Neural Dynamics in Parkinsonian Brain:The Boundary Between Synchronized and Nonsynchronized Dynamics

Synchronous oscillatory dynamics is frequently observed in the human brain. We analyze the fine temporal structure of phase-locking in a realistic network model and match it with the experimental data from parkinsonian patients. We show that the experimentally observed intermittent synchrony can be generated just by moderately increased coupling strength in the basal ganglia circuits due to the lack of dopamine. Comparison of the experimental and modeling data suggest that brain activity in Parkinson's disease resides in the large boundary region between synchronized and nonsynchronized dynamics. Being on the edge of synchrony may allow for easy formation of transient neuronal assemblies

Rapid turnover of effector-memory CD4(+) T cells in healthy humans

Memory T cells can be divided into central-memory (T(CM)) and effector-memory (T(EM)) cells, which differ in their functional properties. Although both subpopulations can persist long term, it is not known whether they are maintained by similar mechanisms. We used in vivo labeling with deuterated glucose to measure the turnover of CD4(+) T cells in healthy humans. The CD45R0(+)CCR7(-) T(EM) subpopulation was shown to have a rapid proliferation rate of 4.7% per day compared with 1.5% per day for CD45R0(+)CCR7(+) T(CM) cells; these values are equivalent to average intermitotic (doubling) times of 15 and 48 d, respectively. In contrast, the CD45RA(+)CCR7(+) naive CD4(+) T cell population was found to be much longer lived, being labeled at a rate of only 0.2% per day (corresponding to an intermitotic time of approximately 1 yr). These data indicate that human CD4(+) T(EM) cells constitute a short-lived cell population that requires continuous replenishment in vivo

Treatment Strategies for Central Nervous System Effects in Primary and Secondary Haemophagocytic Lymphohistiocytosis in Children

Purpose of Review: This review presents an appraisal of current therapeutic options for the treatment of central nervous system haemophagocytic lymphohistiocytosis (CNS-HLH) in the context of systemic disease, as well as when CNS features occur in isolation. We present the reader with a diagnostic approach to CNS-HLH and commonly used treatment protocols. We discuss and evaluate newer treatments on the horizon. Recent Findings: Mortality is high in patients who do not undergo HSCT, and while larger studies are required to establish benefit in many treatments, a number of new treatments are currently being evaluated. Alemtuzumab is being used as a first-line treatment for CNS-HLH in a phase I/II multicentre prospective clinical trial as an alternative to traditional HLH-1994 and 2004 protocols. It has also been used successfully as a second-line agent for the treatment of isolated CNS-HLH that is refractory to standard treatment. Ruxolitinib and emapalumab are new immunotherapies that block the Janus kinase—Signal Transducer and Activator of Transcription (JAK-STAT) pathway that have shown efficacy in refractory HLH, including for CNS-HLH disease. Summary: Treatment of CNS-HLH often requires HLH-94 or 2004 protocols followed by haematopoietic stem cell transplantation (HSCT) to maintain remission, although relapse can occur, particularly with reduced intensity conditioning if donor chimerism falls. CNS features have been shown to improve or stabilise following HSCT in CNS-HLH in the context of systemic disease and in isolated CNS-HLH. Encouraging reports of early cohort studies suggest alemtuzumab and the Janus kinase (JAK) inhibitor ruxolitinib offer potential salvage therapy for relapsed and refractory CNS-HLH. Newer immunotherapies such as tocilizumab and natalizumab have been shown to be beneficial in sporadic cases. CNS-HLH due to primary gene defects may be amenable to gene therapy in the future

Summertime Nutrient Supply to Near-Surface Waters of the Northeastern Gulf of Mexico: 1998, 1999, and 2000

In the summers of 1998, 1999, and 2000, deep water eddies induced strong anticyclonic currents along the upper slope and outer shelf from the Mississippi River delta to the west Florida shelf. Those currents transported Mississippi River discharge eastward along the outer shelf and slope, reversing the normal offshore increase in salinity, with the exception of a few regions very near the coast that were influenced by the discharges from other rivers or bays. The entrainment of low-salinity river water resulted in anomalously high chlorophyll a concentrations in the upper 15 m over the outer shelf and upper slope, in contrast to the concentrations that typically occur over deep water in the subtropics in summer. Nitrate concentrations in this surface water were quite low except near the mouths of rivers, which act as point sources for nutrients; presumably, this was because of the rapid utilization of nitrate by phytoplankton. A significant supply of nutrients to the euphotic zone at regions quite removed from these point sources resulted from eddies intruding onto or formed over the slope. These caused mid-depth water rich in nutrients to be uplifted to within the euphotic zone, the uplift depending on the location and intensity of the eddies. Based on measurements at approximately 100 stations on each cruise, estimates were made of the quantity of nitrate and silicate in the upper 15 m of the water column and in the depth interval from 15m to 60 m, the nominal depth of the euphotic zone. Study results suggest that the nitrate and silicate in the near-surface interval of 0-15 m largely resulted from riverine discharge and subsequent advection, while the nutrients between 15 and 60 m resulted from uplift of waters by circulation features. The euphotic zone occupied at least the upper 60 m of the water column, but standing stocks of nitrate and silicate in the 15- to 60-m layer were between two and six times those in the upper 15 m on all three cruises and appeared to depend on the strength and relative proximity to the shelf break of local anticyclonic features. The effects of these circulation features were potentially significant in supplying nutrients to the euphotic zone during these summers

Comparing media and family predictors of alcohol use: a cohort study of US adolescents

