Frequency and clinical progression of the vitamin E deficiency neurologic disorder in children with prolonged neonatal cholestasis.
To determine the frequency of biochemical vitamin E deficiency and of the clinical signs of the vitamin E deficiency neurologic syndrome in children with prolonged neonatal cholestatic disorders, we studied 46 children (aged 1 month to 17.0 years) with chronic forms of intrahepatic neonatal cholestasis and 47 children (aged 4 months to 8.0 years) with extrahepatic biliary atresia. Based on serum vitamin E concentrations and the ratios of serum vitamin E concentration to total serum lipid concentration, 64% of the intrahepatic and 77% of the extrahepatic cholestasis groups were vitamin E deficient. Prior to age 1 year, neurologic function was normal in all children. Between ages 1 and 3 years, neurologic abnormalities were present in approximately 50% of the vitamin E-deficient children; after age 3 years, neurologic abnormalities were present in all vitamin E-deficient children. Areflexia was the first abnormality to develop between ages 1 and 4 years; truncal and limb ataxia, peripheral neuropathy, and ophthalmoplegia developed between ages 3 and 6 years. Neurologic dysfunction progressed to a disabling combination of findings by ages 8 to 10 years in the majority of vitamin E-deficient children. Neurologic function was normal in the vitamin E-sufficient children. We conclude that vitamin E status should be evaluated in infants in whom cholestasis is diagnosed, and effective therapy should be initiated to prevent or treat vitamin E deficiency at an early age.


A Subtle Profile With a Significant Impact: Language and Communication Difficulties for Autistic Females Without Intellectual Disability.
The presentation of autism in females is poorly understood, which is thought to contribute to missed or later- age diagnosis, especially for those without intellectual disability. Dedicated research into social and behavioral differences has indicated a specific female phenotype of autism. However, less has been done to explore language and communication profiles, despite known sex/gender differences in typically developing populations. This article provides a synthesis of recent work from this small but emerging field. It focuses on a series of four preliminary and explorative studies conducted by the authors and embeds this within the wider literature. Findings suggest a specific profile of language and communication strengths and weaknesses for autistic females without intellectual disability (compared to autistic males and typically developing females). Furthermore, despite the relatively subtle presentation of difficulties (compared to autistic males), the impact on functionality, social inter-relations and emotional well-being, appears to be equitable and significant. The discussion highlights the need for further empirical research and proposes areas for investigation. Implications for clinical practice include the need for better recognition, testing and provision of interventions dedicated to the language and communication difficulties for autistic females. This has relevance for diagnostic, mental health and speech and language therapy services.


Grand Challenges Canada: inappropriate emphasis and missed opportunities in global health research?
In May 2010, Grand Challenges Canada (GCC) was launched with the mandate to identify global challenges in health that could be supported through the Government of Canada's Development Innovations Fund (DIF: $225 million over five years). The GCC offers a potentially excellent mechanism for taking Canada's participation in global health challenges "to a higher level". Recent GCC announcements raise new questions about the emphasis being placed on technological discovery or "catalytic" research. Missing so far are opportunities that the Fund could offer in order to support innovative research addressing i) health systems strengthening, ii) more effective delivery of existing interventions, and iii) policies and programs that address broader social determinants of health. The Canadian Grand Challenges announced to date risk pushing to the sidelines good translational and implementation science and early career-stage scientists addressing important social, environmental and political conditions that affect disease prevalence, progress and treatment; and the many unresolved challenges faced in bringing to scale proven interventions within resource-constrained health systems. We wish to register our concern at the apparent prioritization of biotechnical innovation research and the subordination of the social, environmental, economic and political context in which human health is either protected or eroded.


Impedance spectra of Fe-doped SrTiO3 thin films upon bias voltage: inductive loops as a trace of ion motion.
Mass and charge transport properties of slightly Fe-doped SrTiO3 (Fe:STO) thin films on a conducting substrate were investigated by means of impedance spectroscopy under different bias voltages and I-V measurements with varying scan rates. At measurement temperatures between 325 °C and 700 °C the applied bias voltage caused an unusual "inductive loop" in the low frequency range of impedance spectra. DC measurements showed that current-voltage curves strongly depend on the scan rate, indicating that different states of the sample became accessible to probe. Both findings can be understood in terms of bias induced ion motion, i.e. by stoichiometry polarization within the Fe:STO thin films upon voltage. Hence, the appearance of an "inductive loop" in the impedance spectra is considered a very general feature that might exist for many materials, particularly in oxide thin films. It may indicate ion motion and stoichiometry variations taking place in the corresponding frequency range.


Interleukin-10 disrupts liver repair in acetaminophen-induced acute liver failure.
Systemic levels of the anti-inflammatory cytokine interleukin 10 (IL-10) are highest in acetaminophen (APAP)-induced acute liver failure (ALF) patients with the poorest prognosis. The mechanistic basis for this counterintuitive finding is not known, as induction of IL-10 is hypothesized to temper the pathological effects of immune cell activation. Aberrant production of IL-10 after severe liver injury could conceivably interfere with the beneficial, pro-reparative actions of immune cells, such as monocytes. To test this possibility, we determined whether IL-10 levels are dysregulated in mice with APAP-induced ALF and further evaluated whether aberrant production of IL-10 prevents monocyte recruitment and/or the resolution of necrotic lesions by these cells. Our studies demonstrate that in mice challenged with 300 mg/kg acetaminophen (APAP), a hepatotoxic dose of APAP that fails to produce ALF (i.e., APAP-induced acute liver injury; AALI), Ly6Chi monocytes were recruited to the liver and infiltrated the necrotic lesions by 48 hours coincident with the clearance of dead cell debris. At 72 hours, IL-10 was upregulated, culminating in the resolution of hepatic inflammation. By contrast, in mice treated with 600 mg/kg APAP, a dose that produces clinical features of ALF (i.e., APAP-induced ALF; AALF), IL-10 levels were markedly elevated by 24 hours. Early induction of IL-10 was associated with a reduction in the hepatic numbers of Ly6Chi monocytes resulting in the persistence of dead cell debris. Inhibition of IL-10 in AALF mice, beginning at 24 hours after APAP treatment, increased the hepatic numbers of monocytes which coincided with a reduction in the necrotic area. Moreover, pharmacologic elevation of systemic IL-10 levels in AALI mice reduced hepatic myeloid cell numbers and increased the area of necrosis. Collectively, these results indicate that during ALF, aberrant production of IL-10 disrupts the hepatic recruitment of monocytes, which prevents the clearance of dead cell debris. These are the first studies to document a mechanistic basis for the link between high IL-10 levels and poor outcome in patients with ALF.


Spatial and temporal variability of myxozoan parasite, Myxobolus inornatus, prevalence in young of the year smallmouth bass in the Susquehanna River Basin, Pennsylvania.
A myxozoan parasite, Myxobolus inornatus, is one disease agent identified in young of the year (YOY) smallmouth bass in the Susquehanna River Basin, Pennsylvania. We investigated spatial and temporal variability in M. Inornatus prevalence across the Susquehanna River Basin and at several out-of-basin sites. We examined potential land use drivers of M. Inornatus prevalence including agricultural and developed land use. In 1,267 YOY smallmouth bass collected from 32 sites during 2013-2016, M. Inornatus was documented in 43.6% of samples. Among-site variability in parasite prevalence was greater than among-year variability. The effect of agricultural land use on M. Inornatus prevalence had a high probability of being positively correlated at multiple spatial scales (probability of positive effect > 0.80). The effect of developed land use on M. Inornatus prevalence had a relatively high probability of being negatively correlated at multiple spatial scales (probability of negative effect > 0.70). Our results suggest that land use practices could be related to M. Inornatus infection of smallmouth bass. Further study will be necessary to determine whether disease dynamics are a consequence of effects on the host, alterations of instream habitat mediating invertebrate host dynamics and/or survival and dispersal of the parasite infective stage.


Incidence and Types of Human Papillomavirus Infections in Adolescent Girls and Young Women Immunized With the Human Papillomavirus Vaccine.
Rates of human papillomavirus (HPV) infection have decreased since the introduction of HPV vaccines in populations with high vaccine uptake. Data are limited for adolescent and young adult populations in US metropolitan centers. To determine HPV infection rates in adolescent girls and young women aged 13 to 21 years in New York City following HPV vaccination. This cohort study of type-specific cervical HPV detection was conducted at a large adolescent-specific integrated health center in New York City between October 2007 and September 2019. Participants included an open cohort of adolescent girls and young adult women who received the HPV vaccine (Gardasil; Merck & Co) over a 12-year period following HPV vaccination introduction. Data analysis was concluded September 2019. Calendar date and time since receipt of first vaccine dose. Temporal associations in age-adjusted postvaccine HPV rates. A total of 1453 participants, with a mean (SD) age at baseline of 18.2 (1.4) years, were included in the cohort (African American with no Hispanic ethnicity, 515 [35.4%] participants; African American with Hispanic ethnicity, 218 [15.0%] participants; Hispanic with no reported race, 637 [43.8%] participants). Approximately half (694 [47.8%] participants) were vaccinated prior to coitarche. Age-adjusted detection rates for quadrivalent vaccine types (HPV-6, HPV-11, HPV-16, and HPV-18) and related types (HPV-31, and HPV-45) decreased year over year, with the largest effect sizes observed among individuals who had been vaccinated before coitarche (adjusted odds ratio [aOR], 0.81; 95% CI, 0.67-0.98). By contrast, detection was higher year over year for nonvaccine high-risk cervical HPV types (aOR, 1.08; 95% CI, 1.04-1.13) and anal HPV types (aOR, 1.11; 95% CI, 1.05-1.17). The largest effect sizes were observed with nonvaccine types HPV-56 and HPV-68. Whereas lower detection rates of vaccine-related HPV types were observed since introduction of vaccines in female youth in New York City, rates of some nonvaccine high-risk HPV types were higher. Continued monitoring of high-risk HPV prevalence is warranted.


