Therapeutic effects of peripheral repetitive magnetic stimulation on myofascial pain syndrome.
To evaluate short- and medium-term effects of peripheral repetitive magnetic stimulation (rMS) on myofascial pain. Eighteen patients who presented with myofascial trigger points (TPs) at the level of the superior trapezius were separated into two groups according to a restricted randomization scheme. Group 1 (n=9) underwent treatment with rMS that consisted of a total of 10 sessions, each lasting 20min, in which 4000 magnetic stimuli were administered in 5s trains at 20Hz at the TP. Group 2 (n=9) received a placebo treatment that consisted of the application of a non-functioning ultrasound therapy device to the TP. Patients were evaluated before treatment, at the end of treatment, and again 1 week and 1 month after the conclusion of the treatment. Clinical evaluation included parameters for measuring pain levels (VAS, NPDVAS and algometry), the myofascial TP characteristics and the range of cervical movement (ROM). The rMS group showed a significant improvement in VAS, NPDVAS, algometry, as well as in the characteristics of the TP after conclusion of treatment. Improvements in the ROM were also present in rotation and controlateral bending. This improvement persisted after 1 month. On the other hand, the placebo group did not show any significant improvement in the tests considered. The results of this study show that peripheral rMS may have positive short- and medium-term therapeutic effects on myofascial pain.


Hodgkin lymphoma treatment with ABVD in the US and the EU: neutropenia occurrence and impaired chemotherapy delivery.
In newly diagnosed patients with Hodgkin lymphoma (HL) the effect of doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD)-related neutropenia on chemotherapy delivery is poorly documented. The aim of this analysis was to assess the impact of chemotherapy-induced neutropenia (CIN) on ABVD chemotherapy delivery in HL patients. Data from two similarly designed, prospective, observational studies conducted in the US and the EU were analysed. One hundred and fifteen HL patients who started a new course of ABVD during 2002-2005 were included. The primary objective was to document the effect of neutropenic complications on delivery of ABVD chemotherapy in HL patients. Secondary objectives were to investigate the incidence of CIN and febrile neutropenia (FN) and to compare US and EU practice with ABVD therapy in HL. Pooled data were analysed to explore univariate associations with neutropenic events. Chemotherapy delivery was suboptimal (with a relative dose intensity < or = 85%) in 18-22% of patients. The incidence of grade 4 CIN in cycles 1-4 was lower in US patients (US 24% vs. EU 32%). Patients in both the US and the EU experienced similar rates of FN across cycles 1-4 (US 12% vs. EU 11%). Use of primary colony-stimulating factor (CSF) prophylaxis and of any CSF was more common in the US than the EU (37% vs. 4% and 78% vs. 38%, respectively). The relative risk (RR) of dose delays was 1.54 (95% confidence interval [CI] 1.08-2.23, p = 0.036) for patients with vs. without grade 4 CIN and the RR of grade 4 CIN was 0.35 (95% CI 0.12-1.06, p = 0.046) for patients with vs. without primary CSF prophylaxis. In this population of HL patients, CIN was frequent and FN occurrence clinically relevant. Chemotherapy delivery was suboptimal. CSF prophylaxis appeared to reduce CIN rates.


AcademyHealth's Delivery System Science Fellowship: Training Embedded Researchers to Design, Implement, and Evaluate New Models of Care.
AcademyHealth's Delivery System Science Fellowship (DSSF) provides a paid postdoctoral pragmatic learning experience to build capacity within learning healthcare systems to conduct research in applied settings. The fellowship provides hands-on training and professional leadership opportunities for researchers. Since its inception in 2012, the program has grown rapidly, with 16 health systems participating in the DSSF to date. In addition to specific projects conducted within health systems (and numerous publications associated with those initiatives), the DSSF has made several broader contributions to the field, including defining delivery system science, identifying a set of training objectives for researchers working in delivery systems, and developing a national collaborative network of care delivery organizations, operational leaders, and trainees. The DSSF is one promising approach to support higher-value care by promoting continuous learning and improvement in health systems.


Long Noncoding RNA Malat1 Regulates Cerebrovascular Pathologies in Ischemic Stroke.
The study was designed to determine the role of long noncoding RNA (lncRNA), metastasis-associated lung adenocarcinoma transcript 1 (Malat1), in ischemic stroke outcome. Primary mouse brain microvascular endothelial cells (BMECs) were cultured and treated with Malat1 GapmeR before 16 h oxygen and glucose depravation (OGD). Cell death was assayed by LDH and MTT methods. Malat1 knock-out and wild-type mice were subjected to 1 h of middle cerebral artery occlusion (MCAO) and 24-72 h of reperfusion. To explore the underlying mechanism, apoptotic and inflammatory factors were measured by qPCR, ELISA, and Western blotting. The physical interaction between Malat1 and apoptotic or inflammatory factors was measured by RNA immunoprecipitation. Increased Malat1 levels were found in cultured mouse BMECs after OGD as well as in isolated cerebral microvessels in mice after MCAO. Silencing of Malat1 by Malat1 GapmeR significantly increased OGD-induced cell death and Caspase 3 activity in BMECs. Silencing of Malat1 also significantly aggravated OGD-induced expression of the proapoptotic factor Bim and proinflammatory cytokines MCP-1, IL-6, and E-selectin. Moreover, Malat1 KO mice presented larger brain infarct size, worsened neurological scores, and reduced sensorimotor functions. Consistent with in vitro findings, significantly increased expression of proapoptotic and proinflammatory factors was also found in the cerebral cortex of Malat1 KO mice after ischemic stroke compared with WT controls. Finally, we demonstrated that Malat1 binds to Bim and E-selectin both in vitro and in vivo Our study suggests that Malat1 plays critical protective roles in ischemic stroke.SIGNIFICANCE STATEMENT Accumulative studies have demonstrated the important regulatory roles of microRNAs in vascular and neural damage after ischemic stroke. However, the functional significance and mechanisms of other classes of noncoding RNAs in cerebrovascular pathophysiology after stroke are less studied. Here we demonstrate a novel role of Malat1, a long noncoding RNA that has been originally identified as a prognostic marker for non-small cell lung cancer, in cerebrovascular pathogenesis of ischemic stroke. Our experiments have provided the first evidence that Malat1 plays anti-apoptotic and anti-inflammatory roles in brain microvasculature to reduce ischemic cerebral vascular and parenchymal damages. Our studies also suggest that lncRNAs can be therapeutically targeted to minimize poststroke brain damage.


Broadly neutralizing antibodies that inhibit HIV-1 cell to cell transmission.
The neutralizing activity of anti-HIV-1 antibodies is typically measured in assays where cell-free virions enter reporter cell lines. However, HIV-1 cell to cell transmission is a major mechanism of viral spread, and the effect of the recently described broadly neutralizing antibodies (bNAbs) on this mode of transmission remains unknown. Here we identify a subset of bNAbs that inhibit both cell-free and cell-mediated infection in primary CD4(+) lymphocytes. These antibodies target either the CD4-binding site (NIH45-46 and 3BNC60) or the glycan/V3 loop (10-1074 and PGT121) on HIV-1 gp120 and act at low concentrations by inhibiting multiple steps of viral cell to cell transmission. These antibodies accumulate at virological synapses and impair the clustering and fusion of infected and target cells and the transfer of viral material to uninfected T cells. In addition, they block viral cell to cell transmission to plasmacytoid DCs and thereby interfere with type-I IFN production. Thus, only a subset of bNAbs can efficiently prevent HIV-1 cell to cell transmission, and this property should be considered an important characteristic defining antibody potency for therapeutic or prophylactic antiviral strategies.


Association of spinal instability due to metastatic disease with increased mortality and a proposed clinical pathway for treatment.
Multidisciplinary treatment including medical oncology, radiation oncology, and surgical consultation is necessary to provide comprehensive therapy for patients with spinal metastases. The goal of this study was to review the use of radiation therapy and/or surgical intervention and their impact on patient outcomes. In this retrospective series, the authors identified at their institution those patients with spinal metastases who had received radiation therapy alone or had undergone surgery with or without radiation therapy within a 6-year period. Data on patient age, chemotherapy, surgical procedure, radiation therapy, Karnofsky Performance Status (KPS), primary tumor pathology, Spinal Instability Neoplastic Score (SINS), and survival after treatment were collected from the patient electronic medical records. N - 1 chi-square testing was used for comparisons of proportions. The Student t-test was used for comparisons of means. A p value < 0.05 was considered statistically significant. A survival analysis was completed using a multivariate Cox proportional hazards model. Two hundred thirty patients with spinal metastases were identified, 109 of whom had undergone surgery with or without radiation therapy. Among the 104 patients for whom the surgical details were reviewed, 34 (33%) had a history of preoperative radiation to the surgical site but ultimately required surgical intervention. In this surgical group, a significantly increased frequency of death within 30 days was noted for the SINS unstable patients (23.5%) as compared to that for the SINS stable patients (2.3%; p < 0.001). The SINS was a significant predictor of time to death among surgical patients (HR 1.11, p = 0.037). Preoperative KPS was not independently associated with decreased survival (p > 0.5) on univariate analysis. One hundred twenty-six patients met the criteria for inclusion in the radiation-only analysis. Ninety-eight of these patients (78%) met the criteria for potential instability (PI) at the time of treatment, according to the SINS system. Five patients (5%) with PI in the radiation therapy group had a documented neurosurgical or orthopedic surgery consultation prior to radiation therapy. At the authors' institution, patients with gross mechanical instability per the SINS system had an increased rate of 30-day postoperative mortality, which remained significant when controlling for other factors. Surgical consultation for metastatic spine patients receiving radiation oncology consultation with PI is low. The authors describe an institutional pathway to encourage multidisciplinary treatment from the initial encounter in the emergency department to expedite surgical evaluation and collaboration.


Small asymmetric Brownian objects self-align in nanofluidic channels.
Although the self-alignment of asymmetric macro-sized objects of a few tens of microns in size have been studied extensively in experiments and theory, access to much smaller length scales is still hindered by technical challenges. We combine molecular dynamics and stochastic rotation dynamics techniques to investigate the self-orientation phenomenon at different length scales, ranging from the micron to the nano scale by progressively increasing the relative strength of diffusion over convection. To this end, we model an asymmetric dumbbell particle in Hele-Shaw flow and explore a wide range of Péclet numbers (Pe) and different particle shapes, as characterized by the size ratio of the two dumbbell spheres (R[combining tilde]). By independently varying these two parameters we analyse the process of self-orientation and characterize the alignment of the dumbbell with the direction of the fluid flow. We identify three different regimes of strong, weak and no alignment and we map out a state diagram in Pe versus R[combining tilde] plane. Based on these results, we estimate dimensional length scales and flow rates for which these findings would be applicable in experiments. Finally, we find that the characteristic reorientation time of the dumbbell is a monotonically decreasing function of the dumbbell anisotropy.


