally consistent with trial findings, but with very low quality evidence. Pooling of the five trials reporting admission for heart failure provided moderate quality evidence for an increased risk in patients treated with DPP-4 inhibitors versus control (622/18,554 v 552/18,474; 1.13 (1.00 to 1.26); 8 more (0 more to 16 more)). The pooling of adjusted estimates from observational studies similarly suggested (with very low quality evidence) a possible increased risk of admission for heart failure (adjusted odds ratio 1.41, 95% confidence interval 0.95 to 2.09) in patients treated with DPP-4 inhibitors (exclusively sitagliptin) versus no use. The relative effect of DPP-4 inhibitors on the risk of heart failure in patients with type 2 diabetes is uncertain, given the relatively short follow-up and low quality of evidence. Both randomised controlled trials and observational studies, however, suggest that these drugs may increase the risk of hospital admission for heart failure in those patients with existing cardiovascular diseases or multiple risk factors for vascular diseases, compared with no use.


Transposon expression in the Drosophila brain is driven by neighboring genes and diversifies the neural transcriptome.
Somatic transposon expression in neural tissue is commonly considered as a measure of mobilization and has therefore been linked to neuropathology and organismal individuality. We combined genome sequencing data with single-cell mRNA sequencing of the same inbred fly strain to map transposon expression in the Drosophila midbrain and found that transposon expression patterns are highly stereotyped. Every detected transposon is resident in at least one cellular gene with a matching expression pattern. Bulk RNA sequencing from fly heads of the same strain revealed that coexpression is a physical link in the form of abundant chimeric transposon-gene mRNAs. We identified 264 genes where transposons introduce cryptic splice sites into the nascent transcript and thereby significantly expand the neural transcript repertoire. Some genes exclusively produce chimeric mRNAs with transposon sequence; on average, 11.6% of the mRNAs produced from a given gene are chimeric. Conversely, most transposon-containing transcripts are chimeric, which suggests that somatic expression of these transposons is largely driven by cellular genes. We propose that chimeric mRNAs produced by alternative splicing into polymorphic transposons, rather than transposon mobilization, may contribute to functional differences between individual cells and animals.


Treatment of anemia in patients with heart disease: a systematic review.
The benefits of anemia treatment in patients with heart disease are uncertain. To evaluate the benefits and harms of treatments for anemia in adults with heart disease. MEDLINE, EMBASE, and Cochrane databases; clinical trial registries; reference lists; and technical advisors. English-language trials of blood transfusions, iron, or erythropoiesis-stimulating agents in adults with anemia and congestive heart failure or coronary heart disease and observational studies of transfusion. Data on study design, population characteristics, hemoglobin levels, and health outcomes were extracted. Trials were assessed for quality. Low-strength evidence from 6 trials and 26 observational studies suggests that liberal transfusion protocols do not improve short-term mortality rates compared with less aggressive protocols (combined relative risk among trials, 0.94 [95% CI, 0.61 to 1.42]; I2 = 16.8%), although decreased mortality rates occurred in a small trial of patients with the acute coronary syndrome (1.8% vs. 13.0%; P = 0.032). Moderate-strength evidence from 3 trials of intravenous iron found improved short-term exercise tolerance and quality of life in patients with heart failure. Moderate- to high-strength evidence from 17 trials of erythropoiesis-stimulating agent therapy found they offered no consistent benefits, but their use may be associated with harms, such as venous thromboembolism. Few trials have examined transfusions in patients with heart disease, and observational studies are potentially confounded by indication. Data supporting iron use come mainly from 1 large trial, and long-term effects are unknown. Higher transfusion thresholds do not consistently improve mortality rates, but large trials are needed. Intravenous iron may help to alleviate symptoms in patients with heart failure and iron deficiency and also warrants further study. Erythropoiesis-stimulating agents do not seem to benefit patients with mild to moderate anemia and heart disease and may be associated with serious harms. U.S. Department of Veterans Affairs.


A multi-worksite analysis of the relationships among body mass index, medical utilization, and worker productivity.
The relationships between worker health and productivity are becoming clearer. However, few large scale studies have measured the direct and indirect cost burden of overweight and obesity among employees using actual biometric values. The objective of this study was to quantify the direct medical and indirect (absence and productivity) cost burden of overweight and obesity in workers. A cross-sectional study of 10,026 employees in multiple professions and worksites across the United States was conducted. The main outcomes were five self-reported measures of workers' annual health care use and productivity: doctor visits, emergency department visits, hospitalizations, absenteeism (days absent from work), and presenteeism (percent on-the-job productivity losses). Multivariate count and continuous data models (Poisson, negative binomial, and zero-inflated Poisson) were estimated. After adjusting for covariates, obese employees had 20% higher doctor visits than normal weight employees (confidence interval [CI] 16%, 24%, P < 0.01) and 26% higher emergency department visits (CI 11%, 42%, P < 0.01). Rates of doctor and emergency department visits for overweight employees were no different than those of normal weight employees. Compared to normal weight employees, presenteeism rates were 10% and 12% higher for overweight and obese employees, respectively (CI 5%, 15% and 5%, 19%, all P < 0.01). Taken together, compared to normal weight employees, obese and overweight workers were estimated to cost employers $644 and $201 more per employee per year, respectively. This study provides evidence that employers face a financial burden imposed by obesity. Implementation of effective workplace programs for the prevention and management of excess weight will benefit employers and their workers.


The Australian Bogong Moth Agrotis infusa: A Long-Distance Nocturnal Navigator.
The nocturnal Bogong moth (Agrotis infusa) is an iconic and well-known Australian insect that is also a remarkable nocturnal navigator. Like the Monarch butterflies of North America, Bogong moths make a yearly migration over enormous distances, from southern Queensland, western and northwestern New South Wales (NSW) and western Victoria, to the alpine regions of NSW and Victoria. After emerging from their pupae in early spring, adult Bogong moths embark on a long nocturnal journey towards the Australian Alps, a journey that can take many days or even weeks and cover over 1000 km. Once in the Alps (from the end of September), Bogong moths seek out the shelter of selected and isolated high ridge-top caves and rock crevices (typically at elevations above 1800 m). In hundreds of thousands, moths line the interior walls of these cool alpine caves where they "hibernate" over the summer months (referred to as "estivation"). Towards the end of the summer (February and March), the same individuals that arrived months earlier leave the caves and begin their long return trip to their breeding grounds. Once there, moths mate, lay eggs and die. The moths that hatch in the following spring then repeat the migratory cycle afresh. Despite having had no previous experience of the migratory route, these moths find their way to the Alps and locate their estivation caves that are dotted along the high alpine ridges of southeastern Australia. How naïve moths manage this remarkable migratory feat still remains a mystery, although there are many potential sensory cues along the migratory route that moths might rely on during their journey, including visual, olfactory, mechanical and magnetic cues. Here we review our current knowledge of the Bogong moth, including its natural history, its ecology, its cultural importance to the Australian Aborigines and what we understand about the sensory basis of its long-distance nocturnal migration. From this analysis it becomes clear that the Bogong moth represents a new and very promising model organism for understanding the sensory basis of nocturnal migration in insects.


Best Practices for Ethical Sharing of Individual-Level Health Research Data From Low- and Middle-Income Settings.
Sharing individual-level data from clinical and public health research is increasingly being seen as a core requirement for effective and efficient biomedical research. This article discusses the results of a systematic review and multisite qualitative study of key stakeholders' perspectives on best practices in ethical data sharing in low- and middle-income settings. Our research suggests that for data sharing to be effective and sustainable, multiple social and ethical requirements need to be met. An effective model of data sharing will be one in which considered judgments will need to be made about how best to achieve scientific progress, minimize risks of harm, promote fairness and reciprocity, and build and sustain trust.