Nutritional Intervention Via Videoconferencing for Older Adults Receiving Home Care - A Pilot Study.
Malnutrition is common in aged home care clients and that affects negatively the health of aged people. Nutritional screening is recommended for early detection of malnutrition. The aim was to assess the nutritional status and food intake of home care receivers and improve their nutrient intake with tailored nutritional advice administered via videoconferencing. Intervention with follow-up. Home care in the city of Helsinki. 25 older (>65 years) adults receiving home care. After an initial assessment determining their needs, participants received tailored nutritional advice via videoconferencing over a six-month follow-up period. Participants nutritional status was assessed with a Mini Nutritional Assessment -test (MNA). Nutrient intake was calculated based on a detailed three-day food diary compiled twice during the six-month follow-up period. Altogether 25 persons participated in the study (mean age 78.5 years, 88 % females). According to the MNA test 80 % were at risk of malnutrition at the outset. Energy (1329 kcal) and mean nutrient intakes of protein (54 g) and folic acid (210 μg), for example, were inadequate. After six months of intervention, the mean energy intake had increased to 1450 (SD 319) kcal, protein to 65 (SD 20) g, and folic acid to 231 (SD 105) μg per day. The energy, protein and other nutrient intake of the study participants increased during the six-month intervention. Videoconferencing seemed to be a well-accepted and feasible method for providing nutritional advice to older home care clients.


Hypertensive heart disease and fibrosis.
The clinical importance of fibrosis in hypertensive heart disease is now well recognized. However, the precise mechanisms involved in the pathophysiology and therefore the potential cardioreparative strategies are still not fully understood. These areas continue to be the focus of extensive research. This review summarizes the work conducted in this field over the past 12 months. This article further confirms the involvement of the renin-angiotensin system in cardiac fibrosis and illustrates the supportive roles of mineralocorticoids, endothelin, and novel signaling pathways. It also summarizes the most recent data examining the genetic aspects of myocardial fibrosis and further clarifies potential cardioreparative strategies. Myocardial fibrosis in hypertensive heart disease remains an area of intensive research. Whereas recent work has expanded our knowledge of the underlying processes in the development of this fibrosis, additional scientific and clinical research is required to assist clinical risk assessment and to provide evidence that therapeutic intervention confers improved clinical outcome in hypertensive heart disease.


Contribution of NAD(P)H:quinone oxidoreductase 1 to protection against carcinogenesis, and regulation of its gene by the Nrf2 basic-region leucine zipper and the arylhydrocarbon receptor basic helix-loop-helix transcription factors.
NAD(P)H:quinone oxidoreductase 1 (NQO1) is a key enzyme involved in defence against reactive forms of oxygen and inhibition of neoplasia. Under conditions of oxidative stress, expression of NQO1 is induced, and the resulting increase in oxidoreductase protein provides the cell with multiple layers of protection against environmental insults. Firstly, the catalytic activity of NQO1 is directed towards the complete reduction and detoxication of highly reactive quinones. Secondly, the oxidoreductase maintains the endogenous lipid-soluble antioxidants, alpha-tocopherol-hydroquinone and ubiquinol in their reduced and active forms. Thirdly, NQO1 is required for the stabilisation of p53 protein in response to DNA-damaging stimuli, and it thereby influences cell fate decisions. In view of the anticarcinogenic actions of NQO1, an understanding of the mechanisms that govern its expression is desirable. The redox sensitivity of NQO1 transcription occurs through a cis-acting antioxidant response element (ARE) located within the regulatory region of the mouse, rat and human genes. This element recruits the positively acting basic leucine zipper (bZip) transcription factor NF-E2 p45-related factor 2 (Nrf2). Under normal constitutive conditions, Nrf2 associates with the cytoskeletal-binding protein Keap1, which regulates the subcellular distribution of the bZip factor and also targets it for proteasome-dependent degradation. Oxidative stress inhibits the Nrf2-Keap1 interaction, thus promoting nuclear accumulation of the transcription factor and transactivation of NQO1 and other ARE-driven genes. Mouse, rat and human NQO1 can also be induced by planar aromatic hydrocarbons through a cis-acting xenobiotic response element (XRE) located in their gene promoters. The XRE recruits the arylhydrocarbon receptor (AhR) and AhR nuclear translocator. Cross-talk may occur between Nrf2 and AhR, but the details of this process remain to be elucidated.


Sox9, a master regulator of chondrogenesis, distinguishes mesenchymal chondrosarcoma from other small blue round cell tumors.
Over the last decade, a number of "master regulator" genes that control distinct pathways of mesenchymal differentiation have been discovered. These genes are expressed early during embryogenesis and initiate a cascade of gene expression responsible for specific cell lineage commitment. Thus, identification of their products may allow the classification of seemingly primitive, morphologically uncommitted tumors such as small blue round cell tumors. The transcription factor Sox9 has been demonstrated to be a master regulator of the differentiation of mesenchymal cells into chondrocytes. For this reason, we examined the utility of Sox9 in distinguishing mesenchymal chondrosarcoma (a small cell malignancy thought to be derived from primitive chondroprogenitor cells) from other primitive small cell malignancies. Representative sections from 90 cases of small blue round cell tumors (22 mesenchymal chodrosarcoma, 10 neuroblastomas, 11 rhabdomyosarcomas, 9 Ewing's sarcomas/primitive neuroectodermal tumors, 5 desmoplastic small round cell tumors, 7 small cell carcinomas, 6 Merkel cell carcinomas, 6 small cell osteosarcomas, 7 diffuse large B-cell lymphomas, 7 lymphoblastic leukemias/lymphomas, and 5 extraskeletal myxoid chondrosarcomas) were immunohistochemically stained with antibodies to Sox9 protein. All but 1 mesenchymal chondrosarcoma showed positive nuclear staining in both primitive mesenchymal and cartilaginous components of the tumor. All other types of small blue round cell tumors, as well as the lymphomas and leukemias, were negative for Sox9 protein. These findings confirm that mesenchymal chondrosarcoma has phenotypic features corresponding to the early condensational phase of cartilaginous differentiation. More important, Sox9 may serve as a useful tool in the differentiation of small cell malignancies.


A community outbreak of Legionnaires' disease in Geneva, Switzerland, June to September 2017.
Eight confirmed cases of Legionnaires' disease were identified at the Geneva University Hospitals between 28 July 2017 and 02 August 2017, leading to a detailed outbreak investigation. Legionnaires' disease cases were defined according to Swiss and European (ELDSNet) consensus guidelines. An outbreak investigation task force was put in place. Patients were interviewed, when feasible, with a standard questionnaire. A Legionella pneumophila urinary antigen test was performed in all cases. Lower respiratory tract (LRT) specimens were collected for culture, polymerase chain-reaction (PCR) assay, monoclonal antibody subtyping and sequenced-based typing (SBT). Multiple environmental samples were collected. Case geographical mapping was performed and local meteorological data were obtained. Thirty-four confirmed cases of Legionnaires' disease were identified between 20 June 2017 and 16 September 2017, including 28 patients living in the Canton of Geneva and 6 cases in neighbouring cantons and France. The case fatality rate was 8.8%. The urinary antigen test was positive in 32/34 (94.1%) cases. Among the 17/34 (50%) cases with available LRT specimens, 8 (47.1%) were culture/PCR positive, 5 (29.4%) were PCR positive only, and 4 (23.5%) were culture/PCR negative. Monoclonal antibody subtyping and SBT on 12 samples allowed subtype identification of 8 samples, with a predominance of L. pneumophila serogroup-1 subtype-France/Allentown ST23 among clinical isolates. A specific city area was identified as a possible outbreak epicentre in 25/34 (73.5%) cases, although molecular analysis of clinical and environmental specimens revealed heterogeneous subtypes of L. pneumophila. In this largest documented outbreak of Legionnaires' disease in Switzerland, we report prompt outbreak identification, leading to timely initiation of a detailed, well-orchestrated clinical and epidemiological investigation.


Impact of universal infant hepatitis B vaccination in the US-affiliated Pacific Islands, 1985-2015.
The US-affiliated Pacific Island countries (USAPI) is an endemic region for hepatitis B virus (HBV) infection. Universal infant hepatitis B vaccination was introduced in the USAPI in the mid-1980s to mitigate the HBV burden. We assessed the impact of universal infant vaccination on the HBV infection prevalence over time among children born in the 1980s, 1990s, and 2000s in the USAPI. Demographic and serologic data from serial sero-surveys conducted between 1985 and 2015 were obtained. Descriptive statistics and analysis of variance were performed. From data obtained from 4827 children (2-11years), HBV prevalence decreased markedly: 8.4% in the 1980s; 2.5% in the 1990s; and 0.2% in the 2000s (P<0.0001) as vaccination coverage increased: 76.4% in the 1980s; 87.3% in the 1990s; and 97.5% in the 2000s (P<0.0001). These findings underscore the protective effect of universal infant hepatitis B vaccination over time on the HBV burden in an HBV endemic region.


