Women with multiple chemical sensitivity have increased harm avoidance and reduced 5-HT(1A) receptor binding potential in the anterior cingulate and amygdala.
Multiple chemical sensitivity (MCS) is a common condition, characterized by somatic distress upon exposure to odors. As in other idiopathic environmental intolerances, the underlying mechanisms are unknown. Contrary to the expectations it was recently found that persons with MCS activate the odor-processing brain regions less than controls, while their activation of the anterior cingulate cortex (ACC) is increased. The present follow-up study was designed to test the hypotheses that MCS subjects have increased harm avoidance and deviations in the serotonin system, which could render them intolerant to environmental odors. Twelve MCS and 11 control subjects, age 22-44, all working or studying females, were included in a PET study where 5-HT(1A) receptor binding potential (BP) was assessed after bolus injection of [(11)C]WAY100635. Psychological profiles were assessed by the Temperament and Character Inventory and the Swedish universities Scales of Personality. All MCS and 12 control subjects were also tested for emotional startle modulation in an acoustic startle test. MCS subjects exhibited significantly increased harm avoidance, and anxiety compared to controls. They also had a reduced 5-HT(1A) receptor BP in amygdala (p = 0.029), ACC (p = 0.005) (planned comparisons, significance level 0.05), and insular cortex (p = 0.003; significance level p<0.005 with Bonferroni correction), and showed an inverse correlation between degree of anxiety and the BP in the amygdala (planned comparison). No group by emotional category difference was found in the startle test. Increased harm avoidance and the observed changes in the 5-HT(1A) receptor BP in the regions processing harm avoidance provides a plausible pathophysiological ground for the symptoms described in MCS, and yields valuable information for our general understanding of idiopathic environmental intolerances.


Path planning versus cue responding: a bio-inspired model of switching between navigation strategies.
In this article, we describe a new computational model of switching between path-planning and cue-guided navigation strategies. It is based on three main assumptions: (i) the strategies are mediated by separate memory systems that learn independently and in parallel; (ii) the learning algorithms are different in the two memory systems-the cue-guided strategy uses a temporal-difference (TD) learning rule to approach a visible goal, whereas the path-planning strategy relies on a place-cell-based graph-search algorithm to learn the location of a hidden goal; (iii) a strategy selection mechanism uses TD-learning rule to choose the most successful strategy based on past experience. We propose a novel criterion for strategy selection based on the directions of goal-oriented movements suggested by the different strategies. We show that the selection criterion based on this "common currency" is capable of choosing the best among TD-learning and planning strategies and can be used to solve navigational tasks in continuous state and action spaces. The model has been successfully applied to reproduce rat behavior in two water-maze tasks in which the two strategies were shown to interact. The model was used to analyze competitive and cooperative interactions between different strategies during these tasks as well as relative influence of different types of sensory cues.


Coping with rheumatoid arthritis pain: catastrophizing as a maladaptive strategy.
The present study examined catastrophizing in rheumatoid arthritis (RA) patients. Subjects were 223 RA patients who were participants in a longitudinal study. Each patient completed the Catastrophizing scale of the Coping Strategies Questionnaire (CSQ) on 2 occasions separated by 6 months (time 1, time 2). The Catastrophizing scale is designed to measure negative self-statements, castastrophizing thoughts and ideation (sample items = 'I worry all the time about whether it will end,' 'It is awful and I feel that it overwhelms me'). Data analysis revealed that the Catastrophizing scale was internally reliable (alpha = 0.91) and had high test-retest reliability (r = 0.81) over a 6 month period. Correlational analyses revealed that catastrophizing recorded at time 1 was related to pain intensity ratings, functional impairment on the Arthritis Impact Measurement scale (AIMS), and depression at time 2. Predictive findings regarding catastrophizing while modest were obtained after controlling for initial scores on the dependent variables, demographic variables (age, sex, socioeconomic status), duration of pain, and disability support status. Taken together, these findings suggest that catastrophizing is a maladaptive coping strategy in RA patients. Further research is needed to determine whether cognitive-behavioral interventions designed to decrease catastrophizing can reduce pain and improve the physical and psychological functioning of RA patients.


Laminin and fibronectin treatment leads to generation of dendritic cells with superior endocytic capacity.
Sampling the microenvironment at sites of microbial exposure by dendritic cells (DC) and their subsequent interaction with T cells in the paracortical area of lymph nodes are key events for initiating immune responses. Most of our knowledge of such events in human is based on in vitro studies performed in the absence of extracellular matrix (ECM) proteins. ECM in basement membranes and interstitial spaces of different tissues, including lymphoid organs, plays an important role in controlling specific cellular functions such as migration, intracellular signalling and differentiation. The aim of this study was, therefore, to investigate the impact of two abundant ECM components, fibronectin and laminin, on the phenotypical and functional properties of DC and how that might influence DC induced T-cell differentiation. Human monocyte derived DC were treated with laminin and fibronectin for up to 48 hours and their morphology and phenotype was analyzed using scanning electron microscopy, flow cytometry and real time PCR. The endocytic ability of DC was determined using flow cytometry. Furthermore, co-culture of DC and T cells were established and T cell proliferation and cytokine profile was measured using H(3)-thymidine incorporation and ELISA respectively. Finally, we assessed formation of DC-T cell conjugates using different cell trackers and flow cytometry. Our data show that in the presence of ECM, DC maintain a 'more immature' phenotype and express higher levels of key endocytic receptors, and as a result become significantly better endocytic cells, but still fully able to mature in response to stimulation as evidenced by their superior ability to induce antigen-specific T cell differentiation. These studies underline the importance of including ECM components in in vitro studies investigating DC biology and DC-T cell interaction. Within the context of antigen specific DC induced T cell proliferation, inclusion of ECM proteins could lead to development of more sensitive assays.


What are the television viewing and eating habits of children in Peru?
While there is already consensus in the scientific community about the deleterious effects of TV exposure, especially through TV advertisements, on children's beliefs, preferences, and food intake, the link between TV and children's eating behaviors is under-studied in Peru, a country experiencing a steady economic growth in recent years and currently with a status of upper-middle-income country. Following research about the effects of media exposure on childhood obesity, we report on a qualitative study of TV viewing and the eating habits of children attending elementary schools in Lima, the capital. Data from eight focus groups with 38 boys and girls between 6 and 11 years old, eight focus groups with 36 female caretakers, and in-depth interviews with two fathers provided consistent information about children's eating habits and media viewing patterns. After dual coding the entire corpus of qualitative data, we found that children watch a great deal of TV during the school season: children watch as early as when they wake up in the morning, then during lunchtime (after returning from school), and then again after completing their homework from 5 pm to 9 pm or 10 pm. Survey data from the parents showed that, on average, children watch about 5 hours of TV on weekdays and more during a weekend-day. This large amount of exposure is concerning, especially because the focus groups revealed that children (1) recall a number of TV advertisements involving food items, (2) request food items seen on TV, and (3) are able to buy food for themselves, which usually involves chocolate, candy, or potato chips. Boys and girls reported different favorite TV shows, suggesting differences in exposure to TV content related to food. In addition, some families reported drinking sodas frequently, underlining a behavior that should be discouraged by public health officials.


Relationship of childhood obesity to coronary heart disease risk factors in adulthood: the Bogalusa Heart Study.
Childhood obesity is related to adult levels of lipids, lipoproteins, blood pressure, and insulin and to morbidity from coronary heart disease (CHD). However, the importance of the age at which obesity develops in these associations remains uncertain. We assessed the longitudinal relationship of childhood body mass index (BMI, kg/m(2)) to adult levels of lipids, insulin, and blood pressure among 2617 participants. All participants were initially examined at ages 2 to 17 years and were reexamined at ages 18 to 37 years; the mean follow-up was 17 years. Of the overweight children (BMI >/=95th percentile), 77% remained obese (>/=30 kg/m(2)) as adults. Childhood overweight was related to adverse risk factor levels among adults, but associations were weak (r ~ 0.1-0.3) and were attributable to the strong persistence of weight status between childhood and adulthood. Although obese adults had adverse levels of lipids, insulin, and blood pressure, levels of these risk factors did not vary with childhood weight status or with the age (</=8 years, 12-17 years, or >/=18 years) of obesity onset. Additional data are needed to assess the independent relationship of childhood weight status to CHD morbidity. Because normal-weight children who become obese adults have adverse risk factor levels and probably will be at increased risk for adult morbidity, our results emphasize the need for both primary and secondary prevention.


A novel DNA topoisomerase inhibitor: dehydroebriconic acid, one of the lanostane-type triterpene acids from Poria cocos.
Traditional Chinese medicinal plants are a treasure house for screening novel inhibitors of DNA polymerases and DNA topoisomerases from mammals; in the present study, nine lanostane-type triterpene acids were found in sclerotium of Poria cocos. Among the nine compounds, only dehydroebriconic acid could potently inhibit DNA topoisomerase II (topo II) activity (IC(50) = 4.6 microM), while the compound moderately inhibited the activities of DNA polymerases alpha, beta, gamma, delta, epsilon, eta, iota, kappa and lambda only from mammals, to similar extents. Another compound, dehydrotrametenonic acid, also showed moderate inhibitory effects against topo II (IC(50) = 37.5 microM) and weak effects against all the polymerases tested. Both compounds showed no inhibitory effect against topo I, higher plant (cauliflower) DNA polymerase I (alpha-like polymerase) or II (beta-like polymerase), calf thymus terminal deoxynucleotidyl transferase, human immunodeficiency virus type-1 reverse transcriptase, prokaryotic DNA polymerases such as the Klenow fragment of E. coli DNA polymerase I, Taq DNA polymerase and T4 DNA polymerase, or DNA metabolic enzymes such as T 7 RNA polymerase, T4 polynucleotide kinase and bovine deoxyribonuclease I. These findings suggest that dehydroebriconic acid and dehydrotrametenonic acid should be designated as topo II-preferential inhibitors, although they also moderately inhibited all the mammalian DNA polymerases tested. Both dehydrotrametenonic acid and dehydroebriconic acid could prevent the growth of human gastric cancer cells, and their LD(50) values were 63.6 and 38.4 microM, respectively. The cells were halted at the G1 phase in the cell cycle. The relation between the structure of triterpene acids and their inhibitory activities is discussed.


