PD-1 Blockade Aggravates Epstein-Barr Virus+ Post-Transplant Lymphoproliferative Disorder in Humanized Mice Resulting in Central Nervous System Involvement and CD4+ T Cell Dysregulations.
Post-transplant lymphoproliferative disorder (PTLD) is one of the most common malignancies after solid organ or allogeneic stem cell transplantation. Most PTLD cases are B cell neoplasias carrying Epstein-Barr virus (EBV). A therapeutic approach is reduction of immunosuppression to allow T cells to develop and combat EBV. If this is not effective, approaches include immunotherapies such as monoclonal antibodies targeting CD20 and adoptive T cells. Immune checkpoint inhibition (ICI) to treat EBV+ PTLD was not established clinically due to the risks of organ rejection and graft-versus-host disease. Previously, blockade of the programmed death receptor (PD)-1 by a monoclonal antibody (mAb) during ex vivo infection of mononuclear cells with the EBV/M81+ strain showed lower xenografted lymphoma development in mice. Subsequently, fully humanized mice infected with the EBV/B95-8 strain and treated in vivo with a PD-1 blocking mAb showed aggravation of PTLD and lymphoma development. Here, we evaluated vis-a-vis in fully humanized mice after EBV/B95-8 or EBV/M81 infections the effects of a clinically used PD-1 blocker. Fifteen to 17 weeks after human CD34+ stem cell transplantation, Nod.Rag.Gamma mice were infected with two types of EBV laboratory strains expressing firefly luciferase. Dynamic optical imaging analyses showed systemic EBV infections and this triggered vigorous human CD8+ T cell expansion. Pembrolizumab administered from 2 to 5 weeks post-infections significantly aggravated EBV systemic spread and, for the M81 model, significantly increased the mortality of mice. ICI promoted Ki67+CD30+CD20+EBER+PD-L1+ PTLD with central nervous system (CNS) involvement, mirroring EBV+ CNS PTLD in humans. PD-1 blockade was associated with lower frequencies of circulating T cells in blood and with a profound collapse of CD4+ T cells in lymphatic tissues. Mice treated with pembrolizumab showed an escalation of exhausted T cells expressing TIM-3, and LAG-3 in tissues, higher levels of several human cytokines in plasma and high densities of FoxP3+ regulatory CD4+ and CD8+ T cells in the tumor microenvironment. We conclude that PD-1 blockade during acute EBV infections driving strong CD8+ T cell priming decompensates T cell development towards immunosuppression. Given the variety of preclinical models available, our models conferred a cautionary note indicating that PD-1 blockade aggravated the progression of EBV+ PTLD.


Breastfeeding Patterns in Preterm Infants Born at 28-33 Gestational Weeks.
Studies of breastfeeding patterns during preterm infants' first year of life are scarce but are important for providing breastfeeding mothers of preterm infants with optimal support. This study aimed to describe breastfeeding patterns in preterm infants up to 1 year of corrected age. As part of a larger study on kangaroo mother care in Sweden, a 24-hour breastfeeding diary was sent home after discharge from hospital, and at 2, 6, and 12 months of the infant's corrected age. Eighty-three mothers responded to the follow-up questionnaires, and the number of respondents to the breastfeeding diary was 48 at discharge, 43 at 2 months, 22 at 6 months, and 8 at 12 months. Infants were born at a median (range) gestational age of 32 (28-33) weeks. Breastfeeding patterns were analyzed according to durations, frequencies per 24 hours, and intervals between sessions. In exclusively breastfed infants, the median (range) breastfeeding session frequency was 14 (8-26) times per 24 hours including 4 (1-9) times per night after discharge (n = 24) and 10 (6-25) times per 24 hours including 2 (0-5) times per night at 2 months (n = 23). In partially breastfed infants, the median (range) frequency was 5 (1-14) times per 24 hours including 2 (0-4) times per night at 6 months (n = 20) and 5.5 (1-12) times per 24 hours including 2 (0-3) times per night at 12 months (n = 8). Mothers reported large variations in breastfeeding patterns, with higher median breastfeeding session frequencies than previously described in term infants in affluent settings.


Expression of the α7 nAChR subunit duplicate form (CHRFAM7A) is down-regulated in the monocytic cell line THP-1 on treatment with LPS.
We investigated the expression of the partially duplicated α7 nAChR subunit gene in three monocytic cell lines: THP-1, U937 and Mono-Mac-6. Qualitative PCR revealed the presence of the classic α7 gene in these lineages, but real-time PCR showed the exclusive expression of α7dup. Both mRNA and protein levels were reduced in THP-1 upon LPS challenge, and it was found that transcriptional down-regulation was mediated by a direct mechanism dependent on NF-κB as its specific inhibitor parthenolide prevented the reduction in the α7dup transcript. Such precise regulation suggests that α7dup may specifically participate in the inflammatory response of the innate immune system.


PA17 Interventions to improve upstream communication about death and dying.
Death is universal. Only 37% of adults have a will and 48% have stated their wishes regarding cremation or burial.(1) Planning and communication can help prevent some of the distress associated with dying and bereavement. To evaluate an intervention to encourage people to plan for the end of their life and to communicate their wishes to those closest to them. Two interventions were delivered via community groups: 'Awareness' presentations aimed to raise awareness of benefits of preparing and talking about end of life issues. 'How to' workshops aimed to give people confidence and tools to open relevant conversations. To evaluate their impact, we conducted a 3-stage questionnaire survey; administered before, immediate after and 3 months after events. At baseline (n = 498; 76% female) 76% had previously discussed end of life care or wishes after death. Most were comfortable talking about these subjects, giving a mean score of 8.28/10. At follow-up (n = 133); 60% indicated they had made changes following the event; 43% had talked about their own end of life wishes, 9% for the first time; and 39% reported making other changes. The change in the proportion of people who had ever talked about their own end of life wishes was statistically significant (p = 0.033). Well designed community events can improve planning and communication of end of life preferences among general population. Dying Matters Survey http://www.comres.co.uk/polls/Dying_Matters_Public_April12.pdf.


WNT11 expression is induced by estrogen-related receptor alpha and beta-catenin and acts in an autocrine manner to increase cancer cell migration.
Elevated expression of the orphan nuclear receptor estrogen-related receptor α (ERRα) has been associated with a negative outcome in several cancers, although the mechanism(s) by which this receptor influences the pathophysiology of this disease and how its activity is regulated remain unknown. Using a chemical biology approach, it was determined that compounds, previously shown to inhibit canonical Wnt signaling, also inhibited the transcriptional activity of ERRα. The significance of this association was revealed in a series of biochemical and genetic experiments that show that (a) ERRα, β-catenin (β-cat), and lymphoid enhancer-binding factor-1 form macromolecular complexes in cells, (b) ERRα transcriptional activity is enhanced by β-cat expression and vice versa, and (c) there is a high level of overlap among genes previously shown to be regulated by ERRα or β-cat. Furthermore, silencing of ERRα and β-cat expression individually or together dramatically reduced the migratory capacity of breast, prostate, and colon cancer cells in vitro. This increased migration could be attributed to the ERRα/β-cat-dependent induction of WNT11. Specifically, using (a) conditioned medium from cells overexpressing recombinant WNT11 or (b) WNT11 neutralizing antibodies, we were able to show that this protein was the key mediator of the promigratory activities of ERRα/β-cat. Together, these data provide evidence for an autocrine regulatory loop involving transcriptional upregulation of WNT11 by ERRα and β-cat that influences the migratory capacity of cancer cells.


High-deductible health plans and costs and utilization of maternity care.
To evaluate the impact of switching from an HMO to a high-deductible health plan on the costs and utilization of maternity care. Pre–post design, with a control group. We compared 229 women who delivered babies before or after their employers mandated a switch from HMO coverage to a high-deductible health plan, with a control group of 2180 matched women who delivered babies while their employers remained in an HMO plan. Administrative claims from a large Massachusetts-based health insurance program were used in a difference-in-differences regression analysis. Mean out-of-pocket maternity care costs for high-deductible group members increased from $356 for women who delivered before the insurance transition (n = 86) to $942 for women who delivered after the transition (n = 143), compared with a change from $262 (n = 711) to $282 (n = 1569) for HMO members, a relative increase of 106% (P <.001) for high-deductible members. Delivery after transition to a high-deductible plan was not associated with changes in the odds of receiving early prenatal care (odds ratio [OR], 1.02; 95% confidence interval [CI], 0.32-3.19), recommended prenatal visits (OR, 1.64; 95% CI, 0.89-3.02), or postpartum care (OR, 0.74; 95% CI, 0.42-1.32). Switching from an HMO to a high-deductible plan with exemptions for routine care increased out-of-pocket member costs for maternity care, but had no apparent adverse impacts on receipt of recommended prenatal and postpartum care.


Long-term persistence of HIV-1 vaccine-induced CD4+CD45RA-CD62L-CCR7- memory T-helper cells.
To determine in chimpanzees if candidate HIV-1 subunit protein vaccines were capable of eliciting long-lasting T-cell memory responses in the absence of viral infection, and to determine the specific characteristics of these responses. A longitudinal study of cell-mediated immune responses induced in three chimpanzees following immunization with subunit envelope glycoproteins of either HIV-1 or herpes simplex virus (HSV)-2. Following these pre-clinical observations, four human volunteers who had been immunized 7 years previously with the same HIV-1 vaccine candidate donated blood for assessment of immune responses. Responses were monitored by protein and peptide based ELISpot assays, lymphocyte proliferation, and intracellular cytokine staining. Humoral responses were assessed by enzyme-linked immunosorbent assay and virus neutralization assays. Although antigen (Ag)-specific CD4 T-cell responses persisted for at least 5 years in chimpanzees, CD8 T-cell responses were discordant and declined within 2 years. Detailed cellular analyses revealed that strong Th1 in addition to Th2 type responses were induced by AS2/gp120 and persisted, whereas CD8 T-cell memory declined in peripheral blood. The specificity of both Th and cytotoxic T-lymphocyte responses revealed that the majority of responses were directed to conserved epitopes. The remarkable persistence of Ag-specific CD4 T-cell memory was characterized as a population of the CD45RA-CD62L-CCR7- "effector phenotype" producing the cytokines IFNgamma, IL-2 and IL-4 upon epitope-specific recognition. Importantly, results in chimpanzees were confirmed in peripheral blood of one of four human volunteers studied more than 7 years after immunization. These studies demonstrate that epitope-specific Th1 and Th2 cytokine-dependent Th responses can be induced and maintained for longer than 5 years by immunization with subunit proteins of HIV-1.