Predictors of Surgical Outcomes in Patients with Abducens Nerve Schwannoma: A Comprehensive Systematic Review and a Case Report.
Abducens nerve (AN) schwannomas are extremely rare tumors. Clinical characteristics and factors that influence postoperative outcomes are not well defined. To characterize clinical features of AN schwannomas and predictors of surgical outcomes. PRISMA-guided systematic review of the literature on AN schwannomas was performed. Subsequently, univariate and multivariate regression analyses were performed to identify the predictive value of variables that influence postoperative outcomes. A total of 42 studies with 55 patients were evaluated. The mean age at presentation was 43.9 ± 14.6 years. The most common presenting symptom was cranial nerve VI palsy (69.1%). Cavernous sinus (49.1%) and prepontine cistern (36.3%) were the most commonly involved locations. Complete recovery after surgery was seen in 36.3% at a median follow-up of 28.4 ± 25.8 months. Preoperative AN palsy (P < 0.001), suboccipital approach (P = 0.007), and subtotal resection of tumor (P = 0.044) were significant protective factors for postoperative complications. Prepontine location and postoperative complications were poor prognostic indicators of AN recovery (odds ratio [OR], 0.10, P = 0.030 and OR, 0.10, P = 0.028, respectively). Subtotal resection was significantly correlated with higher odds of AN recovery (OR, 6.06; P = 0.040). AN schwannomas are rare but serious tumors that can cause significant morbidity, with only approximately one third of patients showing complete recovery after surgery. The suboccipital approach was a protective factor for postoperative complications, especially when combined with subtotal resection. Knowledge of these factors along with tumor characteristics helps optimize surgical planning and preoperative counseling.


Increasing sodium bicarbonate level in high-concentrate diets for heifers. I. Effects on intake, water consumption and ruminal fermentation.
Four ruminally fistulated Holstein heifers (BW = 264 ± 12 kg) were used in a 4 × 4 Latin square design experiment to determine the effect of increasing levels of sodium bicarbonate (BICARB; 0%, 1.25%, 2.50% and 5%, on concentrate dry matter (DM) basis) on DM intake (DMI), water consumption and ruminal fermentation. Sampling was carried out in the last week of each four 21-day experimental periods. Heifers were offered concentrate (13.4 ± 0.04% crude protein (CP), 13.3 ± 0.44% NDF, 51.7 ± 0.97% starch) and barley straw once daily at 0830 h ad libitum. There was a linear decrease in concentrate DMI and a linear increase in straw DMI with increasing buffer level in the diet, resulting in a tendency towards a linear decrease in total DMI. Intake of concentrate was 6.89, 7.66, 6.72 and 5.72 ± 0.83 kg/day, whereas straw intakes were 0.73, 0.84, 0.94 and 1.06 ± 0.14 kg/day, for the 0%, 1.25%, 2.5% and 5% BICARB, respectively. Water consumption was not affected by treatments when expressed as l/day or percentage of BW, but increased linearly when expressed as l/kg of DMI. The percentage of total daily water drunk in the morning (from 0830 to 1230 h) increased linearly with the level of buffer. Mean ruminal pH and total area under the pH curve were not affected with increasing buffer level. The lowest daily pH (5.65 ± 0.09) was not affected by treatments. A quadratic tendency (P 0.10) was observed in the number of hours and the area under the pH curve in which ruminal pH was below 5.8, with high values only at the 0% BICARB. Additionally, increasing bicarbonate level caused a linear increase in the ruminal pH at 2 and 4 h after feeding. Daily average NH3 N (2.4 ± 0.9 mg N/100 ml) and total volatile fatty acids (VFA) (143 ± 12 mM) concentrations were not affected by treatments. Daily average molar proportion of propionate decreased linearly, and acetate proportion and the acetate-to-propionate ratio were increased with increasing buffer level in the diet. Molar percentage of butyrate, isobutyrate and isovalerate, and branched-chain VFA concentration increased linearly as the level of bicarbonate increased in the diet. Results indicate that high levels of BICARB to finishing heifers fed high-concentrate diets may result in a decreased DMI without significant effects on mean ruminal pH, which may affect animal performance. All individual VFA proportions, except valerate, were changed by the addition of bicarbonate.


Discordant antibody and cellular responses to Pneumocystis major surface glycoprotein variants in mice.
The major surface glycoprotein (Msg) of Pneumocystis is encoded by approximately 50 to 80 unique but related genes. Msg diversity may represent a mechanism for immune escape from host T cell responses. We examined splenic T cell proliferative and cytokine as well as serum antibody responses to recombinant and native Pneumocystis antigens in immunized or Pneumocystis-infected mice. In addition, immune responses were examined in 5 healthy humans. Proliferative responses to each of two recombinant Msg variant proteins were seen in mice immunized with either recombinant protein, but no proliferation to these antigens was seen in mice immunized with crude Pneumocystis antigens or in mice that had cleared infection, although the latter animals demonstrated proliferative responses to crude Pneumocystis antigens and native Msg. IL-17 and MCP-3 were produced in previously infected animals in response to the same antigens, but not to recombinant antigens. Antibody responses to the recombinant P. murina Msg variant proteins were seen in all groups of animals, demonstrating that all groups were exposed to and mounted immune responses to Msg. No human PBMC samples proliferated following stimulation with P. jirovecii Msg, while antibody responses were detected in sera from 4 of 5 samples. Cross-reactive antibody responses to Msg variants are common, while cross-reactive T cell responses are uncommon; these results support the hypothesis that Pneumocystis utilizes switching of Msg variant expression to avoid host T cell responses.


Expression profile of luteinizing hormone receptor gene in hierarchal follicles and regressing oviduct tissues of White Leghorn hens during moulting.
In the present study, the expression profile of luteinizing hormone receptor (LHR) was investigated in the ovary, magnum and uterus and in hierarchcal follicles (F-1, F-2, F-3 and F-4) of hens subjected to moulting to establish their involvement in moulting and presence in non-gonadal tissues. Fifty-two layers (72 weeks) were subjected to moult for a period of 14 days. Four birds were sacrificed each time on 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12 and 14 days of moulting, and samples (ovary, magnum, uterus and hierarchal follicles) were collected aseptically for the quantitative study by real-time polymerase chain reaction. The ovary, isthmus, uterus and magnum weight reduced significantly during induced moulting. From the 4 DOM, this reduction was drastic and reached approximately 80% of original weight in the case of ovary, isthmus and magnum and approximately 65% of original weight in the case of uterus on 14 DOM. Ovarian yellow follicles decreased gradually from 1 DOM to 4 DOM, after that no normal yellow follicle was observed in moulted bird. The number of atretic follicles increased gradually during the course of induced moulting, reaching the peak at 5 DOM. The LHR mRNA was detected in non-gonadal tissues like magnum and uterus. The LHR expression was significantly (p < 0.05) down regulated in ovary, magnum and uterus throughout the treatment. These results indicated that LHR may have a role in reproductive tissue regression during moulting.


Biodegradable poly(L-lactide)-poly(ethylene glycol) multiblock copolymer: synthesis and evaluation of cell affinity.
A series of poly(L-lactide)-poly(ethylene glycol) multiblock copolymers (Multi-PLE) with high molecular weight were synthesized and successfully used to fabricate three-dimensional scaffolds. Using mouse NIH 3T3 fibroblasts as model cells, the cell affinity of various Multi-PLE copolymers was evaluated and compared with that of poly(L-lactide) (PLLA) by means of cell attachment efficiency measurement, scanning electron microscopy observation and MTT assay. On one hand, the results showed that the cell attachment efficiency on Multi-PLE 4/1(4/1 refers to the molar ratio of lactidyl units to ethylene oxide units) films was close to that on PLLA film, however, the other Multi-PLE films exhibited much lower cell attachment efficiency than PLLA film, such as Multi-PLE 2/1 and Multi-PLE 1/1, which had higher PEG content. On the other hand, it was interesting to find that cell proliferation on Multi-PLE4/1 and Multi-PLE2/1 scaffolds was better than that on PLLA scaffold, which was closely related to the improved hydrophilicity of Multi-PLE copolymers due to the incorporation of PEG in comparison with pure PLLA. The Multi-PLE copolymer scaffolds with appropriate hydrophilicity were in favor of mass transportation, and then of cell proliferation and cell affinity. It meant that the cell proliferation would be much improved by increasing the hydrophilicity of the three-dimensional scaffolds, which even outweighed the disadvantages of the cell attachment efficiency reduction with the incorporation of PEG.


[Gunshot damage inflicted by a short shot from some special-purpose arms].
Inlet damage to clothes material caused by point-blank shots from a special submachine guns Val, 9-A-91, sniper complex BCK-4 furnished with a soundless non-flame shooting devices (SNSD) was studied in experiment. Specific features of the affection and shot products distribution (shape, size, topography, accumulation of soot metals, etc.) were specified which allow judgement about guns and range of shot. How SNSD construction and shot range influence the above characteristics is shown. A relevant case is reported.