Tension of the ulnar, median, and radial nerves during ulnar nerve neurodynamic testing: observational cadaveric study.
The ulnar nerve upper limb neurodynamic test (ULNT3) uses upper limb positioning to investigate symptoms arising from the ulnar nerve. It is proposed to selectively increase tension of the nerve; however, this property of the test is not well established. The aim of this study was to determine the upper limb position that results in: (1) the greatest tension of the ulnar nerve and (2) the greatest difference in tension between the ulnar nerve and the other 2 major nerves of the upper limb: median and radial. This was an observational cadaver study. Tension (in newtons) of the ulnar, median, and radial nerves was measured simultaneously using 3 buckle force transducers in 5 upper limb positions in 10 embalmed human cadavers (N=20 limbs). Repeated-measures analysis of variance (ANOVA) with Bonferroni post hoc tests determined differences in tension among nerves and among limb positions. The addition of shoulder horizontal abduction (H.Abd; 12.62 N; 95% confidence interval [95% CI]=10.76, 14.47) and combined shoulder abduction and internal rotation (H.Abd+IR; 11.86 N; 95% CI=9.96, 13.77) to ULNT3 (scapular depression, shoulder abduction and external rotation, elbow flexion, forearm pronation, and wrist and finger extension) produced significantly greater ulnar nerve tension compared with the ULNT3 alone (8.71 N; 95% CI=7.25, 10.17). The ULNT3+H.Abd test demonstrated the greatest difference in tension among nerves (mean difference between ulnar and median nerves=11.87 N; 95% CI=9.80, 13.92; mean difference between ulnar and radial nerves=8.47 N; 95% CI=6.41, 10.53). These results pertain only to the biomechanical plausibility of the ulnar nerve neurodynamic test and do not account for other factors that may affect the clinical application of this test. The ULNT3+H.Abd is a biomechanically plausible test for detecting peripheral neuropathic pain related to the ulnar nerve. In situations where the shoulder complex will not tolerate the combination of shoulder external rotation in abduction, performing upper limb neurodynamic tests with internal rotation instead of external rotation is a biomechanically plausible alternative.


[The importance of Binswanger's phenomenology for the concept of delusion].
In his book entitled 'Wahn' (delusion), Binswanger develops a new line of thinking which is important for the neurosciences today. Unlike Jaspers, Binswanger believes that in a delusion normal perceptions do not acquire an abnormal significance. However, a delusion can develop as a result of a disturbance in sensations, perceptions and structure of consciousness. Binswanger was inspired to express these views after studying the philosophy of Heidegger, Aristotle, Kant and Husserl. In Binswanger's opinion, spontaneous mental activity is disturbed in delusion and perceptions are freezed. This can create a situation where the subject is dominated by mental images that can overpower and even destroy his own self-image. As a result the subject no longer has access to the human horizon which he would normally share with others. Consequently, the subject 'is convinced' that he is in the clutches of an alien power. On the basis of a case study, we investigate how a delusion arises and show how by analysing a patient's perceptions and sensations psychiatrists can help a patient to 'repossess his own mind'.


Investigations of immunotoxicity and allergic potential induced by topical application of triclosan in mice.
Triclosan is an antimicrobial chemical commonly used occupationally and by the general public. Using select immune function assays, the purpose of these studies was to evaluate the immunotoxicity of triclosan following dermal exposure using a murine model. Triclosan was not identified to be a sensitizer in the murine local lymph node assay (LLNA) when tested at concentrations ranging from 0.75-3.0%. Following a 28-day exposure, triclosan produced a significant increase in liver weight at concentrations of ≥ 1.5%. Exposure to the high dose (3.0%) also produced a significant increase in spleen weights and number of platelets. The absolute number of B-cells, T-cells, dendritic cells and NK cells were significantly increased in the skin draining lymph node, but not the spleen. An increase in the frequency of dendritic cells was also observed in the lymph node following exposure to 3.0% triclosan. The IgM antibody response to sheep red blood cells (SRBC) was significantly increased at 0.75% - but not at the higher concentrations - in the spleen and serum. These results demonstrate that dermal exposure to triclosan induces stimulation of the immune system in a murine model and raise concerns about potential human exposure.


Disparities in service quality among insured adult patients seen in physicians' offices.
To examine racial disparities in health care service quality. Secondary data analyses of visits by primary care service users in the Community Tracking Study household sample. Sixty communities across the United States. A total of 41,537 insured adult patients making sick visits to primary care physicians in 1996-1997, 1998-1999, 2000-2001, and 2003. Lag between appointment and physician visit, waiting time in physician office, and satisfaction with care were analyzed. Blacks but not other minorities were more likely to have an appointment lag of more than 1 week (13% white vs. 21% black, p < 0.001). Blacks, Hispanics, and other minorities were more likely to wait more than 30 min before being seen by the physician (16% white vs. 26% black, p < 0.001; vs. 27% Hispanic and 22% other minority, p < 0.001 and p = 0.02, respectively) and were less likely to report that they were very satisfied with their care (65% white vs. 60% black, p = 0.02; vs. 57% Hispanic and 48% other minority, p = 0.004 and p < 0.001, respectively). The differences in appointment lag and wait time remain large and statistically significant after the inclusion of multiple covariates, including geographic controls for CTS site. For all groups, satisfaction with care was affected by objective measures of service quality. Differences in objective measures of service quality explained much of the black-white difference in satisfaction, though not differences for other minority groups. There are substantial racial/ethnic disparities in satisfaction with care, and these are related to objective quality measures that can be improved.


Gender differences in the associations between perceived environment and walking for recreation in Taiwanese adults.
This study examined gender differences in the associations between perceived environmental factors and walking for recreation in Taiwanese adults. In 2014, a telephone-based, cross-sectional survey targeting Taiwanese adults (20-64 years) was conducted. Data on nine items about environmental perception, time spent in walking for recreation, and socio-demographic variables were obtained from 1,065 adults using the International Physical Activity Questionnaire-long version and its environmental module. Adults who perceived good aesthetics (adjusted odds ratio [AOR] = 1.74; 95% confidence interval [CI]: 1.36-2.23) and reported seeing people being active (AOR = 1.58; 95% CI: 1.21-2.06) were more likely to perform 150 minutes of recreational walking per week. Furthermore, significant interactions regarding walking for recreation were observed between gender and five environmental correlates: access to shops (p = .046), the presence of sidewalks (p < .001), access to recreational facilities (p = .02), seeing people being active (p = .001), and aesthetics (p < .001). These five perceived environmental factors were positively associated with recreational walking in women but not in men. Gender is a potential modifier between perceived environment and walking for recreation in adults. Perceived environmental factors appear to be more critical for women in performing health-enhancing levels of recreational walking than they are for men.


Upper Limb Robotic Rehabilitation After Stroke: A Multicenter, Randomized Clinical Trial.
After stroke, only 12% of survivors obtain complete upper limb (UL) functional recovery, while in 30% to 60% UL deficits persist. Despite the complexity of the UL, prior robot-mediated therapy research has used only one robot in comparisons to conventional therapy. We evaluated the efficacy of robotic UL treatment using a set of 4 devices, compared with conventional therapy. In a multicenter, randomized controlled trial, 247 subjects with subacute stroke were assigned either to robotic (using a set of 4 devices) or to conventional treatment, each consisting of 30 sessions. Subjects were evaluated before and after treatment, with follow-up assessment after 3 months. The primary outcome measure was change from baseline in the Fugl-Meyer Assessment (FMA) score. Secondary outcome measures were selected to assess motor function, activities, and participation. One hundred ninety subjects completed the posttreatment assessment, with a subset (n = 122) returning for follow-up evaluation. Mean FMA score improvement in the robotic group was 8.50 (confidence interval: 6.82 to 10.17), versus 8.57 (confidence interval: 6.97 to 10.18) in the conventional group, with no significant between-groups difference (adjusted mean difference -0.08, P = 0.948). Both groups also had similar change in secondary measures, except for the Motricity Index, with better results for the robotic group (adjusted mean difference 4.42, P = 0.037). At follow-up, subjects continued to improve with no between-groups differences. Robotic treatment using a set of 4 devices significantly improved UL motor function, activities, and participation in subjects with subacute stroke to the same extent as a similar amount of conventional therapy. Video Abstract is available for more insights from the authors (see the Video, Supplemental Digital Content 1, available at: http://links.lww.com/JNPT/A291).