[Biocompatibility of porous calcium phosphate ceramic nanocomposite].
To study the biocompatibility of porous calcium phosphate ceramics nanocomposite. The biocompatibility was evaluated via experiments including the hemolysis test, hemopexis test, acute systemic toxicity test, pyrogen test, and intramuscular implant test, in which biphasic calcium phosphate nanocomposite (NanoBCP) presented as leaching solution, suspension or blocks of 5 mmx5 mmxl mm. Animals including New Zealand Rabbits, Kunming mice, SD rats were selected as the host. The hemolysis of NanoBCP was 1.1% (<5%). Four coagulation index levels were within the normal range. In pyrogen test, the temperature of each experimental rat increased by 0.35, 0.40, 0.28 degrees C (<0.60 degrees C, in accordance with the pyrogen-free criterion for biomedical materials). No consequent death, dyspnoea, organ dysfunction, severe peritoneal irritation or ptosis was observed in acute systemic toxic test. Newly-formed fibrous tissue could be found after the implantation. The material possesses outstanding biocompatibility and degradability with no toxicity or irritation, contains no pyrogen, as well as better degradation properties than biphasic calcium phosphate.


Maternal residential proximity to waste sites and industrial facilities and conotruncal heart defects in offspring.
Most studies of the relationship between maternal residential proximity to sources of environmental pollution and congenital cardiovascular malformations have combined heart defects into one group or broad subgroups. The current case-control study examined whether risk of conotruncal heart defects, including subsets of specific defects, was associated with maternal residential proximity to hazardous waste sites and industrial facilities with recorded air emissions. Texas Birth Defects Registry cases were linked to their birth or fetal death certificate. Controls without birth defects were randomly selected from birth certificates. Distances from maternal addresses at delivery to National Priority List (NPL) waste sites, state superfund waste sites, and Toxic Release Inventory (TRI) facilities were determined for 1244 cases (89.5% of those eligible) and 4368 controls (88.0%). Living within 1 mile of a hazardous waste site was not associated with risk of conotruncal heart defects [adjusted odds ratio (aOR) = 0.83, 95% confidence interval (CI) = 0.54, 1.27]. This was true whether looking at most types of defects or waste sites. Only truncus arteriosus showed statistically elevated ORs with any waste site (crude OR: 2.80, 95% CI 1.19, 6.54) and with NPL sites (crude OR: 4.63, 95% CI 1.18, 13.15; aOR 4.99, 95% CI 1.26, 14.51), but the latter was based on only four exposed cases. There was minimal association between conotruncal heart defects and proximity to TRI facilities (aOR = 1.10, 95% CI = 0.91, 1.33). Stratification by maternal age or race/ethnic group made little difference in effect estimates for waste sites or industrial facilities. In this study population, maternal residential proximity to waste sites or industries with reported air emissions was not associated with conotruncal heart defects or its subtypes in offspring, with the exception of truncus arteriosus.


Deep endometriosis: definition, pathogenesis, and clinical management.
"Deep endometriosis" includes rectovaginal lesions as well as infiltrative forms that involve vital structures such as bowel, ureters, and bladder. The available evidence suggests the same pathogenesis for deep infiltrating vesical and rectovaginal endometriosis (i.e., intraperitoneal seeding of regurgitated endometrial cells, which collect and implant in the most dependent portions of the peritoneal cavity and the anterior and posterior cul-de-sac, and trigger an inflammatory process leading to adhesion of contiguous organs with creation of false peritoneal bottoms). According to anatomic, surgical, and pathologic findings, deep endometriotic lesions seem to originate intraperitoneally rather than extraperitoneally. Also the lateral asymmetry in the occurrence of ureteral endometriosis is compatible with the menstrual reflux theory and with the anatomic differences of the left and right hemipelvis. Peritoneal, ovarian, and deep endometriosis may be diverse manifestations of a disease with a single origin (i.e., regurgitated endometrium). Based on different pathogenetic hypotheses, several schemes have been proposed to classify deep endometriosis, but further data are needed to demonstrate their validity and reliability. Drugs induce temporary quiescence of active deep lesions and may be useful in selected circumstances. Progestins should be considered as first-line medical treatment for temporary pain relief. However, in most cases of severely infiltrating disease, surgery is the final solution. Great importance must be given to complete and balanced counseling, as awareness of the real possibilities of different treatments will enhance the patient's collaboration.


Data-based fault-tolerant control of high-speed trains with traction/braking notch nonlinearities and actuator failures.
This paper investigates the position and velocity tracking control problem of high-speed trains with multiple vehicles connected through couplers. A dynamic model reflecting nonlinear and elastic impacts between adjacent vehicles as well as traction/braking nonlinearities and actuation faults is derived. Neuroadaptive fault-tolerant control algorithms are developed to account for various factors such as input nonlinearities, actuator failures, and uncertain impacts of in-train forces in the system simultaneously. The resultant control scheme is essentially independent of system model and is primarily data-driven because with the appropriate input-output data, the proposed control algorithms are capable of automatically generating the intermediate control parameters, neuro-weights, and the compensation signals, literally producing the traction/braking force based upon input and response data only--the whole process does not require precise information on system model or system parameter, nor human intervention. The effectiveness of the proposed approach is also confirmed through numerical simulations.


Investigating harmful and helpful effects of watching season 2 of 13 Reasons Why: Results of a two-wave U.S. panel survey.
The Netflix show 13 Reasons Why (2017) aroused widespread concern regarding potential contagious effects of its graphic depiction of an adolescent girl's suicide and the events that led to her death. To explore the effects of the second season of the show in 2018. We recruited a sample of young adults (ages 18-29; N = 729) with access to Netflix who completed surveys shortly before and one month after the release of the show's second season. Based on theories of narrative empathy, we hypothesized that those who discontinued watching the show would be most vulnerable to its adverse effects on suicide-relevant outcomes. We further identified a higher risk subset of viewers who were more likely to have stopped watching the first season (those currently enrolled in school) in order to observe if the show had more adverse effects on this audience. Finally, we examined effects of the show on all viewers' intentions to help a suicidal person as a prosocial consequence of viewing the entire second season. We used both covariance and "genetic" matching to control for selection effects. In support of predictions, viewers who stopped watching the second season exhibited greater suicide risk and less optimism about the future than those who continued to the end. However, unexpectedly, current students who watched the entire second season reported declines in suicide ideation and self-harm relative to those who did not watch the show at all (ps < .01). Moreover, those who watched the entire second season were also more likely to express interest in helping a suicidal person, especially compared to those who stopped watching. The results suggest that a fictional story with a focus on suicidal content can have both harmful and helpful effects.


Genetic background modulates phenotypes of serotonin transporter Ala56 knock-in mice.
Previously, we identified multiple, rare serotonin (5-HT) transporter (SERT) variants in children with autism spectrum disorder (ASD). Although in our study the SERT Ala56 variant was over-transmitted to ASD probands, it was also seen in some unaffected individuals, suggesting that associated ASD risk is influenced by the epistatic effects of other genetic variation. Subsequently, we established that mice expressing the SERT Ala56 variant on a 129S6/S4 genetic background display multiple biochemical, physiological and behavioral changes, including hyperserotonemia, altered 5-HT receptor sensitivity, and altered social, communication, and repetitive behavior. Here we explore the effects of genetic background on SERT Ala56 knock-in phenotypes. To explore the effects of genetic background, we backcrossed SERT Ala56 mice on the 129 background into a C57BL/6 (B6) background to achieve congenic B6 SERT Ala56 mice, and assessed autism-relevant behavior, including sociability, ultrasonic vocalizations, and repetitive behavior in the home cage, as well as serotonergic phenotypes, including whole blood serotonin levels and serotonin receptor sensitivity. One consistent phenotype between the two strains was performance in the tube test for dominance, where mutant mice displayed a greater tendency to withdraw from a social encounter in a narrow tube as compared to wildtype littermate controls. On the B6 background, mutant pup ultrasonic vocalizations were significantly increased, in contrast to decreased vocalizations seen previously on the 129 background. Several phenotypes seen on the 129 background were reduced or absent when the mutation was placed on the B6 background, including hyperserotonemia, 5-HT receptor hypersensivity, and repetitive behavior. Our findings provide a cogent example of how epistatic interactions can modulate the impact of functional genetic variation and suggest that some aspects of social behavior may be especially sensitive to changes in SERT function. Finally, these results provide a platform for the identification of genes that may modulate the risk of ASD in humans.


PD-1hi CD8+ resident memory T cells balance immunity and fibrotic sequelae.
CD8+ tissue-resident memory T (TRM) cells provide frontline immunity in mucosal tissues. The mechanisms regulating CD8+ TRM maintenance, heterogeneity, and protective and pathological functions are largely elusive. Here, we identify a population of CD8+ TRM cells that is maintained by major histocompatibility complex class I (MHC-I) signaling, and CD80 and CD86 costimulation after acute influenza infection. These TRM cells have both exhausted-like phenotypes and memory features and provide heterologous immunity against secondary infection. PD-L1 blockade after the resolution of primary infection promotes the rejuvenation of these exhausted-like TRM cells, restoring protective immunity at the cost of promoting postinfection inflammatory and fibrotic sequelae. Thus, PD-1 serves to limit the pathogenic capacity of exhausted-like TRM cells at the memory phase. Our data indicate that TRM cell exhaustion is the result of a tissue-specific cellular adaptation that balances fibrotic sequelae with protective immunity.