Investigation of Drug Release from PEO Tablet Matrices in the Presence of Vitamin E as Antioxidant.
The objective of this study was to investigate the influence of drug type on the release of drug from PEO matrix tablets accompanied with the impact of vitamin E succinate as antioxidant. The result showed that the presence of vitamin E promoted a stable release rate of soluble drug propranolol HCl from aged PEO matrix tablets, which was similar to fresh sample, regardless of molecular weight (MW) of PEO. However, the influence of the presence of vitamin E on the release rate of partially soluble drug, theophylline, was dependent on the MW of PEO; i.e., fast and unstable drug release was obtained in the case of low MW PEO 750 whereas stable drug release was obtained in the case of high MW PEO 303. The release of low water-soluble drug zonisamide was stable regardless of both the presence of vitamin E and the MW of PEO. The presence of vitamin E slightly slowed the release of zonisamide from aged PEO 303 matrices but not PEO 750 matrices. Therefore, in order to achieve a suitable controlled release profile from PEO matrices, not only the presence of vitamin E but also the solubility of the drug and the MW of polyox should be considered.


High dosage of cannabidiol (CBD) alleviates pentylenetetrazole-induced epilepsy in rats by exerting an anticonvulsive effect.
The study was designed to investigate the effect of various concentrations of cannabidiol (CBD) in rats with chronic epilepsy. The chronic epilepsy rat model was prepared by intraperitoneally injecting pentylenetetrazole to the rats pre-treated with CBD (10, 20 and 50 mg/kg) for 28 consecutive days. Behavioral measurements of convulsion following pentylenetetrazole treatment and morphological changes of the hippocampal neurons with hematoxylin and eosin staining were used to observe the epileptic behaviour. Immunohistochemistry was used to detect the expression levels of glial fibrillary acidic protein and inducible nitric oxide synthase (iNOS) in the hippocampus. The mRNA expression of N-methyl-D-aspartic acid (NMDA) receptor subunits (NR1 and NR2B) was detected by reverse transcription polymerase chain reaction. The results revealed a significant decrease in the daily average grade of epileptic seizures on treatment with CBD (50 mg/kg). The neuronal loss and astrocyte hyperplasia in the hippocampal area were also decreased. CBD treatment did not affect the expression of iNOS in the hippocampus; however, the expression of NR1 was decreased significantly. Thus, CBD administration inhibited the effect of pentylenetetrazole in rats, decreased the astrocytic hyperplasia, decreased neuronal damage in the hippocampus caused by seizures and selectively reduced the expression of the NR1 subunit of NMDA. Therefore, CBD exhibits an anticonvulsive effect in the rats with chronic epilepsy.


Non-O1, non-O139 Vibrio cholerae bacteraemia in a cirrhotic patient.
Vibrio cholerae serogroups O1 or O139 are the aetiological agents of cholera. The pathogenicity of non-O1, non-O139 V. cholerae is less well known. These worldwide bacteria are responsible for gastrointestinal infections or, more rarely, bacteraemia in patients with an underlying disease, leading to life-threatening complications. We report a case of non-O1, non-O139 V. cholerae bacteraemia due to a haemolytic strain in a cirrhotic patient. Early antibiotherapy allowed a good outcome. The aim of this case report is to underline the virulence of non-choleragenic Vibrio strains, possibly linked to haemolysin production, and the potential danger of consuming undercooked seafood or exposing wounds to sea water in cirrhotic patients.


Lymphocytic infiltration of epithelium in diagnosis of gluten-sensitive enteropathy.
The macroscopic appearance of the mucosa of the small intestine and the lymphocytic infiltration of the epithelium were studied in 27 patients with dermatitis herpetiformis and in 11 control subjects. The mucosa was abnormal in appearance in 13 of the patients and normal in 14 patients and in all the controls. In 25 (93%) of the patients the intraepithelial lymphocyte count was significantly raised compared with the controls. The increased lymphocytic infiltration of the epithelium in the patients probably represented an underlying immunological reaction of the small intestine to gluten, since the infiltration lessened in five out of six patients after a year on a gluten-free diet and in all of four patients after three years on a gluten-free diet.Increased lymphocytic infiltration of the epithelium of the small intestine seems a surer sign of gluten sensitivity than the macroscopic appearance of the mucosa, and a diagnosis of gluten-sensitive enteropathy may no longer be excluded when the mucosa appears normal. Further evidence of the significance of increased lymphocytic infiltration is that patients with normal-looking mucosa but with raised intraepithelial lymphocyte counts often had low serum folate levels.


GDNF Gene Therapy to Repair the Injured Peripheral Nerve.
A spinal root avulsion is the most severe proximal peripheral nerve lesion possible. Avulsion of ventral root filaments disconnects spinal motoneurons from their target muscles, resulting in complete paralysis. In patients that undergo brachial plexus nerve repair, axonal regeneration is a slow process. It takes months or even years to bridge the distance from the lesion site to the distal targets located in the forearm. Following ventral root avulsion, without additional pharmacological or surgical treatments, progressive death of motoneurons occurs within 2 weeks (Koliatsos et al., 1994). Reimplantation of the avulsed ventral root or peripheral nerve graft can act as a conduit for regenerating axons and increases motoneuron survival (Chai et al., 2000). However, this beneficial effect is transient. Combined with protracted and poor long-distance axonal regeneration, this results in permanent function loss. To overcome motoneuron death and improve functional recovery, several promising intervention strategies are being developed. Here, we focus on GDNF gene-therapy. We first introduce the experimental ventral root avulsion model and discuss its value as a proxy to study clinical neurotmetic nerve lesions. Second, we discuss our recent studies showing that GDNF gene-therapy is a powerful strategy to promote long-term motoneuron survival and improve function when target muscle reinnervation occurs within a critical post-lesion period. Based upon these observations, we discuss the influence of timing of the intervention, and of the duration, concentration and location of GDNF delivery on functional outcome. Finally, we provide a perspective on future research directions to realize functional recovery using gene therapy.


The endoscopic transnasal transsphenoidal approach for the treatment of cranial base chordomas and chondrosarcomas.
We report our experience with endoscopic transsphenoidal or extended endoscopic transsphenoidal approaches for the treatment of cranial base lesions such as clival chordomas and chondrosarcomas. Between May 1998 and April 2004, 11 patients (four were recurrences because they previously had been treated with surgery and/or radiotherapy) underwent transnasal transsphenoidal endoscopic surgery for cranial base chordomas and chondrosarcomas at the Neurosurgical Department of Bellaria Hospital in Bologna. The transsphenoidal endoscopic approach and the ethmoid-pterygo-sphenoidal endoscopic approach were used to accomplish resection of the lesions involving the clivus and extending up to the parasellar region and to the petrous apex, or within the cavernous sinus. Patient follow-up periods ranged from 15 to 69 months (mean, 27 mo). Three patients died of chordoma progression at 20, 14, and 10 months, respectively, after endoscopic treatment. One patient experienced two recurrences; the first was treated using a new endoscopic approach, whereas the second, 1 year later, was treated by means of a far lateral approach. Four patients underwent postoperative proton beam radiotherapy, whereas one underwent a conventional megavoltage x-radiation therapy. However, postoperative radiotherapy was not administered in the two patients treated for cranial base chondrosarcoma. The flexibility of this new technique with respect to the classical microscopic transsphenoidal approach permits us to widen the horizon of surgical management of aggressive cranial base tumors such as clival chordomas and chondrosarcomas.


Flavopiridol: An Old Drug With New Perspectives? Implication for Development of New Drugs.
Glioblastoma, the most common brain tumor, is characterized by high proliferation rate, invasion, angiogenesis, and chemo- and radio-resistance. One of most remarkable feature of glioblastoma is the switch toward a glycolytic energetic metabolism that leads to high glucose uptake and consumption and a strong production of lactate. Activation of several oncogene pathways like Akt, c-myc, and ras induces glycolysis and angiogenesis and acts to assure glycolysis prosecution, tumor proliferation, and resistance to therapy. Therefore, the high glycolytic flux depends on the overexpression of glycolysis-related genes resulting in an overproduction of pyruvate and lactate. Metabolism of glioblastoma thus represents a key issue for cancer research. Flavopiridol is a synthetic flavonoid that inhibits a wide range of Cyclin-dependent kinase, that has been demonstrate to inactivate glycogen phosphorylase, decreasing glucose availability for glycolysis. In this work the study of glucose metabolism upon flavopiridol treatment in the two different glioblastoma cell lines. The results obtained point towards an effect of flavopiridol in glycolytic cells, thus suggesting a possible new use of this compound or flavopiridol-derived formulations in combination with anti-proliferative agents in glioblastoma patients. J. Cell. Physiol. 232: 312-322, 2017. © 2016 Wiley Periodicals, Inc.


Comparative trends in incident fracture rates for all long-term care and community-dwelling seniors in Ontario, Canada, 2002-2012.
In this population-based study, we compared incident fracture rates in long-term care (LTC) versus community seniors between 2002 and 2012. Hip fracture rates declined more rapidly in LTC than in the community. An excess burden of fractures occurred in LTC for hip, pelvis, and humerus fractures in men and hip fractures only in women. This study compares trends in incident fracture rates between long-term care (LTC) and community-dwelling seniors ≥65 years, 2002-2012. This is a population-based cohort study using administrative data. Measurements were age/sex-adjusted incident fracture rates and rate ratios (RR) and annual percent change (APC). Over 11 years, hip fracture rates had a marked decline occurring more rapidly in LTC (APC, -3.49 (95% confidence interval (CI), -3.97, -3.01)) compared with the community (APC, -2.93 (95% CI, -3.28, -2.57); p < 0.05 for difference in slopes). Humerus and wrist fracture rates decreased; however, an opposite trend occurred for pelvis and spine fractures with rates increasing over time in both cohorts (all APCs, p < 0.05). In 2012, incident hip fracture rates were higher in LTC than the community (RRs: women, 1.55 (95% CI, 1.45, 1.67); men, 2.18 (95% CI, 1.93, 2.47)). Higher rates of pelvis (RR, 1.48 (95% CI, 1.22, 1.80)) and humerus (RR, 1.40 (95% CI, 1.07, 1.84)) fractures were observed in LTC men, not women. In women, wrist (RR, 0.76 (95% CI, 0.71, 0.81)) and spine (RR, 0.52 (95% CI, 0.45, 0.61)) fracture rates were lower in LTC than the community; in men, spine (RR, 0.75 (95% CI, 0.57, 0.98) but not wrist fracture (RR, 0.91 (95% CI, 0.67, 1.23)) rates were significantly lower in LTC than the community. Previous studies in the community have shown declining hip fracture rates over time, also demonstrated in our study but at a more rapid rate in LTC. Rates of humerus and wrist fractures also declined. An excess burden of fractures in LTC occurred for hip fractures in women and for hip, pelvis, and humerus fractures in men.