Dynamic inhibitory control prevents salience-driven capture of visual attention.
The salience-driven selection theory is comprised of three main tenets: (a) the most salient stimulus within a monitored region of the visual field captures attention, (b) the only way to prevent salience-driven distraction is by narrowly focusing attention elsewhere, and (c) all other goal-driven processes are possible only after the most salient item has been attended. Evidence for and against this theory has been provided from two experimental paradigms. Here, event-related potentials (ERPs) recorded in a novel Go/No-Go paradigm disconfirmed all three of tenets of the theory. Participants were instructed to search cyan-item displays for a salient orientation singleton (Go trials) and to ignore randomly intermixed yellow-item displays that could also contain an orientation singleton (No-Go trials). ERP components associated with attentional orienting (posterior contralateral N2; N2pc), distractor suppression (distractor positivity; PD), and stimulus relevance (P2a) were isolated to test predictions stemming from the salience-driven selection theory. On No-Go trials, the salient oddball elicited a PD rather than an N2pc, indicating that it was suppressed, not attended. Moreover, a P2a emerged before the N2pc on Go trials, demonstrating that observers first evaluated the global color of each display and then decided to search for the oddball (Go trials) or to ignore it (No-Go trials). We conclude that goal-driven processes can lead to the prevention of salience-driven attention capture by salient visual objects within the attentional window. (PsycInfo Database Record (c) 2022 APA, all rights reserved).


Mechanisms of action of loperamide.
The beneficial effect of loperamide in some children with severe protracted diarrhoea which persisted when nil by mouth, made us suspect that loperamide may have an antisecretory action. Using a steady-state perfusion technique in rat jejunum we showed that loperamide inhibits cholera toxin induced secretion of water, sodium and chloride (p less than 0.001). This antisecretory action was blocked by naloxone and not mediated via an effect on tissue cyclic AMP level or adenylate cyclase activity. More recently we have studied the effect of loperamide on secretion of water in the rat jejunum induced by other agents with differing mechanisms of action. The first set of observations suggest that loperamide's antisecretory effect is mediated via opiate receptors either distal to, or separate from the adenylate cyclase/cyclic AMP pathway. Our more recent studies support the notion that loperamide has an effect on specific transport systems rather than non-specific passive diffusional processes.


Sensemaking Sans Power: Interactive Data Visualization Using Color-Changing Ink.
We present an approach for interactively visualizing data using color-changing inks without the need for electronic displays or computers. Color-changing inks are a family of physical inks that change their color characteristics in response to an external stimulus such as heat, UV light, water, and pressure. Visualizations created using color-changing inks can embed interactivity in printed material without external computational media. In this article, we survey current color-changing ink technology and then use these findings to derive a framework for how it can be used to construct interactive data representations. We also enumerate the interaction techniques possible using this technology. We then show some examples of how to use color-changing ink to create interactive visualizations on paper. While obviously limited in scope to situations where no power or computing is present, or as a complement to digital displays, our findings can be employed for paper, data physicalization, and embedded visualizations.


A preliminary study of daily interpersonal stress and C-reactive protein levels among adolescents from Latin American and European backgrounds.
To examine the association between the experience of daily interpersonal stress and levels of C-reactive protein (CRP), an inflammatory marker that is a key indicator of cardiovascular risk, during the teenage years. A total of 69 adolescents (Mage= 17.78 years) completed daily diary checklists each night for 14 days in which they reported their experience of negative interpersonal interactions in the domains of family, peers, and school (e.g., conflict with family and friends, peer harassment, punishment by parents and teachers). Blood samples were obtained an average of 8.63 months later and assayed for circulating levels of CRP, using enzyme-linked immunosorbent assay. Measures of body mass index (BMI), socioeconomic status (SES), substance use, stressful life events, rejection sensitivity, and psychological distress were obtained. A greater frequency of daily interpersonal stress was associated with higher levels of CRP, even after controlling for BMI, SES, substance use, life events, rejection sensitivity, psychological distress, and frequency of daily interpersonal stress 2 years earlier. Experiencing a high frequency of interpersonal stressors that are typical of adolescent life is associated with higher levels of inflammation even among a normative, healthy sample of adolescents. Additional work should focus on other daily experiences during the adolescent period and their implications for elevated risk for later cardiovascular disease.


Face coverings differentially alter valence judgments of emotional expressions.
Face masks that prevent disease transmission obscure facial expressions, impairing nonverbal communication. We assessed the impact of lower (masks) and upper (sunglasses) face coverings on emotional valence judgments of clearly valenced (fearful, happy) and ambiguously valenced (surprised) expressions, the latter of which have both positive and negative meaning. Masks, but not sunglasses, impaired judgments of clearly valenced expressions compared to faces without coverings. Drift diffusion models revealed that lower, but not upper, face coverings slowed evidence accumulation and affected differences in non-judgment processes (i.e., stimulus encoding, response execution time) for all expressions. Our results confirm mask-interference effects in nonverbal communication. The findings have implications for nonverbal and intergroup communication, and we propose guidance for implementing strategies to overcome mask-related interference.


Cytochemical studies of cell viability and gene expression in Bacillus subtilis macrofibres.
The viability of cells and the expression of a reporter gene in Bacillus subtilis macrofibres have been examined using cytochemical approaches. Previous studies have shown that macrofibres grow at an exponential rate in fluid environments and undergo complex dynamic motions as they elongate but the behaviour of individual cells in them has never been examined. A fluorescence staining procedure that distinguishes living cells from dead cells was used in the experiments described to examine cells in both left- and right-handed macrofibres. Very few dead cells were found in individual fibres. Their locations appeared to be random, suggesting that neither the extreme shape deformation imposed upon cells in the loop ends of fibres, nor the entrapment of cells in the interior of a fibre compromise viability. In related experiments, initial studies of reporter gene expression during fibre morphogenesis were conducted using a strain previously studied as conventional colonies. Spatial and temporal differences in the appearance of the blue cleavage product of X-Gal were found, suggesting that differential gene expression may arise in macrofibres in contrast to the results found in colonies. Two conclusions may be drawn from the findings: (i) virtually all cells in macrofibres are viable and (ii) all the cells in macrofibres do not always behave in an identical manner.


Greenhouse gas emissions during cattle feedlot manure composting.
The emission of greenhouse gases (GHG) during feedlot manure composting reduces the agronomic value of the final compost and increases the greenhouse effect. A study was conducted to determine whether GHG emissions are affected by composting method. Feedlot cattle manure was composted with two aeration methods--passive (no turning) and active (turned six times). Carbon lost in the forms of CO2 and CH4 was 73.8 and 6.3 kg C Mg-1 manure for the passive aeration treatment and 168.0 and 8.1 kg C Mg-1 manure for the active treatment. The N loss in the form of N2O was 0.11 and 0.19 kg N Mg-1 manure for the passive and active treatments. Fuel consumption to turn and maintain the windrow added a further 4.4 kg C Mg-1 manure for the active aeration treatment. Since CH4 and N2O are 21 and 310 times more harmful than CO2 in their global warming effect, the total GHG emission expressed as CO2-C equivalent was 240.2 and 401.4 kg C Mg-1 manure for passive and active aeration. The lower emission associated with the passive treatment was mainly due to the incomplete decomposition of manure and a lower gas diffusion rate. In addition, turning affected N transformation and transport in the window profile, which contributed to higher N2O emissions for the active aeration treatment. Gas diffusion is an important factor controlling GHG emissions. Higher GHG concentrations in compost windrows do not necessarily mean higher production or emission rates.


Incompatible effects of p53 and HDAC inhibition on p21 expression and cell cycle progression.
Nutlin-3 selectively activates p53 by inhibiting the interaction of this tumor suppressor with its negative regulator murine double minute 2 (mdm2), while trichostatin A (TSA) is one of the most potent histone deacetylase (HDAC) inhibitors currently available. As both Nutlin-3 and TSA increase the levels of the cell cycle inhibitor p21(cip1/waf1) in cells, we investigated whether a combination of these compounds would further augment p21 levels. Contrary to expectations, we found that short-term exposure to Nutlin-3 and TSA in combination did not have an additive effect on p21 expression. Instead, we observed that activation of p53 prevented the ability of TSA to increase p21 levels. Furthermore, TSA inhibited Nutlin-3-induced expression of p53-dependent mRNAs including P21. This negative effect of TSA on Nutlin-3 was significantly less pronounced in the case of hdm2, another p53 downstream target. Aside from suggesting a model to explain these incompatible effects of Nutlin-3 and TSA, we discuss the implications of our findings in cancer therapy and cell reprogramming.


Self-administration of cocaine derivatives by squirrel monkeys.
Lever pressing by squirrel monkeys was maintained under a 5-min fixed-interval schedule of drug self-administration; the first response after 5 min elapsed produced an i.v. injection of cocaine (2.7-267.7 micrograms/kg), the phenyltropane analog of cocaine, WIN 35,065-2 (0.6-64.3 micrograms/kg) or their respective N-demethylated derivatives, norcocaine (3.0-1,000.0 micrograms/kg) and WIN 35,981 (0.8-245.5 micrograms/kg). As the dose per injection was increased, responding maintained by each drug first increased and then decreased. When saline was substituted for the drugs, responding occurred irregularly and at low rates. The drugs were equally effective in maintaining responding, but WIN 35,065-2 was 3 to 10 times more potent than cocaine; cocaine and WIN 35,065-2 were each 3 to 10 times more potent than their N-demethylated derivatives, norcocaine and WIN 35,981. There was a high degree of stereoselectivity in the effects of the phenyltropane analogs; the (-)-isomer, WIN 35,065-2, was the most potent drug studied, yet its enantiomer, WIN 35,065-3, did not maintain responding at any dose tested (0.6-6427.7 micrograms/kg/injection). These structure-activity relations correspond to those observed previously for the effects of cocaine derivatives on schedule-controlled responding by pigeons and squirrel monkeys, suggesting that the reinforcing and other behavioral effects of these drugs reflect common pharmacological actions.