Bilateral carotid body resection for the relief of dyspnea in severe chronic obstructive pulmonary disease. Physiologic and clinical observations in three patients.
For many patients with advanced chronic airflow limitation (COPD) the treatment of dyspnea remains inadequate despite medications, rehabilitation programs, and supplemental oxygen. Bilateral carotid body resection (BCBR) is a controversial operation which has been reported anecdotally to relieve dyspnea in such patients, but its risks and long-term effects are not known. We studied pulmonary function and the ventilatory response to exercise of three severely dyspneic COPD patients who had chosen independently and without our knowledge to undergo this operation. All three patients reported improvement in dyspnea following BCBR despite the absence of improvement in their severe airflow limitation (mean FEV1 = 0.71 L before and 0.67 L after BCBR). The three patients died 6, 18 and 36 months after the removal of their carotid bodies, still convinced of the efficacy of their surgery. Their reported relief of dyspnea was associated with substantial decreases in minute ventilation and deterioration in arterial blood gases. Arterial blood gases worsened both at rest (PO2 fell from 57 to 45 mm Hg; PCO2 rose from 45 to 57 mm Hg) and during identical steady state exercise (at peak exercise, PO2 fell from 46 to 37 mm Hg and PCO2 rose from 50 to 61 mm Hg) postoperatively. Total minute ventilation decreased postoperatively both at rest (-3.4 L/min, -25 percent) and with exercise (-9.4 L/min, -39 percent) primarily because of decreases in respiratory rate (from 21 to 16 breaths/min at rest and from 25 to 18 breaths/min with exercise), and this was associated with decreases in both oxygen uptake (-26 percent) and carbon dioxide production (-22 percent) for the same external exercise workload. Whether the reported improvement in dyspnea was due to decrease in ventilation resulting from decrease in respiratory drive, a surgical placebo effect or some other unestablished effect of removal of the carotid bodies deserves further study.


Evaluation of the mental health impacts of Universal Credit: protocol for a mixed methods study.
The UK social security system is being transformed by the implementation of Universal Credit (UC), which combines six existing benefits and tax credits into a single payment for low-income households. Despite extensive reports of hardship associated with the introduction of UC, no previous studies have comprehensively evaluated its impact on mental health. Because payments are targeted at low-income households, impacts on mental health will have important consequences for health inequalities. We will conduct a mixed methods study. Work package (WP) 1 will compare health outcomes for new recipients of UC with outcomes for legacy benefit recipients in two large population surveys, using the phased rollout of UC as a natural experiment. We will also analyse the relationship between the proportion of UC claimants in small areas and a composite measure of mental health. WP2 will use data collected by Citizen's Advice to explore the sociodemographic and health characteristics of people who seek advice when claiming UC and identify features of the claim process that prompt advice-seeking. WP3 will conduct longitudinal in-depth interviews with up to 80 UC claimants in England and Scotland to explore reasons for claiming and experiences of the claim process. Up to 30 staff supporting claimants will also be interviewed. WP4 will use a dynamic microsimulation model to simulate the long-term health impacts of different implementation scenarios. WP5 will undertake cost-consequence analysis of the potential costs and outcomes of introducing UC and cost-benefit analyses of mitigating actions. We obtained ethical approval for the primary data gathering from the University of Glasgow, College of Social Sciences Research Ethics Committee, application number 400200244. We will use our networks to actively disseminate findings to UC claimants, the public, practitioners and policy-makers, using a range of methods and formats. The study is registered with the Research Registry: researchregistry6697.


Aberrant expression of cell-cycle regulatory proteins in human mesenchymal neoplasia.
We previously demonstrated that approximately one-half of soft-tissue sarcomas were devoid of either pRB, the product of the retinoblastoma gene, or 16, the product of the MTS1/CDKN2 gene, while a smaller subset of aggressive mesenchymal tumors without metastatic potential did not express RB by immunohistochemistry. We now studied the expression of two additional important cell-cycle regulators, namely cyclin D1 and p53, in the same cohort of high- and low-grade lesions. In the aggregate, our data provide a comprehensive overview of the importance of cell-cycle deregulation in mesenchymal neoplasia. Paraffin sections of 58 sarcomas and 23 soft-tissue tumors of low malignant potential (STT-LMP) were reacted with monoclonal antibodies against cyclin D1 and p53, using optimized immunohistochemical staining protocols. The staining data were correlated with expression of pRB and p15 and with a variety of pathologic parameters. A total of 33 of 58 sarcomas (57%) and 9 of 23 STT-LMP (39%) overexpressed p53. Fourteen sarcomas (24%) and 4 STT-LMP (17%) overexpressed cyclin D1. There was no correlation between expression of these two genes and histologic tumor type or grade. Loss of RB and loss of p16 or overexpression of cyclin D1 were mutually exclusive events. Considering all four cell-cycle regulators, sarcomas had a significantly higher abnormality rate than did STT-LMP (P < .005). Only 10% of the sarcomas but 39% of STT-LMP showed normal expression of all four gene products. Based on our findings, overexpression of cyclin D1 and (presumably mutant) p53 appear to be among the most common molecular alterations in human mesenchymal neoplasia, and abrogation of cell-cycle control is observed in the great majority of sarcomas; it is present significantly less frequently in low-grade lesions.


Optimization of terminal-restriction fragment length polymorphism analysis for complex marine bacterioplankton communities and comparison with denaturing gradient gel electrophoresis.
The potential of terminal-restriction fragment length polymorphism (T-RFLP) and the detection of operational taxonomic units (OTUs) by capillary electrophoresis (CE) to characterize marine bacterioplankton communities was compared with that of denaturing gradient gel electrophoresis (DGGE). A protocol has been developed to optimize the separation and detection of OTUs between 20 and 1, 632 bp by using CE and laser-induced fluorescence detection. Additionally, we compared T-RFLP fingerprinting to DGGE optimized for detection of less abundant OTUs. Similar results were obtained with both fingerprinting techniques, although the T-RFLP approach and CE detection of OTUs was more sensitive, as indicated by the higher number of OTUs detected. We tested the T-RFLP fingerprinting technique on complex marine bacterial communities by using the 16S rRNA gene and 16S rRNA as templates for PCR. Samples from the Northern and Middle Adriatic Sea and from the South and North Aegean Sea were compared. Distinct clusters were identifiable for different sampling sites. Thus, this technique is useful for rapid evaluation of the biogeographical distribution and relationships of bacterioplankton communities.


Medicare Part D's Effects on Drug Utilization and Out-of-Pocket Costs: A Systematic Review.
To update a past systematic review on whether Medicare Part D changed drug utilization and out-of-pocket (OOP) costs overall and within subpopulations, and to identify evidence gaps. Published and gray literature from 2010 to 2015 meeting prespecified screening criteria, including having a comparison group, and utilization or OOP cost outcomes. We conducted a systematic literature review with a quality assessment. For each study, we extracted information on study design, data sources, analytic methods, outcomes, and limitations. Because outcome measures vary across studies, we did a qualitative synthesis rather than meta-analysis. Sixty-five studies met screening criteria. Overall, Medicare Part D enrollees have increased drug utilization and decreased OOP costs, but coverage gaps limit the program's impact. Beneficiaries whose insurance becomes more generous after enrollment had disproportionately increased drug utilization and decreased OOP costs. Outcomes among dual-eligibles were mixed. There is strong evidence on how Medicare Part D and the donut hole coverage gap affect utilization and OOP costs, but weak evidence on how effects vary among dual-eligibles or across diseases. Findings suggest that the Affordable Care Act's provisions to expand coverage and reduce the donut hole should improve patient outcomes.


Final analysis of a phase 1/2b study of ibrutinib combined with carfilzomib/dexamethasone in patients with relapsed/refractory multiple myeloma.
Patients with multiple myeloma (MM) inevitably relapse on initial treatment regimens, and novel combination therapies are needed. Ibrutinib is a first-in-class, once-daily inhibitor of Bruton's tyrosine kinase, an enzyme implicated in growth and survival of MM cells. Preclinical data suggest supra-additivity or synergy between ibrutinib and proteasome inhibitors (PIs) against MM. This phase 1/2b study evaluated the efficacy and safety of ibrutinib plus the PI carfilzomib and dexamethasone in patients with relapsed/refractory MM (RRMM). In this final analysis, we report results in patients who received the recommended phase 2 dose (RP2D; ibrutinib 840 mg and carfilzomib 36 mg/m2 with dexamethasone), which was determined in phase 1. The primary efficacy endpoint was overall response rate (ORR). Fifty-nine patients with RRMM received the RP2D (18 in phase 1 and 41 in phase 2b). These patients had received a median of three prior lines of therapy; 69% were refractory to bortezomib, and 90% were refractory to their last treatment. ORR in the RP2D population was 71% (stringent complete response and complete response: 3% each). Median duration of clinical benefit and median duration of response were both 6.5 months. Median progression-free survival (PFS) was 7.4 months, and median overall survival (OS) was 35.9 months. High-risk patients had comparable ORR and median PFS (67% and 7.7 months, respectively) to non-high-risk patients, whose ORR was 73% and median PFS was 6.9 months, whereas median OS in high-risk patients was 13.9 months and not reached in non-high-risk patients. The most common grade ≥3 hematologic treatment-emergent adverse events (TEAEs) were anemia and thrombocytopenia (17% each); the most common grade ≥3 non-hematologic TEAE was hypertension (19%). In patients with RRMM treated with multiple previous lines of therapy, ibrutinib plus carfilzomib demonstrated anticancer activity within the expected efficacy range. No new safety signals were identified and the combination was well-tolerated.


