Exergaming (XBOX Kinect™) versus traditional gym-based exercise for postural control, flow and technology acceptance in healthy adults: a randomised controlled trial.
The use of exergaming is a potential alternative to traditional methods of balance training, which can be repetitive and somewhat monotonous. The purpose of this study was to assess the effects of exergaming using XBOX Kinect™ versus traditional gym-based exercise with no virtual stimuli (TGB) on postural control, technology acceptance, flow experience and exercise intensity, in young healthy adults. Fifty healthy active adults (age: 33.8 ± 12.7 years, height: 172.9 ± 11.9 cm, weight: 75 ± 15.8 kg) were recruited; 44 completed both baseline and post-intervention data collection. Participants were randomised (blind card) allocation to one of two groups: (1) received balance training using the XBOX Kinect™ and (2) performed traditional gym-based exercise. Exercises were matched for intensity, duration and movement patterns across groups. All participants completed three, 30-minute, exercise sessions a week for four weeks. Postural sway was measured using a Kistler™ Force platform during unipedal standing. Mean heart rate (HR) and rate of perceived exertion (RPE) were collected during each exercise session to determine and verify that intensity of exercise was matched between groups. Technology acceptance was measured with the Unified Theory of Acceptance and Use of Technology (UTAUT) and flow experience with the Flow State Scale (FSS). Heart rate was matched between groups and BORG RPE was significantly lower in the Kinect™ group. There were significant between-group differences in postural sway in the medial-lateral direction and CoP. There were also significant differences in technology acceptance between groups for performance expectancy, social influence and behavioral intention, with higher values in the Kinect exercise group. The flow state scale showed significant differences between the groups on several dimensions, with higher values in the Kinect exercise group. Objective physiological demand of exercise (HR) was matched across groups, but the exergaming group perceived it as being less demanding and of lower intensity. This suggests that exergaming may offer an alternative method of rehabilitation exercise through improved concordance. Balance training in healthy adults using the Kinect is both accepted and intrinsically motivating. Retrospectively registered on 27th July 2016. Trial number NCT02851017.


Smokers' responses to television advertisements about the serious harms of tobacco use: pre-testing results from 10 low- to middle-income countries.
While television advertisements (ads) that communicate the serious harms of smoking are effective in prompting quitting-related thoughts and actions, little research has been conducted among smokers in low- to middle-income countries to guide public education efforts. 2399 smokers aged 18-34 years in 10 low- to middle-income countries (Bangladesh, China, Egypt, India, Indonesia, Mexico, Philippines, Russia, Turkey and Vietnam) viewed and individually rated the same five anti-smoking ads on a standard questionnaire and then engaged in a structured group discussion about each ad. Multivariate logistic regression analysis, with robust SEs to account for the same individual rating multiple ads, was performed to compare outcomes (message acceptance, perceived personalised effectiveness, feel uncomfortable, likelihood of discussing the ad) across ads and countries, adjusting for covariates. Ads by country interactions were examined to assess consistency of ratings across countries. Three ads with graphic imagery performed consistently highly across all countries. Two of these ads showed diseased human tissue or body parts, and a third used a disgust-provoking metaphor to demonstrate tar accumulation in smokers' lungs. A personal testimonial ad performed more variably, as many smokers did not appreciate that the featured woman's lung cancer was due to smoking or that her altered physical appearance was due to chemotherapy. An ad using a visual metaphor for lung disease was also more variable, mostly due to lack of understanding of the term 'emphysema'. Television ads that graphically communicate the serious harms of tobacco use are likely to be effective with smokers in low- to middle-income countries and can be readily translated and adapted for local use. Ads with complex medical terms or metaphors, or those that feature personal testimonials, are more variable and at least require more careful pre-testing and adaptation to maximise their potential.


The durability of public goods changes the dynamics and nature of social dilemmas.
An implicit assumption underpins basic models of the evolution of cooperation, mutualism and altruism: The benefits (or pay-offs) of cooperation and defection are defined by the current frequency or distribution of cooperators. In social dilemmas involving durable public goods (group resources that can persist in the environment-ubiquitous from microbes to humans) this assumption is violated. Here, we examine the consequences of relaxing this assumption, allowing pay-offs to depend on both current and past numbers of cooperators. We explicitly trace the dynamic of a public good created by cooperators, and define pay-offs in terms of the current public good. By raising the importance of cooperative history in determining the current fate of cooperators, durable public goods cause novel dynamics (e.g., transient increases in cooperation in Prisoner's Dilemmas, oscillations in Snowdrift Games, or shifts in invasion thresholds in Stag-hunt Games), while changes in durability can transform one game into another, by moving invasion thresholds for cooperation or conditions for coexistence with defectors. This enlarged view challenges our understanding of social cheats. For instance, groups of cooperators can do worse than groups of defectors, if they inherit fewer public goods, while a rise in defectors no longer entails a loss of social benefits, at least not in the present moment (as highlighted by concerns over environmental lags). Wherever durable public goods have yet to reach a steady state (for instance due to external perturbations), the history of cooperation will define the ongoing dynamics of cooperators.


Discrimination between incomplete and atypical Kawasaki syndrome versus other febrile diseases in childhood: results from an international registry-based study.
Kawasaki syndrome (KS) is an acute systemic vasculitis of unknown origin predominantly affecting young children. Early diagnosis is crucial to prevent cardiac complications. However, the differential diagnosis of patients with the incomplete or atypical form of the disease poses a heavy challenge for the paediatrician. Our aim was to evaluate the prevalence of incomplete and atypical cases among children with KS and to identify clinical and laboratory variables that may help differentiate incomplete and atypical KS from other febrile diseases at this age. We established an international registry to recruit patients with KS, including those with incomplete and atypical forms. The control group included age-matched febrile children admitted to the hospital with a variety of diseases mimicking KS. The aim was to define clinical or laboratory clues to help in the discrimination of incomplete and atypical KS patients from others. Two hundred and twenty-eight patients with incomplete KS (78%) and atypical KS (22%) were compared to 71 children with other febrile diseases. Patients with incomplete and atypical KS presented a statistically significant higher frequency of mucosal changes, conjunctivitis, extremity abnormalities and perineal desquamation compared to the group of other febrile diseases. In addition, C-reactive protein and platelet counts were significantly higher in incomplete and atypical KS compared to the other group. This is the largest series of incomplete and atypical KS patients of non East-Asian ancestry: we suggest that in patients with the aforementioned clinical features and laboratory evidence of systemic inflammation in terms of increased C-reactive protein and platelet counts an echocardiogram should be performed and diagnosis of KS considered.


A community-based obesity prevention program for minority children: rationale and study design for Hip-Hop to Health Jr.
BACKGROUND; The increasing prevalence of overweight among children in the United States presents a national health priority. Higher rates of overweight/obesity among minority women place their children at increased risk. Although increased rates of overweight are observed in 4- to 5-year-old children, they are not observed in 2- to 3-year-old children. Therefore, early prevention efforts incorporating families are critical. The primary aim of Hip-Hop to Health Jr. is to alter the trajectory toward overweight/obesity among preschool African-American and Latino children. This 5-year randomized intervention is conducted in 24 Head Start programs, where each site is randomized to either a 14-week dietary/physical activity intervention or a general health intervention. This paper presents the rationale and design of the study. Efficacy of the intervention will be determined by weight change for the children and parent/caretaker. Secondary measures include reductions in dietary fat and increases in fiber, fruit/vegetable intake, and physical activity. Baseline data will be presented in future papers. The problem of overweight/obesity is epidemic in the United States. Behaviors related to diet and physical activity are established early in life and modeled by family members. Early intervention efforts addressing the child and family are needed to prevent obesity later in life. This paper describes a comprehensive, family-oriented obesity prevention program for minority preschool children.


Phase transition in crowd synchrony of delay-coupled multilayer laser networks.
An analogy between crowd synchrony and multi-layer neural network architectures is proposed. It indicates that many non-identical dynamical elements (oscillators) communicating indirectly via a few mediators (hubs) can synchronize when the number of delayed couplings to the hubs or the strength of the couplings is large enough. This phenomenon is modeled using a system of semiconductor lasers optically delay-coupled in either a fully connected or a diluted manner to a fixed number of non-identical central hub lasers. A universal phase transition to crowd synchrony with hysteresis is observed, where the time to achieve synchronization diverges near the critical coupling independent of the number of hubs.


The immediate influence of various whole-body vibration frequency on balance and walking ability in children with cerebral palsy: a pilot study.
The purpose of this pilot study is to examine the immediate effect of interventions based on the frequency of whole-body vibration on children with cerebral palsy's balance and walking abilities. A total of 12 were selected as subjects. All subjects measured 10-m walking test (10MWT), Timed Up and Go (TUG) test and measured sway length (SL) and limit of stability (LOS) by bio-rescue. And those were performed again after the frequencies of the 12, 18, and 26 Hz were applied respectively. To check the immediate effect, all subjects performed only one frequency of interventions per day and no other treatment was performed in parallel to control the foreign variables. After intervention, 10MWT were significantly increased in the 12 and 18 Hz groups (P<0.05). TUG test and LOS were significantly increased in the 18 Hz group (P<0.05). There were no significant differences on TUG, SL, and LOS in the 12 Hz group. There were no significant differences on 10MWT, TUG, SL, and LOS in the 26 Hz group. Looking at the results of this study, the immediate effect of whole-body vibration shows that the frequency of the 18 Hz group is the most effective interventions in promoting walking and balancing abilities in children with cerebral palsy than frequencies of the 12 and 26 Hz groups.


Comparison of fibrinogen- and collagen-based treatments for penetrating wounds with comminuted femur fractures in a Swine model.
Military servicemembers in combat operations often sustain injuries to the extremities from highspeed projectiles, resulting in bleeding and comminuted open fractures. Severe injury with bone fragmentation can result in limb amputation. Surgical treatment options include materials that promote osteogenesis and bone proliferation, such as growth hormones, stem cells, or mineralized matrix adjuncts. However, none of these are amenable to use by the first responder, nor do they address the question of hemorrhage control, which is a common problem in traumatic injuries. Our hypothesis was that treatment with a fibrinogen-based protein mixture at the time of the bone injury will provide both hemostasis and a supportive environment for preservation of injured bone. A comminuted femur fracture was produced in 28 female Yorkshire swine, and one of four treatments was instilled into the wound immediately after injury. Each animal was evaluated for the following parameters: inflammation, new bone growth, osteoclast proliferation, callus formation, and femur wound cavity fill, using post-mortem computed tomography and analysis of histological sections. Overall, salmon fibrinogen?thrombin and porcine fibrinogen?thrombin showed a trend for improved healing based on bone filling and calcification. However, statistically significant differences could not be established between treatment groups. These findings indicate that a fibrinogen?thrombin matrix may be a useful as an immediate response product to enhance fracture healing. Salmon fibrinogen?thrombin has the advantages of cost and a pathogen profile compared to mammalian fibrinogens.