Housing shortage and communal politics in European cities around 1900: the cases of Basel 1889 and Belgrade 1906.
In the second half of the nineteenth century, European cities faced a problem well known in postindependence India: the population escalated due to immigration from the rural areas causing rapid and considerable housing shortage. This forced large parts of the poorer classes into miserable living conditions. Lack of space, money and hygiene facilitated the epidemic spread of diseases such as tuberculosis and diarrhoea. The town authorities were called upon to stop speculation and to launch state financed housing projects. However, in reality the situation was very different depending on the place, political aims and financial possibilities arising out of the particular crisis. This article discusses the issue in two continental European cities of around 100,000 inhabitants. The Swiss town of Basel was a hub of trade in Central Europe, while Belgrade was the capital of the Southeastern European kingdom of Serbia.


Polyomavirus major capsid protein VP1 is modified by tyrosine sulfuration.
Polyomavirus was propagated in primary mouse kidney cell monolayers and 35S-sulfate labeled by maintaining the infected cells in serum-free Eagle medium supplemented with 35S-labeled sodium sulfate. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of CsCI gradient-purified 35S-sulfate-labeled virions followed by fluorography indicated that the polyomavirus-coded major capsid protein VP1 incorporated this radiolabel. Two-dimensional gel electrophoresis followed by fluorography revealed 35S-sulfate incorporation into only two of the six VP1 isoelectric species (E and F). Amino acid analysis of 35S-sulfate labeled VP1 by enzymatic hydrolysis followed by two-dimensional thin-layer electrophoresis revealed the presence of 35S-sulfate-labeled tyrosine-O-sulfate.


Comparing the greenhouse gas emissions from three alternative waste combustion concepts.
Three alternative condensing mode power and combined heat and power (CHP) waste-to-energy concepts were compared in terms of their impacts on the greenhouse gas (GHG) emissions from a heat and power generation system. The concepts included (i) grate, (ii) bubbling fluidised bed (BFB) and (iii) circulating fluidised bed (CFB) combustion of waste. The BFB and CFB take advantage of advanced combustion technology which enabled them to reach electric efficiency up to 35% and 41% in condensing mode, respectively, whereas 28% (based on the lower heating value) was applied for the grate fired unit. A simple energy system model was applied in calculating the GHG emissions in different scenarios where coal or natural gas was substituted in power generation and mix of fuel oil and natural gas in heat generation by waste combustion. Landfilling and waste transportation were not considered in the model. GHG emissions were reduced significantly in all of the considered scenarios where the waste combustion concepts substituted coal based power generation. With the exception of condensing mode grate incinerator the different waste combustion scenarios resulted approximately in 1 Mton of fossil CO(2)-eq. emission reduction per 1 Mton of municipal solid waste (MSW) incinerated. When natural gas based power generation was substituted by electricity from the waste combustion significant GHG emission reductions were not achieved.


Consumption of exogenous bifidobacteria does not alter fecal bifidobacteria and breath hydrogen excretion in humans.
The hypothesis that consumption of bifidobacteria by humans would increase colonic bifidobacteria and decrease breath hydrogen excretion was examined. A commercially available strain of bifidobacteria was tracked through the gastrointestinal tract. We determined that a 12-d feeding period of 10(10) cells of exogenous bifidobacteria daily was adequate to achieve a stable number of exogenous bifidobacteria in the colon. A 12-d washout period was chosen because the exogenous bifidobacteria could no longer be detected at that time. A double-blind crossover study used both male and female subjects. The order of treatment with skim milk alone or skim milk + bifidobacteria was randomized. Breath hydrogen excretion (micromol/L) and fecal counts of total bifidobacteria [log colony forming units (CFU)/g feces] were not significantly different between males and females and were not affected by consumption of exogenous bifidobacteria. Calculations based on the numbers of exogenous bifidobacteria consumed and the fecal numbers of exogenous bifidobacteria excreted suggested that numbers of the exogenous strain increased within the gastrointestinal tract. These data suggest that it is difficult to permanently alter total colonic bifidobacteria and affect physiologic function (net hydrogen in the colon as reflected by breath hydrogen) by feeding bifidobacteria, although the percentage of the total bifidobacteria represented by the exogenous strain can be affected.


Molecular characterization of the waxy locus in sorghum.
A comparison of approximately 4.5 kb of nucleotide sequence from the waxy locus (the granule-bound starch synthase I [GBSS I] locus) from a waxy line, BTxARG1, and a non-waxy line, QL39, revealed an extremely high level of sequence conservation. Among a total of 24 nucleotide differences and 9 indels, only 2 nucleotide changes resulted in altered amino acid residues. Protein folding prediction software suggested that one of the amino acid changes (Glu to His) may result in an altered protein structure, which may explain the apparently inactive GBSS I present in BTxARG1. This SNP was not found in the second waxy line, RTx2907, which does not produce GBSS I, and no other SNPs or indels were found in the approximately 4 kb of sequence obtained from RTx2907. Using one indel, the waxy locus was mapped to sorghum chromosome SBI-10, which is syntenous to maize chromosome 9; the waxy locus has been mapped to this maize chromosome. The distribution of indels in a diverse set of sorghum germplasm suggested that there are two broad types of non-waxy GBSS I alleles, each type comprising several alleles, and that the two waxy alleles in BTxARG1 and RTx2907 have evolved from one of the non-waxy allele types. The Glu/His polymorphism was found only in BTxARG1 and derived lines and has potential as a perfect marker for the BTxARG1 source of the waxy allele at the GBSS I locus. The indels correctly predicted the non-waxy phenotype in approximately 65% of diverse sorghum germplasm. The indels co-segregated perfectly with phenotype in two sorghum populations derived from crosses between a waxy and a non-waxy sorghum line, correctly identifying heterozygous lines. Thus, these indel markers or sequence-based SNP markers can be used to follow waxy alleles in sorghum breeding programs in selected pedigrees.


Segregation and mapping in the root-knot nematode Meloidogyne hapla of quantitatively inherited traits affecting parasitism.
The root-knot nematode Meloidogyne hapla can reproduce on a wide range of crop species but there is variability in host range and pathogenicity both within and between isolates. The inbred strain VW9 causes galling but does not reproduce on Solanum bulbocastanum clone SB22 whereas strain VW8 causes little galling and reproduces poorly on this host. Comparison of reproduction on SB22 of nematode F2 lines generated from hybrids between strains VW8 and VW9 revealed that, whereas over half the lines produced no progeny, some lines reproduced to higher levels than did either parental strain. Using a genetic map previously generated using the same set of F2 lines, three quantitative trait loci (QTLs) were identified and positioned on linkage groups. A combination of two QTL alleles from one parent and one from the other was highly represented in F2 lines that exhibited higher reproduction than either parental strain but was absent from lines that failed to reproduce on SB22. This result suggests that sexual hybridization and assortment of opposing alleles leads to segregation of individuals with improved reproductive ability on a particular host. The genome sequence and integrated genetic and physical linkage map of M. hapla provide resources for identification of genes responsible for the identified QTL.


HIV Care Outcomes Among Men Who Have Sex With Men With Diagnosed HIV Infection - United States, 2015.
Gay, bisexual, and other men who have sex with men (collectively referred to as MSM) represent approximately 2% of the U.S. population (1), yet in 2015, MSM accounted for 70% of all diagnoses of human immunodeficiency virus (HIV) infection, including 3% who also were persons who inject drugs (2). During 2008-2014, incidence of HIV infection decreased for groups in all transmission categories except MSM (3). Testing, linkage to and retention in care, and viral suppression are important in reducing HIV transmission. National HIV Surveillance System (NHSS)* data are used to monitor progress toward reaching national goals.† To better guide prevention measures, CDC analyzed data from NHSS for MSM aged ≥13 years (excluding MSM who inject drugs) to determine stage at diagnosis of HIV infection and care outcomes. Among the 19,170 MSM with HIV infection diagnosed in 2015 in 38 jurisdictions with complete laboratory reporting, 3,666 (19.1%) had infection classified as stage 3 (acquired immunodeficiency syndrome [AIDS]) at diagnosis and 74.7% and 84.0% were linked to care within 1 month and 3 months, respectively. Among MSM living with diagnosed HIV infection at year-end 2014, 74.1% received any HIV care, 57.7% were retained in continuous care, and 61.2% had achieved viral suppression. Younger MSM and black or African American (black) MSM had the least favorable HIV care outcomes. Strengthening interventions that increase care and viral suppression among MSM, particularly those aged <25 years and black MSM with public and private partners is important.


Ouabain's Influence on TRPV4 Channels of Epithelial Cells: An Exploration of TRPV4 Activity, Expression, and Signaling Pathways.
Ouabain, a substance originally obtained from plants, is now classified as a hormone because it is produced endogenously in certain animals, including humans. However, its precise effects on the body remain largely unknown. Previous studies have shown that ouabain can influence the phenotype of epithelial cells by affecting the expression of cell-cell molecular components and voltage-gated potassium channels. In this study, we conducted whole-cell clamp assays to determine whether ouabain affects the activity and/or expression of TRPV4 channels. Our findings indicate that ouabain has a statistically significant effect on the density of TRPV4 currents (dITRPV4), with an EC50 of 1.89 nM. Regarding treatment duration, dITRPV4 reaches its peak at around 1 h, followed by a subsequent decline and then a resurgence after 6 h, suggesting a short-term modulatory effect related to on TRPV4 channel activity and a long-term effect related to the promotion of synthesis of new TRPV4 channel units. The enhancement of dITRPV4 induced by ouabain was significantly lower in cells seeded at low density than in cells in a confluent monolayer, indicating that the action of ouabain depends on intercellular contacts. Furthermore, the fact that U73122 and neomycin suppress the effect caused by ouabain in the short term suggests that the short-term induced enhancement of dITRPV4 is due to the depletion of PIP2 stores. In contrast, the fact that the long-term effect is inhibited by PP2, wortmannin, PD, FR18, and IKK16 suggests that cSrc, PI3K, Erk1/2, and NF-kB are among the components included in the signaling pathways.


