Characterization of intra-graft B cells during renal allograft rejection

Intra-graft CD20+ B-cell clusters are found during acute rejection of renal allografts and correlate with graft recovery following rejection injury. Here using archived kidney tissue we conducted immunohistochemical studies to measure specific subsets of pathogenic B cells during graft rejection. Cluster-forming CD20+ B cells in the rejected graft are likely derived from the recipient and are composed of mature B cells. These cells are activated (CD79a+), and present MHC Class II antigen (HLADR+) to CD4+ T cells. Some of these clusters contained memory B cells (CD27+) and they did not correlate with intra-graft C4d deposition or with detection of donor-specific antibody. Further, several non-cluster forming CD20− B-lineage CD38+ plasmablasts and plasma cells were found to infiltrate the rejected grafts and these cells strongly correlated with circulating donor-specific antibody, and to a lesser extent with intra-graft C4d. Both CD20+ B cells and CD38+ cells correlated with poor response of the rejection to steroids. Reduced graft survival was associated with the presence of CD20 cells in the graft. In conclusion, a specific subset of early lineage B cells appears to be an antigen-presenting cell and which when present in the rejected graft may support a steroid-resistant T-cell-mediated cellular rejection. Late lineage interstitial plasmablasts and plasma cells may also support humoral rejection. These studies suggest that detailed analysis of interstitial cellular infiltrates may allow better use of B-cell lineage specific treatments to improve graft outcomes

Combined impact of lifestyle factors on mortality: prospective cohort study in US women

Objective To evaluate the impact of combinations of lifestyle factors on mortality in middle aged women

Randomized Crossover Study Showing Nurse-Led Same Day Review Replacing Next Day Review in Uneventful Phacoemulsification to Be Safe and Efficacious

Purpose. To study whether nurse led same-day review (SDR) after uneventful phacoemulsification can replace next-day review (NDR) in terms of safety and efficacy. Setting. Patients are recruited from an ophthalmology outpatient clinic in Hong Kong. Design. A prospective, randomized crossover study conducted from November 2012 to 2014. Methods. Inclusion criteria include cataract surgery naïve patients undergoing phacoemulsification under local anaesthesia. All patients were seen by our ophthalmic nurse 2 hours after surgery. Before undergoing phacoemulsification of the first eye, patients were randomized to be reviewed on day 1 or 7 after surgery. Surgeons and reviewing doctors were blinded to patient allocation. For the patients’ second eye surgery, group allocation will cross over. Primary outcome measures include visual improvement and patient satisfaction questionnaire. Other measures include cataract characteristics, surgical details, and complications. Statistical tests include paired t-test, Wilcoxon signed rank test, and Chi-square test. Results. 164 eyes from 82 patients were available. Visual improvement, satisfaction, and complications were comparable between both groups. Conclusions. A nurse led SDR can replace NDR in uneventful phacoemulsification in terms of safety and efficacy. Patient satisfaction is also comparable in the setting of Asian culture and when transportation is not a major concern

Weakly activated core neuroinflammation pathways were identified as a central signaling mechanism contributing to the chronic neurodegeneration in Alzheimer\u27s disease

OBJECTIVES: Neuroinflammation signaling has been identified as an important hallmark of Alzheimer\u27s disease (AD) in addition to amyloid β plaques (Aβ) and neurofibrillary tangles (NFTs). However, the molecular mechanisms and biological processes of neuroinflammation remain unclear and have not well delineated using transcriptomics data available. Our objectives are to uncover the core neuroinflammation signaling pathways in AD using integrative network analysis on the transcriptomics data. MATERIALS AND METHODS: From a novel perspective, i.e., investigating weakly activated molecular signals (rather than the strongly activated molecular signals), we developed integrative and systems biology network analysis to uncover potential core neuroinflammation signaling targets and pathways in AD using the two large-scale transcriptomics datasets, i.e., Mayo Clinic (77 controls and 81 AD samples) and ROSMAP (97 controls and 260 AD samples). RESULTS: Our analysis identified interesting core neuroinflammation signaling pathways, which are not systematically reported in the previous studies of AD. Specifically, we identified 7 categories of signaling pathways implicated on AD and related to virus infection: immune response, x-core signaling, apoptosis, lipid dysfunctional, biosynthesis and metabolism, and mineral absorption signaling pathways. More interestingly, most of the genes in the virus infection, immune response, and x-core signaling pathways are associated with inflammation molecular functions. The x-core signaling pathways were defined as a group of 9 signaling proteins: MAPK, Rap1, NF-kappa B, HIF-1, PI3K-Akt, Wnt, TGF-beta, Hippo, and TNF, which indicated the core neuroinflammation signaling pathways responding to the low-level and weakly activated inflammation and hypoxia and leading to the chronic neurodegeneration. It is interesting to investigate the detailed signaling cascades of these weakly activated neuroinflammation signaling pathways causing neurodegeneration in a chronic process, and consequently uncover novel therapeutic targets for effective AD treatment and prevention. CONCLUSIONS: The potential core neuroinflammation and associated signaling targets and pathways were identified using integrative network analysis on two large-scale transcriptomics datasets of AD