Fear conditioning induced by interpersonal conflicts in healthy individuals.
Psychophysiological markers have been focused to investigate the psychopathology of psychiatric disorders and personality subtypes. In order to understand neurobiological mechanisms underlying these conditions, fear-conditioning model has been widely used. However, simple aversive stimuli are too simplistic to understand mechanisms because most patients with psychiatric disorders are affected by social stressors. The objective of this study was to test the feasibility of a newly-designed conditioning experiment using a stimulus to cause interpersonal conflicts and examine associations between personality traits and response to that stimulus. Twenty-nine healthy individuals underwent the fear conditioning and extinction experiments in response to three types of stimuli: a simple aversive sound, disgusting pictures, and pictures of an actors' face with unpleasant verbal messages that were designed to cause interpersonal conflicts. Conditioned response was quantified by the skin conductance response (SCR). Correlations between the SCR changes, and personality traits measured by the Zanarini Rating Scale for Borderline Personality Disorder (ZAN-BPD) and Revised NEO Personality Inventory were explored. The interpersonal conflict stimulus resulted in successful conditioning, which was subsequently extinguished, in a similar manner as the other two stimuli. Moreover, a greater degree of conditioned response to the interpersonal conflict stimulus correlated with a higher ZAN-BPD total score. Fear conditioning and extinction can be successfully achieved, using interpersonal conflicts as a stimulus. Given that conditioned fear caused by the interpersonal conflicts is likely associated with borderline personality traits, this paradigm could contribute to further understanding of underlying mechanisms of interpersonal fear implicated in borderline personality disorder.


The age of a unique event polymorphism.
We develop a Markov chain Monte Carlo approach for estimating the distribution of the age of a mutation that is assumed to have arisen just once in the history of the population of interest. We assume that in addition to the presence or absence of this mutation in a sample of chromosomes, we have DNA sequence data from a region completely linked to the mutant site. We apply our method to a mitochondrial data set in which the DNA sequence data come from hypervariable region I and the mutation of interest is the 9-bp region V deletion.


Treatable inherited rare movement disorders.
There are many rare movement disorders, and new ones are described every year. Because they are not well recognized, they often go undiagnosed for long periods of time. However, early diagnosis is becoming increasingly important. Rapid advances in our understanding of the biological mechanisms responsible for many rare disorders have enabled the development of specific treatments for some of them. Well-known historical examples include Wilson disease and dopa-responsive dystonia, for which specific and highly effective treatments have life-altering effects. In recent years, similarly specific and effective treatments have been developed for more than 30 rare inherited movement disorders. These treatments include specific medications, dietary changes, avoidance or management of certain triggers, enzyme replacement therapy, and others. This list of treatable rare movement disorders is likely to grow during the next few years because a number of additional promising treatments are actively being developed or evaluated in clinical trials. © 2017 International Parkinson and Movement Disorder Society.


Ki-67 expression in relation to clinicopathological variables and prognosis in colorectal adenocarcinomas.
Ki-67 is a protein associated with cell proliferation which is expressed in all phases of the cell cycle except Go. In the present study, Ki-67 expression in 255 human colorectal adenocarcinomas was examined using immunohistochemistry with the monoclonal antibody MIB-1. One hundred and fifty-seven (62%) cases had more than 50% positive tumour cells and 98 (38%) cases less than 50%. The tumours showed a wide range of Ki-67 expression, from 13% to 90%, which indicated a variation in proliferative activity. There was no significant relationship between Ki-67 expression and sex, age, tumour location, Dukes' stage, growth pattern, differentiation, DNA content, S-phase fraction or survival (p > 0.05). In conclusion, the proliferative activity as measured by Ki-67 antibody was not related to clinicopathology and prognosis in colorectal cancer.


Histone 3 lysine 9 (H3K9) methyltransferase recruitment to the interleukin-2 (IL-2) promoter is a mechanism of suppression of IL-2 transcription by the transforming growth factor-β-Smad pathway.
Suppression of IL-2 βproduction from T cells is an important process for the immune regulation by TGF-β. However, the mechanism by which this suppression occurs remains to be established. Here, we demonstrate that Smad2 and Smad3, two major TGF-β-downstream transcription factors, are redundantly essential for TGF-β-mediated suppression of IL-2 production in CD4(+) T cells using Smad2- and Smad3-deficient T cells. Both Smad2 and Smad3 were recruited into the proximal region of the IL-2 promoter in response to TGF-β. We then investigated the histone methylation status of the IL-2 promoter. Although both histone H3 lysine 9 (H3K9) and H3K27 trimethylation have been implicated in gene silencing, only H3K9 trimethylation was increased in the proximal region of the IL-2 promoter in a Smad2/3-dependent manner, whereas H3K27 trimethylation was not. The H3K9 methyltransferases Setdb1 and Suv39h1 bound to Smad3 and suppressed IL-2 promoter activity in collaboration with Smad3. Overexpression of Suv39h1 in 68-41 T cells strongly inhibited IL-2 production in response to T cell receptor stimulation irrespective of the presence or absence of TGF-β, whereas Setdb1 overexpression only slightly suppressed IL-2 production. Silencing of Suv39h1 by shRNA reverted the suppressive effect of TGF-β on IL-2 production. Furthermore, TGF-β induced Suv39h1 recruitment to the proximal region of the IL-2 promoter in wild type primary T cells; however, this was not observed in Smad2(-/-)Smad3(+/-) T cells. Thus, we propose that Smads recruit H3K9 methyltransferases Suv39h1 to the IL-2 promoter, thereby inducing suppressive histone methylation and inhibiting T cell receptor-mediated IL-2 transcription.


A Narrative Review of Influenza: A Seasonal and Pandemic Disease.
Influenza is an acute respiratory disease caused by the influenza A or B virus. It often occurs in outbreaks and epidemics worldwide, mainly during the winter season. Significant numbers of influenza virus particles are present in the respiratory secretions of infected persons, so infection can be transmitted by sneezing and coughing via large particle droplets. The mean duration of influenza virus shedding in immunocompetent adult patients is around 5 days but may continue for up to 10 days or more-particularly in children, elderly adults, patients with chronic illnesses, and immunocompromised hosts. Influenza typically begins with the abrupt onset of high-grade fever, myalgia, headache, and malaise. These manifestations are accompanied by symptoms of respiratory tract illnesses such as nonproductive cough, sore throat, and nasal discharge. After a typical course, influenza can affect other organs such as the lungs, brain, and heart more than it can affect the respiratory tract and cause hospitalization. The best way to prevent influenza is to administer annual vaccinations. Among severely ill patients, an early commencement of antiviral treatment (<2 d from illness onset) is associated with reduced morbidity and mortality, with greater benefits allied to an earlier initiation of treatment. Given the significance of the disease burden, we reviewed the latest findings in the diagnosis and management of influenza.


Maslinic acid derivatives induce significant apoptosis in b16f10 murine melanoma cells.
Maslinic acid (2α,3β-dihydroxyolean-12-en-28-oic acid), a natural dihydroxylated pentacyclic triterpene acid isolated from olive-pressing residues, has been investigated together with some of its derivatives regarding the induction of apoptosis in B16F10 melanoma cells. Some of the compounds tested are described in this work, but others come from previous studies. Ten of these derivatives induce over 80% of apoptosis, clearly promoting cell death in B16F10 melanoma. By contrast, the induction cell death through necrosis was very slightly significant with these compounds. These results indicate that maslinic acid derivatives are promising chemopreventive and chemotherapeutic agents.


Associations Between Mistreatment by a Provider during Childbirth and Maternal Health Complications in Uttar Pradesh, India.
Objectives This study assesses associations between mistreatment by a provider during childbirth and maternal complications in Uttar Pradesh, India. Methods Cross-sectional survey data were collected from women (N = 2639) who had delivered at 68 public health facilities in Uttar Pradesh, participating in a quality of care study. Participants were recruited from April to July 2015 and surveyed on demographics, mistreatment during childbirth (measure developed for this study, Cronbach's alpha = 0.70), and maternal health complications. Regression models assessed associations between mistreatment during childbirth and maternal complications, at delivery and postpartum, adjusting for demographics and pregnancy complications. Results Participants were aged 17-48 years, and 30.3% were scheduled caste/scheduled tribe. One in five (20.9%) reported mistreatment by their provider during childbirth, including discrimination and abuse; complications during delivery (e.g., obstructed labor) and postpartum (e.g., excessive bleeding) were reported by 45.8 and 41.5% of women, respectively. Health providers at delivery included staff nurses (81.8%), midwives (14.0%), and physicians (2.2%); Chi square analyses indicate that women were significantly more likely to report mistreatment when their provider was a nurse rather than a physician or midwife. Women reporting mistreatment by a provider during childbirth had higher odds of complications at delivery (AOR = 1.32; 95% CI 1.05-1.67) and postpartum (AOR = 2.12; 95% CI 1.67-2.68). Conclusions for Practice Mistreatment of women by their provider during childbirth is a pervasive health and human rights violation, and is associated with increased risk for maternal health complications in Uttar Pradesh. Efforts to improve quality of maternal care should include greater training and monitoring of providers to ensure respectful treatment of patients.