Preoperative pulmonary evaluation of liver transplant candidates: results from 341 adult patients.
Pulmonary disorders are among the commonly encountered and prognostically important problems in patients with chronic liver disease. To define the prevalence and types of respiratory disorders in patients with advanced liver disease evaluated for liver transplant (LT) candidacy, and to determine factors affecting postoperative outcome. The records of 341 adult patients evaluated for LT candidacy were retrospectively examined. Demographic, clinical and laboratory data including chest X-ray, spirometry and echocardiography results were collected. Postoperative pulmonary complications and mortality rates were determined. With a mean age of 45.1 years, 73 (21.4%) patients presented with respiratory symptoms or signs. The most common radiographic abnormality on chest X-ray was right diaphragm elevation (53.2%). Hypoxemia was detected in 38.1% of the patients. Pulmonary hypertension was detected in 100 of 327 (30.6%) patients on Doppler echocardiography. There were 141 patients who underwent surgery. Postoperative pulmonary complications developed in 60 patients, with pneumonia being the most prevalent complication (n=28). Smoking, emphysema, abnormal spirometry, pulmonary hypertension, hypoxia and orthodeoxia were found to be factors associated with increased postoperative pulmonary complications (P<0.05 for all). Mortality rate was 24.1% (n=34) and found to be significantly higher in patients who developed a postoperative complication than in those who did not (38.7% vs. 13.8%, respectively; p=0.001). The authors' findings indicate that pulmonary disorders impact prognosis and are common in patients evaluated for LT candidacy. Postoperative pulmonary complication is one of the major factors affecting mortality. Therefore, in order to increase the success of the transplant operation, a thorough preoperative pulmonary evaluation is of paramount importance.


Cannabis and other drug use among trauma patients in three South African cities, 1999-2001.
To assess the extent of cannabis and other drug use among patients presenting with recent injuries at trauma units in Cape Town, Port Elizabeth and Durban from 1999 to 2001. Cross-sectional surveys were conducted during a 4-week period at each of the above sites in 1999, 2000 and 2001. The concept of an idealised week was used to render representative samples. Cause of injury and biological markers to assess use of cannabis, methaqualone (Mandrax), opiates, cocaine, amphetamine, and methamphetamine. Over half of all patients tested experienced violent injuries. Excluding opiates, across sites and over time between 33% and 62% of patients tested positive for at least one drug (N = 1565). In most cases the drugs were cannabis and/or methaqualone. While no inter-city differences were found, male patients were typically more likely to test positive for drugs in general and specific drugs such as cannabis and the cannabis/methaqualone ('white pipe') combination than female patients. Drug positivity was higher in 2001 than in the previous 2 years in Cape Town, and patients injured as a result of violence in Cape Town and Durban were more likely to test positive for drugs than patients with certain other types of injuries. Drug use among trauma patients has remained consistently high for each of the 3 study periods. Efforts to combat the abuse of drugs such as cannabis and methaqualone would appear to be paramount in reducing the burden of injuries on health care services. The study has raised numerous issues requiring further research.


Elucidating the mechanism of the CO2 methanation reaction over Ni-Fe hydrotalcite-derived catalysts via surface-sensitive in situ XPS and NEXAFS.
Hydrotalcite-derived Ni and Fe-promoted hydrotalcite-derived Ni catalysts were found to outperform industrial catalysts in the CO2 methanation reaction, however the origin of the improved activity and selectivity of these catalysts is not clear. Here, we report a study of these systems by means of in situ X-ray photoelectron spectroscopy and near-edge X-ray absorption spectroscopy elucidating the chemical nature of the catalysts surface under reaction conditions and revealing the mechanism by which Fe promotes activity and selectivity towards methane. We show that the increase of the conversion leads to hydroxylation of the Ni surface following the formation of water during the reaction. This excessive Ni surface hydroxylation has however a detrimental effect as shown by a controlled study. A dominant metallic Ni surface exists in conditions of higher selectivity towards methane whereas if an increase of the Ni surface hydroxylation occurs, a higher selectivity towards carbon monoxide is observed. The electronic structure analysis of the Fe species under reaction conditions reveals the existence of predominantly Fe(iii) species at the surface, whereas a mixture of Fe(ii)/Fe(iii) species is present underneath the surface when selectivity to methane is high. Our results highlight that Fe(ii) exerts a beneficial effect on maintaining Ni in a metallic state, whereas the extension of the Fe oxidation is accompanied by a more extended Ni surface hydroxylation with a negative impact on the selectivity towards methane.


Outstanding Scientific Achievement Award Lecture 2010: deconstructing leptin: from signals to circuits.
Martin G. Myers Jr., MD, PhD, received the American Diabetes Association's prestigious 2010 Outstanding Scientific Achievement Award at the Association's 70th Scientific Sessions in Orlando, Florida, on 28 June 2010. The Outstanding Scientific Achievement Award recognizes outstanding scientific achievement in the field of diabetes, taking into consideration independence of thought and originality. Currently the Marilyn H. Vincent Professor of Diabetes Research at the University of Michigan, Ann Arbor, and Associate Professor in internal medicine and in molecular and integrative physiology at the University of Michigan Medical School, Dr. Myers began his impressive track record in diabetes research as a graduate student in the laboratory of Dr. Morris White at the Joslin Diabetes Center/Harvard Medical School. There, Dr. Myers deciphered many of the insulin signaling pathways engaged by insulin receptor substrate proteins. Following his graduation from the Harvard MD-PhD Program in 1997, Dr. Myers was promoted to instructor in medicine at the Joslin Diabetes Center/Harvard Medical School. He began his independent work by building a molecular framework for understanding the mechanisms of leptin signaling, including how individual phosphorylation sites on the leptin receptor recruit distinct signaling molecules. He was promoted to assistant professor at Harvard in 1999. In 2004, Dr. Myers moved to the University of Michigan, where he built upon the molecular framework of leptin signaling to probe the regulation of metabolism by individual leptin signals. Dr. Myers' laboratory revealed the specificity of leptin signals in metabolic control, including the role for leptin-STAT3 signaling in the regulation of energy balance and glucose homeostasis. His group also defined roles for leptin receptor feedback inhibition and hypothalamic mTor signaling in metabolism. Dr. Myers' laboratory has recently developed novel molecular approaches to elucidate the leptin-regulated brain circuits that contribute to metabolic control, enabling the discovery of novel brain systems and their functions. In 1998, Dr. Myers received the American Diabetes Association's Career Development Award for his scientific abilities. Dr. Myers' current support includes the National Institute of Diabetes and Digestive and Kidney Diseases MERIT Award.


A potentially implantable enzyme electrode for amperometric measurement of glucose.
A membrane limited amperometric enzyme electrode suitable for glucose measurement in biological fluids was developed. The sensor consists of a central platinum wire (0.3 mm) surrounded by a stainless steel tubing (0.8-1.0 mm outer diameter; 2-4 cm length). By successive dipcoating procedures, layers from cellulose acetate, glucose oxidase (crosslinked with glutaraldehyde) and polyurethane are placed on its surface. The platinum is polarized at +700 mV against steel. In vitro results: Electrodes are stable for at least 6 days. They exhibit a linear range extending to 500 mg/dl glucose. Response times are less than 100 sec. The sensors are not dependent on stirring and are relatively insensitive to changes of pH. Dependency of glucose measurement upon dissolved oxygen is negligible at oxygen concentrations above 0.5 mg/l. In vivo results: Preliminary studies in sheep using subcutaneously implanted needles indicate that short term glucose monitoring is feasible.


Lesser of two evils? Foraging choices in response to threats of predation and parasitism.
Predators have documented post-encounter (density-mediated) effects on prey but their pre-encounter impacts, including behavioural alterations, can be substantial as well. While it is increasingly evident that this "ecology of fear" is important to understand for natural enemy-victim relationships, fear responses of hosts to the threat of infection by a parasite are relatively unknown. We examined larval amphibian (Lithobates pipiens) foraging choices by experimentally manipulating the presence of cues relating to predator (larval odonate) or parasite (the trematode Ribeiroia ondatrae) threats. Tadpoles avoided foraging where predator or parasite cues were present; however, they did not treat these as equal hazards. When both threats were simultaneously present, tadpoles strongly preferred to forage under the threat of parasitism compared to predation, likely driven by their relative lethality in our study. Our results indicate that altered spatial use is an important anti-parasite behaviour, and demonstrate that parasite avoidance can affect foraging in a manner similar to predators, warranting greater study of the pre-encounter effects of this enemy type.


The CD1 system: antigen-presenting molecules for T cell recognition of lipids and glycolipids.
Recent studies have identified the CD1 family of proteins as novel antigen-presenting molecules encoded by genes located outside of the major histocompatibility complex. CD1 proteins are conserved in all mammalian species so far examined and are prominently expressed on cells involved in antigen presentation, which suggests a role in activation of cell-mediated immunity. This has now been confirmed by functional studies demonstrating the ability of CD1 proteins to restrict the antigen-specific responses of T cells in humans and mice. Identification of naturally occurring antigens presented by CD1 has revealed the surprising finding that these are predominantly a variety of foreign lipids and glycolipids, including several found prominently in the cell walls and membranes of pathogenic mycobacteria. Structural, biochemical, and biophysical studies support the view that CD1 proteins bind the hydrophobic alkyl portions of these antigens directly and position the polar or hydrophilic head groups of bound lipids and glycolipids for highly specific interactions with T cell antigen receptors. Presentation of antigens by CD1 proteins requires uptake and intracellular processing by antigen presenting cells, and evidence exists for cellular pathways leading to the presentation of both exogenous and endogenous lipid antigens. T cells recognizing antigens presented by CD1 have a range of functional activities that suggest they are likely to mediate an important component of antimicrobial immunity and may also contribute to autoimmunity and host responses against neoplastic cells.


Rebound of affective symptoms following acute cessation of deep brain stimulation in obsessive-compulsive disorder.
Deep brain stimulation (DBS) is regarded as an effective way to treat refractory obsessive-compulsive disorder (OCD). Little is known about the effects of DBS cessation following a longer period of stimulation. To determine the relapse and rebound effects of psychiatric symptoms, and their impact on Quality of Life (QoL) following acute cessation of DBS in OCD patients. We included 16 out of 32 patients who were treated with DBS between April 2005 and January 2011 at the Academic Medical Center, Amsterdam. After treatment for at least one year, patients entered a 1-week phase in which DBS was switched off. We evaluated psychiatric symptoms and QoL at three time points: before DBS surgery (pre-DBS), following at least one year of DBS treatment (DBS-on) and following 1 week of DBS off (DBS-off). Psychiatric symptoms were assessed with the Yale-Brown obsessive-compulsive disorder scale (Y-BOCS), the Hamilton anxiety rating scale (HAM-A) and the Hamilton depression rating scale (HAM-D). QoL was assessed using the World Health Organization QOL scale (WHOQOL-Bref). Switching from DBS-on to DBS-off, Y-BOCS scores increased with 50%, HAM-A scores with 80% and HAM-D scores with 83%. In the DBS-off period, HAM-A and HAM-D scores exceeded pre-surgery levels with approximately 40%, suggesting a rebound phenomenon. Furthermore, a deterioration of physical and psychological QoL to levels comparable with pre-surgery was found during DBS-off. Acute DBS cessation causes a relapse of obsessions and compulsions and a rebound of anxiety and depression. Additionally, improvements on QoL disappear.