Objective: To compare media/marketing exposures and family factors in predicting adolescent alcohol use. Design: Cohort study. Setting: Confidential telephone survey of adolescents in their homes. Participants: Representative sample of 6522 US adolescents, aged 10–14 years at baseline and surveyed four times over 2 years. Primary: outcome measure Time to alcohol onset and progression to binge drinking were assessed with two survival models. Predictors were movie alcohol exposure (MAE), ownership of alcohol-branded merchandise and characteristics of the family (parental alcohol use, home availability of alcohol and parenting). Covariates included sociodemographics, peer drinking and personality factors. Results: Over the study period, the prevalence of adolescent ever use and binge drinking increased from 11% to 25% and from 4% to 13%, respectively. At baseline, the median estimated MAE from a population of 532 movies was 4.5 h and 11% owned alcohol-branded merchandise at time 2. Parental alcohol use (greater than or equal to weekly) was reported by 23% and 29% of adolescents could obtain alcohol from home. Peer drinking, MAE, alcohol-branded merchandise, age and rebelliousness were associated with both alcohol onset and progression to binge drinking. The adjusted hazard ratios for alcohol onset and binge drinking transition for high versus low MAE exposure were 2.13 (95% CI 1.76 to 2.57) and 1.63 (1.20 to 2.21), respectively, and MAE accounted for 28% and 20% of these transitions, respectively. Characteristics of the family were associated with alcohol onset but not with progression. Conclusion: The results suggest that family focused interventions would have a larger impact on alcohol onset while limiting media and marketing exposure could help prevent both onset and progression

Persistent low-level variants in a subset of viral genes are highly predictive of poor outcome in immunocompromised patients with cytomegalovirus infection

ABSTRACT Background Human cytomegalovirus is the most common and serious opportunistic infection after solid organ and haematopoietic stem cell transplantation. In this study, we used whole-genome cytomegalovirus data to investigate viral factors associated with the clinical outcome. Methods We sequenced cytomegalovirus samples from 16 immunocompromised paediatric patients with persistent viraemia. 8/16 patients died of complications due to cytomegalovirus infection. We also sequenced samples from 35 infected solid organ adult recipients of whom one died with cytomegalovirus infection. Results We showed that samples from both groups have fixed variants at resistance sites and mixed infections. NGS sequencing also revealed non-fixed variants at resistance sites in most of the patients who died (6/9). A machine learning approach identified 10 genes with non-fixed variants in these patients. These genes formed a viral signature which discriminated patients with cytomegalovirus infection who died from those that survived with high accuracy (AUC=0.96). Lymphocyte numbers for a subset of patients showed no recovery post-transplant in the patients who died. Conclusions We hypothesise that the viral signature identified in this study may be a useful biomarker for poor response to antiviral drug treatment and indirectly for poor T cell function, potentially identifying early, those patients requiring non-pharmacological interventions

The role of healthcare professionals in encouraging parents to see and hold their stillborn baby: a meta-synthesis of qualitative studies.

Background: Globally, during 2013 there were three million recorded stillbirths. Where clinical guidelines exist some recommend that professionals do not encourage parental contact. The guidance is based on quantitative evidence that seeing and holding the baby is not beneficial for everyone, but has been challenged by bereaved parents' organisations. We aim to inform future guideline development through a synthesis of qualitative studies reporting data relevant to the research question; how does the approach of healthcare professionals to seeing and holding the baby following stillbirth impact parents views and experiences? Methods/Findings: Using a predetermined search strategy of PubMed and PsychINFO we identified robust qualitative studies reporting bereaved parental views and/or experiences relating to seeing and holding their stillborn baby (final search 24 February, 2014). Eligible studies were English language, reporting parental views, with gestational loss >20weeks. Quality was independently assessed by three authors using a validated tool. We used meta-ethnographic techniques to identify key themes and a line of argument synthesis. We included 12 papers, representing the views of 333 parents (156 mothers, 150 fathers, and 27 couples) from six countries. The final themes were: "[Still]birth: Nature of care is paramount", "Real babies: Perfect beauties, monsters and spectres", and "Opportunity of a lifetime lost." Our line-of-argument synthesis highlights the contrast between all parents need to know their baby, with the time around birth being the only time memories can be made, and the variable ability that parents have to articulate their preferences at that time. Thus, we hypothesised that how health professionals approach contact between parents and their stillborn baby demands a degree of active management. An important limitation of this paper is all included studies originated from high income, westernised countries raising questions about the findings transferability to other cultural contexts. We do not offer new evidence to answer the question "Should parents see and hold their stillborn baby?", instead our findings advance understanding of how professionals can support parents to make appropriate decisions in a novel, highly charged and dynamic situation. Conclusions: Guidelines could be more specific in their recommendations regarding parental contact. The role of healthcare professionals in encouraging parents to see and hold their stillborn baby is paramount. Parental choice not to see their baby, apprehension, or uncertainty should be continuously revisited in the hours after birth as the opportunity for contact is fleeting and final

Making sense of illness: the experiences of users of complementary medicine

The present study investigated the experiences of users of complementary and alternative medicine (CAM) using a qualitative approach. In-depth interviews were conducted with 11 frequent users and analysed using interpretative phenomenological analysis (IPA). Results indicated that the patient-practitioner relationship and explanatory frameworks provided by CAM were perceived as important components of the therapeutic process, irrespective of treatment efficacy. CAM served a variety of functions beyond the explicit relief of symptoms by increasing energy and relaxation, facilitating coping and enhancing self/other awareness. It is therefore important that these wider effects are taken into account when evaluating complementary medicine in order to accurately reflect patients' experiences