Activation of procaspases by FK506 binding protein-mediated oligomerization.
Oligomerization is an important biological mechanism for regulating signal transduction. Activation of caspases during apoptosis is triggered by adaptor protein-mediated oligomerization of initiator procaspases. To facilitate the study of initiator caspase activation, a system that allows inducible activation of various caspases both in vitro and in vivo is highly desired. Here we describe such a caspase activation system that is based on FK506 binding protein (FKBP)-mediated oligomerization. The NH(2)-terminal prodomains of initiator procaspases that facilitate the interaction between procaspases and their adaptor proteins are replaced by a derivative of FKBP called Fv. The Fv-caspase fusions can then be dimerized by a synthetic divalent Fv ligand, AP20187, which binds strongly to Fv but weakly to the endogenous FKBPs. This FKBP-based system may be widely applicable to the study of the regulation and functions of caspases.


Early Microglia Activation Precedes Photoreceptor Degeneration in a Mouse Model of CNGB1-Linked Retinitis Pigmentosa.
Retinitis pigmentosa (RP) denotes a family of inherited blinding eye diseases characterized by progressive degeneration of rod and cone photoreceptors in the retina. In most cases, a rod-specific genetic defect results in early functional loss and degeneration of rods, which is followed by degeneration of cones and loss of daylight vision at later stages. Microglial cells, the immune cells of the central nervous system, are activated in retinas of RP patients and in several RP mouse models. However, it is still a matter of debate whether activated microglial cells may be responsible for the amplification of the typical degenerative processes. Here, we used Cngb1-/- mice, which represent a slow degenerative mouse model of RP, to investigate the extent of microglia activation in retinal degeneration. With a combination of FACS analysis, immunohistochemistry and gene expression analysis we established that microglia in the Cngb1-/- retina were already activated in an early, predegenerative stage of the disease. The evidence available so far suggests that early retinal microglia activation represents a first step in RP, which might initiate or accelerate photoreceptor degeneration.


Clustered ChIP-Seq-defined transcription factor binding sites and histone modifications map distinct classes of regulatory elements.
Transcription factor binding to DNA requires both an appropriate binding element and suitably open chromatin, which together help to define regulatory elements within the genome. Current methods of identifying regulatory elements, such as promoters or enhancers, typically rely on sequence conservation, existing gene annotations or specific marks, such as histone modifications and p300 binding methods, each of which has its own biases. Herein we show that an approach based on clustering of transcription factor peaks from high-throughput sequencing coupled with chromatin immunoprecipitation (Chip-Seq) can be used to evaluate markers for regulatory elements. We used 67 data sets for 54 unique transcription factors distributed over two cell lines to create regulatory element clusters. By integrating the clusters from our approach with histone modifications and data for open chromatin, we identified general methylation of lysine 4 on histone H3 (H3K4me) as the most specific marker for transcription factor clusters. Clusters mapping to annotated genes showed distinct patterns in cluster composition related to gene expression and histone modifications. Clusters mapping to intergenic regions fall into two groups either directly involved in transcription, including miRNAs and long noncoding RNAs, or facilitating transcription by long-range interactions. The latter clusters were specifically enriched with H3K4me1, but less with acetylation of lysine 27 on histone 3 or p300 binding. By integrating genomewide data of transcription factor binding and chromatin structure and using our data-driven approach, we pinpointed the chromatin marks that best explain transcription factor association with different regulatory elements. Our results also indicate that a modest selection of transcription factors may be sufficient to map most regulatory elements in the human genome.


The effect of radial head implant length on radiocapitellar articular properties and load transfer within the forearm.
The effect of radial head implant length on forearm biomechanics is not well understood. This study examined the influence of an increase or a decrease in radial head implant length on forearm load transfer as measured by interosseous membrane (IOM) tension and changes in radiocapitellar joint contact properties. An upper extremity simulator was used to examine 6 cadaveric specimens with 5 different radial head implant lengths (-4 mm, -2 mm, anatomically correct, +2 mm, and +4 mm). A load-sensing device was woven into the fibers of IOM to quantify its tension. An interpositional pressure measurement sensor was used to determine radiocapitellar joint contact area and pressure. Axial loads of 160 N were applied to the forearm through active pronation and supination with the elbow fixed at 90 degrees of flexion. Increasing radial head implant length by 4 mm unloaded the IOM in all cases. Decreasing implant length by 4 mm significantly increased the IOM tension (P = 0.005). No significant differences were found in IOM tension between the correct head implant length and the -2 mm implant (P = 0.29). Contact pressure significantly increased with increasing radial head implant length (P = 0.021) and contact area diminished with both an increase and a decrease in radial head implant length, but this was not statistically significant (P = 0.051). Increasing radial head implant length decreased IOM tension and increased radiocapitellar joint contact pressure. These findings illustrate the importance of precise restoration of radial length when performing a radial head replacement. If the native radial head length is difficult to accurately assess, avoid increasing the length of the radial head to prevent detrimental changes in the biomechanics of the forearm and the potential for clinically important radiocapitellar joint pathology.


Acetate and formate stress: opposite responses in the proteome of Escherichia coli.
Acetate and formate are major fermentation products of Escherichia coli. Below pH 7, the balance shifts to lactate; an oversupply of acetate or formate retards growth. E. coli W3110 was grown with aeration in potassium-modified Luria broth buffered at pH 6.7 in the presence or absence of added acetate or formate, and the protein profiles were compared by two-dimensional sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Acetate increased the steady-state expression levels of 37 proteins, including periplasmic transporters for amino acids and peptides (ArtI, FliY, OppA, and ProX), metabolic enzymes (YfiD and GatY), the RpoS growth phase regulon, and the autoinducer synthesis protein LuxS. Acetate repressed 17 proteins, among them phosphotransferase (Pta). An ackA-pta deletion, which nearly eliminates interconversion between acetate and acetyl-coenzyme A (acetyl-CoA), led to elevated basal levels of 16 of the acetate-inducible proteins, including the RpoS regulon. Consistent with RpoS activation, the ackA-pta strain also showed constitutive extreme-acid resistance. Formate, however, repressed 10 of the acetate-inducible proteins, including the RpoS regulon. Ten of the proteins with elevated basal levels in the ackA-pta strain were repressed by growth of the mutant with formate; thus, the formate response took precedence over the loss of the ackA-pta pathway. The similar effects of exogenous acetate and the ackA-pta deletion, and the opposite effect of formate, could have several causes; one possibility is that the excess buildup of acetyl-CoA upregulates stress proteins but excess formate depletes acetyl-CoA and downregulates these proteins.


Type I and Type III Interferons Display Different Dependency on Mitogen-Activated Protein Kinases to Mount an Antiviral State in the Human Gut.
Intestinal epithelial cells (IECs) are constantly exposed to commensal flora and pathogen challenges. How IECs regulate their innate immune response to maintain gut homeostasis remains unclear. Interferons (IFNs) are cytokines produced during infections. While type I IFN receptors are ubiquitously expressed, type III IFN receptors are expressed only on epithelial cells. This epithelium specificity strongly suggests exclusive functions at epithelial surfaces, but the relative roles of type I and III IFNs in the establishment of an antiviral innate immune response in human IECs are not clearly defined. Here, we used mini-gut organoids to define the functions of types I and III IFNs to protect the human gut against viral infection. We show that primary non-transformed human IECs, upon viral challenge, upregulate the expression of both type I and type III IFNs at the transcriptional level but only secrete type III IFN in the supernatant. However, human IECs respond to both type I and type III IFNs by producing IFN-stimulated genes that in turn induce an antiviral state. Using genetic ablation of either type I or type III IFN receptors, we show that either IFN can independently restrict virus infection in human IECs. Importantly, we report, for the first time, differences in the mechanisms by which each IFN establishes the antiviral state. Contrary to type I IFN, the antiviral activity induced by type III IFN is strongly dependent on the mitogen-activated protein kinases signaling pathway, suggesting a pathway used by type III IFNs that non-redundantly contributes to the antiviral state. In conclusion, we demonstrate that human intestinal epithelial cells specifically regulate their innate immune response favoring type III IFN-mediated signaling, which allows for efficient protection against pathogens without producing excessive inflammation. Our results strongly suggest that type III IFN constitutes the frontline of antiviral response in the human gut. We propose that mucosal surfaces, particularly the gastrointestinal tract, have evolved to favor type III IFN-mediated response to pathogen infections as it allows for spatial segregation of signaling and moderate production of inflammatory signals which we propose are key to maintain gut homeostasis.