Small theropod teeth from the Late Cretaceous of the San Juan Basin, northwestern New Mexico and their implications for understanding latest Cretaceous dinosaur evolution.
Studying the evolution and biogeographic distribution of dinosaurs during the latest Cretaceous is critical for better understanding the end-Cretaceous extinction event that killed off all non-avian dinosaurs. Western North America contains among the best records of Late Cretaceous terrestrial vertebrates in the world, but is biased against small-bodied dinosaurs. Isolated teeth are the primary evidence for understanding the diversity and evolution of small-bodied theropod dinosaurs during the Late Cretaceous, but few such specimens have been well documented from outside of the northern Rockies, making it difficult to assess Late Cretaceous dinosaur diversity and biogeographic patterns. We describe small theropod teeth from the San Juan Basin of northwestern New Mexico. These specimens were collected from strata spanning Santonian - Maastrichtian. We grouped isolated theropod teeth into several morphotypes, which we assigned to higher-level theropod clades based on possession of phylogenetic synapomorphies. We then used principal components analysis and discriminant function analyses to gauge whether the San Juan Basin teeth overlap with, or are quantitatively distinct from, similar tooth morphotypes from other geographic areas. The San Juan Basin contains a diverse record of small theropods. Late Campanian assemblages differ from approximately coeval assemblages of the northern Rockies in being less diverse with only rare representatives of troodontids and a Dromaeosaurus-like taxon. We also provide evidence that erect and recurved morphs of a Richardoestesia-like taxon represent a single heterodont species. A late Maastrichtian assemblage is dominated by a distinct troodontid. The differences between northern and southern faunas based on isolated theropod teeth provide evidence for provinciality in the late Campanian and the late Maastrichtian of North America. However, there is no indication that major components of small-bodied theropod diversity were lost during the Maastrichtian in New Mexico. The same pattern seen in northern faunas, which may provide evidence for an abrupt dinosaur extinction.


A C-terminal HSP90 inhibitor restores glucocorticoid sensitivity and relieves a mouse allograft model of Cushing disease.
One function of the glucocorticoid receptor (GR) in corticotroph cells is to suppress the transcription of the gene encoding proopiomelanocortin (POMC), the precursor of the stress hormone adrenocorticotropin (ACTH). Cushing disease is a neuroendocrine condition caused by partially glucocorticoid-resistant corticotroph adenomas that excessively secrete ACTH, which leads to hypercortisolism. Mutations that impair GR function explain glucocorticoid resistance only in sporadic cases. However, the proper folding of GR depends on direct interactions with the chaperone heat shock protein 90 (HSP90, refs. 7,8). We show here that corticotroph adenomas overexpress HSP90 compared to the normal pituitary. N- and C-terminal HSP90 inhibitors act at different steps of the HSP90 catalytic cycle to regulate corticotroph cell proliferation and GR transcriptional activity. C-terminal inhibitors cause the release of mature GR from HSP90, which promotes its exit from the chaperone cycle and potentiates its transcriptional activity in a corticotroph cell line and in primary cultures of human corticotroph adenomas. In an allograft mouse model, the C-terminal HSP90 inhibitor silibinin showed anti-tumorigenic effects, partially reverted hormonal alterations, and alleviated symptoms of Cushing disease. These results suggest that the pathogenesis of Cushing disease caused by overexpression of heat shock proteins and consequently misregulated GR sensitivity may be overcome pharmacologically with an appropriate HSP90 inhibitor.


Efficacy and safety of colesevelam in patients with type 2 diabetes mellitus and inadequate glycemic control receiving insulin-based therapy.
Poor glycemic control is a risk factor for microvascular complications in patients with type 2 diabetes mellitus. Achieving glycemic control safely with insulin therapy can be challenging. A prospective, 16-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study conducted at 50 sites in the United States and 1 site in Mexico between August 12, 2004, and December 28, 2005. Subjects had type 2 diabetes mellitus that was not adequately controlled (glycated hemoglobin level, 7.5%-9.5%, inclusive) receiving insulin therapy alone or in combination with oral antidiabetes agents. In total 287 subjects (52% men; mean age, 57 years; with a mean baseline glycated hemoglobin level of 8.3%) were randomized: 147 to receive colesevelam hydrochloride, 3.75 g/d, and 140 to receive placebo. Using the least squares method, the mean (SE) change in glycated hemoglobin level from baseline to week 16 was -0.41% (0.07%) for the colesevelam-treated group and 0.09% (0.07%) for the placebo group (treatment difference, -0.50% [0.09%]; 95% confidence interval, -0.68% to -0.32%; P < .001). Consistent reductions in fasting plasma glucose and fructosamine levels, glycemic-control response rate, and lipid control measures were observed with colesevelam. As expected, the colesevelam-treated group had a 12.8% reduction in low-density lipoprotein cholesterol concentration relative to placebo (P < .001). Of recipients of colesevelam and placebo, respectively, 30 and 26 discontinued the study prematurely; 7 and 9 withdrew because of protocol-specified hyperglycemia, and 10 and 4 withdrew because of adverse events. Both treatments were generally well tolerated. Colesevelam treatment seems to be safe and effective for improving glycemic control and lipid management in patients with type 2 diabetes mellitus receiving insulin-based therapy, and it may provide a novel treatment for improving dual cardiovascular risk factors.


Cardioprotection by controlling hyperamylinemia in a "humanized" diabetic rat model.
Chronic hypersecretion of the pancreatic hormone amylin is common in humans with obesity or prediabetic insulin resistance and induces amylin aggregation and proteotoxicity in the pancreas. We recently showed that hyperamylinemia also affects the cardiovascular system. Here, we investigated whether amylin aggregates interact directly with cardiac myocytes and whether controlling hyperamylinemia protects the heart. By Western blot, we found abundant amylin aggregates in lysates of cardiac myocytes from obese patients, but not in controls. Aggregated amylin was elevated in failing hearts, suggesting a role in myocyte injury. Using rats overexpressing human amylin in the pancreas (HIP rats) and control myocytes incubated with human amylin, we show that amylin aggregation at the sarcolemma induces oxidative stress and Ca(2+) dysregulation. In time, HIP rats developed cardiac hypertrophy and left-ventricular dilation. We then tested whether metabolites with antiaggregation properties, such as eicosanoid acids, limit myocardial amylin deposition. Rats were treated with an inhibitor of soluble epoxide hydrolase, the enzyme that degrades endogenous eicosanoids. Treatment doubled the blood concentration of eicosanoids, which drastically reduced incorporation of aggregated amylin in cardiac myocytes and blood cells, without affecting pancreatic amylin secretion. Animals in the treated group showed reduced cardiac hypertrophy and left-ventricular dilation. The cardioprotective mechanisms included the mitigation of amylin-induced cardiac oxidative stress and Ca(2+) dysregulation. The results suggest blood amylin as a novel therapeutic target in diabetic heart disease and elevating blood levels of antiaggregation metabolites as a pharmacological strategy to reduce amylin aggregation and amylin-mediated cardiotoxicity.


Behavioral and neural correlates of disrupted orienting attention in posttraumatic stress disorder.
Prior work has revealed that posttraumatic stress disorder (PTSD) is associated with altered (a) attentional performance and (b) resting-state functional connectivity (rsFC) in brain networks linked to attention. Here, we sought to characterize and link these behavioral and brain-based alterations in the context of Posner and Peterson's tripartite model of attention. Male military veterans with PTSD (N = 49; all deployed to Iraq or Afghanistan) and healthy age-and-gender-matched community controls (N = 26) completed the Attention Network Task. A subset of these individuals (36 PTSD and 21 controls) also underwent functional magnetic resonance imaging (fMRI) to assess rsFC. The behavioral measures revealed that the PTSD group was impaired at disengaging spatial attention, relative to the control group. FMRI measures further revealed that, relative to the control group, the PTSD group exhibited greater rsFC between the salience network and (a) the default mode network, (b) the dorsal attention network, and (c) the ventral attention network. Moreover, problems with disengaging spatial attention increased the rsFC between the networks above in the control group, but not in the PTSD group. The present findings link PTSD to both altered orienting of spatial attention and altered relationships between spatial orienting and functional connectivity involving the salience network. Interventions that target orienting and disengaging spatial attention may be a new avenue for PTSD research.


Consumption of iodized salt among households of Basra city, south Iraq.
Progress towards universal salt iodization in Iraq is uncertain. A cross-sectional study with cluster sampling was carried out to investigate the sources and packaging of salt in 900 households in Basra and assess the knowledge and practice of household members regarding iodized salt and iodine deficiency disorders. Adequately iodized salt was found in only 68.3% of households. Salt from local sources was significantly less likely to be iodized than salt from imported sources (15.3% versus 86.9% had > or = 15 ppm). Salt in plastic packages was mostly adequately iodized (95.0%) compared with loose packages (70.3%). Most respondents had heard about iodized salt (92.6%), yet only 27.1% knew about the health benefits. Significantly more household members with university education had iodized salt in the household than those who were illiterate or only could read/write (82.0% versus 57.7%). Better monitoring of local salt supplies and more education to improve the population's awareness of iodization are needed.


The prevalence of premalignant gastric lesions in asymptomatic patients: predicting the future incidence of gastric cancer.
Helicobacter pylori is the main risk-factor for gastric cancer through a cascade from gastritis through atrophic gastritis (AG), intestinal metaplasia (IM), dysplasia (DYS) to malignancy. The presence of these lesions in the general population predicts the gastric cancer incidence in the coming decades. Prevalence data are mostly obtained from serological studies and endoscopy data in symptomatic patients. To investigate the prevalence of H. pylori infection and its related gastric changes in asymptomatic subjects. 383 Patients undergoing routine colonoscopy were included. All subjects underwent upper GI endoscopy and completed the Gastrointestinal Symptom Rating Scale (GSRS). Biopsies were taken from antrum and corpus. H. pylori infection was present in 22%. Non-Caucasian subjects had a significantly higher H. pylori prevalence (p < 0.001). AG, IM and DYS were together found in 9.3% of subjects. Subjects with AG, IM or DYS were significantly older (p < 0.001). No differences were found with respect to gender, presence of GI symptoms as scored by GSRS, lifestyle and medication use. The prevalence of premalignant gastric lesions is considerable in general Western population with increasing age as the main risk factor. One time screening for premalignant lesions at the age of 60 years is a reasonable strategy since the numbers found imply that gastric cancer will remain a prevalent disease.