Thalamic amnesia after infarct: The role of the mammillothalamic tract and mediodorsal nucleus.
To improve current understanding of the mechanisms behind thalamic amnesia, as it is unclear whether it is directly related to damage to specific nuclei, in particular to the anterior or mediodorsal nuclei, or indirectly related to lesions of the mammillothalamic tract (MTT). We recruited 12 patients with a left thalamic infarction and 25 healthy matched controls. All underwent a comprehensive neuropsychological assessment of verbal and visual memory, executive functions, language, and affect, and a high-resolution structural volumetric MRI scan. Thalamic lesions were manually segmented and automatically localized with a computerized thalamic atlas. As well as comparing patients with controls, we divided patients into subgroups with intact or damaged MTT. Only one patient had a small lesion of the anterior nucleus. Most of the lesions included the mediodorsal (n = 11) and intralaminar nuclei (n = 12). Patients performed worse than controls on the verbal memory tasks, but the 5 patients with intact MTT who showed isolated lesions of the mediodorsal nucleus (MD) only displayed moderate memory impairment. The 7 patients with a damaged MTT performed worse on the verbal memory tasks than those whose MTT was intact. Lesions in the MTT and in the MD result in memory impairment, severely in the case of MTT and to a lesser extent in the case of MD, thus highlighting the roles played by these 2 structures in memory circuits.


Interleukin-12 p40 secretion by cutaneous CD11c+ and F4/80+ cells is a major feature of the innate immune response in mice that develop Th1-mediated protective immunity to Schistosoma mansoni.
Radiation-attenuated (RA) schistosome larvae are potent stimulators of innate immune responses at the skin site of exposure (pinna) that are likely to be important factors in the development of Th1-mediated protective immunity. In addition to causing an influx of neutrophils, macrophages, and dendritic cells (DCs) into the dermis, RA larvae induced a cascade of chemokine and cytokine secretion following in vitro culture of pinna biopsy samples. While macrophage inflammatory protein 1alpha and interleukin-1beta (IL-1beta) were produced transiently within the first few days, the Th1-promoting cytokines IL-12 and IL-18 were secreted at high levels until at least day 14. Assay of C3H/HeJ mice confirmed that IL-12 secretion was not due to lipopolysaccharide contaminants binding Toll-like receptor 4. Significantly, IL-12 p40 secretion was sustained in pinnae from vaccinated mice but not in those from nonprotected infected mice. In contrast, IL-10 was produced from both vaccinated and infected mice. This cytokine regulates IL-12-associated dermal inflammation, since in vaccinated IL-10(-/-) mice, pinna thickness was greatly increased concurrent with elevated levels of IL-12 p40. A significant number of IL-12 p40(+) cells were detected as emigrants from in vitro-cultured pinnae, and most were within a population of rare large granular cells that were Ia(+), consistent with their being antigen-presenting cells. Labeling of IL-12(+) cells for CD11c, CD205, CD8alpha, CD11b, and F4/80 indicated that the majority were myeloid DCs, although a proportion were CD11c(-) F4/80(+), suggesting that macrophages were an additional source of IL-12 in the skin.


Effect of preservatives on IgG aggregation, complement-activating effect and hypotensive activity of horse polyvalent antivenom used in snakebite envenomation.
Intravenous administration of antivenoms is associated with early adverse reactions in a number of cases, but the causes of this phenomenon are still unclear. The effect of preservatives (phenol and thimerosal) on IgG aggregate and dimer formation, in vitro complement-activating effect and hypotensive activity of a whole IgG horse liquid polyvalent antivenom, produced by caprylic acid fractionation, was assessed. These parameters were studied since they have been associated with the development of early adverse reactions to the administration of antivenoms and human immunoglobulins. After a three-year storage period at 4 degrees C, antivenoms with preservatives had an increased content of IgG aggregates and dimers when compared with antivenom devoid of phenol and thimerosal. These observations correlate with a slight increment in the turbidity of preservative-containing antivenoms. The three antivenoms studied (formulation: no preservatives; with phenol and thimerosal; with thimerosal alone) activated human complement in vitro, with only minor quantitative differences among them. When antivenoms were administered as a bolus intravenous injection in rats, a rapid and prominent hypotension of short duration was observed after injection of phenol-containing antivenom, whereas such an effect was absent in antivenom free of preservative and in the one containing only thimerosal. Bolus injection of saline solution with phenol resulted in a similar hypotension, indicating that the effect is due to phenol. However, when phenol-containing antivenom was diluted 1:5 with saline solution before infusion, as occurs in the clinical use of this product, no hypotension was observed. Our results stress the need to evaluate the effects of preservatives on the physicochemical and pharmacological characteristics of antivenoms.


A partisan divide on the uninsured.
The partisan split in Congress over health reform may reflect a broader divide among the public in attitudes toward the uninsured. Despite expert consensus over the harms suffered by the uninsured as a group, Americans disagree over whether the uninsured get the care they need and whether reform legislation providing universal coverage is necessary. We examined public perceptions of health care access and quality for the uninsured over time, and we found that Democrats are far more likely than Republicans to believe that the uninsured have difficulty gaining access to care. Senior citizens are less aware than others of the problems faced by the uninsured. Even among those Americans who perceive that the uninsured have poor access to care, Republicans are significantly less likely than Democrats to support reform. Thus, our findings indicate that even if political obstacles are overcome and health reform is enacted, future political support for ongoing financing to cover the uninsured could be uncertain.


Fundus autofluorescence in the diagnosis of cystoid macular oedema.
To determine the sensitivity and specificity of the non-invasive imaging technique, fundus autofluorescence (AF), in the diagnosis of cystoid macular oedema (CMO), using fluorescein angiography as the reference standard. Retrospective, consecutive, observational case series. Ninety-six consecutive patients with CMO suspected clinically were selected from the AF database of the Retina Unit, Ophthalmology Department, Grampian University Hospitals-NHS Trust, between August 2004 and June 2006. Only patients in whom CMO was secondary to (1) cataract extraction, (2) inherited retinopathies, (3) inflammatory eye disease or (4) idiopathic cases were included in this study. Only patients in whom AF images had been performed within 2 weeks of FFA and, when obtained following FFA, there was a minimum gap of 4 days ("washing out" period), were considered eligible for this study. A total of 34 eyes from 34 patients were eligible and were included in this study. FFA was used as the reference test to confirm the presence of CMO, and, based on fluorescein angiography (FFA), CMO was graded as either mild or florid. AF images were examined in a masked fashion for the presence or absence of CMO. The sensitivity and specificity of AF in detecting CMO were then calculated. CMO was seen on AF imaging as round or oval areas at the fovea with an AF signal similar to that of background levels. At this site (fovea), the AF signal is usually reduced compared with background, due to the blockage caused by luteal pigment. The diagnosis of CMO based on AF imaging had 81% sensitivity and 69% specificity when compared with the reference standard FFA. Based on the FFA, there were 12 cases of florid CMO and eight of mild CMO. Of the former, CMO was detected with AF imaging in 100% (12/12 eyes), and of the latter, in 50% (4/8 eyes). AF imaging can be used as a rapid, non-invasive technique in the diagnosis of CMO.


New microsatellite markers for assessment of genetic diversity in date palm (Phoenix dactylifera L.).
New primer pairs of genomic DNA microsatellite markers were tested to assess the genetic diversity of eleven date palm genotypes. The results indicated that out of thirty, only seven primers (23.3%) failed to amplify the expected PCR fragments, while thirteen primers (43.3%) amplified monomorphic banding patterns and the remaining ten primers (33.4%) generated polymorphic banding patterns. A total of 77 alleles have been observed with a mean of 7.7 alleles per locus. The average of gene diversity was 0.80 ranging from 0.6 (in marker DP168) to 0.9 (in two markers DP157 and DP175). These new co-dominant markers will be a starting point for researchers making use of the markers for genetic mapping and diversity analysis of date palm.


Properties of Visual Field Defects Around the Monocular Preferred Retinal Locus in Age-Related Macular Degeneration.
To compare microperimetric sensitivity around the monocular preferred retinal locus (mPRL) in age-related macular degeneration (AMD) to normative data, and to describe the characteristics of visual field defects around the mPRL in AMD. Participants with AMD (total n = 185) were either prospectively recruited (n = 135) or retrospectively reviewed from an existing database (n = 50). Participants underwent microperimetry using a test pattern (37 point, 5° radius) centered on their mPRL. Sensitivities were compared to normative data by spatial interpolation, and conventional perimetric indices were calculated. The location of the mPRL relative to the fovea and to visual field defects was also investigated. Location of mPRL varied approximately 15° horizontally and vertically. Visual field loss within 5° of the mPRL was considerable in the majority of participants (median mean deviation -14.7 dB, interquartile range [IQR] -19.6 to -9.6 dB, median pattern standard deviation 7.1 dB [IQR 4.8-9.0 dB]). Over 95% of participants had mean total deviation worse than -2 dB across all tested locations and similarly within 1° of their mPRL. A common pattern of placing the mPRL just foveal to a region of normal pattern deviation was found in 78% of participants. Total deviation was outside normal limits in this region in 68%. Despite altering fixation to improve vision, people with AMD exhibit considerable visual field loss at and around their mPRL. The location of the mPRL was typically just foveal to, but not within, a region of relatively normal sensitivity for the individual, suggesting that a combination of factors drives mPRL selection.


SMAD4 Prevents Flow Induced Arteriovenous Malformations by Inhibiting Casein Kinase 2.
Hereditary hemorrhagic telangiectasia (HHT) is an inherited vascular disorder that causes arteriovenous malformations (AVMs). Mutations in the genes encoding Endoglin ( ENG) and activin-receptor-like kinase 1 ( AVCRL1 encoding ALK1) cause HHT type 1 and 2, respectively. Mutations in the SMAD4 gene are present in families with juvenile polyposis-HHT syndrome that involves AVMs. SMAD4 is a downstream effector of transforming growth factor-β (TGFβ)/bone morphogenetic protein (BMP) family ligands that signal via activin-like kinase receptors (ALKs). Ligand-neutralizing antibodies or inducible, endothelial-specific Alk1 deletion induce AVMs in mouse models as a result of increased PI3K (phosphatidylinositol 3-kinase)/AKT (protein kinase B) signaling. Here we addressed if SMAD4 was required for BMP9-ALK1 effects on PI3K/AKT pathway activation. The authors generated tamoxifen-inducible, postnatal, endothelial-specific Smad4 mutant mice ( Smad4iΔEC). We found that loss of endothelial Smad4 resulted in AVM formation and lethality. AVMs formed in regions with high blood flow in developing retinas and other tissues. Mechanistically, BMP9 signaling antagonized flow-induced AKT activation in an ALK1- and SMAD4-dependent manner. Smad4iΔEC endothelial cells in AVMs displayed increased PI3K/AKT signaling, and pharmacological PI3K inhibitors or endothelial Akt1 deletion both rescued AVM formation in Smad4iΔEC mice. BMP9-induced SMAD4 inhibited casein kinase 2 ( CK2) transcription, in turn limiting PTEN phosphorylation and AKT activation. Consequently, CK2 inhibition prevented AVM formation in Smad4iΔEC mice. Our study reveals SMAD4 as an essential effector of BMP9-10/ALK1 signaling that affects AVM pathogenesis via regulation of CK2 expression and PI3K/AKT1 activation.