Spatiotemporal Scan and Age-Period-Cohort Analysis of Hepatitis C Virus in Henan, China: 2005-2012.
Studies have shown that hepatitis C virus (HCV) infection increased during the past decades in China. However, little evidence is available on when, where, and who were infected with HCV. There are gaps in knowledge on the epidemiological burden and evolution of the HCV epidemic in China. Data on HCV cases were collected by the disease surveillance system from 2005 to 2012 to explore the epidemic in Henan province. Spatiotemporal scan statistics and age-period-cohort (APC) model were used to examine the effects of age, period, birth cohort, and spatiotemporal clustering. 177,171 HCV cases were reported in Henan province between 2005 and 2012. APC modelling showed that the HCV reported rates significantly increased in people aged > 50 years. A moderate increase in HCV reported rates was observed for females aged about 25 years. HCV reported rates increased over the study period. Infection rates were greatest among people born between 1960 and 1980. People born around 1970 had the highest relative risk of HCV infection. Women born between 1960 and 1980 had a five-fold increase in HCV infection rates compared to men, for the same birth cohort. Spatiotemporal mapping showed major clustering of cases in northern Henan, which probably evolved much earlier than other areas in the province. Spatiotemporal mapping and APC methods are useful to help delineate the evolution of the HCV epidemic. Birth cohort should be part of the criteria screening programmes for HCV in order to identify those at highest risk of infection and unaware of their status. As Henan is unique in the transmission route for HCV, these methods should be used in other high burden provinces to help identify subpopulations at risk.


Is there need for radioimmunotherapy? results of a phase I/II study in patients with indolent B-cell lymphomas using lutetium-177-DOTA-rituximab.
The aim of the study was to explore the clinical response to 177Lutetium-DOTA-rituximab (177Lu-D-R) and to determine the maximum tolerated dose (MTD) in the treatment of patients with relapsed follicular, mantle cell or other indolent lymphomas such as marginal zone lymphoma as well as to put these results into context with other therapy options for these patients. Treatment consisted of cold rituximab (250 mg/m2) on day 1 and day 8 and 177Lu-DOTA-Rituximab on day 8. Reassessment was done at week 10. Thirty-one patients (males=17, females=14, median number of pretreatments: 3) were treated in seven cohorts. Escalation of injected activity was carried out in steps of 5 mCi/m². Dosimetry was performed in the first 20 patients. The MTD was found to be 45 mCi/m2. Thrombocytopenia and leukopenia were the dose-limiting toxicities. Significant anemia only occurred at dose level 7. We observed the nadir of platelets after a median of 36 days from treatment with 177Lu-D-R and a nadir of granulocytes after a median of 50 days from 177Lu-D-R treatment. Non-hematological toxicity was negligible. We observed clinical responses at all dose levels and for all lymphoma entities. Some of the responses were durable; the longest follow up in complete remission is currently over eight years. The MTD of 177Lu-DOTA-Rituximab was found to be 45 mCi/m². Non hematologic toxicity was negligible. Responses were seen in all lymphoma entities and at all dose levels tested. Further testing seems to be most promising mainly in follicular and marginal zone lymphoma in particular as the results compare well to other therapy options for these patients with regard to effectiveness, toxicity and discomfort for the patients.


Inexact Picard iterative scheme for steady-state nonlinear diffusion in random heterogeneous media.
In this paper, we present a numerical scheme for the analysis of steady-state nonlinear diffusion in random heterogeneous media. The key idea is to iteratively solve the nonlinear stochastic governing equations via an inexact Picard iteration scheme, wherein the nonlinear constitutive law is linearized using the current guess of the solution. The linearized stochastic governing equations are then spatially discretized and approximately solved using stochastic reduced basis projection schemes. The approximation to the solution process thus obtained is used as the guess for the next iteration. This iterative procedure is repeated until an appropriate convergence criterion is met. Detailed numerical studies are presented for diffusion in a square domain for varying degrees of nonlinearity. The numerical results are compared against benchmark Monte Carlo simulations, and it is shown that the proposed approach provides good approximations for the response statistics at modest computational effort.


[Development of adrenal chromaffin tissue].
The purpose of the present investigation was to study the morphological peculiarities of chromaffinoblasts and to determine their interrelations with the surrounding cellular elements of the fetal cortex at the early stages (embryonic weeks 4-7) of their migration into the developing adrenal gland of a pig. At week 5 neuro-cellular cords, consisting of so-called "naked" axons, neuroblasts, lemmoblasts, undifferentiated cells, chromaffinoblast clusters and chromaffinocytes, grow into the fetal cortex from side of abdominal aorta. In fetal cortex parenchyma chromaffin elements form cords, lobes, "medullary globes", which are enveloped by a basal membrane, which is a derivative of satellitocytes. Chromaffinocytes are stained with Wood's stain, potassium bichromate and, judging by the presence of secretory granules in their cytoplasm, are capable to synthesize summary catecholamines and to release them into the blood at the early stages of development. "Medullary globes" are the centers of proliferation and differentiation of the chromaffin cells in the adrenal medulla. The problem of chromaffin tissue stem cells is discussed.


Cyclin E transgenic mice: discovery tools for lung cancer biology, therapy, and prevention.
Lung cancer is the leading cause of cancer-related mortality in the United States and many other countries. This fact underscores the need for clinically relevant models to increase our understanding of lung cancer biology and to help design and implement preventive and more effective therapeutic interventions for lung cancer. New murine transgenic models of non-small cell lung cancer (NSCLC) have been engineered for this purpose. In one such model, overexpression of the cell-cycle regulator cyclin E is targeted to type II alveolar lung cells; dysplasia, hyperplasia, and adenocarcinoma forming in this model have features recapitulating key features of carcinogenesis found in NSCLC patients. These features include the presence of chromosomal instability, pulmonary dysplasia, and hyperplasia, hedgehog-pathway activation, single and multiple adenocarcinomas, and even metastases. Cell lines that expressed either a human wild-type or mutant (proteasome-degradation-resistant) form of cyclin E were derived from the transgenic mouse lung cancers. These cell lines are transplantable into syngeneic host mice, which rapidly develop lung tumors and thus facilitate the rapid testing of agents targeting lung carcinogenesis. These transgenic and transplantable models have already aided in the discovery of oncogenic and growth-suppressive microRNAs and in the identification of a novel antineoplastic mechanism of action for inhibitors of cyclin-dependent kinase 2. This review discusses the general utility of murine carcinogen-induced and transgenic models of lung carcinogenesis and describes the optimization of cyclin E-overexpressing lung carcinogenesis models and their use in testing candidate agents for the prevention and therapy of lung cancer.


Early-onset neonatal sepsis: rate and organism pattern between 2003 and 2008.
Organisms causing early-onset neonatal sepsis (EONS) have consistently changed over time. The distribution of organisms in EONS helps to influence the appropriate type of antibiotic prophylaxis strategy during labor and the antibiotics used in neonates with suspected sepsis. To compare the organisms distribution for EONS between 2003 and 2008 for infants admitted to neonatal intensive care units (NICUs) in Canada. Data were retrieved from infants with a positive bacterial blood or cerebrospinal fluid culture in the first 72 h after birth who were admitted to NICUs participating in the Canadian Neonatal Network from 2003 to 2008. Comparisons of incidence rate, demographics and causative organisms were carried out between earlier cohort (2003 to 2005) and later cohort (2006 to 2008). A total of 405 infants had positive blood and/or cerebral spinal fluid cultures over the study period. The EONS rate was 6.8/1000 admissions (n=24969) in the earlier cohort compared with 6.2/1000 admissions (n=37484) in the later cohort (P=0.36). Rate of clinical chorioamnionitis was higher in the later cohort (38 vs 26%; P=0.02). For term infants, coagulase-negative Staphylococcus (CONS) (2.4/1000) followed by group B Streptococcus (GBS) (1.9/1000) were the most common organisms identified. For preterm infants, CONS (2.5/1000) followed by Escherichia coli (2.6/1000) were the most common organisms identified. There was a significant reduction in GBS EONS over time (P<0.01) and a trend toward an increase in other organisms. Although the rate of EONS among neonates admitted to NICUs has not changed, the pattern of infection has changed over the past 6 years. With the increased use of prophylactic antibiotics to mothers, careful surveillance of the changing trend of bacterial organisms among neonates is warranted.


A novel allele of RAD52 that causes severe DNA repair and recombination deficiencies only in the absence of RAD51 or RAD59.
With the use of an intrachromosomal inverted repeat as a recombination reporter, we have shown that mitotic recombination is dependent on the RAD52 gene, but reduced only fivefold by mutation of RAD51. RAD59, a component of the RAD51-independent pathway, was identified previously by screening for mutations that reduced inverted-repeat recombination in a rad51 strain. Here we describe a rad52 mutation, rad52R70K, that also reduced recombination synergistically in a rad51 background. The phenotype of the rad52R70K strain, which includes weak gamma-ray sensitivity, a fourfold reduction in the rate of inverted-repeat recombination, elevated allelic recombination, sporulation proficiency, and a reduction in the efficiency of mating-type switching and single-strand annealing, was similar to that observed for deletion of the RAD59 gene. However, rad52R70K rad59 double mutants showed synergistic defects in ionizing radiation resistance, sporulation, and mating-type switching. These results suggest that Rad52 and Rad59 have partially overlapping functions and that Rad59 can substitute for this function of Rad52 in a RAD51 rad52R70K strain.