The plasma concentration of activated protein C appears normal in patients with haemophilia.
Increased concentration of activated protein C (APC) has been observed in patients with thromboembolic disorders, but whether the level of APC in patients with bleeding disorders is decreased remains unknown. Seventy patients with haemophilia A or B with mild, moderate or severe form were studied. Detailed information on bleeding, arthropathy and factor consumption was collected during a 10-year period. The clinical severity of the disease was expressed as the Hemophilia Severity Score (HSS). Plasma concentration of APC was measured as APC in complex with protein C inhibitor. The median concentration of APC-PCI complex in patients with haemophilia was 0.14 microg L(-1) and it did not differ between the types and forms. In 16 patients with severe haemophilia A and the inversion mutation in intron 22, there was no correlation between clinical severity and the concentration of APC-PCI complex. Patients with haemophilia appear to generate normal concentrations of APC during basal conditions. APC does not seem to be an important modulator of the phenotypic expression of haemophilia.


Family of origin and educational inequalities in mortality: Results from 1.7 million Swedish siblings.
Circumstances in the family of origin have short- and long-term consequences for people's health. Family background also influences educational achievements - achievements that are clearly linked to various health outcomes. Utilizing population register data, we compared Swedish siblings with different levels of education (1,732,119 individuals within 662,095 sibships) born between 1934 and 1959 and followed their death records until the end of 2012 (167,932 deaths). The educational gradient in all-cause mortality was lower within sibships than in the population as a whole, an attenuation that was strongest at younger ages (< 50 years of age) and for those with a working class or farmer background. There was substantial variation across different causes of death with clear reductions in educational inequalities in, e.g., lung cancer and diabetes, when introducing shared family factors, which may indicate that part of the association can be ascribed to circumstances that siblings have in common. In contrast, educational inequalities in suicide and, for women, other mental disorders increased when adjusting for factors shared by siblings. The vast variation in the role of childhood conditions for the education-mortality association may help us to further understand the interplay between family background, education, and mortality. The increase in the education gradient in suicide when siblings are compared may point towards individually oriented explanations ('non-shared environment'), perhaps particularly in mental disorders, while shared family factors primarily seem to play a more important role in diseases in which health behaviors are most significant.


Obestatin Plays Beneficial Role in Cardiomyocyte Injury Induced by Ischemia-Reperfusion In Vivo and In Vitro.
BACKGROUND Obestatin, primarily recognized as a peptide within the gastrointestinal system, has been shown to benefit the cardiovascular system. We designed this experiment to study the protective role and underlying mechanism of obestatin against ischemia-reperfusion(I/R) injury in myocardial cells. MATERIAL AND METHODS In an In vivo experiment, LAD was ligated for 0.5 h and then opened for reperfusion with obestatin for 24 h. Then, the infarction area was shown with TTC staining, and inflammation factors in serum were analyzed by qRT-PCR. In primary cultured cardiomyocytes, we measured the level of LDH, MDA, GSH, and SOD. Finally, we assessed cells apoptosis using flow cytometry and detected the concentrations of caspase-3, Bax, and Bcl-2 using Western blot analysis. RESULTS TTC staining showed that in the 3 obestatin groups, the infarct area became smaller with the increase of obestatin concentration. Obestatin also inhibited LDH expression in rat serum and decreased mRNA levels of TNF-α, IL-6, ICAM-1, and iNOS in rat cardiomyocytes after reperfusion. In primary cultured cardiomyocytes, obestatin decreased LDH content and increased GSH level after I/R injury. Obestatin was also found to antagonize the apoptosis of cardiomyocytes in a dose-dependent manner. Western blot analysis showed that obestatin downregulated the expression of caspase-3 and Bax and upregulated the expression of Bcl-2. CONCLUSIONS Obestatin can protect cardiomyocyte from I/R-induced injury in vitro and in vivo. This beneficial effect is closely related with its properties of anti-inflammation, anti-cytotoxicity, and anti-apoptosis. The protective effect of obestatin might be associated with activation of Bcl-2 and inhibition of caspase-3 and Bax.


A case of severe adolescent obsessive-compulsive disorder treated with inpatient hospitalization, risperidone and sertraline.
The initial treatment of obsessive-compulsive disorder (OCD) has generally been limited to serotonergic agents, cognitive-behavioral therapy (CBT), or a combination of the two. These findings were supported by the POTS study for OCD in children and adolescents. However, treatment with serotonergic agents or CBT can take several weeks before benefit is seen; severe cases of OCD may require more immediate treatment. The authors present a case of severe OCD in an adolescent that required immediate treatment due to her critical medical condition. The patient's symptoms included not eating or taking medications or fluids by mouth due to fears of contamination. A medical hospitalization was previously required due to dehydration. As treatment with an SSRI would not have quick enough onset and the patient was initially resistant to participating in CBT, the patient was psychiatrically hospitalized and first started on liquid risperidone. After several doses of risperidone, the patient was able to participate in CBT and start sertraline. The authors discuss the differential diagnosis of such a patient, including the continuum of OCD symptoms and psychotic symptoms. The authors discuss the different treatment options, including the utilization of inpatient psychiatric hospitalization. The authors discuss the potential risks and benefits of using atypical antipsychotics in lieu of benzodiazepines for the initial treatment of severe adolescent OCD. The authors also discuss other current treatment recommendations and rationale for the treatment that was pursued. This patient received benefit of her symptoms relatively quickly with psychiatric hospitalization and an atypical antipsychotic. The diagnosis of a psychotic disorder should be considered. These treatment options must be weighed against the risks of atypical antipsychotics, including extrapyramidal symptoms, weight gain, and metabolic syndrome; benzodiazepines also have their risks and benefits. Additionally, the cost of time and finances of inpatient hospitalization must be considered. More research is needed regarding the short- and long-term efficacy and safety of antipsychotics in the treatment of OCD in the child and adolescent population.


TreeDyn: towards dynamic graphics and annotations for analyses of trees.
Analyses of biomolecules for biodiversity, phylogeny or structure/function studies often use graphical tree representations. Many powerful tree editors are now available, but existing tree visualization tools make little use of meta-information related to the entities under study such as taxonomic descriptions or gene functions that can hardly be encoded within the tree itself (if using popular tree formats). Consequently, a tedious manual analysis and post-processing of the tree graphics are required if one needs to use external information for displaying or investigating trees. We have developed TreeDyn, a tool using annotations and dynamic graphical methods for editing and analyzing multiple trees. The main features of TreeDyn are 1) the management of multiple windows and multiple trees per window, 2) the export of graphics to several standard file formats with or without HTML encapsulation and a new format called TGF, which enables saving and restoring graphical analysis, 3) the projection of texts or symbols facing leaf labels or linked to nodes, through manual pasting or by using annotation files, 4) the highlight of graphical elements after querying leaf labels (or annotations) or by selection of graphical elements and information extraction, 5) the highlight of targeted trees according to a source tree browsed by the user, 6) powerful scripts for automating repetitive graphical tasks, 7) a command line interpreter enabling the use of TreeDyn through CGI scripts for online building of trees, 8) the inclusion of a library of packages dedicated to specific research fields involving trees. TreeDyn is a tree visualization and annotation tool which includes tools for tree manipulation and annotation and uses meta-information through dynamic graphical operators or scripting to help analyses and annotations of single trees or tree collections.


Toxoplasma gondii and anxiety disorders in a community-based sample.
A growing body of literature suggests that exposure to the neurotropic parasite Toxoplasma gondii (T. gondii) is associated with increased risk of mental disorders, particularly schizophrenia. However, a potential association between T. gondii exposure and anxiety disorders has not been rigorously explored. Here, we examine the association of T. gondii infection with both anxiety and mood disorders. Participants (n=484) were drawn from the Detroit Neighborhood Health Study, a population-representative sample of Detroit residents. Logistic regression was used to examine the associations between T. gondii exposure (defined by seropositivity and IgG antibody levels) and three mental disorders: generalized anxiety disorder (GAD), posttraumatic stress disorder (PTSD) and depression. We found that T. gondii seropositivity was associated with a 2 times greater odds of GAD (odds ratio (OR), 2.25; 95% confidence interval (CI), 1.11-4.53) after adjusting for age, gender, race, income, marital status, and medication. Individuals in the highest antibody level category had more than 3 times higher odds of GAD (OR, 3.35; 95% CI, 1.41-7.97). Neither T. gondii seropositivity nor IgG antibody levels was significantly associated with PTSD or depression. Our findings indicate that T. gondii infection is strongly and significantly associated with GAD. While prospective confirmation is needed, T. gondii infection may play a role in the development of GAD.


Guidelines for implant placement to minimize impingement during activities of daily living after total hip arthroplasty.
Impingement, both prosthetic and bony, precedes the vast majority of dislocations after total hip arthroplasty and may adversely impact component wear. Reconstructed computer hip models of 8 subjects were used to evaluate hip range of motion for activities of daily living (ADLs) associated with posterior instability and anterior instability. Variables examined included acetabular position, femoral offset, and head size. The majority of flexion ADLs (associated with posterior instability) encountered prosthetic impingement, whereas extension ADLs demonstrated bony impingement with the 45/20 cup placement position. Cup placement in natural anteversion and adduction allowed normal joint motion in anterior and posterior impinging activities. Insufficient femoral offset and smaller head size negatively impacted range of motion. Any anterior cup and posterior cup protrusions greater than 5 mm should be avoided.


Stimulation of Striga asiatica (Witchweed) Seed Germination by 6-Substituted Purines.
Kinetin [6-(2-furfuryl) aminopurine] and certain other 6-substituted aminopurines stimulated germination of seed of Striga asiatica (L.) Kuntze. Optimum concentration for most active compounds was in the range of 5 to 25 mg/lit. Derivatives which showed high activity possessed an adenine nucleus with a phenyl, benzyl, phenethyl, or furfuryl radical substituted on the amino group.