Physical activity beliefs, barriers, and enablers among postpartum women.
Physical activity during postpartum is both a recommended and an essential contributor to maternal health. Understanding the beliefs, barriers, and enablers regarding physical activity during the postpartum period can more effectively tailor physical activity interventions. The objective of this study was to document self-reported beliefs, barriers, and enablers to physical activity among a cohort of women queried at 3 and 12 months postpartum. Five questions about beliefs and two open-ended questions about their main barriers and enablers regarding physical activity and exercise were asked of 667 women at 3 months postpartum. Among the sample, 530 women answered the same questions about barriers and enablers to physical activity at 12 months postpartum. Agreement on all five beliefs statements was high (>or=89%), indicating that women thought that exercise and physical activity were appropriate at 3 months postpartum, even if they continued to breastfeed. For the cohort, the most common barriers to physical activity at both 3 and 12 months postpartum were lack of time (47% and 51%, respectively) and issues with child care (26% and 22%, respectively). No barrier changed by more than 5% from 3 to 12 months postpartum. For the cohort, the most common enablers at 3 months postpartum were partner support (16%) and desire to feel better (14%). From 3 to 12 months postpartum, only one enabler changed by >5%; women reported baby reasons (e.g., baby older, healthier, not breastfeeding, more active) more often at 12 months than at 3 months postpartum (32% vs. 10%). Environmental/policy and organizational barriers and enablers were reported less often than intrapersonal or interpersonal barriers at both time points. A number of barriers and enablers were identified for physical activity, most of which were consistent at 3 and 12 months postpartum. This study provides information to create more successful interventions to help women be physically active postpartum.


Barriers to the acceptance of electronic medical records by physicians from systematic review to taxonomy and interventions.
The main objective of this research is to identify, categorize, and analyze barriers perceived by physicians to the adoption of Electronic Medical Records (EMRs) in order to provide implementers with beneficial intervention options. A systematic literature review, based on research papers from 1998 to 2009, concerning barriers to the acceptance of EMRs by physicians was conducted. Four databases, "Science", "EBSCO", "PubMed" and "The Cochrane Library", were used in the literature search. Studies were included in the analysis if they reported on physicians' perceived barriers to implementing and using electronic medical records. Electronic medical records are defined as computerized medical information systems that collect, store and display patient information. The study includes twenty-two articles that have considered barriers to EMR as perceived by physicians. Eight main categories of barriers, including a total of 31 sub-categories, were identified. These eight categories are: A) Financial, B) Technical, C) Time, D) Psychological, E) Social, F) Legal, G) Organizational, and H) Change Process. All these categories are interrelated with each other. In particular, Categories G (Organizational) and H (Change Process) seem to be mediating factors on other barriers. By adopting a change management perspective, we develop some barrier-related interventions that could overcome the identified barriers. Despite the positive effects of EMR usage in medical practices, the adoption rate of such systems is still low and meets resistance from physicians. This systematic review reveals that physicians may face a range of barriers when they approach EMR implementation. We conclude that the process of EMR implementation should be treated as a change project, and led by implementers or change managers, in medical practices. The quality of change management plays an important role in the success of EMR implementation. The barriers and suggested interventions highlighted in this study are intended to act as a reference for implementers of Electronic Medical Records. A careful diagnosis of the specific situation is required before relevant interventions can be determined.


Evidence that phospholipase D mediates ADP ribosylation factor-dependent formation of Golgi coated vesicles.
Formation of coatomer-coated vesicles from Golgi-enriched membranes requires the activation of a small GTP-binding protein, ADP ribosylation factor (ARF). ARF is also an efficacious activator of phospholipase D (PLD), an activity that is relatively abundant on Golgi-enriched membranes. It has been proposed that ARF, which is recruited onto membranes from cytosolic pools, acts directly to promote coatomer binding and is in a 3:1 stoichiometry with coatomer on coated vesicles. We present evidence that cytosolic ARF is not necessary for initiating coat assembly on Golgi membranes from cell lines with high constitutive PLD activity. Conditions are also described under which ARF is at most a minor component relative to coatomer in coated vesicles from all cell lines tested, including Chinese hamster ovary cells. Formation of coated vesicles was sensitive to ethanol at concentrations that inhibit the production of phosphatidic acid (PA) by PLD. When PA was produced in Golgi membranes by an exogenous bacterial PLD, rather than with ARF and endogenous PLD, coatomer bound to Golgi membranes. Purified coatomer also bound selectively to artificial lipid vesicles that contained PA and phosphatidylinositol (4,5)-bisphosphate (PIP2). We propose that activation of PLD and the subsequent production of PA are key early events for the formation of coatomer-coated vesicles.


Brain parenchyma involvement as isolated central nervous system relapse of systemic non-Hodgkin lymphoma: an International Primary CNS Lymphoma Collaborative Group report.
Isolated central nervous system (CNS) relapse involving the brain parenchyma is a rare complication of systemic non-Hodgkin lymphoma. We retrospectively analyzed patient characteristics, management, and outcomes of this complication. After complete response to initial non-Hodgkin lymphoma treatment, patients with isolated CNS relapse with the brain parenchyma as initial relapse site were eligible. Patients with isolated CNS relapse involving only the cerebrospinal fluid were not eligible. Information on 113 patients was assembled from 13 investigators; 94 (83%) had diffuse large B-cell lymphoma. Median time to brain relapse was 1.8 years (range, 0.25-15.9 years). Brain relapse was identified by neuroimaging in all patients; in 54 (48%), diagnostic brain tumor specimen was obtained. Median overall survival from date of brain relapse was 1.6 years (95% confidence interval, 0.9-2.6 years); 26 (23%) have survived 3 years or more. Median time to progression was 1.0 year (95% confidence interval, 0.7-1.7 years). Age less than 60 years (P = .006) at relapse and methotrexate use (P = .008) as front-line treatment for brain relapse were significantly associated with longer survival in a multivariate model. Our results suggest systemic methotrexate is the optimal treatment for isolated CNS relapse involving the brain parenchyma. Long-term survival is possible in some patients.


Matriptase-2 suppresses hepcidin expression by cleaving multiple components of the hepcidin induction pathway.
Systemic iron homeostasis is maintained by regulation of iron absorption in the duodenum, iron recycling from erythrocytes, and iron mobilization from the liver and is controlled by the hepatic hormone hepcidin. Hepcidin expression is induced via the bone morphogenetic protein (BMP) signaling pathway that preferentially uses two type I (ALK2 and ALK3) and two type II (ActRIIA and BMPR2) BMP receptors. Hemojuvelin (HJV), HFE, and transferrin receptor-2 (TfR2) facilitate this process presumably by forming a plasma membrane complex with BMP receptors. Matriptase-2 (MT2) is a protease and key suppressor of hepatic hepcidin expression and cleaves HJV. Previous studies have therefore suggested that MT2 exerts its inhibitory effect by inactivating HJV. Here, we report that MT2 suppresses hepcidin expression independently of HJV. In Hjv-/- mice, increased expression of exogenous MT2 in the liver significantly reduced hepcidin expression similarly as observed in wild-type mice. Exogenous MT2 could fully correct abnormally high hepcidin expression and iron deficiency in MT2-/- mice. In contrast to MT2, increased Hjv expression caused no significant changes in wild-type mice, suggesting that Hjv is not a limiting factor for hepcidin expression. Further studies revealed that MT2 cleaves ALK2, ALK3, ActRIIA, Bmpr2, Hfe, and, to a lesser extent, Hjv and Tfr2. MT2-mediated Tfr2 cleavage was also observed in HepG2 cells endogenously expressing MT2 and TfR2. Moreover, iron-loaded transferrin blocked MT2-mediated Tfr2 cleavage, providing further insights into the mechanism of Tfr2's regulation by transferrin. Together, these observations indicate that MT2 suppresses hepcidin expression by cleaving multiple components of the hepcidin induction pathway.