Exploring variation in patient access of post-discharge physiotherapy following total hip and knee arthroplasty under a choice based system in the UK: an observational cohort study.
To assess a targeted 'therapy as required' model of post-discharge outpatient physiotherapy provision. Specifically, we investigated what proportion of patients accessed post-discharge physiotherapy following total hip arthroplasty (THA) and total knee arthroplasty (TKA), whether accessing therapy was associated with post-arthroplasty patient reported outcomes and whether it was possible to predict which patients would access post-discharge physiotherapy from pre-operative data. Prospective, observational, longitudinal cohort study. Single National Health Service orthopaedic teaching hospital in the UK. 1395 patients undergoing total hip arthroplasty and 1374 patients undergoing total knee arthroplasty. Self-reported access of post-discharge physiotherapy, the Oxford Hip or Knee Score, EuroQol 5-dimension questionnaire and post-operative surgical episode satisfaction metric. 662 (48.2%) patients with TKA and 493 (35.3%) patients with THA accessed additional post-discharge physiotherapy. Patient-reported outcomes (p<0.001) and surgical episode satisfaction (p=0.001) in both THA and TKA were higher in patients that did not participate in post-discharge physiotherapy. Regression models using pre-operative symptom burden and demographic data predicted post-discharge therapy access with an accuracy of only 17% greater than chance in patients with THA and 7% greater than chance in patients with TKA. In a choice-based service model of 'therapy as required' following hip and knee arthroplasty only a third of THA and half of TKA patients accessed post-discharge therapy. Patients who did not access physiotherapy reported greater post-operative outcomes. This variation in the need for post-discharge physiotherapy suggests that targeting of rehabilitation may be a cost-effective model, however it was not possible to reliably predict which patients would access post-discharge physiotherapy from pre-operative data.


The flavonoid glabridin attenuates 2-deoxy-D-ribose-induced oxidative damage and cellular dysfunction in MC3T3-E1 osteoblastic cells.
Reducing sugar 2-deoxy-D-ribose (dRib) produces reactive oxygen species (ROS) through autoxidation and protein glycosylation and causes dysfunction of osteoblasts. In the present study, glabridin, a natural flavonoid, was investigated to determine whether it could influence dRib-induced oxidative damage and cellular dysfunction in the MC3T3-E1 mouse osteoblastic cell line. Osteoblastic cells were treated with dRib in the presence or absence of glabridin. Cell viability, apoptosis, ROS production and mitochondrial membrane potential (ΔΨm) were subsequently examined. It was observed that dRib reduced cell survival and ΔΨm, while it markedly increased intracellular levels of ROS and apoptosis. However, pretreatment of cells with glabridin attenuated all the dRib-induced effects. The antioxidant N-acetyl-L-cysteine (NAC) also prevented dRib-induced oxidative cell damage. In addition, treatment with glabridin resulted in a significant elevation of alkaline phosphatase (ALP) activity, collagen contents and osteoblast differentiation genes [ALP, collagen, osteopontin (OPN), osteoprotegerin (OPG) and osteocalcin (OC)] and bone morphogenetic protein (BMP) genes (BMP2, BMP4 and BMP7). In mechanistic studies of the antioxidative potential of glabridin, we found that glabridin activated dRib-induced decreased expression of phosphatidylinositol 3'-kinase (PI3K) and protein kinase B 2 (AKT2) genes, which are master regulators of survival-related signaling pathways. Glabridin also upregulated the gene expression of antioxidant enzymes, superoxide dismutase 1 (SOD1) and glutathione peroxidase 4 (GPX4), which were inhibited by dRib. Taken together, these results suggest that glabridin attenuates dRib-induced cell damage in osteoblastic cells and may be useful for the treatment of diabetes-related bone disease.


Identification of ATF-3, caveolin-1, DLC-1, and NM23-H2 as putative antitumorigenic, progesterone-regulated genes for ovarian cancer cells by gene profiling.
Although progesterone (P4) has been implicated to offer protection against ovarian cancer (OCa), little is known of its mechanism of action. The goal of this study was to identify P4-regulated genes that have anti-OCa action. Three immortalized nontumorigenic human ovarian surface epithelial (HOSE) cell lines and three OCa (OVCA) cell lines were subjected to 5 days of P4 treatment. Transcriptional profiling with a cDNA microarray containing approximately 2400 known genes was used to identify genes (1) whose expression was consistently downregulated in OVCA cell lines compared to HOSE cell lines, and (2) whose expression was restored in OCa cell lines by P4 treatment. From the candidates selected, activating transcription factor-3 (ATF-3), caveolin-1, deleted in liver cancer-1 (DLC-1), and nonmetastatic clone 23 (NM23-H2) were chosen for post hoc functional studies based on their previously reported action as tumor suppressors or apoptosis inducers. Semiquantitative RT-PCR analyses confirmed loss of or reduced transcription of these genes in OVCA cells when compared to HOSE cells and their upregulation following P4 treatment. Hormonal specificity was demonstrated by blockade experiments with a progestin antagonist RU 38486. Ectopic expression of caveolin-1, DLC-1, and NM23-H2 caused growth inhibition in OVCA cell cultures, but not in HOSE cell cultures, while forced expression of ATF-3 suppressed growth in both. Overexpression of AFT-3 also enhanced caspase-3 activity in both HOSE and OVCA cells, whereas ectopic expression of caveolin-1 and DLC-1 only activated this enzyme in OCa cells. In contrast, NM23-H2 overexpression was ineffective in activating caspase-3. Overexpression of any of the four genes in OCa cells reduced soft-agar colony formation and cell invasiveness. Taken together, we have identified four new P4-regulated, antitumor genes for OCa. However, their modes of action differ significantly; ATF-3 primarily functions as an apoptosis inducer, NM23-H2 as a suppressor of cell motility, and caveolin-1 and DLC-1 exhibiting features of classical tumor suppressors. To the best of our knowledge, except for NM23-H2, this is the first report linking P4 to the regulation of these tumor suppressor/proapoptotic genes, which could serve as future therapeutic targets.


A comprehensive assessment of exposures to respirable dust and silica in the taconite mining industry.
This study assessed the present-day levels (year 2010-2011) of exposure to respirable dust (RD) and respirable silica (RS) in taconite mines and evaluated how the mining process influences exposure concentrations. Personal samples (n = 679) were collected to assess exposure levels of workers to RD and RS at six mines in the Mesabi Iron Range of Minnesota. The RD and RS concentrations were measured using the National Institute for Occupational Safety and Health (NIOSH) 0600 and NIOSH 7500, respectively. Between-mine, between-SEG (similar exposure groups), within-SEG, and within-worker components of variability for RD and RS exposures were estimated using a two- or three-way nested random-effects ANOVA model. The majority of RD concentrations across all mines were below the Mine Safety and Health Administration (MSHA) Permissible Exposure Limit (PEL). The highest concentrations of RD were often observed in either the Pelletizing or Crushing departments, which are inherently dusty operations. With a few exceptions, the concentrations of RS in the crushing and concentrating processes were higher than those in the other mining processes, as well as higher than the American Conference of Governmental Industrial Hygienists (ACGIH) Threshold Limit Value (TLV) for RS. The magnetic separation and flotation processes in the concentrating department reduced the levels of RS significantly, and lowered the percentage of quartz in RD in the pelletizing department. There was little variability among the six mines or between the two mineralogically distinct zones for either RD or RS exposures. The between-SEG variability for RS did not differ substantially across most of the mines and was a major component of exposure variance. The within-SEG (or between-worker) variance component was typically the smallest because in many instances one worker from a SEG within a mine was monitored multiple times. Some of these findings were affected by the degree of censoring in each SEG and mine, characteristics of the taconite rock, seasonal effects during sampling, or the tasks assigned to each job in that mine.


Antidiabetic Evaluation of Momordica charantia L Fruit Extracts.
To investigate hypoglycaemic, hypolipidaemic and pancreatic beta cell regeneration activities of Momordica charantia L fruits(MC). Alloxan induced diabetic rabbits were treated with methanolic and ethanolic MC extract. Effects of plant extracts and the drug glibenclamide on serum glucose, lipid profile and pancreatic beta cell were determined after two weeks of treatment. Serum glucose and lipid profiles were assayed by kit methods. Pancreatic tissue histopathology was performed to study pancreatic beta cells regeneration. Momordica charantia extracts produced significant hypoglycaemic effects (p < 0.05). Hypolipidaemic activity of MC was negligible. Momordica charantia supplementations were unable to normalize glucose and lipid profiles. Glibenclamide, a standard drug, not only lowered the hyperglycaemia and hyperlipidaemia but also restored the normal levels. Regeneration of pancreatic beta cells by MC extracts was minimal, with fractional improvement produced by glibenclamide. The most significant finding of the present study was a 28% reduction in hyperglycaemia by MC ethanol extracts. To determine reliable antidiabetic potentials of MC, identification of the relevant antidiabetic components and underlying mechanisms is warranted.