Porcine Prediction of Pharmacokinetic Parameters in People: A Pig in a Poke?
The minipig has become an animal of considerable interest in preclinical drug development. It has been used in toxicology research and in examining/establishing regulatory guidelines as a nonrodent animal model. We have reviewed some basic issues that one would want to consider in the development and testing of any animal model for humans. The pig is a reasonable alternative to the dog, but there are some clear limitations and unexplained disparities in the literature, which require further study; primary among these is the need for standardization in choice of breed and sex and routine protocols. The minipig offers numerous advantages over other established animal models, and it has similarities to the human with regard to anatomy, physiology, and biochemistry. The gastrointestinal tract is structurally and functionally similar to humans. This appears to be true for enzymes and transporters in the gut as well, but more study is needed. One major concern is assessment of oral drug absorption, especially with regard to potential food effects due to gastric emptying differences, yet this does not appear to be a consistent observation. Hepatic metabolism seems to reflect enzymatic patterns in humans, with some differences. Kidney function seems similar to humans but requires further study. We have analyzed literature data that suggest the pig would offer a reasonable model for human oral bioavailability and for allometric predictions of clearance. The minipig appears to be the model for dermal absorption in humans, and we discuss this in terms of literature data and our own in-house experience.


Self-Screening and Non-Physician Screening for Hypertension in Communities: A Systematic Review.
Community-based self-screening may provide opportunities to increase detection of hypertension, and identify raised blood pressure (BP) in populations who do not access healthcare. This systematic review aimed to evaluate the effectiveness of non-physician screening and self-screening of BP in community settings. We searched the Cochrane Central Trials Register, Medline, Embase, CINAHL, and Science Citation Index & Conference Proceedings Citation Index-Science to November 2013 to identify studies reporting community-based self-screening or non-physician screening for hypertension in adults. Results were stratified by study site, screener, and the cut-off used to define high screening BP. We included 73 studies, which described screening in 9 settings, with pharmacies (22%) and public areas/retail (15%) most commonly described. We found high levels of heterogeneity in all analyses, despite stratification. The highest proportions of eligible participants screened were achieved by mobile units (range 21%-88%) and pharmacies (range 40%-90%). Self-screeners had similar median rates of high BP detection (25%-35%) to participants in studies using other screeners. Few (16%) studies reported referral to primary care after screening. However, where participants were referred, a median of 44% (range 17%-100%) received a new hypertension diagnosis or antihypertensive medication. Community-based non-physician or self-screening for raised BP can detect raised BP, which may lead to the identification of new cases of hypertension. However, current evidence is insufficient to recommend specific approaches or settings. Studies with good follow-up of patients to definitive diagnosis are needed.


Relation between economic disadvantage and psychosocial morbidity in children.
To examine the relation between low income and child psychosocial morbidity cross-sectionally and longitudinally. Cross-sectional survey with follow-up. Ontario. Children aged 4 to 16 years from families selected by means of stratified, clustered and random sampling of 1981 Canada Census data. Results were based on the responses of 2503 children interviewed in 1983 and 1076 re-interviewed in 1987. Prevalence rates of psychiatric disorders, poor school performance and social impairment. There was a significant relation between low income and psychosocial morbidity, with a threshold at an income level of less than $10,000. Poor children 4 to 11 years of age were at greater risk of morbidity than poor children 12 to 16, but there were no significant age differences. Logistic regression revealed that low income and noneconomic factors (low maternal education and family dysfunction) shared significant independent influences on the prevalence of psychosocial morbidity. Low income is strongly associated with psychosocial morbidity in children. Both economic and noneconomic factors showed independent influences on morbidity. These findings have important clinical, scientific and policy implications.


Clinical performance of the Solana® Point-of-Care Trichomonas Assay from clinician-collected vaginal swabs and urine specimens from symptomatic and asymptomatic women.
Solana® (Quidel) is a new rapid (<40 min.) point-of-care (POC) test for qualitative detection of Trichomonas vaginalis (TV) DNA. The assay has two steps: 1) specimen preparation, and 2) amplification and detection using isothermal Helicase-Dependent Amplification (HDA). The objective was to demonstrate the performance of Solana for vaginal swabs and female urines based on comparison to wet mount and TV culture. Performance was also compared to the Aptima-TV assay. Urine and four clinician-collected vaginal swabs were collected. The first two were used for FDA composite reference (wet mount; InPouch TV Culture). The third swab was used for Solana. Sensitivity/specificity were based on the reference method. A specimen was considered positive if either test was positive. The fourth swab was for Aptima-TV. Vaginal swabs and urines were obtained from 501 asymptomatic and 543 symptomatic women. Prevalence of TV by was 11.5%. For swabs, Solana® demonstrated high sensitivity and specificity from asymptomatic (100%/98.9%) and symptomatic (98.6%/98.5%) women, as well as for urines from asymptomatic (98.0%/98.4%) and symptomatic (92.9%/97.9%) women, compared to the reference method. Compared to Aptima-TV, the sensitivity/specificity was 89.7%/99.0% for swabs and 100%/98.9% for urines. The Solana® assay performed well compared to the reference assays.


Effect of Surfactant Type and Sonication Energy on the Electrical Conductivity Properties of Nanocellulose-CNT Nanocomposite Films.
We present a detailed study on the influence of sonication energy and surfactant type on the electrical conductivity of nanocellulose-carbon nanotube (NFC-CNT) nanocomposite films. The study was made using a minimum amount of processing steps, chemicals and materials, to optimize the conductivity properties of free-standing flexible nanocomposite films. In general, the NFC-CNT film preparation process is sensitive concerning the dispersing phase of CNTs into a solution with NFC. In our study, we used sonication to carry out the dispersing phase of processing in the presence of surfactant. In the final phase, the films were prepared from the dispersion using centrifugal cast molding. The solid films were analyzed regarding their electrical conductivity using a four-probe measuring technique. We also characterized how conductivity properties were enhanced when surfactant was removed from nanocomposite films; to our knowledge this has not been reported previously. The results of our study indicated that the optimization of the surfactant type clearly affected the formation of freestanding films. The effect of sonication energy was significant in terms of conductivity. Using a relatively low 16 wt. % concentration of multiwall carbon nanotubes we achieved the highest conductivity value of 8.4 S/cm for nanocellulose-CNT films ever published in the current literature. This was achieved by optimizing the surfactant type and sonication energy per dry mass. Additionally, to further increase the conductivity, we defined a preparation step to remove the used surfactant from the final nanocomposite structure.


A paired kidney analysis on the impact of pre-transplant anti-HLA antibodies on graft survival.
Pre-transplant donor-specific anti-human leucocyte antigen (HLA) antibodies (DSAs) are associated with impaired kidney graft survival while the clinical relevance of non-donor-specific anti-HLA antibodies (nDSAs) is more controversial. The aim of the present paired kidney graft study was to compare the clinical relevance of DSAs and nDSAs. To eliminate donor and era-dependent factors, a post hoc paired kidney graft analysis was performed as part of a Dutch multicentre study evaluating all transplantations between 1995 and 2005 with available pre-transplant serum samples. Anti-HLA antibodies were detected with a Luminex single-antigen bead assay. Among 3237 deceased donor transplantations, we identified 115 recipient pairs receiving a kidney from the same donor with one recipient being DSA positive and the other without anti-HLA antibodies. Patients with pre-transplant DSAs had a significantly lower 10-year death-censored graft survival (55% versus 82%, P=0.0001). We identified 192 pairs with one recipient as nDSA positive (against Class I and/or II) and the other without anti-HLA antibodies. For the patients with nDSAs against either Class I or II, graft survival did not significantly differ compared with patients without anti-HLA antibodies (74% versus 77%, P = 0.79). Only in patients with both nDSAs Class I and II was there a trend towards a lower graft survival (58%, P = 0.06). Lastly, in a small group of 42 recipient pairs, 10-year graft survival in recipients with DSAs was 49% compared with 68% in recipients with nDSAs (P=0.11). This paired kidney analysis confirms that the presence of pre-transplant DSAs in deceased donor transplantations is a risk marker for graft loss, whereas nDSAs in general are not associated with a lower graft survival. Subgroup analysis indicated that only in broadly sensitized patients with nDSAs against Class I and II, nDSAs may be a risk marker for graft loss in the long term.


Crx-L253X Mutation Produces Dominant Photoreceptor Defects in TVRM65 Mice.
The cone-rod homeobox (CRX) transcription factor is essential for photoreceptor gene expression, differentiation, and survival. Human CRX mutations can cause dominant retinopathies of varying onset and phenotype severity. In animal models, dominant frameshift Crx mutations introduce a premature termination codon (PTC), producing inactive truncated proteins that interfere with normal CRX function. Previously, a mutant mouse, TVRM65, was reported to carry a recessive late PTC mutation, Crx-L253X. More detailed phenotype analysis of the pathogenicity of Crx-L253X sheds new light on the variability of CRX-linked diseases. Homozygous (L253X/X); heterozygous (L253X/+); Crx-/- and control C57BL/6J (WT) mice were analyzed at various ages for changes in retinal function (ERG), morphology (histology) and photoreceptor gene expression (qRT-PCR). At 1 month, L253X/X mice lack visual function, show greater reductions in retinal thickness, and distinct gene expression changes relative to Crx-/-, suggesting that the phenotype of L253X/X is more severe than Crx-/-. L253X/+ mice have reduced rod/cone function, but normal retinal morphology at all ages tested. qRT-PCR assays described a complex phenotype in which both developing and mature photoreceptors are unable to maintain proper gene expression. L253X mRNA/protein is overexpressed relative to normal Crx, suggesting a pathogenic mechanism similar to early PTC mutations. However, the overexpression is less pronounced, correlating with a relatively mild dominant phenotype. The L253X mouse provides a valuable model for CRX-associated retinopathy. The pathogenicity of CRX frameshift mutations depends on the position of the PTC, which in turn determines the degree of mutant mRNA/protein overproduction.