The TRPM6/EGF pathway is downregulated in a rat model of cisplatin nephrotoxicity.
Cisplatin-induced hypomagnesemia is described in humans and rats, but the underlying mechanisms are still unclear. Recent studies have shown that epidermal growth factor (EGF) stimulates Mg(2+) re-absorption in the distal convoluted tubule via the Mg(2+) channel TRPM6. This study investigates the role of TRPM Mg(2+) channels, claudines, and EGF in the Mg(2+) homeostasis in a rat model of cisplatin-induced nephrotoxicity. Wistar rats were given 2.5 mg/kg cisplatin per week for 3 weeks and were euthanized 4 or 9 weeks after the first administration. The cisplatin treatment significantly increased the fractional excretion of Mg(2+). Real-time RT-PCR and/or Western blots were performed to assess the renal expression TRPM6, TRPM7, claudin-16, claudin-19, EGF, EGF receptor (EGFR) and EGFR-pathway components. The renal mRNA expression of TRPM6 and EGF showed a significant decrease after cisplatin treatment, while the TRPM7, claudin-16 and EGFR expressions remained stable. The claudin-19 mRNA expression was significantly upregulated after cisplatin treatment. Western blotting confirmed the mRNA expression data for the claudins, but an showed upregulation of EGFR only at week 9. The role of the EGFR pathway, involving Pi3-AKT-Rac1, in cisplatin-induced nephropathy, could not be substantiated in further detail. This study shows that cisplatin treatment results in EGF and TRPM6 downregulation in the rat kidney, causing renal Mg(2+) loss. Our results are in line with the hypothesis that EGF influences the renal expression or activation of TRPM6 and plays a significant role in Mg(2+) loss in medication-induced nephropathy.


Adolescent treatment initiation and engagement in an evidence-based practice initiative.
This study examined client and program factors predicting initiation and engagement for 2,191 adolescents at 28 outpatient substance abuse treatment sites implementing evidence-based treatments. Using Washington Circle criteria for treatment initiation and engagement, 76% of the sample initiated, with 59% engaging in treatment. Analyses used a 2-stage Heckman probit regression, accounting for within-site clustering, to identify factors predictive of initiation and engagement. Adolescents treated in a pay-for-performance (P4P) group were more likely to initiate, whereas adolescents in the race/ethnicity category labeled other (Native American, Asian, Pacific Islander, Native Alaskan, Native Hawaiian, mixed race/ethnicity), or who reported high truancy, were less likely to initiate. Race/ethnicity groups other than Latinos were equally likely to engage. Among White adolescents, each additional day from first treatment to next treatment reduced likelihood of engagement. Although relatively high initiation and engagement rates were achieved, the results suggest that attention to program and client factors may further improve compliance with these performance indicators.


[Merkel cell carcinoma--immunohistochemical study in a group of 11 patients].
The aim of our work was to confirm an immunohistochemical profile of routine markers of epithelial and neuroendocrine differentiation in eleven cases of Merkel cell carcinoma, as well as to study the expression of two markers of early phases of neuronal differentiation, namely reelin and class III beta-tubulin, markers which have not yet been studied in Merkel cell carcinomas. In all the investigated tumours the characteristic "dot-like" pattern of cytokeratin 20 immunoexpression, as well as negative immunostaining for cytokeratin 7 and thyroid transcription factor 1 (TTF-1) were disclosed; all the tumours showed neuroendocrine differentiation, expressing either neuron specific enolase (NSE) or chromogranin A(CgA), or both. An interesting finding was observed when the anti-cytokeratin monoclonal antibody MNF 116 was used. The characteristic "dot-like" pattern was detected in high proportion of tumours, including two samples of local recurrence of one of the carcinomas, where neoplastic cells have lost the expression of cytokeratin 20. The majority (91%) of Merkel cell carcinomas included in our group showed positive immunodetection of class III beta-tubulin when TU-20 antibody was used, while TuJ-1 immunostaining was surprisingly negative in all the investigated tumours. Detection of reelin was negative in almost all the studied Merkel cell carcinomas except for cases, where neoplastic cells revealed weak focal immunostaining in a minor portion of neoplastic cells.


Pulsed-field profile diversities of Salmonella Enteritidis, S. Infantis, and S. Corvallis in Japan.
The diversity of pulsed-field profiles (PFPs) within non-typhoidal Salmonella subtypes influences epidemiological analyses of Salmonella outbreaks. Therefore, determining the PFP diversity of each Salmonella serovar is important when evaluating current circulating strains. This study examined the PFP diversity of three important public health Salmonella enterica subspecies enterica serovars, S. Enteritidis (n=177), S. Infantis (n=205), and S. Corvallis (n=90), using pulsed-field gel electrophoresis. Isolates were collected from several sources, primarily from chicken-derived samples, in the Kyushu-Okinawa region of Japan between 1989 and 2005. S. Enteritidis isolates displayed 51 distinct PFPs (E-PFPs), with 92 (52.0%) and 32 (18.1%) isolates displaying types E-PFP1 and E-PFP10, respectively. The 205 S. Infantis isolates showed 54 distinct PFPs (I-PFPs), with 87 (42.4%) and 36 (17.6%) isolates being I-PFP4 and I-PFP2, respectively. I-PFP18 was the dominant I-PFP of layer chicken isolates across a 5-year period. Fourteen distinct S. Corvallis PFPs were detected. Simpson's index results for the genetic diversities of S. Enteritidis, S. Infantis, and S. Corvallis isolates were 0.70, 0.79, and 0.78, respectively. None of the E-PFPs or I-PFPs of layer chicken isolates overlapped with those of broiler chicken isolates, and the dominant clonal lines existed for >10 years. In conclusion, limited PFP diversities were detected amongst S. Enteritidis, S. Infantis, and S. Corvallis isolates of primarily chicken-derived origins in the Kyushu-Okinawa region of Japan. Therefore, it is important to take into account these limitations in PFP diversities in epidemiological analyses of Salmonella outbreaks.


Image informatics at a national research center.
Image informatics at the Communications Engineering Branch of the Lister Hill National Center for Biomedical Communications (LHNCBC), an R&D division of the National Library of Medicine (NLM), includes document and biomedical images. In both domains, research into computer-assisted methods for information extraction, and the implementation of prototype systems incorporating such methods, is central to our mission. Current document image research focuses on extracting bibliographic data from scanned journal articles. Current biomedical imaging work focuses on content-based image retrieval (CBIR) and related problems in segmentation, indexing, and classifying collections of images of the spine and of the uterine cervix.


A microfluidic biochip platform for electrical quantification of proteins.
Sepsis, an adverse auto-immune response to an infection often causing life-threatening complications, results in the highest mortality and treatment cost of any illness in US hospitals. Several immune biomarker levels, including Interleukin 6 (IL-6), have shown a high correlation to the onset and progression of sepsis. Currently, no technology diagnoses and stratifies sepsis progression using biomarker levels. This paper reports a microfluidic biochip platform to detect proteins in undiluted human plasma samples. The device uses a differential enumeration platform that integrates Coulter counting principles, antigen specific capture chambers, and micro size bead based immunodetection to quantify cytokines. This microfluidic biochip was validated as a potential point of care technology by quantifying IL-6 from plasma samples (n = 29) with good correlation (R2 = 0.81) and agreement (Bland-Altman) compared to controls. In combination with previous applications, this point of care platform can potentially detect cell and protein biomarkers simultaneously for sepsis stratification.


Cryptococcal choroidoretinitis and immunodeficiency.
A 30 year old man with Hodgkin's disease, clinically in remission, presented with blurred vision in one eye due to a choroiditis. He developed headaches 10 days after commencing oral steroids and was subsequently found to have cryptococcal meningitis. The meningitis and choroiditis resolved on antifungal medication. This is the first case of cryptococcal choroiditis recorded in the United Kingdom.


Is cancer dangerous to the immune system?
The hypothesis of immunologic surveillance of neoplasia is predicated on the theory that the immune system is capable of discriminating self from foreign antigens, and that tumor-specific antigens are regarded by the immune system as nonself. We propose here an alternate view, that the immune system has evolved to detect danger by employing 'professional' antigen-presenting cells as sentinels of tissue distress. In this model, cancers do not appear dangerous to the immune system, so that the default response of T cells to tumors is to be turned off. We discuss the implications for immunotherapy of malignancy.


Development of Sarcocystis falcatula in its intermediate host, the Brown-headed Cowbird (Molothrus ater).
Sporocysts of Sarcocystis falcatula obtained from experimentally infected Virginia opossums (Didelphis virginiana) were inoculated orally to 60 wild-caught Brown-headed Cowbirds (Molothrus ater). Another 30 Brown-headed Cowbirds were not challenged and served as uninfected controls. Two inoculated and one control cowbird were necropsied every 2 weeks and the pectoral and thigh muscles were examined grossly for cyst development. Stained histologic sections of pectoral muscle, thigh muscle, and lung were examined by light microscopy and presence, density, and size of sarcocysts were determined. Sarcocysts were present by 6 weeks post-inoculation (PI) and were still growing at 40 weeks PI. The sarcocysts from birds 40 weeks post-infection were infective to an opossum. The morphology of the sarcocyst wall by transmission electron microscopy substantiated the identification as S. falcatula. Lung sections were examined for the presence of schizonts, but were seen only at 2 weeks PI. This evaluation was complicated by the presence of unidentified microfilariae. These birds are migratory and the continued growth and development of muscle cysts would allow them to be a source of infection at both extremes of their geographic range, regardless of which end of the migration at which they were infected.


BRACHYURY directs histone acetylation to target loci during mesoderm development.
T-box transcription factors play essential roles in multiple aspects of vertebrate development. Here, we show that cooperative function of BRACHYURY (T) with histone-modifying enzymes is essential for mouse embryogenesis. A single point mutation (TY88A) results in decreased histone 3 lysine 27 acetylation (H3K27ac) at T target sites, including the T locus, suggesting that T autoregulates the maintenance of its expression and functions by recruiting permissive chromatin modifications to putative enhancers during mesoderm specification. Our data indicate that T mediates H3K27ac recruitment through a physical interaction with p300. In addition, we determine that T plays a prominent role in the specification of hematopoietic and endothelial cell types. Hematopoietic and endothelial gene expression programs are disrupted in TY88A mutant embryos, leading to a defect in the differentiation of hematopoietic progenitors. We show that this role of T is mediated, at least in part, through activation of a distal Lmo2 enhancer.