Molecular regulation of GLUT-4 targeting in 3T3-L1 adipocytes.
Insulin stimulates glucose transport in muscle and adipose tissue by triggering the movement of the glucose transporter GLUT-4 from an intracellular compartment to the cell surface. Fundamental to this process is the intracellular sequestration of GLUT-4 in nonstimulated cells. Two distinct targeting motifs in the amino and carboxy termini of GLUT-4 have been previously identified by expressing chimeras comprised of portions of GLUT-4 and GLUT-1, a transporter isoform that is constitutively targeted to the cell surface, in heterologous cells. These motifs-FQQI in the NH2 terminus and LL in the COOH terminus-resemble endocytic signals that have been described in other proteins. In the present study we have investigated the roles of these motifs in GLUT-4 targeting in insulin-sensitive cells. Epitope-tagged GLUT-4 constructs engineered to differentiate between endogenous and transfected GLUT-4 were stably expressed in 3T3-L1 adipocytes. Targeting was assessed in cells incubated in the presence or absence of insulin by subcellular fractionation. The targeting of epitope-tagged GLUT-4 was indistinguishable from endogenous GLUT-4. Mutation of the FQQI motif (F5 to A5) caused GLUT-4 to constitutively accumulate at the cell surface regardless of expression level. Mutation of the dileucine motif (L489L490 to A489A490) caused an increase in cell surface distribution only at higher levels of expression, but the overall cells surface distribution of this mutant was less than that of the amino-terminal mutants. Both NH2- and COOH-terminal mutants retained insulin-dependent movement from an intracellular to a cell surface locale, suggesting that neither of these motifs is involved in the insulin-dependent redistribution of GLUT-4. We conclude that the phenylalanine-based NH2-terminal and the dileucine-based COOH-terminal motifs play important and distinct roles in GLUT-4 targeting in 3T3-L1 adipocytes.


Depression and incident lower limb amputations in veterans with diabetes.
Depression is associated with a higher risk of macrovascular and microvascular complications and mortality in diabetes, but whether depression is linked to an increased risk of incident amputations is unknown. We examined the association between diagnosed depression and incident non-traumatic lower limb amputations in veterans with diabetes. This was a retrospective cohort study from 2000-2004 that included 531,973 veterans from the Diabetes Epidemiology Cohorts, a national Veterans Affairs (VA) registry with VA and Medicare data. Depression was defined by diagnostic codes or antidepressant prescriptions. Amputations were defined by diagnostic and procedural codes. We determined the HR and 95% CI for incident non-traumatic lower limb amputation by major (transtibial and above) and minor (ankle and below) subtypes, comparing veterans with and without diagnosed depression and adjusting for demographics, health care utilization, diabetes severity and comorbid medical and mental health conditions. Over a mean 4.1 years of follow-up, there were 1289 major and 2541 minor amputations. Diagnosed depression was associated with an adjusted HR of 1.33 (95% CI: 1.15-1.55) for major amputations. There was no statistically significant association between depression and minor amputations (adjusted HR 1.01, 95% CI: 0.90-1.13). Diagnosed depression is associated with a 33% higher risk of incident major lower limb amputation in veterans with diabetes. Further study is needed to understand this relationship and to determine whether depression screening and treatment in patients with diabetes could decrease amputation rates.


Determinants of Intimate Partner Violence Among Young Men Who Have Sex With Men: The P18 Cohort Study.
Intimate Partner Violence (IPV) is an understudied health problem among young gay, bisexual, and other non-identified young men who have sex with men (YMSM). According to cross-sectional studies, IPV is associated with psychosocial and mental health problems, such as stigma and depression, among YMSM. IPV is also associated with health-risk behaviors, such as substance use, among this population. Yet, to date, no studies have used longitudinal data to examine determinants of IPV among YMSM. This gap in the extant literature is problematic, as it limits our understanding of how to intervene to interrupt cycles of violence. The aim of the present study was to examine longitudinal determinants of IPV among a sample of (N = 526) YMSM living in the New York City area. Longitudinal analyses using Generalized Estimating Equations (GEE) were used to examine individual, relationship, mental health, psychosocial, and substance use factors in relation to IPV victimization and perpetration. Most notably, early experiences of IPV were a robust predictor of later experiences of IPV victimization and perpetration. Relationship status, depression, public gay-related stigma, and illicit substance use were associated with IPV victimization over time. Similarly, relationship status, depression, public gay-related stigma, marijuana, and other illicit substance were associated with IPV perpetration. These findings suggest that prevention programs and awareness campaigns should aim to reach YMSM before their first experiences of relationship violence, as these early experiences of violence are strongly linked to later experiences of violence. Also, IPV interventions should be tailored to the needs of YMSM and should target depressive symptoms, gay-related stigma, and substance use behaviors. Additionally, substance use interventions may be improved by addressing IPV. Finally, policymakers should support policies that improve the social climate for LGBTQ people, thereby reducing gay-related stigma, and potentially stemming violence against and among YMSM.


Impact of acetazolamide and CPAP on cortical activity in obstructive sleep apnea patients.
1) To investigate the impact of acetazolamide, a drug commonly prescribed for altitude sickness, on cortical oscillations in patients with obstructive sleep apnea syndrome (OSAS). 2) To examine alterations in the sleep EEG after short-term discontinuation of continuous positive airway pressure (CPAP) therapy. Data from two double-blind, placebo-controlled randomized cross-over design studies were analyzed. Polysomnographic recordings in sleep laboratory at 490 m and at moderate altitudes in the Swiss Alps: 1630 or 1860 m and 2590 m. Study 1: 39 OSAS patients. Study 2: 41 OSAS patients. Study 1: OSAS patients withdrawn from treatment with CPAP. Study 2: OSAS patients treated with autoCPAP. Treatment with acetazolamide (500-750 mg) or placebo at moderate altitudes. An evening dose of 500 mg acetazolamide reduced slow-wave activity (SWA; approximately 10%) and increased spindle activity (approximately 10%) during non-REM sleep. In addition, alpha activity during wake after lights out was increased. An evening dose of 250 mg did not affect these cortical oscillations. Discontinuation of CPAP therapy revealed a reduction in SWA (5-10%) and increase in beta activity (approximately 25%). The higher evening dose of 500 mg acetazolamide showed the "spectral fingerprint" of Benzodiazepines, while 250 mg acetazolamide had no impact on cortical oscillations. However, both doses had beneficial effects on oxygen saturation and sleep quality.


Mapping the IkappaB kinase beta (IKKbeta)-binding interface of the B14 protein, a vaccinia virus inhibitor of IKKbeta-mediated activation of nuclear factor kappaB.
The IκB kinase (IKK) complex regulates activation of NF-κB, a critical transcription factor in mediating inflammatory and immune responses. Not surprisingly, therefore, many viruses seek to inhibit NF-κB activation. The vaccinia virus B14 protein contributes to virus virulence by binding to the IKKβ subunit of the IKK complex and preventing NF-κB activation in response to pro-inflammatory stimuli. Previous crystallographic studies showed that the B14 protein has a Bcl-2-like fold and forms homodimers in the crystal. However, multi-angle light scattering indicated that B14 is in monomer-dimer equilibrium in solution. This transient self-association suggested that the hydrophobic dimerization interface of B14 might also mediate its interaction with IKKβ, and this was investigated by introducing amino acid substitutions on the dimer interface. One mutant (Y35E) was entirely monomeric but still co-immunoprecipitated with IKKβ and blocked both NF-κB nuclear translocation and NF-κB-dependent gene expression. Therefore, B14 homodimerization is nonessential for binding and inhibition of IKKβ. In contrast, a second monomeric mutant (F130K) neither bound IKKβ nor inhibited NF-κB-dependent gene expression, demonstrating that this residue is required for the B14-IKKβ interaction. Thus, the dimerization and IKKβ-binding interfaces overlap and lie on a surface used for protein-protein interactions in many viral and cellular Bcl-2-like proteins.


X-linked B-lymphocyte immune defect in CBA/HN mice. I. Studies of the function and composition of spleen cells.
A study of the composition and functional properties of spleen cells from the immune deficient CBA/HN mice and their F1 progeny is reported. While abnormalities were seen in both the numbers and function of thymus-independent (B) lymphocytes, all studies involving thymus-dependent (T) lymphocytes were normal. The X-linked nature of the immune defect in these mice was therefore attributed to abnormal or absent B lymphocytes. The possible nature of this defect and the similarity of the immune defect in these mice to certain human X-linked immunodeficiency diseases are discussed.


Pharmacokinetics of delta9-tetrahydrocannabinol in dogs.
The pharmacokinetics of intravenously administered 14C-delta9-tetrahydrocannabinol and derived radiolabeled metabolites were studied in three dogs at two doses each at 0.1 or 0.5 and 2.0 mg/kg. Two dogs were biliary cannulated; total bile was collected in one and sampled in the other. The time course for the fraction of the dose per milliliter of plasma was best fit by a sum of five exponentials, and there was no dose dependency. No drug was excreted unchanged. The mean apparent volume of distribution of the central compartment referenced to total drug concentration in the plasma was 1.31 +/- 0.07 liters, approximately the plasma volume, due to the high protein binding of 97%. The mean metabolic clearance of drug in the plasma was 124 +/- 3.8 ml/min, half of the hepatic plasma flow, but was 4131 +/- 690 ml/min referenced to unbound drug concentration in the plasma, 16.5 times the hepatic plasma flow, indicating that net metabolism of both bound and unbound drug occurs. Apparent parallel production of several metabolites occurred, but the pharmacokinetics of their appearance were undoubtedly due to their sequential production during liver passage. The apparent half-life of the metabolic process was 6.9 +/- 0.3 min. The terminal half-life of delta9-tetrahydrocannabinol in the pseudo-steady state after equilibration in an apparent overall volume of distribtuion of 2170 +/- 555 liters referenced to total plasma concentration was 8.2 +/- 0.23 days, based on the consistency of all pharmacokinetic data. The best estimate of the terminal half-life, based only on the 7000 min that plasma levels could be monitored with the existing analytical sensitivity, was 1.24 days. However, this value was inconsistent with the metabolite production and excretion of 40-45% of dose in feces, 14-16.5% in urine, and 55% in bile within 5 days when 24% of the dose was unmetabolized and in the tissue at that time. These data were consistent with an enterohepatic recirculation of 10-15% of the metabolites. Intravenously administered radiolabeled metabolites were totally and rapidly eliminated in both bile and urine; 88% of the dose in 300 min with an apparent overall volume of distribution of 6 liters. These facts supported the proposition that the return of delta9-tetrahydrocannabinol from tissue was the rate-determining process of drug elimination after initial fast distribution and metabolism and was inconsistent with the capability of enzyme induction to change the terminal half-life.