Periventricular microglial cells interact with dividing precursor cells in the nonhuman primate and rodent prenatal cerebral cortex.
Cortical proliferative zones have been studied for over 100 years, yet recent data have revealed that microglial cells constitute a sizeable proportion of ventricular zone cells during late stages of cortical neurogenesis. Microglia begin colonizing the forebrain after neural tube closure and during later stages of neurogenesis populate regions of the developing cortex that include the proliferative zones. We previously showed that microglia regulate the production of cortical cells by phagocytosing neural precursor cells (NPCs), but how microglia interact with NPCs remains poorly understood. Here we report on a distinct subset of microglial cells, which we term periventricular microglia, that are located near the lateral ventricle in the prenatal neocortex. Periventricular microglia exhibit a set of similar characteristics in embryonic rat and fetal rhesus monkey cortex. In both species, these cells occupy ~60 μm of the ventricular zone in the tangential axis and make contact with the soma and processes of NPCs dividing at the ventricle for over 50 μm along the radial axis. Periventricular microglia exhibit notable differences across species, including distinct morphological features such as terminal bouton-like structures that contact mitotic NPCs in the fetal rhesus monkey but not in rat. These morphological distinctions suggest differential functions of periventricular microglia in rat and rhesus monkey, yet are consistent with the concept that microglia regulate NPC function in the developing cerebral cortex of mammalian species.


Statins and erectile dysfunction: results of a case/non-case study using the French Pharmacovigilance System Database.
HMG-CoA reductase inhibitors, more commonly called statins, are widely used in the pharmacological management of hyperlipidaemias. The most common adverse drug reactions (ADRs) of statins are muscular. Other reported ADRs of statins along with other lipid-lowering drugs, namely fibrates, include erectile dysfunction (ED). The relationship between ED and exposure to statins has not clearly been established even though a number of significant case reports have associated ED with exposure to statins. To investigate the association between exposure to statins and the occurrence of ED on the French Pharmacovigilance System Database. Within the French Pharmacovigilance System Database, the case/non-case method was used to measure the disproportionality of combination between a statin and ED. Cases are defined as those reports corresponding to the ADR of interest (i.e. ED) and non-cases are all reports of ADRs other than that being studied. The study period was from 1 January 1985 to 31 December 2006, limited to males aged 13-80 years. We estimated the association between ED and statins by calculating a reporting odds ratio (ROR) of exposure to each drug, with its 95% confidence interval (CI). Among the total of spontaneous reports selected (110 685), exposure to statins was identified in 4471 cases (4%), of which 51 reports (1.1%) concerned ED, whereas 431 (0.4%) cases of ED were found in the 106 214 reports without exposure to statins (p < 0.0001). The mean delay of onset of ED after starting statins, known for 19 cases, was 62 days (median 29 days). In 56.9% of cases, recovery occurred after withdrawal of statin, and rechallenge was positive in five cases. The association was statistically significant for all statins (adjusted ROR [aROR] = 2.4; 95% CI 1.8, 3.3), simvastatin (aROR = 2.6; 1.6, 4.1), atorvastatin (aROR = 3.4; 2.1, 5.4) and rosuvastatin (aROR = 7.1; 2.6, 19.4) [p < 0.001 for all] but not for pravastatin and fluvastatin. We did not find any relationship between the occurrence of ED and the daily dose or the duration of exposure to statins (data not shown). Assessment of the association between drugs other than statins known to be at risk of ED confirmed a significant association for finasteride (aROR = 14.5; 95% CI 8.3, 25.4), fibrates (aROR = 3.6; 2.6, 5.1), beta-adrenergic receptor antagonists (aROR = 1.5; 1.01, 2.1) and tricyclic antidepressants (aROR = 2.0; 1.2, 3.4) [all p < 0.05]. Despite some methodological limitations, the present study suggests that statins may induce or worsen ED in accordance with other data. Further pharmacoepidemiological studies are necessary to confirm this conclusion and to improve the precision of the prevalence and/or the risk factors of this ADR.


The cell biology of TRIM5α.
The tripartite motif (TRIM)-containing proteins are involved in many cellular functions such as cell signaling, apoptosis, cell differentiation, and immune modulation. TRIM5 proteins, including TRIM5α and TRIM-Cyp, are known to possess antiretroviral activity against many different retroviruses. Besides being retroviral restriction factors, TRIM5 proteins participate in other cellular functions that have recently emerged in the study of TRIM5α. In this review, we discuss properties of TRIM5α such as cytoplasmic body formation, protein turnover, and trafficking. Also, we discuss recent insights into innate immune modulation mediated by TRIM5α, highlighting the various functions TRIM5α has in cellular processes.


The impact of moderate-intensity swimming exercise on learning and memory in aged rats: The role of Sirtuin-1.
The purpose of this study was to evaluate the effect of moderate-intensity swimming exercise on learning and memory by the Morris water maze test. Changes in the expressions of cyclic AMP-response element-binding protein (CREB) and brain-derived neurotrophic factor (BDNF) proteins alternative pathway which were activated by sirtuin-1 (SIRT-1) were investigated. The study included thirty-two male Sprague-Dawley rats (350-500 g, 11-12 and 15-16 months old). The rats were randomly divided into four groups with 8 rats in each group. The groups were designed as follows: Control-1 (11-12 months), Exercise-1 (11-12 months), Control-2 (15-16 months), Exercise-2 (15-16 months). Moderate-intensity exercise was assigned for 30 min/day, 5 days/week, for the whole training period of 8 weeks. There were statistically significant differences between the groups on the third day (P=0.005) when swim speeds increased in the exercise groups. There was a statistically significant difference between Exercise 1 and Exercise 2 groups, the entries in the platform zone decreased in Exercise 2 group (P=0.026). While there were no histopathological findings observed in any group, increased SIRT-1, BNDF, and CREB expressions were seen in exercise groups compared with control groups. In aged rats exercising at moderate intensity, increased expression of CREB and BDNF, and SIRT-1 could improve hippocampal-dependent memory.


MARCKS-related peptide modulates in vivo the secretion of airway Muc5ac.
In a mouse model of neutrophil elastase-induced bronchitis that exhibits goblet cell metaplasia and inflammation, we investigated the effects of intratracheal instillation of the MANS peptide, a peptide identical to the NH(2) terminus of the myristoylated alanine-rich C kinase substrate (MARCKS) on mucin protein airway secretion, inflammation, and airway reactivity. To induce mucus cell metaplasia in the airways, male BALB/c mice were treated repetitively with the serine protease, neutrophil elastase, on days 1, 4, and 7. On day 11, when goblet cell metaplasia was fully developed and profiles of proinflammatory cytokines were maximal, the animals were exposed to aerosolized methacholine after intratracheal instillation of MANS or a missense control peptide (RNS). MANS, but not RNS, attenuated the methacholine-stimulated secretion of the major respiratory mucin protein, Muc5ac (50% reduction). Concurrently, elastase-induced proinflammatory cytokines typically recovered in bronchoalveolar lavage (BAL), including KC, IL-1beta, IL-6, MCP-1, and TNFalpha, were reduced by the MANS peptide (mean levels decreased 50-60%). Secondary to the effects of MANS on mucin secretion and inflammation, mechanical lung function by forced oscillation technique was characterized with respect to airway reactivity in response to cumulative aerosol stimulation with serotonin. The MANS peptide was also found to effectively attenuate airway hyperresponsiveness to serotonin in this airway hypersecretory model. Collectively, these findings support the concept that even in airway epithelia remodeled with goblet cell metaplasia and in a state of mucin hypersecretion, exogenous attenuation of function of MARCKS protein via the MANS peptide decreases airway mucin secretion, inflammation, and hyperreactivity.


Surface antigens of melanocytes and melanomas. Markers of melanocyte differentiation and melanoma subsets.
The surface antigens of melanocytes from newborn and adult skin have been analyzed with monoclonal antibodies detecting cell surface antigens of malignant melanoma. Antigenic markers that distinguish early, intermediate, and mature stages in melanocyte differentiation have been defined. The characteristics of the normal melanocyte precursor have been inferred from the features of melanomas that express early markers of melanocyte differentiation. A rudimentary surface antigen map of cells undergoing melanocyte differentiation and a new classification of melanomas based on the expression of melanocyte differentiation antigens are proposed.


Communicating uncertainty in policy analysis.
The term "policy analysis" describes scientific evaluations of the impacts of past public policies and predictions of the outcomes of potential future policies. A prevalent practice has been to report policy analysis with incredible certitude. That is, exact predictions of policy outcomes are routine, while expressions of uncertainty are rare. However, predictions and estimates often are fragile, resting on unsupported assumptions and limited data. Therefore, the expressed certitude is not credible. This paper summarizes my work documenting incredible certitude and calling for transparent communication of uncertainty. I present a typology of practices that contribute to incredible certitude, give illustrative examples, and offer suggestions on how to communicate uncertainty.