Traumatic brain injuries from work accidents: a retrospective study.
The United Arab Emirates is a rapidly developing country with recent expansion in construction and manufacturing. To investigate the occurrence and outcomes following occupational traumatic brain injury (TBI) requiring hospital admission. Records for all TBI cases admitted to an Abu Dhabi hospital between 2005 and 2009 were reviewed. Data on mechanisms of occupational injuries, Glasgow Coma Scale (GCS) on admission and Glasgow Outcome Scale (GOS) on follow-up, were analysed. Of 581 TBI cases reviewed, 56 (10%) cases were reported as occupational by either the patient or the informant accompanying the patient. All cases were male migrants, and 63% were aged 25-44. Falls accounted for 63% of cases, falling objects 34% and motor vehicle collisions 4%. Median GCS score was 13 for all cases. Median hospital stay was 7.5 days. Intensive care unit admission data were available in 47 cases, of which 34% (16) were admitted with a median stay of 5 days. GOS data were available in 95% (53) of cases, with good recovery in 81% cases, moderate-to-severe disability in 11% of cases and death in 8% (4) cases. Occupational TBI requiring hospitalization is most frequently due to falls and falling objects, with potentially grave consequences. This study further highlights the urgent need to implement preventative measures to improve construction worker safety.


DaT-SPECT assessment depicts dopamine depletion among asymptomatic G2019S LRRK2 mutation carriers.
Identification of early changes in Dopamine-Transporter (DaT) SPECT imaging expected in the prodromal phase of Parkinson's disease (PD), are usually overlooked. Carriers of the G2019S LRRK2 mutation are known to be at high risk for developing PD, compared to non-carriers. In this work we aimed to study early changes in Dopamine uptake in non-manifesting PD carriers (NMC) of the G2019S LRRK2 mutation using quantitative DaT-SPECT analysis and to examine the potential for early prediction of PD. Eighty Ashkenazi-Jewish subjects were included in this study: eighteen patients with PD; thirty-one NMC and thirty-one non-manifesting non-carriers (NMNC). All subjects underwent a through clinical assessment including evaluation of motor, olfactory, affective and non-motor symptoms and DaT-SPECT imaging. A population based DaT-SPECT template was created based on the NMNC cohort, and data driven volumes-of-interest (VOIs) were defined. Comparisons between groups were performed based on VOIs and voxel-wise analysis. The striatum area of all three cohorts was segmented into four VOIs, corresponding to the right/left dorsal and ventral striatum. Significant differences in clinical measures were found between patients with PD and non-manifesting subjects with no differences between NMC and NMNC. Significantly lower uptake (p<0.001) was detected in the right and left dorsal striatum in the PD group (2.2±0.3, 2.3±0.4) compared to the NMC (4.2±0.6, 4.3±0.5) and NMNC (4.5±0.6, 4.6±0.6), and significantly (p = 0.05) lower uptake in the right dorsal striatum in the NMC group compared to NMNC. Converging results were obtained using voxel-wise analysis. Two NMC participants, who later phenoconverted into PD, demonstrated reduced uptake mainly in the dorsal striatum. No significant correlations were found between the DaT-SPECT uptake in the different VOIs and clinical and behavioral assessments in the non-manifesting groups. This study shows the clinical value of quantitative assessment of DaT-SPECT imaging and the potential for predicting PD by detection of dopamine depletion, already at the pre-symptomatic stage. Clinical registration numbers: NCT01089270 and NCT01089283.


The efficacy and safety of muscle relaxants in inflammatory arthritis: a Cochrane systematic review.
To determine the efficacy and safety of muscle relaxants in pain management in patients with inflammatory arthritis (IA). We searched the Cochrane Central Register of Controlled Trials, Medline, Embase, and PsychINFO for randomized controlled trials in adults with IA that compared any muscle relaxant (administered via any route) to another analgesic intervention or placebo. We also searched the 2008-2009 American College of Rheumatology and European League Against Rheumatism abstracts and performed a hand search of reference lists of relevant articles. Primary outcomes were patient-reported pain relief ≥ 30% and withdrawals due to adverse events. Two authors independently assessed methodological quality and extracted data. Six trials (126 participants) were included in this review. All trials were deemed to have a high risk of bias. Five crossover trials evaluated benzodiazepine; 4 assessed diazepam (n = 71), and one assessed triazolam (n = 15). The sixth trial, a parallel-group study, evaluated zopiclone (non-benzodiazepine, n = 40). No trial was longer than 2 weeks and 3 single-dose trials assessed outcomes at 24 hours only. Overall, the included trials failed to find evidence of a beneficial effect of muscle relaxants over placebo (at 24 hours, 1 week, or 2 weeks) or in addition to nonsteroidal antiiflammatory drugs (at 24 hours) on pain intensity, function, or quality of life. Data from 2 trials of longer than 24-hour duration (diazepam and zopiclone, n = 74) found that participants who received a muscle relaxant had significantly more adverse events compared with those who received placebo [number needed to harm (NNTH) 3, 95% CI 2 to 7]. These were predominantly central nervous system side effects including dizziness and drowsiness (NNTH 3, 95% CI 2 to 11). Based upon the currently available evidence in patients with IA, benzodiazepines (diazepam and triazolam) do not appear to be beneficial in improving pain over 24 hours or 1 week. The non-benzodiazepine agent zopiclone also did not significantly reduce pain over 2 weeks. However, even short-term muscle relaxant use (24 hours to 2 weeks) is associated with significant adverse events, predominantly drowsiness and dizziness.


Use of a secure Internet Web site for collaborative medical research.
Researchers who collaborate on clinical research studies from diffuse locations need a convenient, inexpensive, secure way to record and manage data. The Internet, with its World Wide Web, provides a vast network that enables researchers with diverse types of computers and operating systems anywhere in the world to log data through a common interface. Development of a Web site for scientific data collection can be organized into 10 steps, including planning the scientific database, choosing a database management software system, setting up database tables for each collaborator's variables, developing the Web site's screen layout, choosing a middleware software system to tie the database software to the Web site interface, embedding data editing and calculation routines, setting up the database on the central server computer, obtaining a unique Internet address and name for the Web site, applying security measures to the site, and training staff who enter data. Ensuring the security of an Internet database requires limiting the number of people who have access to the server, setting up the server on a stand-alone computer, requiring user-name and password authentication for server and Web site access, installing a firewall computer to prevent break-ins and block bogus information from reaching the server, verifying the identity of the server and client computers with certification from a certificate authority, encrypting information sent between server and client computers to avoid eavesdropping, establishing audit trails to record all accesses into the Web site, and educating Web site users about security techniques. When these measures are carefully undertaken, in our experience, information for scientific studies can be collected and maintained on Internet databases more efficiently and securely than through conventional systems of paper records protected by filing cabinets and locked doors. JAMA. 2000;284:1843-1849.


Age-related neurodegenerative disease associated pathways identified in retinal and vitreous proteome from human glaucoma eyes.
Glaucoma is a chronic disease that shares many similarities with other neurodegenerative disorders of the central nervous system. This study was designed to evaluate the association between glaucoma and other neurodegenerative disorders by investigating glaucoma-associated protein changes in the retina and vitreous humour. The multiplexed Tandem Mass Tag based proteomics (TMT-MS3) was carried out on retinal tissue and vitreous humour fluid collected from glaucoma patients and age-matched controls followed by functional pathway and protein network interaction analysis. About 5000 proteins were quantified from retinal tissue and vitreous fluid of glaucoma and control eyes. Of the differentially regulated proteins, 122 were found linked with pathophysiology of Alzheimer's disease (AD). Pathway analyses of differentially regulated proteins indicate defects in mitochondrial oxidative phosphorylation machinery. The classical complement pathway associated proteins were activated in the glaucoma samples suggesting an innate inflammatory response. The majority of common differentially regulated proteins in both tissues were members of functional protein networks associated brain changes in AD and other chronic degenerative conditions. Identification of previously reported and novel pathways in glaucoma that overlap with other CNS neurodegenerative disorders promises to provide renewed understanding of the aetiology and pathogenesis of age related neurodegenerative diseases.


Lifetime Cocaine and Opiate Use and Chronic Kidney Disease.
More than 50% of American adolescents and adults report having used illicit drugs in their lifetime. We examined the association of lifetime opiate and cocaine use with reduced kidney function, albuminuria and rapid kidney function decline among urban-dwelling adults. Our prospective cohort included 2,286 Healthy Aging in Neighborhoods of Diversity across the Life Span study participants who were community-dwelling adults residing in Baltimore, MD. The predictive variables were lifetime opiate and cocaine use, defined as use of opiates or crack/cocaine ≥5 times. Outcomes included prevalent reduced estimated glomerular filtration rate (eGFR; <60 ml/min/1.73 m2 by Chronic Kidney Disease (CKD)-Epidemiology Collaboration), albuminuria (albumin-to-creatinine ratio >30 mg/g, n = 1,652) and rapid kidney function decline (>3 ml/min/1.73 m2 per year over a median of 4.7 years, n = 1,660). Participants' mean age was 48 years, 15% reported opiate use, and 22% reported cocaine use. A total of 115 (5.0%) participants had reduced eGFR, 190 (11.5%) had albuminuria and 230 (13.8%) experienced rapid decline in kidney function. In adjusted logistic regression analyses, both substances were associated with greater odds of reduced eGFR (OR 2.71, 95% CI 1.50-4.89 for opiates; OR 1.40, 95% CI 0.87-2.24 for cocaine). Both substances were associated with greater odds of albuminuria (OR 1.20, 95% CI 0.83-1.73 for opiates; OR 1.80, 95% CI 1.29-2.51 for cocaine). Neither substance was associated with the rapid decline of kidney function. Lifetime opiate and cocaine use was associated with prevalent reduced eGFR and albuminuria, yet not with rapid kidney function decline. The use of opiate and cocaine may be an important risk factor for CKD in urban populations.


Experimental verification of n = 0 structures for visible light.
We fabricate and characterize a metal-dielectric nanostructure with an effective refractive index n = 0 in the visible spectral range. Light is excited in the material at deep subwavelength resolution by a 30-keV electron beam. From the measured spatially and angle-resolved emission patterns, a vanishing phase advance, corresponding to an effective [Symbol: see text] = 0 and n = 0, is directly observed at the cutoff frequency. The wavelength at which this condition is observed can be tuned over the entire visible or near-infrared spectral range by varying the waveguide width. This n = 0 plasmonic nanostructure may serve as a new building block in nanoscale optical integrated circuits and to control spontaneous emission as experimentally demonstrated by the strongly enhanced radiative optical density of states over the entire n = 0 structure.