Glycerol inhibits the primary pathways and transforms the secondary pathway of insulin aggregation.
Aggregation of insulin initiated from the monomeric form proceeds via the secondary pathway of fragmentation. It was interesting to find that glycerol had the potential to transform the secondary pathway of aggregation from fragmentation to heterogeneous nucleation in a concentration dependent manner. Such a change in the secondary pathway was manifested by a change in the fibrillar morphology, wherein, longer fibrils were formed in the presence of glycerol. Glycerol could inhibit all the major steps of insulin aggregation. The analysis of the kinetic traces suggested that the inhibitory effect was most significant on the primary pathways, although secondary nucleation and elongation were also inhibited. In fact, at higher glycerol concentrations, the primary pathways were inhibited to such an extent that the majority of the aggregation was now driven by the secondary pathways. Our data suggest that glycerol binds to the early intermediates in the insulin aggregation pathway, and inhibits them from forming the aggregation competent species capable of elongation. As higher order species are formed in the aggregation pathway, the relative stabilization rendered by glycerol diminishes due to the exclusion of glycerol from the interface.


COVID-19 symptoms at hospital admission vary with age and sex: ISARIC multinational study.
The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. International, prospective observational study of 60,109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. 'Typical' symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80%, 79%, 69%; at least one 95%). They were reported less frequently in children (≤18 years: 69%, 48%, 23%; 85%), older adults (≥70 years: 61%, 62%, 65%; 90%), and women (66%, 66%, 64%; 90%; vs men 71%, 70%, 67%; 93%). The most common atypical presentation under 60 years of age was nausea and vomiting, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men.


Attenuation by Tetrahydrocurcumin of Adiposity and Hepatic Steatosis in Mice with High-Fat-Diet-Induced Obesity.
Diet-induced obesity is strongly associated with nonalcoholic fatty-liver disease (NAFLD) and insulin resistance. We aimed to investigate the in vivo therapeutic value of tetrahydrocurcumin (THC) intervention in high-fat-diet (HFD)-induced obesity and hepatic steatosis. C57BL/6 mice were fed an HFD for 10 weeks, and then they received 20 or 100 mg/kg THC along with the HFD for another 10 weeks. Mice fed an HFD for 20 weeks experienced obesity, hepatic steatosis, hyperlipidemia, and insulin resistance. Tetrahydrocurcumin (THC) intervention for 10 weeks significantly reduced adiposity (epididymal-fat weights of 6.6 ± 0.4 g for the HFD-only group and 5.3 ± 0.8 and 5.6 ± 0.7 g for the HFD with 20 mg/kg THC and HFD with 100 mg/kg THC groups, respectively; p < 0.05) via downregulation of adipogenic factors. Inflammatory macrophage infiltration and polarization were decreased by THC in mouse epididymal adipose tissues. In the liver, THC markedly alleviated steatosis by approximately 28-37% ( p < 0.05) via the downregulation of lipogenesis, the activation of AMP-activated protein kinase (AMPK), and the increase of fatty acid oxidation. Elevated blood glucose and insulin resistance were also improved by THC, which might be caused by regulation of the hepatic insulin signaling cascade, gene transcription involved in glucose metabolism, and reduced macrophage infiltration in the liver and adipose tissue. Our results demonstrated the beneficial effects of THC-mediated intervention against obesity and NAFLD as well as other metabolic syndromes, revealing a novel therapeutic use of THC in obese populations.


Biofilm in group A streptococcal necrotizing soft tissue infections.
Necrotizing fasciitis caused by group A streptococcus (GAS) is a life-threatening, rapidly progressing infection. At present, biofilm is not recognized as a potential problem in GAS necrotizing soft tissue infections (NSTI), as it is typically linked to chronic infections or associated with foreign devices. Here, we present a case of a previously healthy male presenting with NSTI caused by GAS. The infection persisted over 24 days, and the surgeon documented the presence of a "thick layer biofilm" in the fascia. Subsequent analysis of NSTI patient tissue biopsies prospectively included in a multicenter study revealed multiple areas of biofilm in 32% of the patients studied. Biopsies associated with biofilm formation were characterized by massive bacterial load, a pronounced inflammatory response, and clinical signs of more severe tissue involvement. In vitro infections of a human skin tissue model with GAS NSTI isolates also revealed multilayered fibrous biofilm structures, which were found to be under the control of the global Nra gene regulator. The finding of GAS biofilm formation in NSTIs emphasizes the urgent need for biofilm to be considered as a potential complicating microbiological feature of GAS NSTI and, consequently, emphasizes reconsideration of antibiotic treatment protocols.


Image super-resolution via sparse representation.
This paper presents a new approach to single-image super-resolution, based on sparse signal representation. Research on image statistics suggests that image patches can be well-represented as a sparse linear combination of elements from an appropriately chosen over-complete dictionary. Inspired by this observation, we seek a sparse representation for each patch of the low-resolution input, and then use the coefficients of this representation to generate the high-resolution output. Theoretical results from compressed sensing suggest that under mild conditions, the sparse representation can be correctly recovered from the downsampled signals. By jointly training two dictionaries for the low- and high-resolution image patches, we can enforce the similarity of sparse representations between the low resolution and high resolution image patch pair with respect to their own dictionaries. Therefore, the sparse representation of a low resolution image patch can be applied with the high resolution image patch dictionary to generate a high resolution image patch. The learned dictionary pair is a more compact representation of the patch pairs, compared to previous approaches, which simply sample a large amount of image patch pairs, reducing the computational cost substantially. The effectiveness of such a sparsity prior is demonstrated for both general image super-resolution and the special case of face hallucination. In both cases, our algorithm generates high-resolution images that are competitive or even superior in quality to images produced by other similar SR methods. In addition, the local sparse modeling of our approach is naturally robust to noise, and therefore the proposed algorithm can handle super-resolution with noisy inputs in a more unified framework.


Comfort evaluation of maternity support garments in a wear trial.
This study aims to evaluate the wear comfort of eight commercially available maternity support garments. The thermophysiological, sensory/tactile and movement comfort were assessed in a wear trial using a 19-item questionnaire. Fourteen pregnant Chinese women aged 32.3 +/- 4.2 years were recruited from a local obstetric clinic. The results show that the tested garments generally provided greater sensory comfort than thermophysiological comfort. The thermophysiological comfort was mainly influenced by the fibre contents and breathability. Significant linear relationships were found between material appearance and hand feel (r = 0.86, p < 0.001), and between non-itchiness and no red mark (r = 0.78, p < 0.001). Movement comfort was influenced by the garment type and style features. Overall, the soft, good-fit, cotton/elastane maternity brief was perceived as the best product. The findings of comfort needs in pregnant women and the effects of various garment attributes would be helpful for the development of maternity support garment design criteria that are required to satisfy critical ergonomic needs. Low back pain during pregnancy is a common and significant health problem. A maternity support garment is regarded as a convenient and safe device to stabilise the lumbar spine so as to relieve pain. However, patient compliance is likely to be affected by discomfort and inconvenience. The results of this study provide guidance for the optimal design of maternity support clothing.


Weighted vest effects on impact forces and joint work during vertical jump landings in men and women.
Weighted vest (WV) use during vertical jump landings (VJL) does not appear to alter peak vertical ground reaction forces (GRF) or peak joint torques. However, WV effects on joint work and sex differences during VJL are not well understood. This study assessed WV effects on vertical GRF and sagittal joint work during VJL in men and women. Twelve men and 12 women performed VJL wearing a WV with zero added mass (unloaded) and with 10% body mass (loaded) while GRF and kinematic data were obtained. Mixed-model analyses of variance (α = 0.05) and effect sizes (ES) were used to assess differences between sexes and/or load conditions. Regardless of sex, greater landing height (p < 0.001; ES = 0.37) and peak vertical GRF (p = 0.001; ES 0.51) occurred when unloaded, while greater landing time (p = 0.001; ES = 0.46) and negative lower extremity work (p < 0.001; ES = 0.41) occurred when loaded through greater negative work about the hip (p = 0.001; ES = 0.27) and ankle (p = 0.020; ES = 0.27). No differences in hip (p = 0.753; ES = 0.03), knee (p = 0.588; ES = 0.07), or ankle (p = 0.580; ES = 0.09) joint displacement were detected between loaded and unloaded conditions. Men exhibited greater landing heights (p < 0.001; ES = 2.49) and greater peak vertical GRF than women (p = 0.007; ES = 1.18), though women exhibited greater negative lower extremity work (p < 0.001; ES = 1.98) than men through greater negative knee (p < 0.001; ES = 1.98) and ankle (p = 0.032; ES = 0.94) work. No sex differences were detected for joint angular displacement about the hip (p = 0.475; ES = 0.30), knee (p = 0.666; ES = 0.18), or ankle (p = 0.084; ES = 0.71). These data revealed a unique load accommodation strategy during VJL with a WV characterized by greater lower extremity joint work performed via increased joint torque despite lesser landing height and peak vertical GRF. Women appear to perform greater lower extremity joint work than men during VJL despite lesser landing height and peak vertical GRF. Current and prospective WV users should be aware of their load accommodation strategy during VJL with an external load. Women may consider developing more refined load accommodation strategies for VJL regardless of whether external loading is applied to avoid performing excessive amounts of lower extremity work.