Nuclear factor of activated T3 is a negative regulator of Ras-JNK1/2-AP-1 induced cell transformation.
The c-jun-NH(2)-kinases (JNK) play a critical role in tumor promoter-induced cell transformation and apoptosis. Here, we showed that the nuclear factor of activated T3 (NFAT3) is phosphorylated by JNK1 or JNK2 at Ser(213) and Ser(217), which are located in the conserved SP motif. The transactivation domain of NFAT3 is found between amino acids (aa) 113 and 260 and includes the phosphorylation targets of JNK1 and JNK2. NFAT3 transactivation activity was suppressed in JNK1(-/-) or JNK2(-/-) mouse embryonic fibroblast (MEF) cells compared with wild-type MEF cells. Moreover, a 3xNFAT-luc reporter gene assay indicated that NFAT3 transcriptional activity was increased in a dose-dependent manner by JNK1 or JNK2. Double mutations at Ser(213) and Ser(217) suppressed NFAT3 transactivation activity; and SP600125, a JNK inhibitor, suppressed NFAT3-induced 3xNFAT-luciferase activity. Knockdown of JNK1 or JNK2 suppressed foci formation in NIH3T3 cells. Importantly, ectopic expression of NFAT3 inhibited AP-1 activity and suppressed foci formation. Furthermore, knockdown of NFAT3 enhanced Ras-JNK1 or JNK2-induced foci formation in NIH3T3 cells. Taken together, these results provided direct evidence for the anti-oncogenic potential of the NFAT3 transcription factor.


Using networks to measure similarity between genes: association index selection.
Biological networks can be used to functionally annotate genes on the basis of interaction-profile similarities. Metrics known as association indices can be used to quantify interaction-profile similarity. We provide an overview of commonly used association indices, including the Jaccard index and the Pearson correlation coefficient, and compare their performance in different types of analyses of biological networks. We introduce the Guide for Association Index for Networks (GAIN), a web tool for calculating and comparing interaction-profile similarities and defining modules of genes with similar profiles.


Dynamics of muscle activation during tonic-clonic seizures.
The purpose of our study was to elucidate the dynamics of muscle activation during generalised tonic-clonic seizures (GTCS). We recorded surface electromyography (EMG) from the deltoid muscle during 26 GTCS from 13 patients and compared it with GTCS-like events acted by 10 control subjects. GTCS consisted of a sequence of phases best described quantitatively by dynamics of the low frequency (LF) wavelet component (2-8Hz). Contrary to the traditional view, the tonic phase started with a gradual increase in muscle activity. A longer clonic phase was associated with a shorter onset of the tonic phase and a higher seizure occurrence. Increase in LF occurred during the onset phase and during the transition from the tonic to the clonic phase, corresponding to the vibratory movements. The clonic phase consisted of EMG discharges of remarkably constant duration (0.2s) separated by silent periods (SP) of exponentially increasing duration - features that could not be reproduced voluntarily. The last SP was longer in seizures with higher EMG peak frequency whereas the energy of the last clonus was higher in seizures with a short clonic phase. We found specific features of muscle activation dynamics during GTCS. Our findings suggest that the same inhibitory mechanisms that contribute to GTCS termination counteract seizure initiation, accounting for the gradual onset. Both active inhibition and mechanisms related to metabolic depletion act synergistically to stop the seizure. Analysis of the ictal EMG dynamics is a valuable tool for monitoring the balance between pro-convulsive and anti-convulsive factors.


The predictive performance of criminal risk assessment tools used at sentencing: Systematic review of validation studies.
Although risk assessment tools have been widely used to inform sentencing decisions, there is uncertainty about the extent and quality of evidence of their predictive performance when validated in new samples. Following PRISMA guidelines, we conducted a systematic review of validation studies of 11 commonly used risk assessment tools for sentencing. We identified 36 studies with 597,665 participants, among which were 27 independent validation studies with 177,711 individuals. Overall, the predictive performance of the included risk assessment tools was mixed, and ranged from poor to moderate. Tool performance was typically overestimated in studies with smaller sample sizes or studies in which tool developers were co-authors. Most studies only reported area under the curve (AUC), which ranged from 0.57 to 0.75 in independent studies with more than 500 participants. The majority did not report key performance measures, such as calibration and rates of false positives and negatives. In addition, most validation studies had a high risk of bias, partly due to inappropriate analytical approach used. We conclude that the research priority is for future investigations to address the key methodological shortcomings identified in this review, and policy makers should enable this research. More sufficiently powered independent validation studies are necessary.


Modeling luminescence behavior for phosphor thermometry applied to doped thermal barrier coating configurations.
Phosphor thermometry is a promising non-destructive method for accurate temperature measurement using phosphor elements that emit temperature-dependent luminescence. The method relies on the intensity and decay of luminescence arising from the phosphor elements upon excitation by an incident laser. In this work, the classical Kubelka-Munk model has been utilized and modified to model the luminescence emitted from phosphor elements that are added into thermal barrier coatings (TBCs) to enable temperature sensing using phosphor thermometry. The collectible luminescence and its time-decay behavior emerging from a tailorable multilayer TBC configuration have been predicted for different rare-earth dopants: Dy, Er, and Sm within an yttria-stabilized zirconia (YSZ) host, and with an operational gradient of temperature acting through its depth. The configurations have been designed by varying the position and thickness of the doped layer into the coating. The decay constant of the collectible luminescence has been used to determine the position in the coating from where the luminescence decay is the same as the decay of the collectible signal. This subsurface position indicates the location at which the temperature measurement is performed using phosphor thermometry under realistic operating conditions. It has been determined that YSZ:Dy provides the highest intensity of the collectible luminescence among the three dopant materials. In the TBC configuration with a fully doped coating, using YSZ:Er as a sensor enables temperature measurement from a more in-depth position in the coating. It has been shown that this position can be tailored by adjusting the geometrical configuration of the TBCs, varying the position and thickness of the doped layer. Due to the sensitivity of the dopants to temperature, the decay behavior of the emerging luminescence is demonstrated to change for different TBC configurations. The model can be used in screening the dopants to design multilayered TBCs for their suitability in temperature sensing by phosphor thermometry.


Clinical features and molecular analysis of the alpha thalassemia/mental retardation syndromes. I. Cases due to deletions involving chromosome band 16p13.3.
We describe eight patients who have alpha thalassemia which cannot be accounted for by the Mendelian inheritance of abnormal alpha globin genes. Apart from the hematologic abnormality, the other universal clinical finding is mild to moderate mental handicap; there is also a broad spectrum of associated dysmorphic features. Initial analysis of the alpha globin gene complex (which maps to chromosome band 16p13.3), demonstrated that the alpha thalassemia results from failure of the patient to inherit an alpha globin allele from one of the parents. Using a combined molecular and cytogenetic approach, we have extended this analysis to show that all of these patients have 16p deletions which are variable in extent but limited to the terminal band 16p13.3; in at least four cases the deletion results from unbalanced chromosome translocation, and hence aneuploidy of a second chromosome is also present. The relatively nonspecific clinical phenotype contrasts with the other currently known microdeletion syndromes; this may reflect ascertainment bias in the recognition of such syndromes. This work represents the first step in the characterization of a new microdeletion syndrome that is probably underdiagnosed at present.


A Novel Parameter Estimation Method for Boltzmann Machines.
We propose a novel estimator for a specific class of probabilistic models on discrete spaces such as the Boltzmann machine. The proposed estimator is derived from minimization of a convex risk function and can be constructed without calculating the normalization constant, whose computational cost is exponential order. We investigate statistical properties of the proposed estimator such as consistency and asymptotic normality in the framework of the estimating function. Small experiments show that the proposed estimator can attain comparable performance to the maximum likelihood expectation at a much lower computational cost and is applicable to high-dimensional data.


An initial meta-analysis of Acceptance and Commitment Therapy for treating substance use disorders.
In the past decade, multiple studies have examined the effectiveness of Acceptance and Commitment Therapy (ACT) for substance use disorders relative to other active treatments. The current meta-analysis examined the aggregate effect size when comparing ACT to other treatments (e.g., CBT, pharmacotherapy, 12-step, treatment as usual) specifically on substance use outcomes. A total of 10 randomized controlled trials were identified through systematic searches. A significant small to medium effect size was found favoring ACT relative to active treatment comparisons following treatment. Effect sizes were comparable across studies for smoking cessation (k=5) and for other drug use disorders (k=5). Based on these findings, ACT appears to be a promising intervention for substance use disorders. Limitations and future directions are discussed.


Effects of Naphthyl Connectivity on the Photophysics of Compact Organic Charge-Transfer Photoredox Catalysts.
Modular chromophoric systems with minimal electronic coupling between donor and acceptor moieties are well suited for establishing predictive relationships between molecular structure and excited-state properties. Here, we investigate the impact of naphthyl-based connectivity on the photophysics of phenoxazine-derived orthogonal donor-acceptor complexes. While compounds in this class are themselves interesting as potent organic photocatalysts useful for visible-light-driven organocatalyzed atom-transfer radical polymerization and small-molecule synthesis, many other systems (e.g., phenazine, phenothiazine, and acridinium) exploit charge-transfer excited states involving a naphthyl substituent. Therefore, aided by the facile tunability of the phenoxazine architecture, we aim to provide mechanistic insight into the effects of naphthyl connectivity that can help inform the understanding of other systems. We do so by employing time-resolved and steady-state spectroscopies, cyclic voltammetry, and temperature-dependent studies on two chemical series of phenoxazine compounds. In the first series ( N-aryl 3,7-dibiphenyl phenoxazine), we find high sensitivity of photophysical behavior to naphthyl connectivity at its 1 versus 2 positions, including a drop in the intersystem-crossing yield (ΦISC) from 0.91 ( N-1-naphthyl) to 0.54 ( N-2-naphthyl), which we attribute to the establishment of an excited-state equilibrium in the singlet manifold. Drawing on the synthetic tunability afforded by phenoxazine, a modified series ( N-aryl 3,7-diphenyl phenoxazine) is chosen to circumvent this equilibrium, thereby isolating the impact of naphthyl connectivity on charge-transfer energy and triplet formation. We conclude that donor-acceptor distance is a key design parameter that influences a host of excited-state and dynamical properties and can have an outsized impact on photochemical function.