Renal adenocarcinoma-associated erythrocytosis in a cat: clinicopathological features and immunohistochemical results.
This report documents a case of secondary inappropriate erythrocytosis in a cat with renal cell adenocarcinoma, its stabilization through manual erythrocytapheresis, and the EPO-immunostaining on the affected kidney. An 11-year-old cat was presented with lethargy, weight loss and polyuria/polydipsia. An abdominal mass was detected upon physical examination. Clinicopathological work-up revealed marked erythrocytosis (HCT value 64.8%), renal azotemia and decreased urine specific gravity (USG). An abdominal ultrasound was performed, localizing the mass in the right kidney. Serum erythropoietin (EPO) was above the reference interval (RI), and the cytology of the mass was indicative of renal carcinoma. Manual erythrocytapheresis was performed in order to stabilize the patient before surgery, improving the cat's clinical and clinicopathological condition. After nephrectomy, EPO and creatinine concentrations returned within the RI, while the USG markedly increased. Histopathology confirmed the diagnosis of renal adenocarcinoma. Immunohistochemistry with anti-EPO antibody revealed diffuse and strong cytoplasmatic positivity in tumor cells.


Effects of the pathogenic water mold Saprolegnia ferax on survival of amphibian larvae.
Infectious diseases are a significant threat to worldwide biodiversity. Amphibian declines, a significant part of current biodiversity losses, are in many cases associated with infectious disease. Water molds are one group of pathogens affecting amphibians on a worldwide basis. Although water molds have been studied extensively for their effects on host embryos, little information is available about how they affect post-embryonic amphibians. We tested the effects of one species of water mold, Saprolegnia ferax, in a comparative study of larvae of 4 amphibian species: Pseudacris regilla (Pacific treefrog), Rana cascadae (Cascades frog), Ambystoma macrodactylum (long-toed salamander), and R. aurora (red-legged frog). S. ferax can kill amphibians at the embryonic and juvenile life history stages, depending on the amphibian species. In the present study, a 1 wk exposure to S. ferax killed P. regilla larvae and a 2 wk exposure killed R. aurora larvae. Larvae of the other host species were unaffected after 1 wk of exposure to S. ferax. Our results suggest that S. ferax can kill amphibian larvae and further suggest that evaluation of how pathogens affect amphibians at the population level requires investigation at various life stages.


Trinucleotide repeat expansions catalyzed by human cell-free extracts.
Trinucleotide repeat expansions cause 17 heritable human neurological disorders. In some diseases, somatic expansions occur in non-proliferating tissues such as brain where DNA replication is limited. This finding stimulated significant interest in replication-independent expansion mechanisms. Aberrant DNA repair is a likely source, based in part on mouse studies showing that somatic expansions are provoked by the DNA repair protein MutSβ (Msh2-Msh3 complex). Biochemical studies to date used cell-free extracts or purified DNA repair proteins to yield partial reactions at triplet repeats. The findings included expansions on one strand but not the other, or processing of DNA hairpin structures thought to be important intermediates in the expansion process. However, it has been difficult to recapitulate complete expansions in vitro, and the biochemical role of MutSβ remains controversial. Here, we use a novel in vitro assay to show that human cell-free extracts catalyze expansions and contractions of trinucleotide repeats without the requirement for DNA replication. The extract promotes a size range of expansions that is similar to certain diseases, and triplet repeat length and sequence govern expansions in vitro as in vivo. MutSβ stimulates expansions in the extract, consistent with aberrant repair of endogenous DNA damage as a source of expansions. Overall, this biochemical system retains the key characteristics of somatic expansions in humans and mice, suggesting that this important mutagenic process can be restored in the test tube.


Substance Use in Pregnancy: Identifying Stigma and Improving Care.
This review examines the impact of stigma on pregnant people who use substances. Stigma towards people who use drugs is pervasive and negatively impacts the care of substance-using people by characterizing addiction as a weakness and fostering beliefs that undermine the personal resources needed to access treatment and recover from addiction, including self-efficacy, help seeking and belief that they deserve care. Stigma acts on multiple levels by blaming people for having a problem and then making it difficult for them to get help, but in spite of this, most pregnant people who use substances reduce or stop using when they learn they are pregnant. Language, beliefs about gender roles, and attitudes regarding fitness for parenting are social factors that can express and perpetuate stigma while facilitating punitive rather than therapeutic approaches. Because of stigmatizing attitudes that a person who uses substances is unfit to parent, pregnant people who use substances are at heightened risk of being screened for substance use, referred to child welfare services, and having their parental rights taken away; these outcomes are even more likely for people of color. Various treatment options can successfully support recovery in substance-using pregnant populations, but treatment is underutilized in all populations including pregnant people, and more knowledge is needed on how to sustain engagement in treatment and recovery activities. To combat stigma when working with substance-using pregnant people throughout the peripartum period, caregivers should utilize a trauma-informed approach that incorporates harm reduction and motivational interviewing with a focus on building trust, enhancing self-efficacy, and strengthening the personal skills and resources needed to optimize health of the parent-baby dyad.


Glutamate presynaptic vesicular transporter and postsynaptic receptor levels correlate with spatial memory status in aging rat models.
In humans, memory capacities are generally affected with aging, even without any reported neurologic disorders. The mechanisms behind cognitive decline are not well understood. We studied here whether postsynaptic glutamate receptor and presynaptic vesicular glutamate transporters (VGLUTs) levels may change in the course of aging and be related to cognitive abilities using various age-impaired (AI) or age-unimpaired rat strains. Twenty-four-month-old Long-Evans (LE) rats with intact spatial memory maintained postsynaptic ionotropic glutamate receptor levels in the hippocampal-adjacent cortex similar to those of young animals. In contrast, AI rats showed significantly reduced expression of ionotropic glutamate receptor GluR2, NR2A and NR2B subunits. In AI LE rats, VGLUT1 and VGLUT2 levels were increased and negatively correlated with receptor levels as shown by principal component analysis and correlation matrices. We also investigated whether glutamatergic receptors and VGLUT levels were altered in the obesity-resistant LOU/C/Jall (LOU) rat strain which is characterized by intact memory despite aging. No difference was observed between 24-month-old LOU rats and their young counterparts. Taken together, the unaltered spatial memory performance of 24-month-old age-unimpaired LE and LOU rats suggests that intact coordination of the presynaptic and postsynaptic hippocampal-adjacent cortex glutamatergic networks may be important for successful cognitive aging. Accordingly, altered expression of presynaptic and postsynaptic glutamatergic components, such as in AI LE rats, could be considered a marker of age-related cognitive deficits.


[Disorders in metabolism of superoxide radicals in tumor-bearing mice during development of Ehrlich ascites carcinoma and their normalization under the effect of ruboxyl].
Activity of the systems involved in generation and utilization of superoxide radicals was studied in microsomes, mitochondria and nuclei of liver tissue from intact mice, mice with developed Ehrlich ascites carcinoma and of the animals treated with antitumoral drug ruboxyl. The ratio between the rate of superoxide radicals formation and activity of superoxide dismutase (SOD) served as specific characteristic of the O2(-)-SOD system in the corresponding compartments. During tumoral development, the pattern studied was altered in all the subcellular organelles used, thus demonstrating an impairment of free radical oxidation status in liver tissue of tumor-bearing animals. Administration of ruboxyl into healthy animals led to distinct increase in this ratio in mitochondria, while the drug normalized patterns of the O-(-)-SOD system in all the cell compartments studied in tumor-bearing animals. Ruboxyl appears to exhibit regulating effect on free radical oxidation.


"We'll be able to take care of ourselves" - A qualitative study of client attitudes toward implementing buprenorphine treatment at syringe services programs.
Background: Syringe services programs (SSPs) complement substance use disorder treatment in providing services that improve the health of people who use drugs (PWUD). Buprenorphine treatment is an effective underutilized opioid use disorder treatment. Regulations allow buprenorphine prescribing from office-based settings, potentially including SSPs although few studies have examined this approach. Our objective was to assess the attitudes among PWUD toward the potential introduction of buprenorphine treatment in an SSP. Methods: In this qualitative study, we recruited 34 participants who were enrolled at a New York City-based SSP to participate in one of seven focus group sessions. The focus group facilitators prompted participants to share their thoughts in five domains: attitudes toward (1) medical clinics; (2) harm reduction in general; (3) SSP-based buprenorphine treatment; (4) potential challenges of SSP-based treatment; and (5) logistical considerations of an SSP-based buprenorphine treatment program. Four researchers analyzed focus group transcripts using thematic analysis. Results: Of the 34 participants, most were white (68%), over the age of 40 years old (56%), and had previously tried buprenorphine (89%). Common themes were: 1) The SSP is a supportive community for people who use drugs; 2) Participants felt less stigmatized at the SSP than in general medical settings; 3) Offering buprenorphine treatment could change the SSP's culture; and 4) SSP participants receiving buprenorphine may be tempted to divert their medication. Participants offered suggestions for a slow intentional introduction of buprenorphine treatment at the SSP including structured appointments, training medical providers in harm reduction, and program eligibility criteria. Conclusion: Overall, participants expressed enthusiasm for onsite buprenorphine treatment at SSPs. Research on SSP-based buprenorphine treatment should investigate standard buprenorphine treatment outcomes but also any effects on the program itself and medication diversion. Implementation should consider cultural and environmental aspects of the SSP and consult program staff and participants.


Whose data set is it anyway? Sharing raw data from randomized trials.
Sharing of raw research data is common in many areas of medical research, genomics being perhaps the most well-known example. In the clinical trial community investigators routinely refuse to share raw data from a randomized trial without giving a reason. Data sharing benefits numerous research-related activities: reproducing analyses; testing secondary hypotheses; developing and evaluating novel statistical methods; teaching; aiding design of future trials; meta-analysis; and, possibly, preventing error, fraud and selective reporting. Clinical trialists, however, sometimes appear overly concerned with being scooped and with misrepresentation of their work. Both possibilities can be avoided with simple measures such as inclusion of the original trialists as co-authors on any publication resulting from data sharing. Moreover, if we treat any data set as belonging to the patients who comprise it, rather than the investigators, such concerns fall away. Technological developments, particularly the Internet, have made data sharing generally a trivial logistical problem. Data sharing should come to be seen as an inherent part of conducting a randomized trial, similar to the way in which we consider ethical review and publication of study results. Journals and funding bodies should insist that trialists make raw data available, for example, by publishing data on the Web. If the clinical trial community continues to fail with respect to data sharing, we will only strengthen the public perception that we do clinical trials to benefit ourselves, not our patients.