Expression analysis of TALE family transcription factors during avian development.
The TALE family of homeodomain containing transcription factors consists of the Meis, Prep and Tgif, and the Pbx subfamily of proteins. Several TALE orthologues have been identified in amniotes, but no comprehensive analysis of their expression pattern during embryogenesis has been performed. Here, we report on TALE gene expression in the avian embryo. During embryonic development, Pbx genes are predominantly expressed in the neural ectoderm and paraxial mesoderm, although Pbx3 is restricted to the intermediate and lateral mesoderm, and anterior central nervous system. Members of the Meis, Prep, and Tgif subfamilies are expressed at high levels in the paraxial mesoderm, and display differential expression along the anterior-posterior and dorsoventral axes of the developing neural tube. Overall the expression patterns reported in this study are consistent with the known function of the TALE gene family in controlling early patterning of limb, neural tube and paraxial mesoderm tissues during embryogenesis.


Evaluation of a role for 1,25-dihydroxyvitamin D3 in the pathogenesis and treatment of X-linked hypophosphatemic rickets and osteomalacia.
Although a defect in renal transport of phosphate seems well established as the primary abnormality underlying the pathogenesis of X-linked hypophosphatemic rickets and osteomalacia, several observations indicate that renal phosphate wasting and hypophosphatemia cannot solely account for the spectrum of abnormalities characteristic of this disease. Thus, in the present study, we investigated the potential role of abnormal vitamin D metabolism in the pathogenesis of this disorder and the effect of 1,25-dihydroxyvitamin D(3) therapy on both the biochemical abnormalities characteristic of this disease and the osteomalacia. Four untreated patients, ages 14-30 yr, had normocalcemia (9.22+/-0.06 mg/dl); hypophosphatemia (2.25+/-0.11 mg/dl); a decreased renal tubular maximum for the reabsorption of phosphate per liter of glomerular filtrate (2.12+/-0.09 mg/dl); normal serum immunoreactive parathyroid hormone concentration; negative phosphate balance; and bone biopsy evidence of osteomalacia. The serum 25-hydroxyvitamin D(3) concentration was 33.9+/-7.2 ng/ml and, despite hypophosphatemia, the serum level of 1,25-dihydroxyvitamin D(3) was not increased, but was normal at 30.3+/-2.8 pg/ml. These data suggested that abnormal homeostasis of vitamin D metabolism might be a second defect central to the phenotypic expression of X-linked hypophosphatemic rickets/osteomalacia. This hypothesis was supported by evaluation of the long-term response to pharmacological amounts of 1,25-dihydroxyvitamin D(3) therapy in three subjects. The treatment regimen resulted in elevation of the serum 1,25-dihydroxyvitamin D levels to values in the supraphysiological range. Moreover, the serum phosphate and renal tubular maximum for the reabsorption of phosphate per liter of glomerular filtrate increased towards normal whereas the phosphate balance became markedly positive. Most importantly, however, repeat bone biopsies revealed that therapy had positively affected the osteomalacic component of the disease, resulting in normalization of the mineralization front activity. Indeed, a central role for 1,25-dihydroxyvitamin D(3) in the mineralization of the osteomalacic bone is suggested by the linear relationship between the serum level of this active vitamin D metabolite and the mineralization front activity. We, therefore, suggest that a relative deficiency of 1,25-dihydroxyvitamin D(3) is a factor in the pathogenesis of X-linked hypophosphatemic rickets and osteomalacia and may modulate the phenotypic expression of this disease.


Exploring nest structures of acorn dwelling ants with X-ray microtomography and surface-based three-dimensional visibility graph analysis.
The physical spaces within which organisms live affect their biology and in many cases can be considered part of their extended phenotype. The nests of social insect societies have a fundamental impact on their ability to function as complex superorganisms. Ants in many species excavate elaborate subterranean nests, but others inhabit relatively small pre-formed cavities within rock crevices and hollow seeds. Temnothorax ants, which often nest within acorns, have become a model system for studying collective decision making. While these ants have demonstrated remarkable degrees of rationality and consistent precision with regard to their nest choices, never before has the fine scale internal architecture and spatial organization of their nests been investigated. We used X-ray microtomography to record high-resolution three-dimensional (3D) scans of Temnothorax colonies within their acorns. These data were then quantified using image segmentation and surface-based 3D visibility graph analysis, a new computational methodology for analysing spatial structures. The visibility graph analysis method integrates knowledge from the field of architecture with the empirical study of animal-built structures, thus providing the first methodological cross-disciplinary synergy of these two research areas. We found a surprisingly high surface area and degree of spatial heterogeneity within the acorn nests. Specific regions, such as those associated with the locations of queens and brood, were significantly more conducive to connectivity than others. From an architect's point of view, spatial analysis research has never focused on all-surface 3D movement, as we describe within ant nests. Therefore, we believe our approach will provide new methods for understanding both human design and the comparative biology of habitat spaces.This article is part of the theme issue 'Interdisciplinary approaches for uncovering the impacts of architecture on collective behaviour'.


Adapting State-of-the-Art Deep Language Models to Clinical Information Extraction Systems: Potentials, Challenges, and Solutions.
Deep learning (DL) has been widely used to solve problems with success in speech recognition, visual object recognition, and object detection for drug discovery and genomics. Natural language processing has achieved noticeable progress in artificial intelligence. This gives an opportunity to improve on the accuracy and human-computer interaction of clinical informatics. However, due to difference of vocabularies and context between a clinical environment and generic English, transplanting language models directly from up-to-date methods to real-world health care settings is not always satisfactory. Moreover, the legal restriction on using privacy-sensitive patient records hinders the progress in applying machine learning (ML) to clinical language processing. The aim of this study was to investigate 2 ways to adapt state-of-the-art language models to extracting patient information from free-form clinical narratives to populate a handover form at a nursing shift change automatically for proofing and revising by hand: first, by using domain-specific word representations and second, by using transfer learning models to adapt knowledge from general to clinical English. We have described the practical problem, composed it as an ML task known as information extraction, proposed methods for solving the task, and evaluated their performance. First, word representations trained from different domains served as the input of a DL system for information extraction. Second, the transfer learning model was applied as a way to adapt the knowledge learned from general text sources to the task domain. The goal was to gain improvements in the extraction performance, especially for the classes that were topically related but did not have a sufficient amount of model solutions available for ML directly from the target domain. A total of 3 independent datasets were generated for this task, and they were used as the training (101 patient reports), validation (100 patient reports), and test (100 patient reports) sets in our experiments. Our system is now the state-of-the-art in this task. Domain-specific word representations improved the macroaveraged F1 by 3.4%. Transferring the knowledge from general English corpora to the task-specific domain contributed a further 7.1% improvement. The best performance in populating the handover form with 37 headings was the macroaveraged F1 of 41.6% and F1 of 81.1% for filtering out irrelevant information. Performance differences between this system and its baseline were statistically significant (P<.001; Wilcoxon test). To our knowledge, our study is the first attempt to transfer models from general deep models to specific tasks in health care and gain a significant improvement. As transfer learning shows its advantage over other methods, especially on classes with a limited amount of training data, less experts' time is needed to annotate data for ML, which may enable good results even in resource-poor domains.


Influence of interleukin-2 deficiency on the generation of autoimmune B cells.
The production of auto-antibodies is one of the predominant characteristics of autoimmune disorders. Because IL-2 deficient mice develop autoimmunity, we asked how IL-2 deficiency might impair endogenous mechanisms of B cell tolerance. To this end, we mated BALB/c anti-dsDNA H chain knock-in mice, in which B cells producing anti-dsDNA antibodies are properly regulated, with IL-2 deficient mice and assessed the phenotype of their offspring. IL-2 deficient mice expressing the anti-dsDNA H chain knock-in allele developed anti-dsDNA antibodies of both IgM and IgG isotypes. Production of these antibodies occurred through the disruption of several mechanisms of endogenous tolerance, including deletion, maturational arrest, and follicular exclusion. In summary, our results suggest that IL-2 plays an important role in regulating B cell tolerance.