Molecular hydrogen emission in the interstellar medium of the Large Magellanic Cloud

We present the detection and analysis of molecular hydrogen emission toward ten interstellar regions in the Large Magellanic Cloud. We examined low-resolution infrared spectral maps of twelve regions obtained with the Spitzer infrared spectrograph (IRS). The pure rotational 0--0 transitions of H$_2$ at 28.2 and 17.1${\,\rm \mu m}$ are detected in the IRS spectra for ten regions. The higher level transitions are mostly upper limit measurements except for three regions, where a 3$\sigma$ detection threshold is achieved for lines at 12.2 and 8.6${\,\rm \mu m}$. The excitation diagrams of the detected H$_2$ transitions are used to determine the warm H$_2$ gas column density and temperature. The single-temperature fits through the lower transition lines give temperatures in the range $86-137\,{\rm K}$. The bulk of the excited H$_2$ gas is found at these temperatures and contributes $\sim$5-17% to the total gas mass. We find a tight correlation of the H$_2$ surface brightness with polycyclic aromatic hydrocarbon and total infrared emission, which is a clear indication of photo-electric heating in photodissociation regions. We find the excitation of H$_2$ by this process is equally efficient in both atomic and molecular dominated regions. We also present the correlation of the warm H$_2$ physical conditions with dust properties. The warm H$_2$ mass fraction and excitation temperature show positive correlations with the average starlight intensity, again supporting H$_2$ excitation in photodissociation regions.Comment: Accepted for publication in MNRA

The treatment of severe child aggression (TOSCA) study: Design challenges

<p>Abstract</p> <p>Background</p> <p>Polypharmacy (the concurrent use of more than one psychoactive drug) and other combination interventions are increasingly common for treatment of severe psychiatric problems only partly responsive to monotherapy. This practice and research on it raise scientific, clinical, and ethical issues such as additive side effects, interactions, threshold for adding second drug, appropriate target measures, and (for studies) timing of randomization. One challenging area for treatment is severe child aggression. Commonly-used medications, often in combination, include psychostimulants, antipsychotics, mood stabilizers, and alpha-2 agonists, which vary considerably in terms of perceived safety and efficacy.</p> <p>Results</p> <p>In designing our NIMH-funded trial of polypharmacy, we focused attention on the added benefit of a second drug (risperidone) to the effect of the first (stimulant). We selected these two drugs because their associated adverse events might neutralize each other (e.g., sleep delay and appetite decrease from stimulant versus sedation and appetite increase from antipsychotic). Moreover, there was considerable evidence of efficacy for each drug individually for the management of ADHD and child aggression. The study sample comprised children (ages 6-12 years) with both diagnosed ADHD and disruptive behavior disorder (oppositional-defiant or conduct disorder) accompanied by severe physical aggression. In a staged sequence, the medication with the least problematic adverse effects (stimulant) was openly titrated in 3 weeks to optimal effect. Participants whose behavioral symptoms were not normalized received additional double-blind medication, either risperidone or placebo, by random assignment. Thus children whose behavioral symptoms were normalized with stimulant medication were not exposed to an antipsychotic. All families participated in an empirically-supported parent training program for disruptive behavior, so that the actual comparison was stimulant+parent training versus stimulant+antipsychotic+parent training.</p> <p>Conclusions</p> <p>We hope that the resolutions of the challenges presented here will be useful to other investigators and facilitate much-needed research on child psychiatric polypharmacy.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov <a href="http://www.clinicaltrials.gov/ct2/show/NCT00796302">NCT00796302</a></p

Self-rated health in middle-aged and elderly Chinese : distribution, determinants and associations with cardio-metabolic risk factors