Characterization of the Temporal Trends in the Rate of Cattle Carcass Condemnations in the US and Dynamic Modeling of the Condemnation Reasons in California With a Seasonal Component.
Based on the 2016 National Cattlemen's Beef Association statistics, the cattle inventory in the US reached 93.5 million head, from which 30.5 million were commercial slaughter in 2016. California ranked fourth among all the US states that raise cattle and calves, with 5.15 million head and approximately 1.18 million slaughtered animals per year. Approximately 0.5% of cattle carcasses in the US are condemned each year, which has an important economic impact on cattle producers.In this study, we first described and compared the temporal trends of cattle carcass condemnations in all the US states from Jan-2005 to Dec-2014. Then, we focused on the condemnation reasons with a seasonal component in California and used dynamic harmonic regression (DHR) models both to model (from Jan-2005 to Dec-2011) and predict (from Jan-2012 to Dec-2014) the carcass condemnations rate in different time horizons (3 to 12 months).Data consisted of daily reports of 35 condemnation reasons per cattle type reported in 684 federally inspected slaughterhouses in the US from Jan-2005 to Dec-2014 and the monthly slaughtered animals per cattle type per states. Almost 1.5 million carcasses were condemned in the US during the 10 year study period (Jan 2005-Dec 2014), and around 40% were associated with three condemnation reasons: malignant lymphoma, septicemia and pneumonia. In California, emaciation, eosinophilic myositis and malignant lymphoma were the only condemnation reasons presenting seasonality and, therefore, the only ones selected to be modeled using DHRs. The DHR models for Jan-2005 to Dec-2011 were able to correctly model the dynamics of the emaciation, malignant lymphoma and eosinophilic myositis condemnation rates with coefficient of determination ( Rt2 ) of 0.98, 0.87 and 0.78, respectively. The DHR models for Jan-2012 to Dec-2014 were able to predict the rate of condemned carcasses 3 month ahead of time with mean relative prediction error of 33, 11, and 38%, respectively. The systematic analysis of carcass condemnations and slaughter data in a more real-time fashion could be used to identify changes in carcass condemnation trends and more timely support the implementation of prevention and mitigation strategies that reduce the number of carcass condemnations in the US.


Shift of leading pacemaker site during reflex vagal stimulation and altered electrical source-to-sink balance.
Vagal reflexes slow heart rate and can change where the heartbeat originates within the sinoatrial node (SAN). The mechanisms responsible for this process - termed leading pacemaker (LP) shift - have not been investigated fully. We used optical mapping to measure the effects of baroreflex, chemoreflex and carbachol on pacemaker entrainment and electrical conduction across the SAN. All methods of stimulation triggered shifts in LP site from the central SAN to one or two caudal pacemaker regions. These shifts were associated with reduced current generation capacity centrally and increased electrical load caudally. Previous studies suggest LP shift is a rate-dependent phenomenon whereby acetylcholine slows central pacemaker rate disproportionately, enabling caudal cells that are less acetylcholine sensitive to assume control. However, our findings indicate the LP region is defined by both pacemaker rate and capacity to drive activation. Shifts in LP site provide an important homeostatic mechanism for rapid switches in heart rate. Reflex vagal activity causes abrupt heart rate slowing with concomitant caudal shifts of the leading pacemaker (LP) site within the sinoatrial node (SAN). However, neither the mechanisms responsible nor their dynamics have been investigated fully. Therefore, the objective of this study was to elucidate the mechanisms driving cholinergic LP shift. Optical maps of right atrial activation were acquired in a rat working heart-brainstem preparation during baroreflex and chemoreflex stimulation or with carbachol. All methods of stimulation triggered shifts in LP site from the central SAN to caudal pacemaker regions, which were positive for HCN4 and received uniform cholinergic innervation. During baroreflex onset, the capacity of the central region to drive activation declined with a decrease in amplitude and gradient of optical action potentials (OAPs) in the surrounding myocardium. Accompanying this decline, there was altered entrainment in the caudal SAN as shown by decreased conduction velocity, OAP amplitude, gradient and activation time. Atropine abolished these responses. Chemoreflex stimulation produced similar effects but central capacity to drive activation was preserved before the LP shift. In contrast, carbachol produced a prolonged period of reduced capacity to drive and altered entrainment. Previous studies suggest LP shift is a rate-dependent phenomenon whereby acetylcholine slows central pacemaker rate disproportionately, enabling caudal cells that are less acetylcholine sensitive to assume control. Our findings indicate that cholinergic LP shifts are also determined by altered electrical source-to-sink balance in the SAN. We conclude that the LP region is defined by both rate and capacity to drive atrial activation.


Joint effects of known type 2 diabetes susceptibility loci in genome-wide association study of Singapore Chinese: the Singapore Chinese health study.
Genome-wide association studies (GWAS) have identified genetic factors in type 2 diabetes (T2D), mostly among individuals of European ancestry. We tested whether previously identified T2D-associated single nucleotide polymorphisms (SNPs) replicate and whether SNPs in regions near known T2D SNPs were associated with T2D within the Singapore Chinese Health Study. 2338 cases and 2339 T2D controls from the Singapore Chinese Health Study were genotyped for 507,509 SNPs. Imputation extended the genotyped SNPs to 7,514,461 with high estimated certainty (r(2)>0.8). Replication of known index SNP associations in T2D was attempted. Risk scores were computed as the sum of index risk alleles. SNPs in regions ± 100 kb around each index were tested for associations with T2D in conditional fine-mapping analysis. Of 69 index SNPs, 20 were genotyped directly and genotypes at 35 others were well imputed. Among the 55 SNPs with data, disease associations were replicated (at p<0.05) for 15 SNPs, while 32 more were directionally consistent with previous reports. Risk score was a significant predictor with a 2.03 fold higher risk CI (1.69-2.44) of T2D comparing the highest to lowest quintile of risk allele burden (p = 5.72 × 10(-14)). Two improved SNPs around index rs10923931 and 5 new candidate SNPs around indices rs10965250 and rs1111875 passed simple Bonferroni corrections for significance in conditional analysis. Nonetheless, only a small fraction (2.3% on the disease liability scale) of T2D burden in Singapore is explained by these SNPs. While diabetes risk in Singapore Chinese involves genetic variants, most disease risk remains unexplained. Further genetic work is ongoing in the Singapore Chinese population to identify unique common variants not already seen in earlier studies. However rapid increases in T2D risk have occurred in recent decades in this population, indicating that dynamic environmental influences and possibly gene by environment interactions complicate the genetic architecture of this disease.


Escherichia coli K-12 possesses multiple cryptic but functional chaperone-usher fimbriae with distinct surface specificities.
Commensal and pathogenic Escherichia coli adherence to host and environmental surfaces is mediated by a variety of adhesins. Although extensively studied as a model bacterium, 34% of the genes in the E. coli K-12 genome have no known function. We hypothesized that some of them may correspond to functional adhesins. We characterized E. coli K-12 ycb, ybg, yfc, yad, yra, sfm and yeh operons, which display sequence and organizational homologies to type 1 fimbriae exported by the chaperone/usher pathway. We showed that, although these operons are poorly expressed under laboratory conditions, six of them are nevertheless functional when expressed, and promote adhesion to abiotic and/or epithelial cell surfaces. While the studied fimbriae display different binding specificities, we obtained evidence of synergy/interference with other adhesins such as Ag43 or type 1 fimbriae. We showed that their expression is under the negative control of H-NS and, except for yad, subjected to cAMP receptor protein-mediated activation and carbon catabolite repression. These results therefore demonstrate that ycb, yfc, yad, yra, sfm and yeh operons encode cryptic but functional fimbriae adhesins whose expression following environmental modifications could contribute to E. coli's ability to adhere to and colonize a wide diversity of surfaces in its various ecological niches.


Systemic immediate allergic reactions to arthropod stings and bites.
Most of the encounters with biting and stinging insects result in more or less pronounced localized reactions. Typically, urticarial wheals and papular reactions are observed. Less often local bullous or hemorrhagic or disseminated papular reactions, particularly in children and immunologically naive adults, may be seen. With the exception of bee and wasp venom allergies, immediate-type allergic reactions to arthropod stings and bites are rare. Systemic IgE-mediated hypersensitivity has also been reported from additional hymenoptera species, e.g. hornets, bumble bees and ants. Rare are systemic reactions to mosquitoes, flies or kissing bugs and exceptional from ticks, bed bugs, moths, caterpillars and spiders. A major problem is the often lacking standardization of extracts for skin testing and for the determination of specific IgE. Some of the allergens have been characterized and few of them synthesized using recombinant techniques. Most investigations have been made with whole-body extracts or extracts from salivary glands, while desensitization has rarely been attempted. Currently, primary prevention by avoidance of stings and bites, and adequate instruction of sensitized individuals in the use of emergency drugs are mandatory.


Rare disruptive mutations and their contribution to the heritable risk of colorectal cancer.
Colorectal cancer (CRC) displays a complex pattern of inheritance. It is postulated that much of the missing heritability of CRC is enshrined in high-impact rare alleles, which are mechanistically and clinically important. In this study, we assay the impact of rare germline mutations on CRC, analysing high-coverage exome sequencing data on 1,006 early-onset familial CRC cases and 1,609 healthy controls, with additional sequencing and array data on up to 5,552 cases and 6,792 controls. We identify highly penetrant rare mutations in 16% of familial CRC. Although the majority of these reside in known genes, we identify POT1, POLE2 and MRE11 as candidate CRC genes. We did not identify any coding low-frequency alleles (1-5%) with moderate effect. Our study clarifies the genetic architecture of CRC and probably discounts the existence of further major high-penetrance susceptibility genes, which individually account for >1% of the familial risk. Our results inform future study design and provide a resource for contextualizing the impact of new CRC genes.


Principal Component Analysis of Working Memory Variables during Child and Adolescent Development.
Correlation and Principal Component Analysis (PCA) of behavioral measures from two experimental tasks (Delayed Match-to-Sample and Oddball), and standard scores from a neuropsychological test battery (Working Memory Test Battery for Children) was performed on data from participants between 6-18 years old. The correlation analysis (p 1), the scores of the first extracted component were significantly correlated (p < .05) to most behavioral measures, suggesting some commonalities of the processes of age-related changes in the measured variables. The results suggest that this first component would be related to age but also to individual differences during the cognitive maturation process across childhood and adolescence stages. The fourth component would represent the speed-accuracy trade-off phenomenon as it presents loading components with different signs for reaction times and errors.


Evaluation of two support methods for the subluxated shoulder of hemiplegic patients.
One of the most troublesome complications in the rehabilitation of hemiplegic patients is inferior subluxation of the glenohumeral joint. The purpose of this study was to determine which of two shoulder supports, the Bobath shoulder roll or the Henderson shoulder ring, would be more effective in the management of hemiplegic patients with a subluxated glenohumeral joint. To determine the degree of subluxation and the amount of reduction after application of a shoulder support, radiographs were taken of 26 hemiplegic patients with subluxated shoulders. Radiographs of the unsupported affected shoulder were compared with radiographs of the same shoulder with each support applied. Radiographs of the unaffected shoulder were used as a comparison in determining the amount of subluxation. An analysis of variance revealed no significant difference in the reduction of inferior subluxation between the two types of shoulder support. A significant difference in subluxation, however, existed between measurements of the unsupported affected shoulder and the unaffected shoulder (p less than .001) and between measurements of the unsupported affected shoulder and the supported affected shoulder (p less than .001). The results of this study demonstrate the benefits of the Bobath shoulder roll and the Henderson shoulder ring in the management of hemiplegic patients with subluxated shoulders.