Complete nucleotide sequence, genomic organization and phylogenetic analysis of Citrus leprosis virus cytoplasmic type.
The complete nucleotide sequence of the genomic RNA 1 (8745 nt) and RNA 2 (4986 nt) of Citrus leprosis virus cytoplasmic type (CiLV-C) was determined using cloned cDNA. RNA 1 contains two open reading frames (ORFs), which correspond to 286 and 29 kDa proteins. The 286 kDa protein is a polyprotein putatively involved in virus replication, which contains four conserved domains: methyltransferase, protease, helicase and polymerase. RNA 2 contains four ORFs corresponding to 15, 61, 32 and 24 kDa proteins, respectively. The 32 kDa protein is apparently involved in cell-to-cell movement of the virus, but none of the other putative proteins exhibit any conserved domain. The 5' regions of the two genomic RNAs contain a 'cap' structure and poly(A) tails were identified in the 3'-terminals. Sequence analyses and searches for structural and non-structural protein similarities revealed conserved domains with members of the genera Furovirus, Bromovirus, Tobravirus and Tobamovirus, although phylogenetic analyses strongly suggest that CiLV-C is a member of a distinct, novel virus genus and family, and definitely demonstrate that it does not belong to the family Rhabdoviridae, as previously proposed. Based on these results it was proposed that Citrus leprosis virus be considered as the type member of a new genus of viruses, Cilevirus.


Peritonitis in a llama caused by Streptococcus equi subsp. zooepidemicus.
A 7-month-old, male llama was diagnosed with peritonitis caused by Streptococcus equi subsp. zooepidemicus. Clinical findings, medical treatment, and case outcome are described. Hematogenous dissemination from suspected pneumonia is proposed as the route of infection in this case. Possible transmission of the organism through contact with horses is discussed.


National Institutes of Health Consensus Development Conference Statement: adjuvant therapy for breast cancer, November 1-3, 2000.
Our goal was to provide health-care providers, patients, and the general public with an assessment of currently available data regarding the use of adjuvant therapy for breast cancer. The participants included a non-Federal, non-advocate, 14-member panel representing the fields of oncology, radiology, surgery, pathology, statistics, public health, and health policy as well as patient representatives. In addition, 30 experts in medical oncology, radiation oncology, biostatistics, epidemiology, surgical oncology, and clinical trials presented data to the panel and to a conference audience of 1000. The literature was searched with the use of MEDLINE(TM) for January 1995 through July 2000, and an extensive bibliography of 2230 references was provided to the panel. Experts prepared abstracts for their conference presentations with relevant citations from the literature. Evidence from randomized clinical trials and evidence from prospective studies were given precedence over clinical anecdotal experience. The panel, answering predefined questions, developed its conclusions based on the evidence presented in open forum and the scientific literature. The panel composed a draft statement, which was read in its entirety and circulated to the experts and the audience for comment. Thereafter, the panel resolved conflicting recommendations and released a revised statement at the end of the conference. The panel finalized the revisions within a few weeks after the conference. The draft statement was made available on the World Wide Web immediately after its release at the conference and was updated with the panel's final revisions. The statement is available at http://consensus.nih.gov. The panel concludes that decisions regarding adjuvant hormonal therapy should be based on the presence of hormone receptor protein in tumor tissues. Adjuvant hormonal therapy should be offered only to women whose tumors express hormone receptor protein. Because adjuvant polychemotherapy improves survival, it should be recommended to the majority of women with localized breast cancer regardless of lymph node, menopausal, or hormone receptor status. The inclusion of anthracyclines in adjuvant chemotherapy regimens produces a small but statistically significant improvement in survival over non-anthracycline-containing regimens. Available data are currently inconclusive regarding the use of taxanes in adjuvant treatment of lymph node-positive breast cancer. The use of adjuvant dose-intensive chemotherapy regimens in high-risk breast cancer and of taxanes in lymph node-negative breast cancer should be restricted to randomized trials. Ongoing studies evaluating these treatment strategies should be supported to determine if such strategies have a role in adjuvant treatment. Studies to date have included few patients older than 70 years. There is a critical need for trials to evaluate the role of adjuvant chemotherapy in these women. There is evidence that women with a high risk of locoregional tumor recurrence after mastectomy benefit from postoperative radiotherapy. This high-risk group includes women with four or more positive lymph nodes or an advanced primary cancer. Currently, the role of postmastectomy radiotherapy for patients with one to three positive lymph nodes remains uncertain and should be tested in a randomized controlled trial. Individual patients differ in the importance they place on the risks and benefits of adjuvant treatments. Quality of life needs to be evaluated in selected randomized clinical trials to examine the impact of the major acute and long-term side effects of adjuvant treatments, particularly premature menopause, weight gain, mild memory loss, and fatigue. Methods to support shared decision-making between patients and their physicians have been successful in trials; they need to be tailored for diverse populations and should be tested for broader dissemination.


Differential allocation of parental investment and the trade-off between size and number of offspring.
When parents decide how much to invest in current versus future offspring and how many offspring to divide their current investments between, the optimal decision can be affected by the quality of their partner. This differential allocation (DA) is highly dependent on exactly how partner quality affects reproductive costs and offspring benefits. We present a stochastic dynamic model of DA in which females care for a series of clutches when mated with males of different quality. In each reproductive event, females choose the size and number of offspring. We find that if partner quality affects reproductive costs, then DA in total reproductive investment occurs only via changes in the number of offspring. DA in the optimal size of the offspring occurs only if partner quality affects the offspring benefit function. This is mostly in the form of greater female investment per offspring as male quality decreases. Simultaneously, we find that adaptive DA increases the number of offspring, and thus the amount of total investment, as male quality increases. Only certain model scenarios produce the positive DA in offspring size seen in empirical studies, providing a predictive framework for DA and how partner quality affects reproductive costs and offspring benefits.


Do parents understand growth charts? A national, Internet-based survey.
The objective of this study was to assess parental knowledge and understanding of growth charts. An online survey was conducted with 1000 parents selected to be demographically representative of the US population. Questions explored awareness of, knowledge of, and attitudes toward growth monitoring, as well as the ability to interpret growth chart data. Seventy-nine percent of parents surveyed claimed to have seen a growth chart before, with the majority thinking that they understood it well. Sixty-four percent of parents thought it was important to be shown growth charts to see how their child was growing, and 40% expressed the need to see their child's growth chart as confirmation of their health care provider's verbal interpretation. However, when provided with multiple-choice questions and answers, only 64% could identify a child's weight when shown a plotted point on a growth chart. Ninety-six percent had heard of the term "percentile," but only 68% identified the percentile of the plotted point, and only 56% could identify the definition of percentile. Up to 77% interpreted incorrectly charts containing height/weight measurements in tandem. Although growth charts are used frequently as visual aids to educate parents about their children's growth, many parents cannot comprehend the data. This finding is significant because many parents prefer to be shown growth charts by their health care provider, and many parents report recording their children's measurements on growth charts at home.


Polypharmacy and effects of apixaban versus warfarin in patients with atrial fibrillation: post hoc analysis of the ARISTOTLE trial.
To determine whether the treatment effect of apixaban versus warfarin differs with increasing numbers of concomitant drugs used by patients with atrial fibrillation. Post hoc analysis performed in 2015 of results from ARISTOTLE (apixaban for reduction in stroke and other thromboembolic events in atrial fibrillation)-a multicentre, double blind, double dummy trial that started in 2006 and ended in 2011. 18 201 ARISTOTLE trial participants. In the ARISTOTLE trial, patients were randomised to either 5 mg apixaban twice daily (n=9120) or warfarin (target international normalised ratio range 2.0-3.0; n=9081). In the post hoc analysis, patients were divided into groups according to the number of concomitant drug treatments used at baseline (0-5, 6-8, ≥9 drugs) with a median follow-up of 1.8 years. Clinical outcomes and treatment effects of apixaban versus warfarin (adjusted for age, sex, and country). Each patient used a median of six drugs (interquartile range 5-9); polypharmacy (≥5 drugs) was seen in 13 932 (76.5%) patients. Greater numbers of concomitant drugs were used in older patients, women, and patients in the United States. The number of comorbidities increased across groups of increasing numbers of drugs (0-5, 6-8, ≥9 drugs), as did the proportions of patients treated with drugs that interact with warfarin or apixaban. Mortality also rose significantly with the number of drug treatments (P<0.001), as did rates of stroke or systemic embolism (1.29, 1.48, and 1.57 per 100 patient years, for 0-5, 6-8, and ≥9 drugs, respectively) and major bleeding (1.91, 2.46, and 3.88 per 100 patient years, respectively). Relative risk reductions in stroke or systemic embolism for apixaban versus warfarin were consistent, regardless of the number of concomitant drugs (Pinteraction=0.82). A smaller reduction in major bleeding was seen with apixaban versus warfarin with increasing numbers of concomitant drugs (Pinteraction=0.017). Patients with interacting (potentiating) drugs for warfarin or apixaban had similar outcomes and consistent treatment effects of apixaban versus warfarin. In the ARISTOTLE trial, three quarters of patients had polypharmacy; this subgroup had an increased comorbidity, more interacting drugs, increased mortality, and higher rates of thromboembolic and bleeding complications. In terms of a potential differential response to anticoagulation therapy in patients with atrial fibrillation and polypharmacy, apixaban was more effective than warfarin, and is at least just as safe.Trial registration ARISTOTLE trial, ClinicalTrials.gov NCT00412984.