Carbon for soils, not soils for carbon.
The role of soil organic carbon (SOC) sequestration as a 'win-win' solution to both climate change and food insecurity receives an increasing promotion. The opportunity may be too good to be missed! Yet the tremendous complexity of the two issues at stake calls for a detailed and nuanced examination of any potential solution, no matter how appealing. Here, we critically re-examine the benefits of global SOC sequestration strategies on both climate change mitigation and food production. While estimated contributions of SOC sequestration to climate change vary, almost none take SOC saturation into account. Here, we show that including saturation in estimations decreases any potential contribution of SOC sequestration to climate change mitigation by 53%-81% towards 2100. In addition, reviewing more than 21 meta-analyses, we found that observed yield effects of increasing SOC are inconsistent, ranging from negative to neutral to positive. We find that the promise of a win-win outcome is confirmed only when specific land management practices are applied under specific conditions. Therefore, we argue that the existing knowledge base does not justify the current trend to set global agendas focusing first and foremost on SOC sequestration. Away from climate-smart soils, we need a shift towards soil-smart agriculture, adaptative and adapted to each local context, and where multiple soil functions are quantified concurrently. Only such comprehensive assessments will allow synergies for land sustainability to be maximised and agronomic requirements for food security to be fulfilled. This implies moving away from global targets for SOC in agricultural soils. SOC sequestration may occur along this pathway and contribute to climate change mitigation and should be regarded as a co-benefit.


Sexually antagonistic genetic variation for fitness in red deer.
Evolutionary theory predicts the depletion of genetic variation in natural populations as a result of the effects of selection, but genetic variation is nevertheless abundant for many traits that are under directional or stabilizing selection. Evolutionary geneticists commonly try to explain this paradox with mechanisms that lead to a balance between mutation and selection. However, theoretical predictions of equilibrium genetic variance under mutation-selection balance are usually lower than the observed values, and the reason for this is unknown. The potential role of sexually antagonistic selection in maintaining genetic variation has received little attention in this debate, surprisingly given its potential ubiquity in dioecious organisms. At fitness-related loci, a given genotype may be selected in opposite directions in the two sexes. Such sexually antagonistic selection will reduce the otherwise-expected positive genetic correlation between male and female fitness. Both theory and experimental data suggest that males and females of the same species may have divergent genetic optima, but supporting data from wild populations are still scarce. Here we present evidence for sexually antagonistic fitness variation in a natural population, using data from a long-term study of red deer (Cervus elaphus). We show that male red deer with relatively high fitness fathered, on average, daughters with relatively low fitness. This was due to a negative genetic correlation between estimates of fitness in males and females. In particular, we show that selection favours males that carry low breeding values for female fitness. Our results demonstrate that sexually antagonistic selection can lead to a trade-off between the optimal genotypes for males and females; this mechanism will have profound effects on the operation of selection and the maintenance of genetic variation in natural populations.


Inhibition of unwinding of G-quadruplex structures by Sgs1 helicase in the presence of N,N'-bis[2-(1-piperidino)ethyl]-3,4,9,10-perylenetetracarboxylic diimide, a G-quadruplex-interactive ligand.
N,N'-Bis[2-(1-piperidino)ethyl]-3,4,9,10-perylenetetracarboxylic diimide (PIPER), a perylene derivative, is a very potent and selective G-quadruplex DNA-interactive agent. It has been shown to inhibit DNA polymerase and telomerase by stacking externally to the G-tetrads in the G-quadruplex structures. Recently, we have demonstrated that this small molecule greatly accelerates the assembly of G-quadruplex structures in a cell-free system. In this report, we present data demonstrating that PIPER prevents the unwinding of G-quadruplex structures by yeast Sgs1 helicase. Sgs1 belongs to the RecQ DNA helicase family whose members include other G-quadruplex DNA unwinding helicases, such as human Bloom's syndrome and human Werner's syndrome helicases. PIPER specifically prevents the unwinding of G-quadruplex DNA but not duplex DNA by Sgs1. Competition experiments indicate that this inhibitory activity is due to the interaction of PIPER with G-quadruplex structures rather than the helicase itself. These results combined with previous studies suggest a possible mechanism of action for these G-quadruplex-interactive agents inside cells: they might induce G-quadruplex formation in G-rich regions on genomic DNA, stabilize these structures, and prevent them from being cleared by enzymes such as helicases. The G-quadruplex structures may, in turn, disrupt some critical cellular events such as DNA replication, transcription regulation, and telomere maintenance.


Living with complexity; marshalling resources: a systematic review and qualitative meta-synthesis of lived experience of mental and physical multimorbidity.
Multimorbidity poses a major health burden worldwide yet most healthcare is still orientated towards the management of single diseases. Literature on the experience of living with multimorbidity is accumulating but has not yet been synthesised in a manner conducive to informing the design of self-management interventions for this population. This study aimed to systematically review and synthesise findings from published, in-depth qualitative studies about the experience of multimorbidity, with a view to identifying the components and motivation for successful self-management in this population. Systematic review of and meta-synthesis of qualitative studies that evaluated patient experience of living with and/or self-managing mental and/or physical multimorbidity. MEDLINE, Embase, PsycINFO, CINAHL, and ASSIA along with reference lists of existing reviews and content pages of non-indexed specialists comorbidity journals were searched. Nineteen studies from 23 papers were included. A line of argument synthesis was articulated around three third-order constructs: 1) Encounters with complexity; 2) Marshalling medicines, emotions, and resources; and 3) Self-preservation and prevention. Our interpretation revealed how mental and physical multimorbidity is experienced as moments of complexity rather than mere counts of illnesses. Successful self-management of physical symptoms was contingent upon the tactical use of medicines, whilst emotional health was more commonly managed by engaging in behavioural strategies, commonly with a social or spiritual component. Motivations for self-management were underpinned by a sense of moral purpose to take responsibility for their health, but also by a desire to live a purposeful life beyond an immediate context of multimorbidity. Understanding how people experience the complexities of mental and physical multimorbidity may be crucial to designing and delivering interventions to support successful self-management in this population. Future self-management interventions should aim to support patients to exert responsibility and autonomy for medical self-management and promote agency and self-determination to lead purposeful lives via improved access to appropriate social and psychological support.


Physiological genomics identifies genetic modifiers of long QT syndrome type 2 severity.
Congenital long QT syndrome (LQTS) is an inherited channelopathy associated with life-threatening arrhythmias. LQTS type 2 (LQT2) is caused by mutations in KCNH2, which encodes the potassium channel hERG. We hypothesized that modifier genes are partly responsible for the variable phenotype severity observed in some LQT2 families. Here, we identified contributors to variable expressivity in an LQT2 family by using induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) and whole exome sequencing in a synergistic manner. We found that iPSC-CMs recapitulated the clinical genotype-phenotype discordance in vitro. Importantly, iPSC-CMs derived from the severely affected LQT2 patients displayed prolonged action potentials compared with cells from mildly affected first-degree relatives. The iPSC-CMs derived from all patients with hERG R752W mutation displayed lower IKr amplitude. Interestingly, iPSC-CMs from severely affected mutation-positive individuals exhibited greater L-type Ca2+ current. Whole exome sequencing identified variants of KCNK17 and the GTP-binding protein REM2, providing biologically plausible explanations for this variable expressivity. Genome editing to correct a REM2 variant reversed the enhanced L-type Ca2+ current and prolonged action potential observed in iPSC-CMs from severely affected individuals. Thus, our findings showcase the power of combining complementary physiological and genomic analyses to identify genetic modifiers and potential therapeutic targets of a monogenic disorder. Furthermore, we propose that this strategy can be deployed to unravel myriad confounding pathologies displaying variable expressivity.


Concordance analysis in mitogenomic phylogenetics.
Here I advocate the utility of Bayesian concordance analysis as a mechanism for exploring the magnitude and source of phylogenetic signal in concatenated mitogenomic phylogenetic studies. While typically applied to the study of independently evolving gene trees, Bayesian concordance analysis can also be applied to linked, but individually analyzed, gene regions using a prior probability that reflects the expectation of similar phylogenetic reconstructions. For true branches in the mitogenomic tree, concordance factors should represent the number of gene regions that contain phylogenetic signal for a particular clade. As a demonstration of the application of Bayesian concordance analysis to empirical data, I analyzed two different salamander (Hynobiidae and Plethodontidae) mitogenomic data sets using a gene-based partitioning strategy. The results revealed many strongly supported clades in the concatenated trees that have high concordance factors, permitting the inference that these are robustly resolved through phylogenetic signal distributed across the mitogenome. In contrast, a number of strongly supported clades in the concatenated tree received low concordance factors, indicating that their reconstruction is either driven primarily by phylogenetic signal in a small number of gene regions, or that they are inconsistent reconstructions influenced by properties of the data that can produce inaccurate trees (e.g., compositional bias, selection, etc.). Exploration of the Bayesian joint posterior distribution of trees highlighted partitions that contribute phylogenetic information to similar clade reconstructions. This approach was particularly insightful in the hynobiid data, where different combinations of genes were identified that support alternative tree reconstructions. Concatenated analysis of these different subsets of genes highlighted through Bayesian concordance analysis produced strongly supported and contrasting trees, demonstrating the potential for inconsistency in concatenated mitogenomic phylogenetics. The overall results presented here suggest that Bayesian concordance analysis can serve as an effective exploration of the influence of different gene regions in mitogenomic (and other organellar genomic) phylogenetic studies.


Drimolen cranium DNH 155 documents microevolution in an early hominin species.
Paranthropus robustus is a small-brained extinct hominin from South Africa characterized by derived, robust craniodental morphology. The most complete known skull of this species is DNH 7 from Drimolen Main Quarry, which differs from P. robustus specimens recovered elsewhere in ways attributed to sexual dimorphism. Here, we describe a new fossil specimen from Drimolen Main Quarry, dated from approximately 2.04-1.95 million years ago, that challenges this view. DNH 155 is a well-preserved adult male cranium that shares with DNH 7 a suite of primitive and derived features unlike those seen in adult P. robustus specimens from other chronologically younger deposits. This refutes existing hypotheses linking sexual dimorphism, ontogeny and social behaviour within this taxon, and clarifies hypotheses concerning hominin phylogeny. We document small-scale morphological changes in P. robustus associated with ecological change within a short time frame and restricted geography. This represents the most highly resolved evidence yet of microevolutionary change within an early hominin species.