Background: Self-rated health (SRH) has been demonstrated to be an accurate reflection of a person's health and a valid predictor of incident mortality and chronic morbidity. We aimed to evaluate the distribution and factors associated with SRH and its association with biomarkers of cardio-metabolic diseases among middle-aged and elderly Chinese. Methods: Survey of 1,458 men and 1,831 women aged 50 to 70 years, conducted in one urban and two rural areas of Beijing and Shanghai in 2005. SRH status was measured and categorized as good (very good and good) vs. not good (fair, poor and very poor). Determinants of SRH and associations with biomarkers of cardio-metabolic diseases were evaluated using logistic regression. Results: Thirty two percent of participants reported good SRH. Males and rural residents tended to report good SRH. After adjusting for potential confounders, residence, physical activity, employment status, sleep quality and presence of diabetes, cardiovascular disease, and depression were the main determinants of SRH. Those free from cardiovascular disease (OR 3.68; 95%CI 2.39; 5.66), rural residents (OR 1.89; 95% CI 1.47; 2.43), non-depressed participants (OR 2.50; 95% CI 1.67; 3.73) and those with good sleep quality (OR 2.95; 95% CI 2.22; 3.91) had almost twice or over the chance of reporting good SRH compared to their counterparts. There were significant associations -and trend- between SRH and levels of inflammatory markers, insulin levels and insulin resistance. Conclusion: Only one third of middle-aged and elderly Chinese assessed their health status as good or very good. Although further longitudinal studies are required to confirm our findings, interventions targeting social inequalities, lifestyle patterns might not only contribute to prevent chronic morbidity but as well to improve populations' perceived health

An atlas of cortical circular RNA expression in Alzheimer disease brains demonstrates clinical and pathological associations.

Parietal cortex RNA-sequencing (RNA-seq) data were generated from individuals with and without Alzheimer disease (AD; ncontrol = 13; nAD = 83) from the Knight Alzheimer Disease Research Center (Knight ADRC). Using this and an independent (Mount Sinai Brain Bank (MSBB)) AD RNA-seq dataset, cortical circular RNA (circRNA) expression was quantified in the context of AD. Significant associations were identified between circRNA expression and AD diagnosis, clinical dementia severity and neuropathological severity. It was demonstrated that most circRNA-AD associations are independent of changes in cognate linear messenger RNA expression or estimated brain cell-type proportions. Evidence was provided for circRNA expression changes occurring early in presymptomatic AD and in autosomal dominant AD. It was also observed that AD-associated circRNAs co-expressed with known AD genes. Finally, potential microRNA-binding sites were identified in AD-associated circRNAs for miRNAs predicted to target AD genes. Together, these results highlight the importance of analyzing non-linear RNAs and support future studies exploring the potential roles of circRNAs in AD pathogenesis

Real-Time Traffic Information for Emergency Evacuation Operations: Phase A Final Report

There are many instances in which it is possible to plan ahead for an emergency evacuation (e.g., an explosion at a chemical processing facility). For those cases, if an accident (or an attack) were to happen, then the best evacuation plan for the prevailing network and weather conditions would be deployed. In other cases (e.g., the derailment of a train transporting hazardous materials), there may not be any previously developed plan to be implemented and decisions must be made ad-hoc on how to proceed with an emergency evacuation. In both situations, the availability of real-time traffic information plays a critical role in the management of the evacuation operations. To improve public safety during a vehicular emergency evacuation it is necessary to detect losses of road capacity (due to incidents, for example) as early as possible. Once these bottlenecks are identified, re-routing strategies must be determined in real-time and deployed in the field to help dissipate the congestion and increase the efficiency of the evacuation. Due to cost constraints, only large urban areas have traffic sensor deployments that permit access to some sort of real-time traffic information; any evacuation taking place in any other areas of the country would have to proceed without real-time traffic information. The latter was the focus of this SERRI/DHS (Southeast Region Research Initiative/Department of Homeland Security) sponsored project. That is, the main objective on the project was to improve the operations during a vehicular emergency evacuation anywhere by using newly developed real-time traffic-information-gathering technologies to assess traffic conditions and therefore to potentially detect incidents on the main evacuation routes. Phase A of the project consisted in the development and testing of a prototype system composed of sensors that are engineered in such a way that they can be rapidly deployed in the field where and when they are needed. Each one of these sensors is also equipped with their own power supply and a GPS (Global Positioning System) device to auto-determine its spatial location on the transportation network under surveillance. The system is capable of assessing traffic parameters by identifying and re-identifying vehicles in the traffic stream as those vehicles pass over the sensors. The system of sensors transmits, through wireless communication, real-time traffic information (travel time and other parameters) to a command and control center via an NTCIP (National Transportation Communication for ITS Protocol) -compatible interface. As an alternative, an existing NTCIP-compatible system accepts the real-time traffic information mentioned and broadcasts the traffic information to emergency managers, the media and the public via the existing channels. A series of tests, both in a controlled environment and on the field, were conducted to study the feasibility of rapidly deploying the system of traffic sensors and to assess its ability to provide real-time traffic information during an emergency evacuation. The results of these tests indicated that the prototype sensors are reliable and accurate for the type of application that is the focus of this project