Differences in insulin treatment satisfaction following randomized addition of biphasic, prandial or basal insulin to oral therapy in type 2 diabetes.
No differences in patient health status as measured by the EuroQol-5 Dimension (EQ-5D) questionnaire were observed at 1 year between groups randomized to addition of biphasic, prandial or basal insulin to oral therapy in the treat-to-target in type 2 diabetes trial. We further investigated insulin treatment satisfaction between groups. Seven hundred and eight patients with suboptimal glycated haemoglobin levels (7.0-10.0%) taking maximally tolerated doses of metformin and sulphonylurea were randomized to biphasic insulin aspart twice-daily, prandial insulin aspart three times daily or basal insulin detemir once-daily (twice if required). At 1 year self-completed Insulin Treatment Satisfaction Questionnaires (ITSQ) were administered. Lower scores indicated lower treatment satisfaction. We tested for differences between the three groups for the ITSQ total score and for each of the five ITSQ domain scores adjusting for age, gender, ethnicity and education. All 22 ITSQ subscales were completed by 554 (78.2%) patients. Their mean (s.d.) age was 61.5 (9.4) years, body weight 86.1 (16) kg and median (IQR) diabetes duration 9 (6-13) years. Sixty-five percent (358) were male. Median (IQR) 1-year ITSQ total score was lower in patients allocated to prandial therapy (76.5, 68.0-88.6) than in patients allocated to biphasic insulin (83.3, 74.2-90.2) or basal insulin (84.1, 73.5-93.2). With the exception of 'perceived glycaemic control', 1-year adjusted ITSQ scores were significantly different between groups for each of the ITSQ domains, with lower scores for prandial insulin compared with the basal or biphasic groups. Median (IQR) ITSQ scores were lower in patients with a gain in body mass index (BMI) > 1.23 kg/m² over 1 year (79.5, 69.7-89.4) compared to those with a lesser or no gain in BMI (84.1, 74.2-92.4) and in those with occurrence of hypoglycaemia (79.5, 69.7-88.6) compared to those with no hypoglycaemia (84.1, 73.7-93.2). Specific measurement of insulin treatment satisfaction identifies differences between regimens used to intensify treatment for type 2 diabetes. Impact of treatment on lifestyle needs to be considered as a factor in the choice of an insulin regimen.


Membrane excitability and fear conditioning in cerebellar Purkinje cell.
In a previous study it has been demonstrated that fear conditioning is associated with a long-lasting potentiation of parallel fiber to Purkinje cell synaptic transmission in vermal lobules V and VI. Since modifications of intrinsic membrane properties have been suggested to mediate some forms of memory processes, we investigated possible changes of Purkinje cell intrinsic properties following the same learning paradigm and in the same cerebellar region. By means of the patch clamp technique, Purkinje cell passive and active membrane properties were evaluated in slices prepared from rats 10 min or 24 h after fear conditioning and in slices from control naïve animals. None of the evaluated parameters (input resistance, inward rectification, maximal firing frequency and the first inter-spike interval, post-burst afterhyperpolarization, action potential threshold and amplitude, action potential afterhyperpolarization) was significantly different between the three studied groups also in those cells where parallel fiber-Purkinje cell synapse was potentiated. Our results show that fear learning does not affect the intrinsic membrane properties involved in Purkinje cell firing. Therefore, at the level of Purkinje cell the plastic change associated with fear conditioning is specifically restricted to synaptic efficacy.


Possible new ways in the pharmacological treatment of bipolar disorder and comorbid alcoholism.
About half of all bipolar patients have an alcohol abuse problem at some point of their lifetime. However, only one randomized, controlled trial of pharmacotherapy (valproate) in this patient population was published as of 2006. Therefore, we reviewed clinical trials in this indication of the last four years (using mood stabilizers, atypical antipsychotics, and other drugs). Priority was given to randomized trials, comparing drugs with placebo or active comparator. Published studies were found through systematic database search (PubMed, Scirus, EMBASE, Cochrane Library, Science Direct). In these last four years, the only randomized, clinically relevant study in bipolar patients with comorbid alcoholism is that of Brown and colleagues (2008) showing that quetiapine therapy decreased depressive symptoms in the early weeks of use, without modifying alcohol use. Several other open-label trials have been generally positive and support the efficacy and tolerability of agents from different classes in this patient population. Valproate efficacy to reduce excessive alcohol consumption in bipolar patients was confirmed and new controlled studies revealed its therapeutic benefit to prevent relapse in newly abstinent alcoholics and to improve alcohol hallucinosis. Topiramate deserves to be investigated in bipolar patients with comorbid alcoholism since this compound effectively improves physical health and quality of life of alcohol-dependent individuals. In conclusion, randomized, controlled research is still needed to provide guidelines for possible use of valproate and other agents in patients with a dual diagnosis of bipolar disorder and substance abuse or dependence.


The Role of the α Cell in the Pathogenesis of Diabetes: A World beyond the Mirror.
Type 2 Diabetes Mellitus (T2DM) is one of the most prevalent chronic metabolic disorders, and insulin has been placed at the epicentre of its pathophysiological basis. However, the involvement of impaired alpha (α) cell function has been recognized as playing an essential role in several diseases, since hyperglucagonemia has been evidenced in both Type 1 and T2DM. This phenomenon has been attributed to intra-islet defects, like modifications in pancreatic α cell mass or dysfunction in glucagon's secretion. Emerging evidence has shown that chronic hyperglycaemia provokes changes in the Langerhans' islets cytoarchitecture, including α cell hyperplasia, pancreatic beta (β) cell dedifferentiation into glucagon-positive producing cells, and loss of paracrine and endocrine regulation due to β cell mass loss. Other abnormalities like α cell insulin resistance, sensor machinery dysfunction, or paradoxical ATP-sensitive potassium channels (KATP) opening have also been linked to glucagon hypersecretion. Recent clinical trials in phases 1 or 2 have shown new molecules with glucagon-antagonist properties with considerable effectiveness and acceptable safety profiles. Glucagon-like peptide-1 (GLP-1) agonists and Dipeptidyl Peptidase-4 inhibitors (DPP-4 inhibitors) have been shown to decrease glucagon secretion in T2DM, and their possible therapeutic role in T1DM means they are attractive as an insulin-adjuvant therapy.


[Infant characteristics and anger reduction].
Konrad Lorenz first suggested in 1943 that certain physical and behavioral characteristics common to infants (babyishness) serve as cues to attract adult attention and care as well as to decrease the likelihood of aggression. The present study was designed to determine whether the visual stimuli of a baby's face alone are sufficient to reduce anger. The subjects were 60 female students between 18 and 30 years of age. Anger was evoked by setting unsolvable tasks and by noise and maintained by adequate instructions and by continuing noise. Three procedures of measurement (heart rate, retrospective self-report, and interpretation of facial affect by two observers) were designed to show the reactions of the subjects viewing photos of babies and adults. We found a slight increase in heart rate to be an expression of happiness and a massive acceleration to be an expression of anger. The self-report measures and interpretation of facial affect supported the hypothesis that there is a more positive response to infants than to adults, and to cute babies also a more positive one than to less attractive infants. We found weak evidence that babyishness reduces anger. As a consequence of the length of the experiment, subjects who should not be aroused became angry. Thus, it was possible to register a reduction of anger as reaction to cute infants.


Early detection of sporadic pancreatic cancer: summative review.
Pancreatic cancer (PC) is estimated to become the second leading cause of cancer death in the United States by 2020. Early detection is the key to improving survival in PC. Addressing this urgent need, the Kenner Family Research Fund conducted the inaugural Early Detection of Sporadic Pancreatic Cancer Summit Conference in 2014 in conjunction with the 45th Anniversary Meeting of the American Pancreatic Association and Japan Pancreas Society. This seminal convening of international representatives from science, practice, and clinical research was designed to facilitate challenging interdisciplinary conversations to generate innovative ideas leading to the creation of a defined collaborative strategic pathway for the future of the field. An in-depth summary of current efforts in the field, analysis of gaps in specific areas of expertise, and challenges that exist in early detection is presented within distinct areas of inquiry: Case for Early Detection: Definitions, Detection, Survival, and Challenges; Biomarkers for Early Detection; Imaging; and Collaborative Studies. In addition, an overview of efforts in familial PC is presented in an addendum to this article. It is clear from the summit deliberations that only strategically designed collaboration among investigators, institutions, and funders will lead to significant progress in early detection of sporadic PC.


Effects of rutin on oxidative stress in mice with kainic acid-induced seizure.
Flavonoids are present in foods such as fruits and vegetables. Several studies have demonstrated a relationship between the consumption of flavonoid-rich foods and prevention of human disease, including neurodegenerative disorders. We assessed the effect of rutin (quercetin-3-O-rutinoside) on oxidative stress in kainic acid (KA)-induced seizure. Thirty-six BALB/c mice were randomly divided into three groups. In the control group, saline (intra-peritoneal, i.p.) was administered for 7 d, and on the last day, KA (10 mg/kg, i.p.) was injected 30 min after administration of saline. In rutin groups, mice were pretreated with rutin (100 and 200 mg/kg, i.p.) for 7 d, and on the last day, KA (10 mg/kg, i.p.) was injected 30 min after administration of rutin. Subsequently, behavioural changes were observed in mice. Lipid peroxidation and oxidative stress were measured respectively in the early and late phases after KA-induced seizures. Seizure scores in the rutin groups were significantly lower than those in the control group (P < 0.01). Furthermore, rutin dose-dependently inhibited the number of wet-dog shakes (WDS) (P < 0.05). Malondialdehyde level in the hippocampus of the rutin groups was significantly lower than that in the hippocampus of the control group on days 1 and 21 after KA administration. In the rutin groups, the thiol levels observed on day 1 after KA administration were higher than that in the control group (P < 0.01). These results indicate that rutin has potential anticonvulsant and antioxidative activities against oxidative stress in KA-induced seizure in mice.


Granulocyte and monocyte adsorption apheresis (GCAP) for refractory skin diseases caused by activated neutrophils and psoriatic arthritis: evidence that GCAP removes Mac-1-expressing neutrophils.
In the present study, we have shown that granulocyte and monocyte adsorption apheresis (GCAP), an extracorporeal apheresis instrument whose column contains cellulose acetate (CA) beads, is useful for skin diseases attributable to activated granulocytes and psoriatic arthritis (PsA). We assessed the clinical effectiveness of GCAP and investigated the mechanisms underlying the adsorption of pathogenic granulocytes. The effect of GCAP was assessed in 14 patients with neutrophilic dermatoses and 16 with PsA. The mechanisms by which the instrument adsorbs activated granulocytes were investigated using an in vitro mini-column system that mimics the GCAP. Skin lesions and arthropathy improved in 22 of 29 patients (75.9%) and 14 of 18 (77.8%), respectively. Mac-1 (CD11b/CD18) expression on the peripheral neutrophils, increased compared with normal subjects, was reduced by GCAP. In the mini-column system, CA beads adsorbed 50% neutrophils; and adsorption was inhibited significantly by treating plasma with EDTA and blood cells with antihuman CD11b monoclonal antibody. GCAP was useful for treating neutrophilic dermatoses and PsA. GCAP adsorbs Mac-1-expressing neutrophils to the CA beads by the binding of complement component (iC3b) on CA beads and CD11b expressed on activated neutrophils.