Genome-Wide Analysis of DNA Methylation in Hyperoxia-Exposed Newborn Rat Lung.
Oxygen therapy is often required to treat newborn infants with respiratory disorders. Prolonged exposure of neonatal rats to hyperoxia reduced alveolar septation, increased terminal air space size, and increased lung fibrosis; these conditions are very similar to those of human bronchopulmonary dysplasia. Epigenetic regulation of gene expression plays a crucial role in bronchopulmonary dysplasia development. We reared Sprague-Dawley rat pups in either room air (RA, n = 24) or an atmosphere containing 85% O2 (n = 26) from Postnatal Days 1 to 14. Methylated DNA immunoprecipitation (MeDIP) was used to analyze genome-wide DNA methylation in lung tissues of neonatal rats. Hyperoxia-exposed rats exhibited larger air spaces and thinner septa than RA-exposed rats did on Postnatal Day 14. The rats exposed to hyperoxia exhibited significantly higher mean linear intercepts than did the rats exposed to RA. We applied MeDIP next-generation sequencing for profiling changes in DNA methylation in the rat lungs exposed to hyperoxia and RA. We performed bioinformatics and pathway analyses on the raw sequencing data to identify differentially methylated candidate genes. Our in vivo model revealed that neonatal hyperoxia exposure arrested alveolarization on Postnatal Day 14. We found that the ErbB, actin cytoskeleton, and focal adhesion signaling pathways are epigenetically modulated by exposure to hyperoxia. We demonstrated that hyperoxia exposure contribute in delaying lung development through an epigenetic mechanism by disrupting the expression of genes in lungs that might be involved in alveolarization. These data indicate that aberrant DNA methylation and deregulation of the actin cytoskeleton and focal adhesion pathways of lung tissues may be involved in the pathophysiology of hyperoxia-induced arrested alveolarization.


Hydrological modelling of Toxoplasma gondii oocysts transport to investigate contaminated snowmelt runoff as a potential source of infection for marine mammals in the Canadian Arctic.
Toxoplasma gondii (T. gondii) is a zoonotic protozoan that sometimes causes serious illness in humans and other animals worldwide, including the Canadian Arctic. Wild and domestic felids, the only hosts able to shed T. gondii oocysts, are practically non-existent in the Canadian Arctic. So here the hypothesis that T. gondii oocysts, shed in the southern areas of the boreal watershed, could contaminate the Arctic coastal marine environment via surface runoff, particularly during the spring snowmelt period, was explored. A watershed model was applied to simulate the hydrological transport of T. gondii oocysts during the snowmelt period and test the possible efficiency of river-to-sea transport as a potential source of marine organisms' exposure to this pathogen. Simulations were run for two pilot watersheds with the ultimate aim of extrapolating the results across the Canadian Arctic watersheds. Results suggest that daily stream flow concentrations of T. gondii oocysts at the river outlet are likely to be very low. However, accumulation of oocysts in the estuarine areas may be large enough to contaminate estuarine/marine filter-feeding molluscs and snails on which seals and other marine mammals may feed. Potential maximum concentrations of T. gondii oocysts in runoff are reached at the beginning of the snowmelt period with maxima varying with discharge rates into rivers and how far upstream oocysts are discharged. Meteorological conditions during the snowmelt period can affect simulated concentrations of oocysts. These findings support the hypothesis that T. gondii oocysts carried in snowmelt runoff could be a source of T. gondii infection for marine mammals in the Canadian Arctic, and for Arctic human populations that hunt and consume raw meat from marine mammals.


Evidence for a link between gut microbiota and hypertension in the Dahl rat.
The gut microbiota plays a critical role in maintaining physiological homeostasis. This study was designed to evaluate whether gut microbial composition affects hypertension. 16S rRNA genes obtained from cecal samples of Dahl salt-sensitive (S) and Dahl salt-resistant (R) rats were sequenced. Bacteria of the phylum Bacteroidetes were higher in the S rats compared with the R rats. Furthermore, the family S24-7 of the phylum Bacteroidetes and the family Veillonellaceae of the phylum Firmicutes were higher in the S rats compared with the R rats. Analyses of the various phylogenetic groups of cecal microbiota revealed significant differences between S and R rats. Both strains were maintained on a high-salt diet, administered antibiotics for ablation of microbiota, transplanted with S or R rat cecal contents, and monitored for blood pressure (BP). Systolic BP of the R rats remained unaltered irrespective of S or R rat cecal transplantation. Surprisingly, compared with the S rats given S rat cecal content, systolic BP of the S rats given a single bolus of cecal content from R rats was consistently and significantly elevated during the rest of their life, and they had a shorter lifespan. A lower level of fecal bacteria of the family Veillonellaceae and increased plasma acetate and heptanoate were features associated with the increased BP observed in the S rats given R rat microbiota compared with the S rats given S rat microbiota. These data demonstrate a link between microbial content and BP regulation and, because the S and R rats differ in their genomic composition, provide the necessary basis to further examine the relationship between the host genome and microbiome in the context of BP regulation in the Dahl rats.


The MAP2K5-linked SNP rs2241423 is associated with BMI and obesity in two cohorts of Swedish and Greek children.
Recent genome-wide association studies have identified a single nucleotide polymorphism within the last intron of MAP2K5 associated with a higher body mass index (BMI) in adults. MAP2K5 is a component of the MAPK-family intracellular signaling pathways, responding to extracellular growth factors such as brain derived neurotrophic factor (BDNF) and nerve growth factor (NGF). In this study, we examined the association of this variant in two cohorts of children from Sweden and Greece. We examine the association of rs2241423 to BMI in a cohort of 474 Swedish children admitted for treatment of childhood obesity and 519 children matched for gender, ethnicity and socioeconomic background from the Stockholm area, as well as a cross-sectional cohort of 2308 Greek school children (Healthy Growth Study). Children were genotyped using a predesigned TaqMan polymorphism assay. Logistic regression was used to test for an association of rs2241423 to obesity in the cohort of Swedish children. Linear regression was used to test for an association of rs2241423 to BMI z-score and phenotypic measurements of body adiposity in the cohort of Greek children. Models were adjusted for age and gender. In the cohort of Greek children the model was also adjusted for stage of pubertal development. The minor allele of rs2241423, allele A, was associated with a protective effect against obesity in the cohort of Swedish children (p = 0.029, OR = 0.79 (95% CI: 0.64-0.98)), and with a lower BMI z-score in the cohort of Greek children (p = 0.028, β = -0.092). No association to phenotypic measurements of body fat distribution could be observed in our study. rs2241423 was associated with BMI and obesity in two independent European cohorts suggesting a role for MAP2K5 in early weight regulation.


Efficacy of thigh protectors in preventing thigh haematomas.
Thigh haematomas are extremely common in Australian Rules Football (ARF). This is in contrast to contact sports overseas, the likely reason is the increased use of thigh protectors as part of team uniforms in contact sports such as American football. Thigh haematomas can have a significant impact on an athlete's performance, ranging from short term performance impairment, muscle deconditioning and compartment syndromes, to long term problems, such as career threatening myositis ossificans and possibly muscle tears. To assess the efficacy of thigh protectors made for Australian Football, a prospective study was undertaken involving two teams in the elite junior (U 18) VSFL competition in SE Australia. One team wore thigh protectors over the course of the season while the other team acted as controls and did not wear thigh protectors. The control group suffered nine thigh haematomas, while the protected group had none (p<0.01). The possible de-conditioning effect of the haematomas was evidenced by two of the control group suffering torn quadriceps within four weeks of the haematoma. The protectors were generally well tolerated by all but one player, except in hot conditions, when they were uncomfortable.


A phase 3 study of three induction regimens and of priming with GM-CSF in older adults with acute myeloid leukemia: a trial by the Eastern Cooperative Oncology Group.
The optimal induction for older adults with acute myeloid leukemia (AML) is unknown. Several anthracyclines have been proposed, but the data remain equivocal. Additionally, few prospective trials of priming with hematopoietic growth factors to cycle leukemia cells prior to induction chemotherapy have been conducted. Three hundred and sixty-two older adults with previously untreated AML were randomized to either daunorubicin, idarubicin or mitoxantrone with a standard dose of cytarabine as induction therapy. In addition, 245 patients were also randomized to receive granulocyte-macrophage colony-stimulating factor (GM-CSF) or placebo beginning 2 days prior to induction chemotherapy and continuing until marrow aplasia. No difference was observed in the disease-free overall survival or in toxicity among patients receiving any of the 3 induction regimens or among those receiving growth factor or placebo for priming. However, the complete remission rate for the first 113 analyzable patients, who did not participate in the priming study and started induction therapy 3 to 5 days earlier than those who did, was significantly higher (50% versus 38%; P =.03). None of the anthracyclines is associated with improved outcome in older adults. Priming with hematopoietic growth factor did not improve response when compared with placebo. Furthermore, delaying induction therapy in older adults may lead to a lower complete remission rate.


Mobility performance in glaucoma.
To determine whether glaucoma affects mobility performance and whether there is a relationship between mobility performance and stage of disease as estimated from vision-function measures. The mobility performance of 47 glaucoma subjects was compared with that of 47 normal-vision subjects who were of similar age. Mobility performance was assessed by the time required to complete an established travel path and the number of mobility incidents. The subjective assessment of falling and fear of falling were also compared. Vision function was assessed by measures of visual acuity, contrast sensitivity, monocular automated threshold perimetry, and suprathreshold; binocular visual fields were assessed with the Esterman test. The glaucoma subjects walked on average 10% more slowly than did the normal-vision subjects. The number of people who experienced bumps, stumbles, or orientation problems was almost twice as high in the glaucoma group than the normal-vision group, but the difference did not reach statistical significance. The difference between groups also was not significant with respect to the number of people who reported falling in the past year (38% for the glaucoma group and 30% for the normal-vision group) or a fear of falling (28% for the glaucoma group and 23% for the normal-vision group). The visual fields assessed with a Humphrey 24-2 test were more highly correlated with walking speed in glaucoma than the visual fields scored by the Esterman scale or than visual acuity or contrast sensitivity. Glaucoma is associated with a modest decrease in mobility performance. Walking speed decreases with severity of the disease as estimated by threshold perimetry.