A DFT based investigation into the electronic structure and properties of hydride rich rhodium clusters.
Density functional theory has been used to investigate the structures, bonding and properties of a family of hydride rich late transition metal clusters of the type [Rh(6)(PH(3))(6)H(12)](x) (x = 0, +1, +2, +3 or +4), [Rh(6)(PH(3))(6)H(16)](x) (x = +1 or +2) and [Rh(6)(PH(3))(6)H(14)](x) (x = 0, +1 or +2). The positions of the hydrogen atoms around the pseudo-octahedral Rh(6) core in the optimized structures of [Rh(6)(PH(3))(6)H(12)](x) (x = 0, +1, +2, +3 or +4) varied depending on the overall charge on the cluster. The number of semi-bridging hydrides increased (semi-bridging hydrides have two different Rh-H bond distances) as the charge on the cluster increased and simultaneously the number of perfectly bridging hydrides (equidistant between two Rh centers) decreased. This distortion maximized the bonding between the hydrides and the metal centers and resulted in the stabilization of orbitals related to the 2T(2g) set in a perfectly octahedral cluster. In contrast, the optimized structures of the 16-hydride clusters [Rh(6)(PH(3))(6)H(12)](x) (x = +1 or +2) were similar and both clusters contained an interstitial hydride, along with one terminal hydride, ten bridging hydrides and two coordinated H(2) molecules which were bound to two rhodium centers in an eta(2):eta(1)-fashion. All the hydrides were on the outside of the Rh(6) core in the lowest energy structures of the 14-hydride clusters [Rh(6)(PH(3))(6)H(14)] and [Rh(6)(PH(3))(6)H(14)](+), which both contained eleven bridging hydrides, one terminal hydride and one coordinated H(2) molecule. Unfortunately, the precise structure of [Rh(6)(PH(3))(6)H(14)](2+) could not be determined as structures both with and without an interstitial hydride were of similar energy. The reaction energetics for the uptake and release of two molecule of H(2) by a cycle consisting of [Rh(6)(PH(3))(6)H(12)](2+), [Rh(6)(PH(3))(6)H(16)](2+), [Rh(6)(PH(3))(6)H(14)](+), [Rh(6)(PH(3))(6)H(12)](+) and [Rh(6)(PH(3))(6)H(14)](2+) were modelled, and, in general, good agreement was observed between experimental and theoretical results. The electronic reasons for selected steps in the cycle were investigated. The 12-hydride cluster [Rh(6)(PH(3))(6)H(12)](2+) readily picks up two molecules of H(2) to form [Rh(6)(PH(3))(6)H(16)](2+) because it has a small HOMO-LUMO gap (0.50 eV) and a degenerate pair of LUMO orbitals available for the uptake of four electrons (which are provided by two molecules of H(2)). The reverse process, the spontaneous release of a molecule of H(2) from [Rh(6)(PH(3))(6)H(16)](+) to form [Rh(6)(PH(3))(6)H(14)](+) occurs because the energy gap between the anti-bonding SOMO and the next highest energy occupied orbital in [Rh(6)(PH(3))(6)H(16)](+) is 0.9 eV, whereas in [Rh(6)(PH(3))(6)H(14)](+) the energy gap between the anti-bonding SOMO and the next highest energy occupied orbital is only 0.3 eV. At this stage the factors driving the conversion of [Rh(6)(PH(3))(6)H(14)](+) to [Rh(6)(PH(3))(6)H(12)](2+) are still unclear.


A rationale for parsimonious laboratory term mapping by frequency.
Mapping local observation codes to a standard vocabulary provides a bridge across the many islands of data that reside in isolated systems, but mapping is resource intensive. To help prioritize the mapping effort, we analyzed laboratory results reported over a thirteen month period from five institutions in the Indiana Network for Patient Care. Overall, more than 4,000 laboratory observation codes accounted for almost 49 million results. Of the observations reported in the thirteen months, 80 codes (2%) accounted for 80% of the total volume from all institutions and 784 codes (19%) accounted for 99% of the volume from all institutions. The 244 to 517 observation codes that represented 99% of the volume at each institution also captured all results for more than 99% of the patients at that institution. Our findings suggest that focusing the mapping effort on this modest set of high-yield codes can reduce the barriers to interoperability.


Mitral valve surgical procedures in the elderly.
Mitral valve (MV) surgical procedures in the elderly are associated with profound operative and long-term mortality. We report our experience and results for MV surgical procedures in the elderly, especially with regard to the influence of comorbidities. Our hospital database was assessed to identify all patients who underwent MV surgical procedures at the age of 70 years and older between 1999 and 2009. The data were retrospectively analyzed. A total of 2,503 patients operated on during this 10-year period were identified. In 97% of patients, mitral regurgitation (MR) was the primary indication for operation, followed by coronary artery disease in 41.6% and aortic valve stenosis in 21.3%. The 30-day mortality rate was 3.1%, and the long-term survival at 5 years was 55.2% (95% confidence interval, 52.3% to 57.5%). Coronary artery bypass grafting was identified to be associated with inferior short-term and long-term survival. Numerous comorbidities significantly influenced long-term survival. The observed mortality was significantly lower than predicted by EuroSCORE (17.2%). MV operations in the elderly can be performed with a low early mortality and promising long-term survival. However, our large series demonstrates that comorbidities are to be attributed as the real burden for successful treatment of elderly patients undergoing MV procedures.


The modification of an estuary.
The San Francisco Bay estuary has been rapidly modified by human activity. Diking and filling of most of its wetlands have eliminated habitats for fish and waterfowl; the introduction of exotic species has transformed the composition of its aquatic communities; reduction of freshwater inflow by more than half has changed the dynamics of its plant and animal communities; and wastes have contaminated its sediments and organisms. Continued disposal of toxic wastes, the probable further reduction in freshwater inflow, and the possible synergy between the two provide the potential for further alteration of the estuary's water quality and biotic communities.


Pancreatic beta cell-specific transcription of the pdx-1 gene. The role of conserved upstream control regions and their hepatic nuclear factor 3beta sites.
To identify potential transactivators of pdx-1, we sequenced approximately 4.5 kilobases of the 5' promoter region of the human and chicken homologs, assuming that sequences conserved with the mouse gene would contain critical cis-regulatory elements. The sequences associated with hypersensitive site 1 (HSS1) represented the principal area of homology within which three conserved subdomains were apparent: area I (-2694 to -2561 base pairs (bp)), area II (-2139 to -1958 bp), and area III (-1879 to -1799 bp). The identities between the mouse and chicken/human genes are very high, ranging from 78 to 89%, although only areas I and III are present within this region in chicken. Pancreatic beta cell-selective expression was shown to be controlled by mouse and human area I or area II, but not area III, from an analysis of pdx-1-driven reporter activity in transfected beta- and non-beta cells. Mutational and functional analyses of conserved hepatic nuclear factor 3 (HNF3)-like sites located within area I and area II demonstrated that activation by these regions was mediated by HNF3beta. To determine if a similar regulatory relationship might exist within the context of the endogenous gene, pdx-1 expression was measured in embryonic stem cells in which one or both alleles of HNF3beta were inactivated. pdx-1 mRNA levels induced upon differentiation to embryoid bodies were down-regulated in homozygous null HNF3beta cells. Together, these results suggest that the conserved sequences represented by areas I and II define the binding sites for factors such as HNF3beta, which control islet beta cell-selective expression of the pdx-1 gene.


The decay of stem cell nourishment at the niche.
One of the main features of human aging is the loss of adult stem cell homeostasis. Organs that are very dependent on adult stem cells show increased susceptibility to aging, particularly organs that present a vascular stem cell niche. Reduced regenerative capacity in tissues correlates with reduced stem cell function, which parallels a loss of microvascular density (rarefraction) and plasticity. Moreover, the age-related loss of microvascular plasticity and rarefaction has significance beyond metabolic support for tissues because stem cell niches are regulated co-ordinately with the vascular cells. In addition, microvascular rarefaction is related to increased inflammatory signals that may negatively regulate the stem cell population. Thus, the processes of microvascular rarefaction, adult stem cell dysfunction, and inflammation underlie the cycle of physiological decline that we call aging. Observations from new mouse models and humans are discussed here to support the vascular aging theory. We develop a novel theory to explain the complexity of aging in mammals and perhaps in other organisms. The connection between vascular endothelial tissue and organismal aging provides a potential evolutionary conserved mechanism that is an ideal target for the development of therapies to prevent or delay age-related processes in humans.


Mechanisms of Aeroallergen Immunotherapy: Subcutaneous Immunotherapy and Sublingual Immunotherapy.
Allergen immunotherapy (AIT) is an effective way to treat allergic disorders, targeting the underlying mechanisms and altering the disease course by inducing a long-lasting clinical and immune tolerance to allergens. Although sublingual and subcutaneous routes are used in daily practice, many novel ways to decrease side effects and duration and increase efficacy have been pursued. Further studies are needed to develop biomarkers for the identification of AIT responder patients and also to use the developed knowledge in allergy prevention studies. Future directions in AIT include treatments for autoimmune diseases, chronic infections, organ transplantation, and breaking immune tolerance to cancer cells.


Global Kalman filter approaches to estimate absolute angles of lower limb segments.
In this paper we propose the use of global Kalman filters (KFs) to estimate absolute angles of lower limb segments. Standard approaches adopt KFs to improve the performance of inertial sensors based on individual link configurations. In consequence, for a multi-body system like a lower limb exoskeleton, the inertial measurements of one link (e.g., the shank) are not taken into account in other link angle estimations (e.g., foot). Global KF approaches, on the other hand, correlate the collective contribution of all signals from lower limb segments observed in the state-space model through the filtering process. We present a novel global KF (matricial global KF) relying only on inertial sensor data, and validate both this KF and a previously presented global KF (Markov Jump Linear Systems, MJLS-based KF), which fuses data from inertial sensors and encoders from an exoskeleton. We furthermore compare both methods to the commonly used local KF. The results indicate that the global KFs performed significantly better than the local KF, with an average root mean square error (RMSE) of respectively 0.942° for the MJLS-based KF, 1.167° for the matrical global KF, and 1.202° for the local KFs. Including the data from the exoskeleton encoders also resulted in a significant increase in performance. The results indicate that the current practice of using KFs based on local models is suboptimal. Both the presented KF based on inertial sensor data, as well our previously presented global approach fusing inertial sensor data with data from exoskeleton encoders, were superior to local KFs. We therefore recommend to use global KFs for gait analysis and exoskeleton control.