[Clinical study of 28 cases of cervical lymph node metastasis from an unknown primary carcinoma].
From 1989 to 2005, 28 patients--20 men and 8 women--with cervical lymph node metastasis from an unknown primary carcinoma were treated and studied retrospectively. In histological diagnosis, open biopsy was conducted in 11 patients and non-open biopsy (FNA or frozen section diagnosis during surgery) in 17. Blind biopsy under general anesthesia was conducted in 10 patients, showing one primary tumor in the nasopharynx. Tonsillectomy for diagnosis was not done. In region of maximum-size lymph node metastasis, the upper cervical region accounted for 22 cases (79%). The N stage of cervical lymph nodes was as follows: N2a in 4, N2b in 14, N2c in 3, and N3 in 7. The histopathological diagnosis of cervical lymph node was as follows: squamous cell carcinoma in 21, adenocarcinoma in 3, mucoepidermoid carcinoma in 2, and others in 2. Therapy was as follows: only neck dissection in 7, neck dissection with postoperative radiation therapy in 13, and irradiation and chemotherapy in 8. All patients treated with irradiation and chemotherapy had been judged to be inoperable. Seven patients were found to have a subsequent primary tumor. Primary tumor sites were as follows: tonsils in 3 and upper gingiva, base of tongue, lung, and nasopharynx in 1 each. FDG-PET was conducted in 7 patients but revealed no primary tumor. Overall 5-year survival in this study was 46%. We should pay particular attention to the tonsils for detecting primary tumors in patients with cervical metastasis from an unknown primary carcinoma.


The Subjective Sensation of Synchrony: An Experimental Study.
People performing actions together have a natural tendency to synchronize their behavior. Consistently, people doing a task together build internal representations not only of their actions and goals, but also of the other people performing the task. However, little is known about which are the behavioral mechanisms and the psychological factors affecting the subjective sensation of synchrony, or "connecting" with someone else. In this work, we sought to find which factors induce the subjective sensation of synchrony, combining motion capture data and psychological measures. Our results show that the subjective sensation of synchrony is affected by performance quality together with task category, and time. Psychological factors such as empathy and negative subjective affects also correlate with the subjective sensation of synchrony. However, when people estimate synchrony as seen from a third person perspective, their psychological factors do not affect the accuracy of the estimation. We suggest that to feel this sensation it is necessary to, first, have a good joint performance and, second, to assume the existence of an attention monitoring mechanism that reports that the attention of both participants (self and other) is focused on the task.


Exercise and manual auricular acupuncture: a pilot assessor-blind randomised controlled trial. (The acupuncture and personalised exercise programme (APEP) trial).
Evidence supports the use of exercise for chronic low back pain (CLBP); however, adherence is often poor due to ongoing pain. Auricular acupuncture is a form of pain relief involving the stimulation of points on the outer ear corresponding with specific body parts. It may be a useful adjunct to exercise in managing CLBP; however, there is only limited evidence to support its use with this patient group. This study was designed to test the feasibility of an assessor-blind randomised controlled trial which assess the effects on clinical outcomes and exercise adherence of adding manual auricular acupuncture to a personalised and supervised exercise programme (PEP) for CLBP. No sample size calculation has been carried out as this study aims to identify CLBP referral rates within the catchment area of the study site. The researchers aim to recruit four cohorts of n = 20 participants to facilitate a power analysis for a future randomised controlled trial. A computer generated random allocation sequence will be prepared centrally and used to allocate participants by cohort to one of the following interventions: 1) six weeks of PEP plus manual auricular acupuncture; 2) six weeks of PEP alone. Both groups will also complete a further six weeks of self-paced exercise with telephone follow-up support. In addition to a baseline and exit questionnaire at the beginning and end of the study, the following outcomes will be collected at baseline, and after 7, 13 and 25 weeks: pain frequency and bothersomeness, back-specific function, objective assessment and recall of physical activity, use of analgesia, perceived self-efficacy, fear avoidance beliefs, and beliefs about the consequences of back pain. Since this is a feasibility study, significance tests will not be presented, and treatment effects will be represented by point estimates and confidence intervals. For each outcome variable, analysis of covariance will be performed on the data, conditioning on the baseline value. The results of this study investigating the adjuvant effects of auricular acupuncture to exercise in managing CLBP will be used to inform the design of a future multi-centre randomised controlled trial. Current Controlled Trials ISRCTN94142364.


Cyclosporine A reduces cerebral vasospasm after subarachnoid hemorrhage in dogs.
The double subarachnoid hemorrhage canine model was used to test the prophylactic value of immunosuppression in the prevention of cerebral vasospasm after subarachnoid hemorrhage. Dogs treated with cyclosporine A following the regimen prescribed for organ transplant procedures in patients showed a significant reduction in the severity of angiographic constriction of cerebral arteries. While basilar artery diameter after double experimental subarachnoid hemorrhage in a series of untreated dogs (n = 34) averaged 65% of baseline diameter, arterial diameter in dogs treated prophylactically (n = 18) with 6 mg/kg/day cyclosporine A and adjunct low-dose steroid averaged 80% of baseline diameter, for a mean reduction in the severity of chronic arterial constriction of 42%. More important than the average effect, however, is the statistical observation that this mean improvement was obtained primarily by a dramatic reduction in the incidence of severe cerebral vasospasm, the situation most likely to account for morbidity and mortality after aneurysmal rupture.


Democratic and Republican physicians provide different care on politicized health issues.
Physicians frequently interact with patients about politically salient health issues, such as drug use, firearm safety, and sexual behavior. We investigate whether physicians' own political views affect their treatment decisions on these issues. We linked the records of over 20,000 primary care physicians in 29 US states to a voter registration database, obtaining the physicians' political party affiliations. We then surveyed a sample of Democratic and Republican primary care physicians. Respondents evaluated nine patient vignettes, three of which addressed especially politicized health issues (marijuana, abortion, and firearm storage). Physicians rated the seriousness of the issue presented in each vignette and their likelihood of engaging in specific management options. On the politicized health issues-and only on such issues-Democratic and Republican physicians differed substantially in their expressed concern and their recommended treatment plan. We control for physician demographics (like age, gender, and religiosity), patient population, and geography. Physician partisan bias can lead to unwarranted variation in patient care. Awareness of how a physician's political attitudes might affect patient care is important to physicians and patients alike.


Cardiovascular disease and vitamin D supplementation: trial analysis, systematic review, and meta-analysis.
Low 25-hydroxyvitamin D status has been associated with increased cardiovascular events in epidemiologic studies. We assessed whether vitamin D supplementation reduces cardiac failure, myocardial infarction (MI), and stroke through an analysis of the Randomised Evaluation of Calcium Or vitamin D (RECORD) randomized controlled trial (RCT), a systematic review, and a meta-analysis. Two analyses were undertaken. The first analysis was a trial analysis. The RECORD was a factorial RCT that compared vitamin D₃ (800 IU/d), calcium (1000 mg/d), vitamin D plus calcium, and a placebo. Cardiovascular events were collected throughout the trial and 3-y posttrial follow-up. Data were analyzed by using Cox regression. The second analysis was a systematic review. MEDLINE, EMBASE, CENTRAL, conference abstracts, and ongoing trials were searched for RCTs that evaluated vitamin D from 1980 to 2013. RCTs with ≥1 y of follow-up and participants mean or median age ≥60 y were included. Meta-analyses were based on a Bayesian fixed-effects model by using a complementary log-log link function to account for varying lengths of follow-up. In the trial analysis, we showed that, for the 5292 participants in the RECORD trial, HRs (95% CIs) for vitamin D compared with no vitamin D for cardiac failure, MI, and stroke were 0.75 (0.58, 0.97), 0.97 (0.75,1.26), and 1.06 (0.8, 1.32), respectively. Twenty-one studies met the inclusion criteria for the systematic review (n = 13,033). Estimated HRs (credible intervals) for vitamin D compared with the placebo or control for on-study events for cardiac failure, MI, and stroke were 0.82 (0.58, 1.15), 0.96 ( 0.83, 1.10), and 1.07 (0.91, 1.29), respectively. Vitamin D supplementation might protect against cardiac failure in older people but does not appear to protect against MI or stroke.


Loss of Smyhc1 or Hsp90alpha1 function results in different effects on myofibril organization in skeletal muscles of zebrafish embryos.
Myofibrillogenesis requires the correct folding and assembly of sarcomeric proteins into highly organized sarcomeres. Heat shock protein 90alpha1 (Hsp90alpha1) has been implicated as a myosin chaperone that plays a key role in myofibrillogenesis. Knockdown or mutation of hsp90alpha1 resulted in complete disorganization of thick and thin filaments and M- and Z-line structures. It is not clear whether the disorganization of these sarcomeric structures is due to a direct effect from loss of Hsp90alpha1 function or indirectly through the disorganization of myosin thick filaments. In this study, we carried out a loss-of-function analysis of myosin thick filaments via gene-specific knockdown or using a myosin ATPase inhibitor BTS (N-benzyl-p-toluene sulphonamide) in zebrafish embryos. We demonstrated that knockdown of myosin heavy chain 1 (myhc1) resulted in sarcomeric defects in the thick and thin filaments and defective alignment of Z-lines. Similarly, treating zebrafish embryos with BTS disrupted thick and thin filament organization, with little effect on the M- and Z-lines. In contrast, loss of Hsp90alpha1 function completely disrupted all sarcomeric structures including both thick and thin filaments as well as the M- and Z-lines. Together, these studies indicate that the hsp90alpha1 mutant phenotype is not simply due to disruption of myosin folding and assembly, suggesting that Hsp90alpha1 may play a role in the assembly and organization of other sarcomeric structures.