The (pro)renin receptor/ATP6AP2 is essential for vacuolar H+-ATPase assembly in murine cardiomyocytes.
The (pro)renin receptor [(P)RR], encoded in ATP6AP2, plays a key role in the activation of local renin-angiotensin system (RAS). A truncated form of (P)RR, termed M8.9, was also found to be associated with the vacuolar H(+)-ATPase (V-ATPase), implicating a non-RAS-related function of ATP6AP2. We investigated the role of (P)RR/ATP6AP2 in murine cardiomyocytes. Cardiomyocyte-specific ablation of Atp6ap2 resulted in lethal heart failure; the cardiomyocytes contained RAB7- and lysosomal-associated membrane protein 2 (LAMP2)-positive multivesicular vacuoles, especially in the perinuclear regions. The myofibrils and mitochondria remained at the cell periphery. Cardiomyocyte death was accompanied by numerous autophagic vacuoles that contained undigested cellular constituents, as a result of impaired autophagic degradation. Notably, ablation of Atp6ap2 selectively suppressed expression of the V(O) subunits of V-ATPase, resulting in deacidification of the intracellular vesicles. Furthermore, the inhibition of intracellular acidification by treatment with bafilomycin A1 or chloroquine reproduced the phenotype observed for the (P)RR/ATP6AP2-deficient cardiomyocytes. Genetic ablation of Atp6ap2 created a loss-of-function model for V-ATPase. The gene product of ATP6AP2 is considered to act as in 2 ways: (1) as (P)RR, exerting a RAS-related function; and (2) as the V-ATPase-associated protein, exerting a non-RAS-related function that is essential for cell survival.


Treatment and outcomes for primary cutaneous extramedullary plasmacytoma: a case series.
Primary cutaneous plasmacytoma (pcp) is a rare disease, with few studies to guide therapy. Our primary study objective was to define treatments used for pcp; a secondary objective was to describe outcomes of patients, including disease recurrence and death. An institutional cancer registry was used to identify cases for retrospective chart review. In a systematic review, treatments for, and outcomes of, all known cases of pcp were described. Three eligible cases identified at our institution; each patient had a solitary pcp. The systematic review identified 66 patients. Radiotherapy was the most commonly used primary treatment modality (31% of all patients; 42% for patients with solitary lesions), followed by surgery (28% of all patients; 36% for patients with solitary lesions). Median survival for all patients was 10.4 years [95% ci: 4.3 years to not reached], with a trend toward a decreased risk of death with solitary lesions compared with multiple lesions (hazard ratio: 0.37; 95% ci: 0.13 to 1.08; p = 0.059). For patients with solitary lesions, the median and recurrence-free survivals were, respectively, 17.0 years (95% ci: 1.7 years to not reached) and 11.0 years (95% ci: 2 years to not reached); for patients with multiple lesions, they were 4.3 years (95% ci: 1.3 to not reached) and 1.4 years (95% ci: 0.6 years to not reached). Disease recurrence, including progression to multiple myeloma, was the most common cause of death. Compared with patients having multiple pcp lesions, those presenting with a single pcp lesion might experience longer overall survival. Local therapy (radiation or surgery) is a reasonable curative treatment for a solitary pcp lesion.


High prevalence and presumptive treatment of schistosomiasis and strongyloidiasis among African refugees.
Schistosomiasis and strongyloidiasis cause substantial morbidity and mortality among hundreds of millions of infected persons worldwide. In the United States, these infections are most commonly found among international travelers, immigrants, and refugees from areas of endemicity. Refugees resettled to the United States since 2000 include >3800 "Lost Boys and Girls" of Sudan and 8000 Somali Bantu. Many Lost Boys and Girls of Sudan reported chronic abdominal pain only since arrival, and some received diagnoses of schistosomiasis or strongyloidiasis. We assessed seroprevalence of these infections among these refugees and hypothesized an association between infection and abdominal pain. We offered a survey assessing chronic abdominal pain and serologic testing for schistosomiasis and strongyloidiasis to all 800 attendees of a Lost Boys and Girls of Sudan reunion in the United States. Serologic testing was performed on preimmigration specimens obtained from 100 United States-bound Somali Bantu refugees. Of the 462 Sudanese refugees (58%) tested, 44% and 46% were seropositive for schistosomiasis (primarily due to Schistosoma mansoni) and strongyloidiasis, respectively; 24% of those who tested positive for schistosomiasis had S. mansoni antigenemia. Forty-six percent reported chronic abdominal pain, which was not associated with either infection. Among 100 Somali Bantu, 73% and 23% tested seropositive for schistosomiasis (primarily due to Schistosoma haematobium) and strongyloidiasis, respectively. The high seroprevalence of schistosomiasis and strongyloidiasis among Sudanese Lost Boys and Girls and Somali Bantu refugees supports presumptive treatment for these refugees. Current refugee resettlement policies inadequately address these diseases; our data support consideration of predeparture presumptive therapy for all refugees from areas of endemicity.


Lead exposure and cardiovascular disease--a systematic review.
This systematic review evaluates the evidence on the association between lead exposure and cardiovascular end points in human populations. We reviewed all observational studies from database searches and citations regarding lead and cardiovascular end points. A positive association of lead exposure with blood pressure has been identified in numerous studies in different settings, including prospective studies and in relatively homogeneous socioeconomic status groups. Several studies have identified a dose-response relationship. Although the magnitude of this association is modest, it may be underestimated by measurement error. The hypertensive effects of lead have been confirmed in experimental models. Beyond hypertension, studies in general populations have identified a positive association of lead exposure with clinical cardiovascular outcomes (cardiovascular, coronary heart disease, and stroke mortality; and peripheral arterial disease), but the number of studies is small. In some studies these associations were observed at blood lead levels < 5 microg/dL. We conclude that the evidence is sufficient to infer a causal relationship of lead exposure with hypertension. We conclude that the evidence is suggestive but not sufficient to infer a causal relationship of lead exposure with clinical cardiovascular outcomes. There is also suggestive but insufficient evidence to infer a causal relationship of lead exposure with heart rate variability. PUBLIC HEALTH IMPLICATIONS: These findings have immediate public health implications. Current occupational safety standards for blood lead must be lowered and a criterion for screening elevated lead exposure needs to be established in adults. Risk assessment and economic analyses of lead exposure impact must include the cardiovascular effects of lead. Finally, regulatory and public health interventions must be developed and implemented to further prevent and reduce lead exposure.


Has the Earth's sixth mass extinction already arrived?
Palaeontologists characterize mass extinctions as times when the Earth loses more than three-quarters of its species in a geologically short interval, as has happened only five times in the past 540 million years or so. Biologists now suggest that a sixth mass extinction may be under way, given the known species losses over the past few centuries and millennia. Here we review how differences between fossil and modern data and the addition of recently available palaeontological information influence our understanding of the current extinction crisis. Our results confirm that current extinction rates are higher than would be expected from the fossil record, highlighting the need for effective conservation measures.


6-Phosphogluconate dehydrogenase from Lactococcus lactis: a role for arginine residues in binding substrate and coenzyme.
A gene encoding 6-phosphogluconate dehydrogenase (6-PGDH, EC 1.1.1. 44) was identified from the homofermentative lactic acid bacterium Lactococcus lactis, by complementation of Escherichia coli mutants. The cloned gene was then expressed to high levels in E. coli and the protein purified for kinetic analysis. The enzyme had a Km for 6-phosphogluconate of 15.4+/-1.4 microM and for NADP of 1.9+/-0.2 microM at pH 7.5. Sequence comparison of the L. lactis 6-PGDH with the corresponding enzyme derived from the pathogenic protozoan Trypanosoma brucei and sheep liver revealed the substrate-binding residues to be identical in all three species, although the three coenzyme-binding pockets differed slightly. A totally conserved arginine residue (Arg-447), believed to bind the 6-phosphate of substrate, was mutated to lysine, aspartate, alanine or tryptophan. In each case enzyme activity was lost, confirming an essential role for this residue on activity. A second arginine (Arg-34), believed to be critical in binding the 2'-phosphate of cofactor NADP+, was mutated to a tyrosine residue, as found in one atypical isoform of the enzyme in Bacillus subtilis. This alteration led to decrease in affinity for NADP+ of nearly three orders of magnitude. A second 6-PGDH gene has been identified from the genome of B. subtilis. This second isoform contains an arginine (Arg-34) in this position, suggesting that B. subtilis has two 6-PGDHs with different coenzyme specificities.


Biological characteristics of the cerebral venous system and its hemodynamic response to intracranial hypertension.
The role of the cerebral venous system (CVS) in intracranial pressure (ICP) regulation remains largely unclear. In the present study, the interaction between ICP and the cerebral venous system and its possible mechanism were investigated with respect to the biological characteristics of the cerebral venous system and its hemodynamic response under increased ICP. We created intracranial hypertension animal model, measured and calculated the venous flow velocity and diameter of the outflow terminal of the CVS with color ultrasonic system and recorded the vascular morphology by 3-dimensional anatomical microscopy. Patients who suffered from raised ICP underwent MRI and digital subtraction angiography (DSA) examination to show the length in the vertical direction of the wall of the bridging vein representing the diameter value. Pathological autopsy was performed from bodies of patients who had died from non-cerebral causes to observe the juncture part between the venous sinuses and tributary vertical brain veins. Under increased ICP conditions, venous drainage through the outlet cuff segment, a unique structure between the bridge vein and sinus, was obstructed and in turn venous blood became congested. Therefore, the increased blood volume worsened the pre-existing ICP according to the well-accepted theory regarding volume-pressure relationship. This phenomenon was described as concurrent "venogenic intracranial hypertension", which is characterized by intracranial venous blood stasis responsive to and together with the original increased ICP. The existence of this special pathophysiological process is prevalent, rather than rare, in various intracranial disorders. This finding would definitely provide new insight into the area of cerebral venous system research.