Endothelial nitric oxide synthase reduces crescentic and necrotic glomerular lesions, reactive oxygen production, and MCP1 production in murine lupus nephritis.
Systemic lupus erythematosus, in both animal models and in humans, is characterized by autoantibody production followed by immune complex deposition in target tissues. Ensuing target organ damage is modulated by reactive intermediates, including reactive nitrogen and oxygen species, through as of now incompletely understood mechanisms. Endothelial nitric oxide synthase is known to impact vascular reactivity; however its impact on reactive intermediate production and inflammatory renal disease is less well defined. In this study, we assessed the impact of endothelial nitric oxide synthase (eNOS) on disease in lupus prone MRL/lpr mice. Mice lacking eNOS developed earlier more severe disease with decreased survival. eNOS deficient mice died sooner and developed significantly more glomerular crescents, necrosis, inflammatory infiltrates and vasculitis, indicating a role for eNOS in modulating these renal lesions. Immune complex deposition was similar between groups, indicating the impact of eNOS is distal to antibody/complement glomerular deposition. Urinary nitric oxide production was decreased in the eNOS deficient mice, while proteinuria was increased. Urinary monocyte chemotactic protein-1 was also increased in the knockout mice. CD4+ T cells from MRL/lpr mice demonstrated mitochondrial hyperpolarization, increased nitric oxide and superoxide production and increased calcium flux compared to B6 control mice. Deficiency of eNOS resulted in decreased nitric oxide and mitochondrial calcium levels but had no effect on mitochondrial hyperpolarization. Renal cortices from MRL/lpr mice that are eNOS deficient demonstrated increased superoxide production, which was blocked by both nitric oxide synthase and NADPH oxidase inhibitors. These studies thus demonstrate a key role for eNOS in modulating renal disease in lupus prone MRL/lpr mice. The impact appears to be mediated by effects on superoxide production in the kidney, impacting downstream mediators such as monocyte chemotactic protein-1. These results suggest that modulation of eNOS may be a novel therapeutic approach to treating lupus nephritis.


Class III P-glycoproteins mediate the formation of lipoprotein X in the mouse.
Cholestasis is associated with hypercholesterolemia and appearance of the abnormal lipoprotein X (LpX) in plasma. Using mice with a disrupted Mdr2 gene, we tested the hypothesis that LpX originates as a biliary lipid vesicle. Mdr2-deficient mice lack Mdr2 P-glycoprotein, the canalicular translocator for phosphatidylcholine, and secrete virtually no phospholipid and cholesterol in bile. Bile duct ligation of Mdr2(+)/+ mice induced a dramatic increase in the plasma cholesterol and phospholipid concentration. Agarose electrophoresis, density gradient ultracentrifugation, gel permeation, and electron microscopy revealed that the majority of phospholipid and cholesterol was present as LpX, a 40-100 nm vesicle with an aqueous lumen. In contrast, the plasma cholesterol and phospholipid concentration in Mdr2(-)/- mice decreased upon bile duct ligation, and plasma fractionation revealed a complete absence of LpX. In mice with various expression levels of Mdr2 or MDR3, the human homolog of Mdr2, we observed that the plasma level of cholesterol and phospholipid during cholestasis correlated very closely with the expression level of these canalicular P-glycoproteins. These data demonstrate that during cholestasis there is a quantitative shift of lipid secretion from bile to the plasma compartment in the form of LpX. The concentration of this lipoprotein is determined by the activity of the canalicular phospholipid translocator.


Online Survey of Digital Reading by Adults with Low Vision.
Access to digital text is increasingly widespread, but its impact on low-vision reading is not well understood. We conducted an online survey of people with low vision to determine what assistive technologies they use for visual reading, their preferred text characteristics, and the time they devote to reading digital and hard-copy text. One hundred thirty-three low-vision participants completed an online survey. Participants reported the nature and history of their low vision, their usage of different assistive technologies, and time devoted to five visual reading activities. The three largest diagnostic categories were albinism (n = 36), retinitis pigmentosa (n = 20), and glaucoma (n = 15). Mean self-reported acuity was 0.93 logMAR (range, 0.1 to 1.6 logMAR). Mean age was 46 years (range, 18 to 98 years). Participants reported on percentage time spent reading using vision, audio, or touch (braille). Seventy-five percent of our participants did more than 50% of their reading visually. Across five categories of reading activities-work or education, news, pleasure, spot reading, and social networking-participants reported more time spent on digital reading than hard-copy reading. Eighty-nine percent of our participants used at least one technology from each of our two major categories of assistive technologies (digital content magnifiers and hard-copy content magnifiers) for visual reading. Despite the growing availability of digital text in audio or braille formats, our findings from an online sample of people with low vision indicate the continuing importance of visual reading. Our participants continue to use technology to access both hard-copy and digital text, but more time is devoted to digital reading. Our findings highlight the need for continued research and development of technology to enhance visual reading accessibility.


Prolactin: the initial luteotropic stimulus of pseudopregnancy in the rat.
The luteotropic stimuli necessary to transform the corpus luteum of the estrous cycle into a corpus luteum of psuedopregnancy on the morning of diestrus-2 (Day 2), as reflected by a dramatic divergence in progesterone secretion, were studied (Day 1 was taken as the first day of diestrus of pseudopregnancy). The requirement of prolactin (PRL) as a luteotropic stimulus was determined by inhibiting the diurnal and nocturnal PRL surges that occur immediately before and during the divergence in progesterone. Following cervical stimulation, 1 mg of 2-Br-alpha-ergocryptine (EC) was injected at 1100 and 2300 h on Day 1 (lights on 0600-1800 h), and the animals were decapitated at 2-4 h intervals from 1100 h on Day 1 to 1700 h on Day 2. In the control animals, the PRL surges on Day 1 and Day 2 were associated with an increase in progesterone secretion on Day 2. However, the regimen of EC treatment resulted in an inhibition of PRL surges, prolactin remaining at baseline values from 1100 h on Day 1 to 1700 h on Day 2. The inhibition of PRL secretion was associated with a fall in progesterone concentration to reach baseline values by 1700h on Day 2. Furthermore, a group of animals similarly treated with EC returned to vaginal estrus 2 days later. LH concentrations did not differ in control and EC-treated animals. The effect of EC on corpus luteum function could be completely reversed by the simultaneous administration of PRL. In addition, if PRL was administered at 1100 h and 2300 h on diestrus-1 of the estrous cycle, in an attempt to mimic the surges os pseudopregnancy, regression of the corpora lutea did not occur. Progesterone levels increased to reach values comparable to those observed in pseudopregnancy on diestrus-2. The role of LH was studied by administering a dose of LH antiserum at 110 and 2300 h on Day 1 of pseudopregnancy. This treatment failed to inhibit the increase in progesterone observed on Day 2. These results demonstrate that the surges of plasma PRL initiated by cervical stimulation are responsible for transforming a corpus luteum of the estrous cycle into a corpus luteum of pseudopregnancy, as reflected by an increase in progesterone secretion of Day 2. LH seems to have a minor role in maintaining corpus luteum function beyond that observed during the estrous cycle.


Severe Burn Injury Induces Thermogenically Functional Mitochondria in Murine White Adipose Tissue.
Chronic cold exposure induces functionally thermogenic mitochondria in the inguinal white adipose tissue (iWAT) of mice. Whether this response occurs in pathophysiological states remains unclear. The purpose of this study was to determine the impact of severe burn trauma on iWAT mitochondrial function in mice. Male BALB/c mice (10-12 weeks) received full-thickness scald burns to ∼30% of the body surface area. Inguinal white adipose tissue was harvested from mice at 1, 4, 10, 20, and 40 days postinjury. Total and uncoupling protein 1 (UCP1)-dependent mitochondrial thermogenesis were determined in iWAT. Citrate synthase activity was determined as a proxy of mitochondrial abundance. Immunohistochemistry was performed to assess iWAT morphology and UCP1 expression. Uncoupling protein 1-dependent respiration was significantly greater at 4 and 10 days after burn compared with sham, peaking at 20 days after burn (P < 0.001). Citrate synthase activity was threefold greater at 4, 10, 20, and 40 days after burn versus sham (P < 0.05). Per mitochondrion, UCP1 function increased after burn trauma (P < 0.05). After burn trauma, iWAT exhibited numerous multilocular lipid droplets that stained positive for UCP1. The current findings demonstrate the induction of thermogenically competent mitochondria within rodent iWAT in a model of severe burn trauma. These data identify a specific pathology that induces the browning of white adipose tissue in vivo and may offer a mechanistic explanation for the chronic hypermetabolism observed in burn victims.


Combined effects of ocean acidification and temperature on planula larvae of the moon jellyfish Aurelia coerulea.
Rapidly rising levels of atmospheric CO2 have caused two environmental stressors, ocean acidification and seawater temperature increases, which represent major abiotic threats to marine organisms. Here, we investigated for the first time the combined effects of ocean acidification and seawater temperature increases on the behavior, survival, and settlement of the planula larvae of Aurelia coerulea, which is considered a nuisance species around the world. Three pH levels (8.1, 7.7 and 7.3) and two temperature levels (24 °C and 27 °C) were used in the present study. There were no interactive effects of temperature and pH on the behavior, survival, and settlement of planula larvae of A. coerulea. We found that the swimming speed and mortality of the planula larvae of A. coerulea were significantly affected by temperature, and low pH significantly affected settlement. Planula larvae of A. coerulea from the elevated temperature treatment moved faster and showed higher mortality than those at the control temperature. The settlement rate of A. coerulea planulae was significantly higher at the pH level of 7.3 than at other pH levels. These results suggest that seawater temperature increase, rather than reduced pH, was the main stress factor affecting the survival of A. coerulea planulae. Overall, the planula larvae of the common jellyfish A. coerulea appeared to be resistant to ocean acidification, but may be negatively affected by future seawater temperature increases.