Divergent phenotypic response of rice accessions to transient heat stress during early seed development.
Increasing global surface temperatures is posing a major food security challenge. Part of the solution to address this problem is to improve crop heat resilience, especially during grain development, along with agronomic decisions such as shift in planting time and increasing crop diversification. Rice is a major food crop consumed by more than 3 billion people. For rice, thermal sensitivity of reproductive development and grain filling is well-documented, while knowledge concerning the impact of heat stress (HS) on early seed development is limited. Here, we aim to study the phenotypic variation in a set of diverse rice accessions for elucidating the HS response during early seed development. To explore the variation in HS sensitivity, we investigated aus (1), indica (2), temperate japonica (2), and tropical japonica (4) accessions for their HS (39/35°C) response during early seed development that accounts for transition of endosperm from syncytial to cellularization, which broadly corresponds to 24 and 96 hr after fertilization (HAF), respectively, in rice. The two indica and one of the tropical japonica accessions exhibited severe heat sensitivity with increased seed abortion; three tropical japonicas and an aus accession showed moderate heat tolerance, while temperate japonicas exhibited strong heat tolerance. The accessions exhibiting extreme heat sensitivity maintain seed size at the expense of number of fully developed mature seeds, while the accessions showing relative resilience to the transient HS maintained number of fully developed seeds but compromised on seed size, especially seed length. Further, histochemical analysis revealed that all the tested accessions have delayed endosperm cellularization upon exposure to the transient HS by 96 HAF; however, the rate of cellularization was different among the accessions. These findings were further corroborated by upregulation of cellularization-associated marker genes in the developing seeds from the heat-stressed samples.


Advanced Glycation End Products Impair Voltage-Gated K+ Channels-Mediated Coronary Vasodilation in Diabetic Rats.
We have previously reported that high glucose impairs coronary vasodilation by reducing voltage-gated K+ (Kv) channel activity. However, the underlying mechanisms remain unknown. Advanced glycation end products (AGEs) are potent factors that contribute to the development of diabetic vasculopathy. The aim of this study was to investigate the role of AGEs in high glucose-induced impairment of Kv channels-mediated coronary vasodilation. Patch-clamp recording and molecular biological techniques were used to assess the function and expression of Kv channels. Vasodilation of isolated rat small coronary arteries was measured using a pressurized myograph. Treatment of isolated coronary vascular smooth muscle cells (VSMCs) and streptozotocin-induced diabetic rats with aminoguanidine, the chemical inhibitor of AGEs formation, was performed to determine the contribution of AGEs. Incubation of VSMCs with high glucose reduced Kv current density by 60.4 ± 4.8%, and decreased expression of Kv1.2 and Kv1.5 both at the gene and protein level, whereas inhibiting AGEs formation or blocking AGEs interacting with their receptors prevented high glucose-induced impairment of Kv channels. In addition, diabetic rats manifested reduced Kv channels-mediated coronary dilation (9.3 ± 1.4% vs. 36.9 ± 1.4%, P < 0.05), which was partly corrected by the treatment with aminoguanidine (24.4 ± 2.2% vs. 9.3 ± 1.4%, P < 0.05). Excessive formation of AGEs impairs Kv channels in VSMCs, then leading to attenuation of Kv channels-mediated coronary vasodilation.


Chronic obstructive pulmonary disease, neutrophils and bacteria: from science to integrated care pathways.
The incidence of chronic obstructive pulmonary disease (COPD) and its effect on morbidity and mortality is rising. Extensive research implicates the role of inflammation and particularly the effect of neutrophil proteinases in generating many of the pathological features seen as part of the COPD syndrome. Exacerbations of COPD are an important cause of morbidity, mortality and progressive deterioration in lung function. These episodes are poorly defined but bacteria in the airways drives neutrophilic inflammation and proteinase release and hence may play a key role. The differentiation between benign colonisation and heightened neutrophilic inflammation can be determined by observation of sputum purulence. This reflects the likelihood of bacteria being present and particularly the number of bacteria. This simple clinical observation enables decision making about the need for antibiotic therapy to be as much a part of patient self-management as physician directed management in the integrated care pathway for COPD.


Prognostic significance of CUB domain containing protein expression in endometrioid adenocarcinoma.
CDCP1, a transmembrane protein with intracellular tyrosine residues which are phosphorylated upon activation, is supposed to be engaged in proliferative activities and resistance to apoptosis of cancer cells. High level of CDCP1 expression proved to be a poor prognosticator for lung adenocarcinoma. Here, expression level of CDCP1 was immunohistochemically examined in 110 cases (median age of 54.7 years) of endometrioid adenocarcinoma, and its clinical implications were evaluated. Tumor stage was stage I in 71 cases (64.5%), II in 5 (4.5%), III in 28 (25.5%), and IV in 6 (5.5%). Staining intensity of tumor cells was divided into two categories; tumor cells with no to weak and moderate to strong membrane staining. The intensity of CDCP1 expression in each case was defined by the staining of major population of cells as follows; cases with tumor cells showing no to weak and moderate to high membrane staining were categorized as CDCP1-low and CDCP1-high, respectively. Eighty-seven of 110 cases were categorized as CDCP1-high, and the remaining as CDCP1-low. Significant positive correlation was observed between low CDCP1 expression and stage (p=0.0091), relapse rate (p=0.0017), and poor prognosis (p=0.0009). Multivariate analysis revealed that low CDCP1 and advanced stage were independent poor prognostic factors for both OS and DFS. As compared to cancer cells, normal endometrium continuously expressed CDCP1. These suggested that the attitude of CDCP1 in cancers of lung and endometrium was different. Different role of CDCP1 by tissues and cancers is discussed.


PTMs in conversation: activity and function of deubiquitinating enzymes regulated via post-translational modifications.
Deubiquitinating enzymes (DUBs) constitute a diverse protein family and their impact on numerous biological and pathological processes has now been widely appreciated. Many DUB functions have to be tightly controlled within the cell, and this can be achieved in several ways, such as substrate-induced conformational changes, binding to adaptor proteins, proteolytic cleavage, and post-translational modifications (PTMs). This review is focused on the role of PTMs including monoubiquitination, sumoylation, acetylation, and phosphorylation as characterized and putative regulative factors of DUB function. Although this aspect of DUB functionality has not been yet thoroughly studied, PTMs represent a versatile and reversible method of controlling the role of DUBs in biological processes. In several cases PTMs might constitute a feedback mechanism insuring proper functioning of the ubiquitin proteasome system and other DUB-related pathways.


Slowing global warming: benefits for patients and the planet.
Global warming will cause significant harm to the health of persons and their communities by compromising food and water supplies; increasing risks of morbidity and mortality from infectious diseases and heat stress; changing social determinants of health resulting from extreme weather events, rising sea levels, and expanding flood plains; and worsening air quality, resulting in additional morbidity and mortality from respiratory and cardiovascular diseases. Vulnerable populations such as children, older persons, persons living at or below the poverty level, and minorities will be affected earliest and greatest, but everyone likely will be affected at some point. Family physicians can help reduce greenhouse gas emissions, stabilize the climate, and reduce the risks of climate change while also directly improving the health of their patients. Health interventions that have a beneficial effect on climate change include encouraging patients to reduce the amount of red meat in their diets and to replace some vehicular transportation with walking or bicycling. Patients are more likely to make such lifestyle changes if their physician asks them to and leads by example. Medical offices and hospitals can become more energy efficient by recycling, purchasing wind-generated electricity, and turning off appliances, computers, and lights when not in use. Moreover, physicians can play an important role in improving air quality and reducing greenhouse gas emissions by advocating for enforcement of existing air quality regulations and working with local and national policy makers to further improve air quality standards, thereby improving the health of their patients and slowing global climate change.


The Identification of Macrophage-enriched Glycoproteins Using Glycoproteomics.
Prostate cancer is a leading cause of cancer-related deaths of men in the United States. Whereas the localized disease is highly treatable by surgical resection and radiation, cancer that has metastasized remains incurable. Immune cells that primarily scavenge debris and promote prostate cancer angiogenesis and wound repair are M2 macrophages. They are phenotypically similar to M2 tumor-associated macrophages (M2-TAMs) and have been reported to associate with solid tumors and aide in proliferation, metastasis, and resistance to therapy. As an invasive species within the tumor microenvironment, this makes M2-TAMs an ideal therapeutic target in prostate cancer. To identify novel surface glycoproteins expressed on M2 macrophages, we developed a novel method of creating homogeneous populations of human macrophages from human CD14+ monocytes in vitro These homogeneous M1 macrophages secrete pro-inflammatory cytokines, and our M2 macrophages secrete anti-inflammatory cytokines as well as vascular endothelial growth factor (VEGF). To identify enriched surface glycoproteins, we then performed solid-phase extraction of N-linked glycopeptides followed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) on our homogeneous macrophage populations. We discovered five novel peptides that are enriched exclusively on human M2 macrophages relative to human M1 macrophages and human CD14+ monocytes. Finally, we determined whether these surface glycoproteins, found enriched on M2 macrophages, were also expressed in human metastatic castrate-resistant prostate cancer (mCRPC) tissues. Using mCRPC tissues from rapid autopsies, we were able to determine M2 macrophage infiltration by using immunohistochemistry and flow cytometry. These findings highlight the presence of macrophage infiltration in human mCRPC but also surface glycoproteins that could be used for prognosis of localized disease and for targeting strategies.


Identification of Associations between Bacterioplankton and Photosynthetic Picoeukaryotes in Coastal Waters.
Photosynthetic picoeukaryotes are significant contributors to marine primary productivity. Associations between marine bacterioplankton and picoeukaryotes frequently occur and can have large biogeochemical impacts. We used flow cytometry to sort cells from seawater to identify non-eukaryotic phylotypes that are associated with photosynthetic picoeukaryotes. Samples were collected at the Santa Cruz wharf on Monterey Bay, CA, USA during summer and fall, 2014. The phylogeny of associated microbes was assessed through 16S rRNA gene amplicon clone and Illumina MiSeq libraries. The most frequently detected bacterioplankton phyla within the photosynthetic picoeukaryote sorts were Proteobacteria (Alphaproteobacteria and Gammaproteobacteria) and Bacteroidetes. Intriguingly, the presence of free-living bacterial genera in the photosynthetic picoeukaryote sorts could suggest that some of the photosynthetic picoeukaryotes were mixotrophs. However, the occurrence of bacterial sequences, which were not prevalent in the corresponding bulk seawater samples, indicates that there was also a selection for specific OTUs in association with photosynthetic picoeukaryotes suggesting specific functional associations. The results show that diverse bacterial phylotypes are found in association with photosynthetic picoeukaryotes. Taxonomic identification of these associations is a prerequisite for further characterizing and to elucidate their metabolic pathways and ecological functions.