Sepsis-induced potentiation of peritoneal macrophage migration is mitigated by programmed cell death receptor-1 gene deficiency.
The effect of programmed cell death receptor-1 (PD-1) on phagocyte function has not been extensively described. Here we report that experimental mouse sepsis, cecal ligation and puncture (CLP), induced a marked increase in peritoneal macrophage random migration, motility and cell spread, but these changes were lost in the absence of PD-1. Alternatively, phagocytic activity was inversely affected. In vitro cell culture imaging studies, with the macrophage cell line J774, documented that blocking PD-1 with antibody led to aggregation of the cytoskeletal proteins α-actinin and F-actin. Further experiments looking at ex vivo peritoneal macrophages from mice illustrated that a similar pattern of α-actinin and F-actin was evident on cells from wild-type CLP mice but not PD-1-/- CLP mouse cells. We also observed that fMLP-induced migration by J774 cells was markedly attenuated using PD-1 blocking antibodies, a nonselective phosphatase inhibitor and a selective Ras-related protein 1 inhibitor. Finally, peritoneal macrophages derived from CLP as opposed to Sham mice demonstrated aspects of both cell surface co-localization with CD11b and internalization of PD-1 within vacuoles independent of CD11b staining. Together, we believe the data support a role for PD-1 in mediating aspects of innate macrophage immune dysfunction during sepsis, heretofore unappreciated.


Climate Tolerances and Habitat Requirements Jointly Shape the Elevational Distribution of the American Pika (Ochotona princeps), with Implications for Climate Change Effects.
Some of the most compelling examples of ecological responses to climate change are elevational range shifts of individual species, which have been observed throughout the world. A growing body of evidence, however, suggests substantial mediation of simple range shifts due to climate change by other limiting factors. Understanding limiting factors for a species within different contexts, therefore, is critical for predicting responses to climate change. The American pika (Ochotona princeps) is an ideal species for investigating distributions in relation to climate because of their unusual and well-understood natural history as well as observed shifts to higher elevation in parts of their range. We tested three hypotheses for the climatic or habitat characteristics that may limit pika presence and abundance: summer heat, winter snowpack, and forage availability. We performed these tests using an index of pika abundance gathered in a region where environmental influences on pika distribution have not been well-characterized. We estimated relative pika abundance via scat surveys and quantified climatic and habitat characteristics across two North-Central Rocky Mountain Ranges, the Wind River and Bighorn ranges in Wyoming, USA. Pika scat density was highest at mid-elevations and increased linearly with forage availability in both ranges. Scat density also increased with temperatures conducive to forage plant growth, and showed a unimodal relationship with the number of days below -5°C, which is modulated by insulating snowpack. Our results provide support for both the forage availability and winter snowpack hypotheses. Especially in montane systems, considering the context-dependent nature of climate effects across regions and elevations as well as interactions between climatic and other critical habitat characteristics, will be essential for predicting future species distributions.


Bipolar disorder and metabolic syndrome: an international perspective.
The ubiquity and hazards posed by abnormal body composition and metabolic parameters in the bipolar population are a priority research and clinical issue. Herein, we summarize and synthesize international studies describing the rate of US National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III [ATP III])- and International Diabetes Federation (IDF)-defined metabolic syndrome and its criterion components in individuals with bipolar disorder. We conducted a PubMed search of all English-language articles published between January 2005 and July 2009 with the following search terms: metabolic syndrome and bipolar disorder, mania and manic-depression. Articles selected for review were based on adequacy of sample size, the use of standardized experimental procedures, validated assessment measures, and overall manuscript quality. The rate of metabolic syndrome in individuals with bipolar disorder is increased relative to the general population. Disparate estimates are reported ranging from comparability to approximately twofold greater than the general population. The increased hazard for metabolic syndrome amongst bipolar individuals is now documented in twelve countries from Europe, Australia, Asia, North and South America. The co-occurrence of metabolic syndrome in the bipolar population is associated with a more complex illness presentation, less favourable response to treatment, and adverse course and outcome. The association between metabolic syndrome and bipolar disorder is mediated/moderated by both iatrogenic and non-iatrogenic factors. The increased hazard for metabolic syndrome in bipolar populations is due to the clustering of traditional (and emerging) risk factors as well as iatrogenic and health systems factors. Extant data support recommendations for prioritizing, surveillance, prevention, diagnosis and management of metabolic syndrome as routine care of the bipolar patient.


ASTX660, an antagonist of cIAP1/2 and XIAP, increases antigen processing machinery and can enhance radiation-induced immunogenic cell death in preclinical models of head and neck cancer.
Inhibitor of apoptosis protein (IAP) antagonists have shown activity in preclinical models of head and neck squamous cell carcinoma (HNSCC), and work across several cancer types has demonstrated diverse immune stimulatory effects including enhancement of T cell, NK cell, and dendritic cell function. However, tumor-cell-intrinsic mechanisms for this immune upregulation have been largely unexplored. In this study, we show that ASTX660, an antagonist of cIAP1/2 and XIAP, induces expression of immunogenic cell death (ICD) markers in sensitive HNSCC cell lines in vitro. Experiments in syngeneic mouse models of HNSCC showed that ASTX660 can also enhance radiation-induced ICD in vivo. On a functional level, ASTX660 also enhanced killing of multiple murine cell lines by cytotoxic tumor-infiltrating lymphocytes, and when combined with XRT, stimulated clonal expansion of antigen-specific T lymphocytes and expression of MHC class I on the surface of tumor cells. Flow cytometry experiments in several human HNSCC cell lines showed that MHC class I (HLA-A,B,C) was reliably upregulated in response to ASTX660 + TNFα, while increases in other antigen processing machinery (APM) components were variable among different cell lines. These findings suggest that ASTX660 may enhance anti-tumor immunity both by promoting ICD and by enhancing antigen processing and presentation.


Are we ready to accept the challenge? Addressing the shortcomings of contemporary qualitative health research.
Qualitative approaches represent an important contributor to health care research. However, several researchers argue that contemporary qualitative research does not live up to its full potential. By presenting a snapshot of contemporary qualitative research in the field of social and administrative pharmacy, this study challenges contributors to the field by asking: Are we ready to accept the challenge and take qualitative research one step further? The purpose of this study was to initiate a constructive dialogue on the need for increased transparency in qualitative data analysis, including explicitly reflecting upon theoretical perspectives affecting the research process. Content analysis was used to evaluate levels of theoretical visibility and analysis transparency in selected qualitative research articles published in Research in Social and Administrative Pharmacy between January 2014 and January 2015. In 14 out of 21 assessed papers, the use of theory was found to be Seemingly Absent (lowest level of theory use), and the data analyses did not include any interpretive endeavors. Only two papers consistently applied theory throughout the entire study and clearly took the data analyses from a descriptive to an interpretive level. It was found that the aim of the majority of assessed papers was to change or modify a given practice, which however, resulted in a lack of both theoretical underpinnings and analysis transparency. This study takes the standpoint that theory and high-quality analysis go hand-in-hand. Based on the content analysis, articles that were deemed to be high in quality were explicit about the theoretical framework of their study and transparent in how they analyzed their data. It was found that theory contributed to the transparency of how the data were analyzed and interpreted. Two ways of improving contemporary qualitative research in the field of social and administrative pharmacy are discussed: engaging with social theory and establishing close collaboration with social scientists.


Tyrosine-free amino acid mixture attenuates amphetamine-induced displacement of [11C]raclopride in striatum in vivo: a rat PET study.
Previous neurochemical and behavioural studies show that tyrosine depletion using a nutritionally balanced tyrosine-free amino acid mixture attenuates the dopamine-releasing and psychostimulant properties of amphetamine. Here we investigate the effect of a tyrosine-free amino acid mixture on striatal binding of [(11)C]raclopride, and amphetamine-induced [(11)C]raclopride displacement, using positron emission tomography in the rat. Rats were scanned for 60 min after an i.v. injection of approximately 11 MBq [(11)C]raclopride using a quad-HIDAC system. Amphetamine (2 mg/kg i.p., 30 min prior to scan) caused a 12% reduction in [(11)C]raclopride distribution volume ratio (DVR) compared to saline-injected controls. The tyrosine-free amino acid mixture (1 g/kg i.p.) caused a small (+7%) but statistically insignificant increase in [(11)C]raclopride DVR and attenuated, although it did not fully block, the amphetamine-induced reduction. These data are in keeping with previous neurochemical, immunocytochemical, and behavioural studies showing that tyrosine-free amino acid mixtures reduce dopamine function and offer promise for future PET studies testing the effect of tyrosine-depleting paradigms on dopamine release in humans.


Carbohydrate metabolism in pregnancy. Part II. Relation between maternal glucose tolerance and glucose metabolism in the newborn.
The objective of clinical management of the pregnant diabetic woman is to prevent the serious adverse effects of an abnormal glucose environment on the fetus. Neonatal glucose assimilation and insulin release over the first two hours of life were correlated with various indices of maternal carbohydrate metabolism in the third trimester. Of the 31 mothers studied 21 were defined as normal and 10 as having chemical diabetes. Neontal glucose assimilation during the first two hours of life correlated strongly with functions of both maternal glucose tolerance and mean diurnal glucose level, the strongest correlation being with the area under the three-hour oral glucose tolerance curve (P less than 0.001), Two-hour neonatal plasma glucose values of under 1.7 mmol/1 (30 mg/100 ml) were found only in the newborn of women whose glucose tolerance area measured over 41.6 area units (750 traditional units); thus, even in the borderline diabetic range glucose tolerance testing during the last trimester of pregnancy may be valuable in predicting likelihood of neonatal hypoglycaemia. The findings also shed light on the possible sensitizing role of mild maternal hyperglycaemia on fetal insulin production and secretion.


Clinical utility of biomarkers of AKI in cardiac surgery and critical illness.
AKI is a common and serious complication that is associated with several adverse outcomes in hospitalized patients. The past several years have seen a large number of multicenter investigations of biomarkers of AKI in the setting of cardiac surgery and critical illness. This review summarizes these biomarker results to identify applications for clinical use. The Translational Research Investigating Biomarker Endpoints in AKI (TRIBE-AKI) study showed that blood and urine biomarkers measured preoperatively, immediately postoperatively, and at the time of the clinical increase in serum creatinine in the setting of cardiac surgery all had the ability to improve patient risk stratification for a variety of important clinical end points. Analyses of biomarkers concentrations from the Acute Respiratory Distress Syndrome Network, EARLY ARF, and other studies of critically ill subjects have similarly shown that biomarkers measured early in the clinical course can forecast the development of AKI and need for renal replacement therapy as well as inpatient mortality. Although biomarkers have informed the diagnosis, prognosis, and treatment of AKI and are inching closer to clinical application, large multicenter interventional clinical trials to prevent AKI using biomarkers should continue to be an active area of clinical investigation.