Determinants of serum adiponectin in persons with and without type 1 diabetes.
Low levels of adiponectin have been related to coronary heart disease, but adiponectin is higher in persons with type 1 diabetes who have an increased rate of coronary disease. In the Coronary Artery Calcification in Type 1 Diabetes Study (2000-2002), the authors investigated potential determinants of elevated adiponectin levels in persons with type 1 diabetes and whether a difference exists compared with nondiabetic persons. Serum adiponectin was measured in 1,393 persons (sex: 48% male; age: 38 (standard deviation: 9) years; diabetes duration: 23 (standard deviation: 9) years; 54% nondiabetic and 46% with type 1 diabetes). Determinants of log-transformed adiponectin levels were evaluated by multiple linear regression analysis with interaction terms to determine whether predictors of adiponectin levels differed by diabetes status. Adiponectin levels were higher in type 1 diabetic than nondiabetic persons (13.5 (standard deviation: 1.0) vs. 8.8 (standard deviation: 1.0) microg/ml; p < 0.0001), adjusting for age, gender, body mass index, and glomerular filtration rate. The final regression model explained 67% of the difference in adiponectin levels between type 1 diabetic and nondiabetic persons. The variables explaining this difference included high density lipoprotein cholesterol, albumin excretion rate, plasminogen activator inhibitor-1, and hemoglobin A1c level. Adiponectin is higher in type 1 diabetic than nondiabetic persons. Although some of the difference can be explained, further study is needed to better understand the relation between elevated adiponectin levels and patient outcomes, including coronary heart disease.


Immunohistochemical evidence for the presence, localization and partial coexistence of insulin, insulin-like growth factor I and relaxin in the protochordate Ciona intestinalis.
The occurrence and coexistence of peptides of the insulin-like growth factor (IGF)/insulin superfamily were investigated in the ovary and gastro-intestinal tract of the protochordate Ciona intestinalis. Antisera specific for mammalian IGF-I, insulin and relaxin were used in a double-immunofluorescence method on paraffin sections and with an immunogold technique on consecutive semi-thin sections. IGF-I and relaxin immunoreactions but no insulin immunoreactions occurred in the ovary and were confined to medium-sized and mature follicle cells. Two subpopulations of reacting follicular cells were present: those containing only IGF-I immunoreactivity (5%) and those containing IGF-I and relaxin immunoreactivities (95%). In the gastro-intestinal tract, IGF-I and insulin immunoreactions coexisted, whereas no relaxin immunoreactions were obtained. Gel chromatography and radioimmunoassay in Ciona ovary revealed IGF-I immunoreactivity in two peaks with apparent molecular masses of approximately 16 kDa and 3 kDa. The present results indicate that (1) the same IGF-I-related peptide probably occurs in gastro-intestinal tract and ovary, (2) three different members of the insulin/IGF family of peptides are probably present in protochordates, (3) different types of coexistence of these peptides seem to exist in protochordates, i.e. an IGF-I-related peptide and an insulin-related peptide in the digestive tract and, as shown previously, in central nervous system, and the IGF-I-related peptide and relaxin in the ovary, (4) an IGF-I-related peptide and relaxin may be involved in oocyte maturation in the protochordate ovary.


Sense of effort and other unpleasant sensations during exercise: clarifying concepts and mechanisms.
The sense of effort is an essential component of all forms of exercise. Although extensively studied, exercise physiologists have failed to reach consensus about whether this sensation is based on afferent sensory feedback or is centrally generated and independent of such feedback. This confusion has led to misunderstandings regarding the neurological mechanisms responsible for the sense of effort as opposed to other specific sensations such as pain and temperature. A mechanism in which the sense of effort is centrally generated and independent of feedback had been proposed more than 150 years ago. However, a more recent concept of sense of effort as a subjective rating of exercise intensity based on various sensations experienced during exercise given by Borg may have caused confusion, especially among exercise physiologists. Many began to use and understand the sense of effort as a sensation that is generated by afferent sensory feedback. The information reviewed in this article, together with the examples given, constitutes a body of evidence in favour of a centrally generated sense of effort. Afferent sensory feedback is important for the conscious awareness of different sensations such as pain and temperature, and plays important roles in the control of homeostasis. However, peripheral sensory feedback does not seem to be important for the generation of the sense of effort. The sense of effort and other specific sensations such as temperature, pain and other muscular sensations present two separate neurological mechanisms. While the former is centrally generated, the latter is based on afferent sensory feedback. An interaction of these sensations is likely the ultimate regulator of exercise performance. However, further investigation is required to fully understand these phenomena.


Is region-of-interest overlap comparison a reliable measure of category specificity?
Analysis of the degree of overlap between functional magnetic resonance imaging-derived regions of interest (ROIs) has been used to assess the functional convergence and/or segregation of category-selective brain areas. An examination of the extant literature reveals no consistent usage for how such overlap is calculated, nor any systematic comparison between different methods. We argue that how ROI overlap is computed, especially the choice of the denominator in the formula, can profoundly affect the results and interpretation of such an analysis. To do this, we compared the overlap of the FFA-FFA (fusiform face area) and FFA-FGA (fusiform Greeble-selective area) in a localizer study testing both Greeble novices and experts. When using a single ROI as the denominator, we found a significant difference in FFA-FFA versus FFA-FGA overlap, consistent with the result of a previous study arguing for face specificity of the FFA [Rhodes, G., Byatt, G., Michie, P. T., & Puce, A. Is the fusiform face area specialized for faces, individuation, or expert individuation? J Cogn Neurosci, 16, 189-203, 2004]. However, these ROI overlap differences disappeared when the denominator combined both of the involved ROIs, and the patterns of such overlap comparisons were dependent on given statistical thresholds. We also found proportionally decreasing FFA-FFA overlap with increasing center-of-FFA distance, resolving an apparent contradiction between the consistency of the location of the FFA and the seemingly low FFA-FFA overlap. Finally, Monte Carlo simulations revealed the most stable formula-the most resistant to ROI size variations-to be the average of the two single-ROI-denominator-based overlap indices. In sum, ROI overlap analysis is not a reliable tool for assessing category specificity, and caution should be exercised with regard to ROI overlap definition, underlying assumptions, and interpretation.


Exercise in Huntington's Disease: Current State and Clinical Significance.
Huntington's disease (HD) is a rare, progressive neurodegenerative disease. Currently, there is no cure for the disease, but treatment may alleviate HD symptoms. In recent years, several exercise training interventions have been conducted in HD patients. In the current article, we review previous studies investigating targeted exercise training interventions in HD patients. We performed a literature search using the PubMed, Scopus, Web of Science, and Google Scholar databases on exercise training interventions in HD patients. Six publications fulfilled the criteria and were included in the review. Exercise training resulted in beneficial effects on cardiovascular and mitochondrial function. Training effects on cognition, motor function, and body composition were less congruent, but a positive effect seems likely. Health-related quality of life during the training interventions was stable. Most studies reported no related adverse events in response to training. Exercise training seems to be safe and feasible in HD patients. However, current knowledge is mainly based on short, small-scale studies and it cannot be transferred to all HD patients. Therefore, longer-term interventions with larger HD patient cohorts are necessary to draw firm conclusions about the potentially positive effects of exercise training in HD patients.


Assessment of visual disability using the WHO disability assessment scale (WHO-DAS-II): role of gender.
To study the role of gender in coping with disability in young visually impaired students attending two schools for blindness. The WHO Disability Assessment Schedule (WHODAS II), 36-Item Interviewer Administered translated Arabic version was used. It evaluates six domains of everyday living in the last 30 days. These domains are: understanding and communicating, getting around, self care, getting along with people, household activities and participation in society. Face-to-face interviews were conducted with 200 students who represented the target population of the study. Binary logistic regression analysis of the scores of the six domains revealed that in all of the domains except getting along with people and coping with school activities, females significantly faced more difficulties in coping with daily life activities than did their male counterparts. Increasing age significantly increased difficulties in coping with school activities. Genetic causes of blindness were associated with increased difficulties. Females face more difficulties in coping with visual disability. Genetic counselling is needed to decrease the prevalence of visual disability. Girls with blindness need additional inputs to help cope with blindness. Early intervention facilitates dealing with school activities of the visually impaired.