Negative health selection into physically light occupations.
Health selection, which transfers workers with health problems from physically heavy to physically light occupations, may be a factor contributing to excessive morbidity in the latter group. The aim of this study was to investigate whether workers who had stopped doing heavy work and moved to occupations with low physical demand are generally more ill than workers who had always done light work. The study population comprised 5436 men and 5486 women aged 25 to 74 years, who were interviewed within the scope of the Statistics Sweden Survey of Living Conditions in the years 1977 and 1979-81. For all respondents detailed recording of the occupational histories was completed. For all the diseases and functional disorders studied an increase in risk could be seen for movers. Moreover, movers who had left their heavy work most recently had the greatest risks. This association was most apparent when studying musculoskeletal disorders and impaired working capacity for men and diseases of the circulatory organs and impaired hearing for women. The findings indicate clearly that there is a negative health selection into physically light occupations, introducing a bias (especially in cross-sectional studies) that causes an apparent excess morbidity in occupations with low physical demand.


Randomized Phase 2 Trial of a Novel Clonidine Mucoadhesive Buccal Tablet for the Amelioration of Oral Mucositis in Patients Treated With Concomitant Chemoradiation Therapy for Head and Neck Cancer.
Oral mucositis (OM) is a frequent and painful sequela of concomitant chemoradiation (CRT) used for the treatment of head and neck cancer (HNC) for which there is no effective intervention. This randomized, placebo-controlled study evaluated the efficacy of a novel, mucoadhesive topical tablet formulation of clonidine in mitigating CRT-induced OM in patients with HNC. Patients with HNC undergoing adjuvant radiation therapy (60-66 Gy; 5 × 1.8-2.2 Gy/wk) with concomitant platinum-based chemotherapy received daily local clonidine at 50 μg (n = 56), 100 μg (n = 65), or placebo (n = 62) via a topical mucobuccal tablet starting 1 to 3 days before and continuing during treatment. The primary endpoint was the incidence of severe OM (severe OM [SOM], World Health Organization grade 3/4). SOM developed in 45% versus 60% (P = .06) of patients treated with clonidine compared with placebo and occurred for the first time at 60 Gy as opposed to 48 Gy (median; hazard ratio, 0.75 [95% confidence interval, 0.484-1.175], P = .21); median time to onset was 45 versus 36 days. Opioid analgesic use, mean patient-reported mouth and throat soreness, and CRT compliance were not significantly different between treatment arms. Adverse events were reported in 90.8% versus 98.4%, nausea in 49.6% versus 71.0%, dysphagia in 32.8% versus 48.4%, and reversible hypotension in 6.7% versus 1.6% of patients on clonidine versus placebo, respectively. Although the primary endpoint was not met, the positive trends of OM-associated outcomes suggest that the novel mucoadhesive tablet delivery of clonidine might favorably affect the course and severity of CRT-induced SOM and support further evaluation.


Reactivated melanophore motility: differential regulation and nucleotide requirements of bidirectional pigment granule transport.
To study the molecular basis for organized pigment granule transport, procedures were developed to lyse melanophores of Tilapia mossambica under conditions in which pigment granule movements could be reactivated. Gentle lysis of the melanophores resulted in a permeabilized cell model, which, in the absence of exogenous ATP, could undergo multiple rounds of pigment granule aggregation and dispersion when sequentially challenged with epinephrine and cAMP. Both directions of transport required ATP, since aggregation or dispersion in melanophores depleted of nucleotides could be reactivated only upon addition of MgATP or MgATP plus cAMP, respectively. Differences between the nucleotide sensitivities for aggregation and dispersion were demonstrated by observations that aggregation had a lower apparent Km for ATP than did dispersion and could be initiated at a lower ATP concentration. Moreover, aggregation could be initiated by ADP, but only dispersion could be reactivated by the thiophosphate ATP analog, ATP gamma S. The direction of pigment transport was determined solely by cAMP, since pigment granules undergoing dispersion reaggregated when cAMP was removed, and those undergoing aggregation dispersed when cAMP was added. These results provide evidence that pigment granule motility may be based on two distinct mechanisms that are differentially activated and regulated to produce bidirectional movements.


Changes of the erythrocyte phenotype and blood biochemistry in dairy calves during the first ten weeks of age.
Bovine erythrocytes undergo important changes in their morphology and chemical composition during the first weeks of age, which must be understood to accurately interpret hematology results in calves. The objectives of this prospective cohort study were to describe physiological changes of calf erythrocytes and to investigate mechanisms potentially causing these changes. Blood samples from 30 clinically healthy dairy calves were obtained from birth to the tenth week of age in weekly intervals. Hematological and plasma biochemical parameters as well as the mineral electrolyte content of erythrocytes were determined and followed over time. The changes of parameters characterizing the erythrocyte phenotype over time were compared to the changes of plasma and erythrocyte biochemical parameters and possible associations were investigated using correlation and stepwise regression analyses. Although the erythrocyte mean corpuscular volume (MCV) declined from 43.6 ± 3.7 fL to 35.6 ± 3.2 fL between the first and seventh week, the red blood cell count (RBC) increased from 7.2 ± 1.1 × 1012/L to 9.3 ± 1.0 × 1012/L until the fifth week of age. The blood hemoglobin (Hb) concentration increased from 0.96 ± 0.16 g/L to 1.16 ± 0.11 g/L in the first three weeks of age and remained at this level until the end of the study. Changes in MCV were accompanied by a decline of the erythrocyte potassium content (KERY) from 91.9 ± 13.5 to 24.6 ± 7.2 mmol/L and a concomitant increase of the erythrocyte sodium content from 45.0 ± 32.0 to 102.7 ± 26.5 mmol/L. MCV was found to be associated with KERY, the primary determinant of the intra-erythrocyte osmotic pressure from the sixth week of age and with blood hemoglobin, the primary determinant of the intra-erythrocyte oncotic pressure from the eighth week of age, when KERY, blood Hb and MCV already had reached or approached normal levels of adult cattle. The plasma iron concentration was not found to be associated to any of the studied hematological parameters. A volume reduction of 20% in bovine neonatal erythrocytes is a physiological change occurring during the first weeks of age and is neither associated with sideropenia nor with anemia in healthy calves. The mechanism driving the observed erythrocyte volume change could not be identified. Results of the correlation and regression analyses indicate that changes in intra-erythrocyte osmotic or oncotic pressure are improbable underlying causes. Results reported here show that KERY is an unreliable indicator for the K homeostasis of the intracellular space in neonatal calves and that a decrease in MCV in early life per-se is an unreliable indicator for the development of microcytic anemia.


Bankart Repair Versus Latarjet Procedure for Recurrent Anterior Shoulder Instability: A Systematic Review and Meta-analysis of 3275 Shoulders.
Little consensus is available regarding the standard treatment for recurrent anterior instability of the shoulder. Typically, treatment selection has been based on training and tradition rather than the available evidence. This study aimed to compare the clinical outcomes between arthroscopic Bankart procedure and the Latarjet procedure in the treatment of recurrent anterior shoulder instability with emphasis on follow-up time. Systematic review and meta-analysis. We searched PubMed, Cochrane Central Register of Controlled Trials, Scopus, Ovid, and Web of Science up to January 2018 and included studies that compared arthroscopic Bankart versus Latarjet for treatment of anterior shoulder instability. Continuous data, such as operative time and patient-reported outcomes, were pooled as mean differences (MDs), whereas dichotomous data, such as recurrence, revision, redislocation, arthropathy, infection, and hematoma, were pooled as risk ratios (RRs), with 95% CIs. Pooling data from 7 cohort studies (3275 patients) showed that arthroscopic Bankart was associated with a higher risk of redislocation (RR, 2.74; 95% CI, 1.48-5.06; P = .03), a higher risk of recurrence (RR, 2.87; 95% CI, 1.91-4.30; P < .0001), and a lower risk of infection (RR, 0.16; 95% CI, 0.06-0.43; P = .0002) compared with Latarjet, while the effect size did not favor arthroscopic Bankart or Latarjet in terms of Rowe score (MD, 0.22; 95% CI, -5.64 to 6.08; P = .94), revision (RR, 0.34; 95% CI, 0.08-1.39; P = .13), and hematoma (RR, 0.20; 95% CI, 0.03-1.19; P = .07). The effect estimate showed a pronounced advantage for Latarjet from 6 to 10 years postoperatively in terms of recurrence and redislocation (RR, 3.00; 95% CI, 1.98-4.56 and RR, 2.85; 95% CI, 1.51-5.38, respectively). Our results showed that Latarjet had less risk of recurrence and redislocation with longer follow-up time. Both procedures were comparable in terms of Rowe score, the need for revision, and postoperative hematoma formation, whereas Bankart repair was associated with a lower risk of infection.


Quality of life, psychosocial health, and antiretroviral therapy among HIV-positive women in Zimbabwe.
Little is known about the psychosocial impact of antiretroviral therapy (ART) among women in sub-Saharan Africa. Therefore, we conducted a cross-sectional study in Zimbabwe to assess the impact of ART on HIV-positive women's health-related quality of life, using the Medical Outcomes Study-HIV Quality of Life (QOL) questionnaire. Additionally, we assessed socio-demographics, reproductive and sexual health, HIV-related history, disclosure, social stigma, self-esteem, and depression. Structured interviews were conducted with 200 HIV-positive women and categorized into three groups by treatment: (1) Group 1 (n=31) did not meet clinical or laboratory criteria to begin treatment; (2) Group 2 (n=73) was eligible to begin treatment but awaiting initiation of treatment; and (3) Group 3 (n=96) was on ART for a median of 13 months. The women had similar socio-demographic characteristics but varied significantly in clinical characteristics. Women on ART reported fewer AIDS-related symptoms in the last week and year and had higher current and lower baseline CD4 counts compared to women not on ART. On most QOL domains women on ART reported higher mean scores as compared to women not on ART (p<0.01). Additionally, women on ART reported less depression compared to women not on ART (p<0.001). Between the two groups of women not on ART, unexpectedly, there were no significant differences in their scores for QOL or depression. Thus, Zimbabwean women living with HIV experience better overall QOL and lower depression on ART. Altogether, our findings suggest that ART delivery in resource-poor communities can enhance overall QOL as well as psychosocial functioning, which has wide-ranging public health implications.