Kir6.2-containing ATP-sensitive potassium channels protect cortical neurons from ischemic/anoxic injury in vitro and in vivo.
ATP-sensitive potassium (K(ATP)) channels are weak inward rectifiers that appear to play an important role in protecting neurons against ischemic damage. Cerebral stroke is a major health issue, and vulnerability to stroke damage is regional within the brain. Thus, we set out to determine whether K(ATP) channels protect cortical neurons against ischemic insults. Experiments were performed using Kir6.2(-/-) K(ATP) channel knockout and Kir6.2(+/+) wildtype mice. We compared results obtained in Kir6.2(-/-) and wildtype mice to evaluate the protective role of K(ATP) channels against focal ischemia in vivo, and, using cortical slices, against anoxic stress in vitro. Immunohistochemistry confirmed the presence of K(ATP) channels in the cortex of wildtype, but not Kir6.2(-/-), mice. Results from in vivo and in vitro experimental models indicate that Kir6.2-containing K(ATP) channels in the cortex provide protection from neuronal death. Briefly, in vivo focal ischemia (15 min) induced severe neurological deficits and large cortical infarcts in Kir6.2(-/-) mice, but not in wildtype mice. Imaging analyses of cortical slices exposed briefly to oxygen and glucose deprivation (OGD) revealed a substantial number of damaged cells (propidium iodide-labeled) in the Kir6.2(-/-) OGD group, but few degenerating neurons in the wildtype OGD group, or in the wildtype and Kir6.2(-/-) control groups. Slices from the three control groups had far more surviving cells (anti-NeuN antibody-labeled) than slices from the Kir6.2(-/-) OGD group. These findings suggest that stimulation of endogenous cortical K(ATP) channels may provide a useful strategy for limiting the damage that results from cerebral ischemic stroke.


Low-level laser therapy (LLLT) associated with aerobic plus resistance training to improve inflammatory biomarkers in obese adults.
Recently, investigations suggest the benefits of low-level laser (light) therapy (LLLT) in noninvasive treatment of cellulite, improvement of body countering, and control of lipid profile. However, the underlying key mechanism for such potential effects associated to aerobic plus resistance training to reduce body fat and inflammatory process, related to obesity in women still unclear. The purpose of the present investigation was to evaluate the effects of combined therapy of LLLT and aerobic plus resistance training in inflammatory profile and body composition of obese women. For this study, it involved 40 obese women with age of 20-40 years. Inclusion criteria were primary obesity and body mass index (BMI) greater than 30 kg/m(2) and less than 40 kg/m(2). The voluntaries were allocated in two different groups: phototherapy group and SHAM group. The interventions consisted on physical exercise training and application of phototherapy (808 nm), immediately after the physical exercise, with special designed device. Proinflammatory/anti-inflammatory adipokines were measured. It was showed that LLLT associated to physical exercise is more effective than physical exercise alone to increase adiponectin concentration, an anti-inflammatory adipokine. Also, it showed reduced values of neck circumference (cm), insulin concentration (μU/ml), and interleukin-6 (pg/ml) in LLLT group. In conclusion, phototherapy can be an important tool in the obesity, mostly considering its potential effects associated to exercise training in attenuating inflammation in women, being these results applicable in the clinical practices to control related risk associated to obesity.


Trajectories of children's social interactions with their infant sibling in the first year: a multidimensional approach.
Individual differences in longitudinal trajectories of children's social behaviors toward their infant sibling were examined simultaneously across multiple social dimensions: Positive engagement (moving toward), antagonism (moving against), and avoidance (moving away). Three distinct social patterns were identified: (C1) positively-engaged (n = 107, 50%); (C2) escalating-antagonism (n = 90, 42%); and (C3) early-onset antagonism (n = 16, 8%). Children in the positively-engaged class had high levels of positive engagement with their infant siblings, coupled with low levels of antagonism and avoidance. The escalating-antagonism class was positively-engaged in sibling interaction with a steep escalation in antagonistic behavior and avoidance from 4 to 12 months. Children in the early-onset antagonism class displayed the highest level of antagonistic behavior starting as early as 4 months, and became increasingly avoidant over time. A path model, guided by a Process × Person × Context × Time model, revealed that low parental self-efficacy heightened by parenting stress and children's dysregulated temperament was directly related to the escalating-antagonism pattern. Punitive parenting in response to children's antagonistic behavior increased the likelihood of being in the early-onset antagonism class. Together, the results highlighted heterogeneity in the earliest emergence of sibling interaction patterns and the interplay of child and parent factors in predicting distinct sibling interaction trajectory patterns.


Multidisciplinary collaboration reporting child abuse: a grounded theory study.
The complexity of reporting child abuse requires multidisciplinary collaboration. The dynamics of a mulidisciplinary team in reporting child abuse which begins the process of child protection remains unclear. To explore the experiences and perspectives of professionals working with other disciplines when reporting child abuse. A qualitative study with grounded theory was used. Participants were recruited from hospitals, the Department of Child Welfare, and schools in Taiwan. Twenty-one professionals from four disciplines agreed to participate. The purposive sample included 5 physicians, 5 nurses, 6 social workers, and 5 teachers. Individual interviews were conducted to explore the experiences in reporting child abuse of a purposive sample of 21 professionals including physicians, nurses, social workers, and teachers. Transcripts were analyzed using a grounded theory approach. Categorical themes were developed that reflected reporters' experiences and perspectives in reporting child abuse. The professionals involved in reported child abuse are described as participants in a relay race. Four themes emerged from the interviews: running the relay race of child protection; reporters as runners with expectations of runners' characteristics and the order of runners; carrying the baton of a mandatory report described using baton characteristics while running in space and time; and team chemistry including trust of and communication with teammates. Systems that encourage and promote team building and collaboration among child abuse reporters are needed. Success in the race to report child abuse across professional disciplines includes runners' skills, speed, a light and easy to carry baton, and team chemistry. As a team of child abuse reporters, when performance is enhanced by practice, the team's success will be measured as victories in child protection. The paradigm of individual disciplines developing their own goals, designing their own training, and practicing within their own regimen needs to be reframed.


Tbx1 is required autonomously for cell survival and fate in the pharyngeal core mesoderm to form the muscles of mastication.
Velo-cardio-facial/DiGeorge syndrome, also known as 22q11.2 deletion syndrome, is a congenital anomaly disorder characterized by craniofacial anomalies including velo-pharyngeal insufficiency, facial muscle hypotonia and feeding difficulties, in part due to hypoplasia of the branchiomeric muscles. Inactivation of both alleles of mouse Tbx1, encoding a T-box transcription factor, deleted on chromosome 22q11.2, results in reduction or loss of branchiomeric muscles. To identify downstream pathways, we performed gene profiling of microdissected pharyngeal arch one (PA1) from Tbx1(+/+) and Tbx1(-/-) embryos at stages E9.5 (somites 20-25) and E10.5 (somites 30-35). Basic helix-loop-helix (bHLH) transcription factors were reduced, while secondary heart field genes were increased in expression early and were replaced by an increase in expression of cellular stress response genes later, suggesting a change in gene expression patterns or cell populations. Lineage tracing studies using Mesp1(Cre) and T-Cre drivers showed that core mesoderm cells within PA1 were present at E9.5 but were greatly reduced by E10.5 in Tbx1(-/-) embryos. Using Tbx1(Cre) knock-in mice, we found that cells are lost due to apoptosis, consistent with increase in expression of cellular stress response genes at E10.5. To determine whether Tbx1 is required autonomously in the core mesoderm, we used Mesp1(Cre) and T-Cre mesodermal drivers in combination with inactivate Tbx1 and found reduction or loss of branchiomeric muscles from PA1. These mechanistic studies inform us that Tbx1 is required upstream of key myogenic genes needed for core mesoderm cell survival and fate, between E9.5 and E10.5, resulting in formation of the branchiomeric muscles.


The ventral-hypothalamic input route: a common neural network for abstract cognition and sexuality.
Classically, external receptors of the body transmit information from the environment to the cerebral cortex via the thalamus. This review explains and argues that only concrete external information is transmitted from peripheral receptors to the cortex via a thalamic route, while abstract and sexual external information are actually transmitted from peripheral receptors to the cortex through a cognitive hypothalamic route. Sexual function typically implies participation of two distinct partners, ensuring reproduction in many species including humans. Human sexual response involves participation of multiple (environmental, biological, psychological) kinds of stimuli and processing, so the understanding of sexual control and response supposes integration between the classical physiological mechanisms with the more complex processes of our 'mind'. Cognition and sexuality are two relational functions, which are dependent on concrete (colours, sounds, etc.) and/or abstract (gestures, facial expression, how you move, the way you say something seemingly trivial, etc.) environmental cues. Abstract cues are encoded independent of the specific object features of the stimuli, suggesting that such cues should be transmitted and interpreted within the brain through a system different than the classical thalamo-cortical network that operates on concrete (material) information. Indeed, data show that the cerebral cortex is capable of interpreting two distinct (concrete and abstract) formats of information via distinct and non-compatible brain areas. We expand upon this abstract-concrete dichotomy of the brain, positing that the two distinct cortical networks should be uploaded with distinct information from the environment via two distinct informational input routes. These two routes would be represented by the two distinct routes of the ascending reticular activating system (ARAS), namely the classical/dorsal thalamic input route for concrete information and the ventral hypothalamic input route for abstract cognition and sexuality. Physiologically, the hypothalamic (dual-autonomic) route of the ARAS that processes abstract and sexual information is incompatible with the thalamic (somatic) route of the ARAS that processes concrete information, such that the two distinct routes would be needed to support the mind processes (awareness, consciousness, sexuality) through their own informational inputs from the environment. Informationally, the concrete external data are differentiated from abstract and sexual external data, so that they should be transmitted to cortex through distinct input routes. Pathologically, the hardware and/or software impairments of the hypothalamic default-mode network generate disturbed messages within the brain (related to information transmitted on this route), laying at the basis of mental and sexual disorders. The novel conceptualisations presented in the present paper help address issues surrounding the mind-brain dichotomy and, in doing so, suggest new possible avenues for exploration in the treatment and interventions for cognitive and sexual problems.