Melanocytes: the new Black.
Melanocytes, pigment-producing cells residing primarily in the hair follicle, epidermis and eye, are responsible for skin hair and eye pigmentation. Pigmentation is achieved by the highly regulated manufacture of the pigment melanin in specialised organelles, melanosomes that are transported along dendritic processes before being transferred to growing hair, or keratinocytes where melanin protects from UV-induced DNA damage. Because loss of melanocytes gives a clear pigmentation phenotype yet is non-lethal, over 130 genes implicated in the development or function of this cell type have been identified to date, and in humans the loss of melanocytes or their ability to produce pigment, or transport or transfer melanosomes is associated with several diseases such as vitiligo, albinism and Hermansky-Pudlak syndrome. Importantly, the effective combination of genetics, cell and molecular biology possible with this cell type is attracting an increasing number of researchers focussed on understanding how cells coordinate survival, proliferation, differentiation and stem cell maintenance.


The T-box transcription factor Brachyury regulates epithelial-mesenchymal transition in association with cancer stem-like cells in adenoid cystic carcinoma cells.
The high frequencies of recurrence and distant metastasis of adenoid cystic carcinoma (AdCC) emphasize the need to better understand the biological factors associated with these outcomes. To analyze the mechanisms of AdCC metastasis, we established the green fluorescence protein (GFP)-transfected subline ACCS-GFP from the AdCC parental cell line and the metastatic ACCS-M GFP line from an in vivo metastasis model. Using these cell lines, we investigated the involvement of the epithelial-mesenchymal transition (EMT) and cancer stem cell (CSCs) in AdCC metastasis by real-time RT-PCR for EMT related genes and stem cell markers. Characteristics of CSCs were also analyzed by sphere-forming ability and tumorigenicity. Short hairpin RNA (shRNA) silencing of target gene was also performed. ACCS-M GFP demonstrated characteristics of EMT and additionally displayed sphere-forming ability and high expression of EMT-related genes (Snail, Twist1, Twist2, Slug, zinc finger E-box binding homeobox 1 and 2 [Zeb1 and Zeb2], glycogen synthase kinase 3 beta [Gsk3β and transforming growth factor beta 2 [Tgf-β2]), stem cell markers (Nodal, Lefty, Oct-4, Pax6, Rex1, and Nanog), and differentiation markers (sex determining region Y [Sox2], Brachyury, and alpha fetoprotein [Afp]). These observations suggest that ACCS-M GFP shows the characteristics of CSCs and CSCs may be involved in the EMT of AdCC. Surprisingly, shRNA silencing of the T-box transcription factor Brachyury (also a differentiation marker) resulted in downregulation of the EMT and stem cell markers. In addition, sphere-forming ability, EMT characteristics, and tumorigenicity were simultaneously lost. Brachyury expression in clinical samples of AdCC was extremely high and closely related to EMT. This finding suggests that regulation of EMT by Brachyury in clinical AdCC may parallel that observed in vitro in this study. The use of a single cell line is a limitation of this study. However, parallel data from in vitro and clinical samples suggest the possibility that EMT is directly linked to CSCs and that Brachyury is a regulator of EMT and CSCs.


Model-based variables for the kinematic assessment of upper-extremity impairments in post-stroke patients.
Common scales for clinical evaluation of post-stroke upper-limb motor recovery are often complemented with kinematic parameters extracted from movement trajectories. However, there is no a general consensus on which parameters to use. Moreover, the selected variables may be redundant and highly correlated or, conversely, may incompletely sample the kinematic information from the trajectories. Here we sought to identify a set of clinically useful variables for an exhaustive but yet economical kinematic characterization of upper limb movements performed by post-stroke hemiparetic subjects. For this purpose, we pursued a top-down model-driven approach, seeking which kinematic parameters were pivotal for a computational model to generate trajectories of point-to-point planar movements similar to those made by post-stroke subjects at different levels of impairment. The set of kinematic variables used in the model allowed for the generation of trajectories significantly similar to those of either sub-acute or chronic post-stroke patients at different time points during the therapy. Simulated trajectories also correctly reproduced many kinematic features of real movements, as assessed by an extensive set of kinematic metrics computed on both real and simulated curves. When inspected for redundancy, we found that variations in the variables used in the model were explained by three different underlying and unobserved factors related to movement efficiency, speed, and accuracy, possibly revealing different working mechanisms of recovery. This study identified a set of measures capable of extensively characterizing the kinematics of upper limb movements performed by post-stroke subjects and of tracking changes of different motor improvement aspects throughout the rehabilitation process.


Forskolin potentiation of cholera toxin-stimulated cyclic AMP accumulation in intact C6-2B cells. Evidence for enhanced Gs-C coupling.
Forskolin directly stimulates adenylate cyclase activity and acts synergistically with receptor-mediated agonists which stimulate cyclic AMP production. We have previously observed that a 3-hr incubation of C6-2B rat astrocytoma cells with 6 nM cholera toxin in the presence of 1 microM forskolin results in cyclic AMP accumulation 9-fold greater than in the absence of forskolin. Since the action of cholera toxin is mediated by the stimulatory guanine nucleotide-binding regulatory component (GS) of the adenylate cyclase complex, we proposed that the mechanism by which forskolin augments hormone responses involves an enhanced coupling of GS with the adenylate cyclase catalytic component (C). In the present communication, we report the detailed characterization of the synergistic interaction between forskolin and cholera toxin as effectors of cyclic AMP accumulation in intact C6-2B cells. After a 3-hr incubation, maximal cholera toxin-stimulated cyclic AMP accumulation was 990 +/- 34 pmol/mg of protein. In the presence of 1 microM forskolin, the response to cholera toxin increased to 13,137 +/- 1,595 pmol of cyclic AMP/mg of protein. The half-maximally effective cholera toxin concentrations estimated by nonlinear least squares regression analysis determined in the absence or presence of 0.1 mM forskolin were 56.6 and 57.5 pM, respectively. The highly reproducible lag in forskolin-stimulated cyclic AMP accumulation in C6-2B cells was abolished by cholera toxin pretreatment, indicating a possible role for GS-associated GTPase in the mechanism of forskolin action. Cholera toxin treatment markedly augmented forskolin-stimulated cyclic AMP accumulation and shifted the forskolin concentration-response curve to the left approximately 1.5 log units. When C6-2B cells were treated for 1 min with 10 nM cholera toxin, the response to forskolin was significantly potentiated by 10 min. No significant increase in cellular cyclic AMP content in the absence of a forskolin challenge was apparent for up to 45 min. It appears that prior promotion of GS-C coupling by cholera toxin treatment enhances the ability of forskolin to stimulate cyclic AMP accumulation. Whether or not forskolin interacts (i.e., binds) exclusively to C remains to be proven. However, the actions of forskolin to stimulate cyclic AMP formation and potentiate agonist-stimulated cyclic AMP formation are modulated by the activity state of GS, and at least part of the response to forskolin is mediated by GS.


Chemical Constituents from Hericium erinaceus Promote Neuronal Survival and Potentiate Neurite Outgrowth via the TrkA/Erk1/2 Pathway.
Hericium erinaceus is a culinary-medicinal mushroom used traditionally in Eastern Asia to improve memory. In this work, we investigated the neuroprotective and neuritogenic effects of the secondary metabolites isolated from the MeOH extract of cultured mycelium of H. erinaceus and the primary mechanisms involved. One new dihydropyridine compound (6) and one new natural product (2) together with five known compounds (1,3-5,7) were obtained and their structures were elucidated by spectroscopic analysis, including 2D NMR and HRMS. The cell-based screening for bioactivity showed that 4-chloro-3,5-dimethoxybenzoic methyl ester (1) and a cyathane diterpenoid, erincine A (3), not only potentiated NGF-induced neurite outgrowth but also protected neuronally-differentiated cells against deprivation of NGF in PC12 pheochromocytoma cells. Additionally, compound 3 induced neuritogenesis in primary rat cortex neurons. Furthermore, our results revealed that TrkA-mediated and Erk1/2-dependant pathways could be involved in 1 and 3-promoted NGF-induced neurite outgrowth in PC12 cells.


Energetic interventions for healthspan and resiliency with aging.
Several behavioral and pharmacological strategies improve longevity, which is indicative of delayed organismal aging, with the most effective interventions extending both life- and healthspan. In free living creatures, maintaining health and function into old age requires resilience against a multitude of stressors. Conversely, in experimental settings, conventional housing of rodents limits exposure to such challenges, thereby obscuring an accurate assessment of resilience. Caloric restriction (CR) and exercise, as well as pharmacologic strategies (resveratrol, rapamycin, metformin, senolytics), are well established to improve indices of health and aging, but some paradoxical effects have been observed on resilience. For instance, CR potently retards the onset of age-related diseases, and improves lifespan to a greater extent than exercise in a variety of models. However, exercise has proven more consistently beneficial to organismal resilience against a broad array of stressors, including infections, surgery, wound healing and frailty. CR can improve cellular stress defenses and protect from frailty, but also impairs the response to infections, bed rest and healing. How an intervention will impact not only longevity, health and function, but also resiliency, is critical to better understanding translational implications. Thus, organismal robustness represents a critical, albeit understudied aspect of aging, which needs more careful attention in order to better inform on how putative age-delaying strategies will impact preservation of health and function in response to stressors with aging in humans.


Craniocerebral injuries in war against terrorism --- a contemporary series from Pakistan.
Terrorism-related bomb attacks on civilian population have increased dramatically over the last decade. Craniocerebral injuries secondary to improvised explosive devices have not been widely reported in the context of unarmored civilians. This series intends to report the spectrum of these injuries secondary to suicidal and implanted bombs as encountered at the Aga Khan University Hospital, Pakistan (AKUH). Further, a few pertinent management guidelines have also been discussed. The hospital database and clinical coding during a 5-year period were examined for head injuries secondary to terrorism-associated blasts. In addition to patient demographics, data analysis for our series included initial Glasgow Coma Scale, presenting neurological complaints, associated non-neurological injuries, management (conservative or operative) to associated complications, and discharge neurological status. A total of 16 patients were included in this series. Among them 9 were victims of suicidal blasts while 7 were exposed to implanted devices. The patients presented with diverse patterns of injury secondary to a variety of shrapnel. A follow-up record was available for 12 of the 16 patients (mean follow-up: 7.8 months), with most patients having no active complaints. The results of this series show that civilian victims of suicidal and improvised bombings present with a wide range of neurological symptoms and injury patterns, which often differ from the neurological injuries incurred by military personnel in similar situations, and thereby often require individualized care.