Enzyme and Mediator-coadsorbed Carbon Felt Electrode for Electrochemical Detection of Glucose Covered with Polymer Layers Based on Layer-by-Layer Technique.
Glucose dehydrogenase (GlDH) and ferrocene were coadsorbed on a carbon felt (CF) sheet (5 × 10 mm, 2 mm thickness), which was used to construct an electrode for the electrochemical detection of glucose. A potential of +0.3 V vs. Ag/AgCl was applied on the base CF, and the current was measured. After the addition of glucose, the current increased and reached a steady state within 50 s. The current response was proportional to the glucose concentration up to 20 μM, with a lower detection limit of 1 μM. The surface of the CF electrode was covered by layers of polystyrene sulfonate and poly-L-lysine using layer-by-layer technique. Again the current response was proportional to glucose concentration up to 20 μM, with a lower detection limit of 2 μM. The oxidation current owing to electrochemical interferents such as L-ascorbate and acetaminophen was 1/8 times of the current observed on the unprotected electrode. In addition, the protection imparted stability to the electrode. Our work demonstrates that a GlDH/ferrocene CF electrode, protected with polystyrene sulfonate and poly-L-lysine, could be used for the electrochemical detection of glucose.


Studies on the surface properties of hybrid cells. I. Sialyl-transferase activity in homogenates of malignant and non-malignant cells.
We report here a method for the assay of the sialyl-transferase activity in crude homogenates of a wide range of cell lines growing in tissue culture. Our results indicate that particulate preparations from both malignant and non-malignant cells show a Km of 0.25 mM towards CMP-sialic acid in the presence of an excess of glycoprotein acceptor. There appear to be increased amounts of the enzyme associated with the preparations from malignant sources which are reflected in an increase in the apparent Vmax of these. The elevated level of sialyl-transferase activity seen in the malignant cell populations is, paradoxically, associated with a decrease in the amount of bound sialic acid associated with both the whole cell homogenate preparations and the surface of these cells.


Treatment of bleeding esophageal varices by transabdominal esophageal transection with the EEA stapling instrument.
Six cirrhotic patients underwent emergency esophageal transection utilizing the EEA Auto Suture stapling instrument for treatment of unrelenting variceal hemorrhage. All were grade C, and the combination of ascites, encephalopathy, and jaundice was present in four. All were critically ill with ancillary medical problems, including recent subtotal gastrectomy with sepsis and dehiscence, coexisting malignant biliary obstruction, and respiratory insufficiency. All were anergic to skin testing. Four died in the postoperative period, primarily of problems related to sepsis and ascites present before operation. Autopsy showed a well-healed anastomosis without stricture and complete interruption of the varices in all. No patient had recurrent bleeding. All received oral or tube feedings after operation. Two survive at 2 and 1.5 years with no recurrence of varices. This is a rapid, simple, and effective technique which can be done with minimal blood loss or training. There is no diversion of portal blood and minimal interruption of collateral circulation. Whereas the long-term benefits in terms of rebleeding are not yet known, results to date suggest a trial earlier and in better risk patients as a definitive treatment procedure.


CCR5Δ32 (rs333) polymorphism is associated with decreased risk of chronic and aggressive periodontitis: A case-control analysis based in disease resistance and susceptibility phenotypes.
Chronic and aggressive periodontitis are infectious diseases characterized by the irreversible destruction of periodontal tissues, which is mediated by the host inflammatory immune response triggered by periodontal infection. The chemokine receptor CCR5 play an important role in disease pathogenesis, contributing to pro-inflammatory response and osteoclastogenesis. CCR5Δ32 (rs333) is a loss-of-function mutation in the CCR5 gene, which can potentially modulate the host response and, consequently periodontitis outcome. Thus, we investigated the effect of the CCR5Δ32 mutation over the risk to suffer periodontitis in a cohort of Brazilian patients (total N=699), representative of disease susceptibility (chronic periodontitis, N=197; and aggressive periodontitis, N=91) or resistance (chronic gingivitis, N=193) phenotypes, and healthy subjects (N=218). Additionally, we assayed the influence of CCR5Δ32 in the expression of the biomarkers TNFα, IL-1β, IL-10, IL-6, IFN-γ and T-bet, and key periodontal pathogens P. gingivalis, T. forsythia, and T. denticola. In the association analysis of resistant versus susceptible subjects, CCR5Δ32 mutant allele-carriers proved significantly protected against chronic (OR 0.49; 95% CI 0.29-0.83; p-value 0.01) and aggressive (OR 0.46; 95% CI 0.22-0.94; p-value 0.03) periodontitis. Further, heterozygous subjects exhibited significantly decreased expression of TNFα in periodontal tissues, pointing to a functional effect of the mutation in periodontal tissues during the progression of the disease. Conversely, no significant changes were observed in the presence or quantity of the periodontal pathogens P. gingivalis, T. forsythia, and T. denticola in the subgingival biofilm that could be attributable to the mutant genotype.


Occupational mental health promotion: a prevention agenda based on education and treatment. The American Psychological Association/National Institute for Occupational Safety and Health, Health Promotion Panel, 1990 Work and Well-Being Conference.
PURPOSE OF THE REVIEW. Psychological disorders are one of the 10 leading work-related diseases and injuries in the United States according to the National Institute for Occupational Safety and Health. This article addresses occupational metal health and preventive stress management in the workplace. The individual and organizational costs are briefly considered with concern for reducing the burden of suffering associated with these problems. SEARCH METHOD. As an American Psychological Association interdisciplinary panel, we searched the psychological, medical, public health, and organizational literature. We selected articles relevant to the problem of psychological disorders in the workplace and to enhancing occupational mental health and preventive stress management. IMPORTANT FINDINGS. The panel proposed a national agenda of education and treatment, combined with a program of evaluation research, for addressing these issues. Target populations are identified, and the need for collaboration among a variety of national constituencies is considered. Advancing occupational mental health and promoting skills in preventive stress management is considered in the context of comprehensive health promotion. MAJOR CONCLUSIONS. The panel concluded that there is a pressing need to: 1) set a 'gold' standard concerning the current state of knowledge in the domains of occupational mental health and stress management; 2) identify Diagnostically Related Groups (DRGs) which are stress-related; 3) establish assessment standards for stress and mental health; 4) set guidelines for reasonable interventions; and 5) establish acceptable post-outcome criteria.


Perspective and agency during video gaming influences spatial presence experience and brain activation patterns.
The experience of spatial presence (SP), i.e., the sense of being present in a virtual environment, emerges if an individual perceives himself as 1) if he were actually located (self-location) and 2) able to act in the virtual environment (possible actions). In this study, two main media factors (perspective and agency) were investigated while participants played a commercially available video game. The differences in SP experience and associated brain activation were compared between the conditions of game play in first person perspective (1PP) and third person perspective (3PP) as well as between agency, i.e., active navigation of the video game character (active), and non-agency, i.e., mere passive observation (passive). SP was assessed using standard questionnaires, and brain activation was measured using electroencephalography (EEG) and sLORETA source localisation (standard low-resolution brain electromagnetic tomography). Higher SP ratings were obtained in the 1PP compared with the 3PP condition and in the active compared with the passive condition. On a neural level, we observed in the 1PP compared with the 3PP condition significantly less alpha band power in the parietal, the occipital and the limbic cortex. In the active compared with the passive condition, we uncovered significantly more theta band power in frontal brain regions. We propose that manipulating the factors perspective and agency influences SP formation by either directly or indirectly modulating the ego-centric visual processing in a fronto-parietal network. The neuroscientific results are discussed in terms of the theoretical concepts of SP.


Efficacy of Coming Out Proud to reduce stigma's impact among people with mental illness: pilot randomised controlled trial.
Facing frequent stigma and discrimination, many people with mental illness have to choose between secrecy and disclosure in different settings. Coming Out Proud (COP), a 3-week peer-led group intervention, offers support in this domain in order to reduce stigma's negative impact. To examine COP's efficacy to reduce negative stigma-related outcomes and to promote adaptive coping styles (Current Controlled Trials number: ISRCTN43516734). In a pilot randomised controlled trial, 100 participants with mental illness were assigned to COP or a treatment-as-usual control condition. Outcomes included self-stigma, empowerment, stigma stress, secrecy and perceived benefits of disclosure. Intention-to-treat analyses found no effect of COP on self-stigma or empowerment, but positive effects on stigma stress, disclosure-related distress, secrecy and perceived benefits of disclosure. Some effects diminished during the 3-week follow-up period. Coming Out Proud has immediate positive effects on disclosure- and stigma stress-related variables and may thus alleviate stigma's negative impact.


Molecular, phenotypic, and sample-associated data to describe pluripotent stem cell lines and derivatives.
The use of induced pluripotent stem cells (iPSC) derived from independent patients and sources holds considerable promise to improve the understanding of development and disease. However, optimized use of iPSC depends on our ability to develop methods to efficiently qualify cell lines and protocols, monitor genetic stability, and evaluate self-renewal and differentiation potential. To accomplish these goals, 57 stem cell lines from 10 laboratories were differentiated to 7 different states, resulting in 248 analyzed samples. Cell lines were differentiated and characterized at a central laboratory using standardized cell culture methodologies, protocols, and metadata descriptors. Stem cell and derived differentiated lines were characterized using RNA-seq, miRNA-seq, copy number arrays, DNA methylation arrays, flow cytometry, and molecular histology. All materials, including raw data, metadata, analysis and processing code, and methodological and provenance documentation are publicly available for re-use and interactive exploration at https://www.synapse.org/pcbc. The goal is to provide data that can improve our ability to robustly and reproducibly use human pluripotent stem cells to understand development and disease.


Atherothrombosis: the role of tissue factor.
Atherothrombosis, defined as atherosclerotic lesion disruption with superimposed thrombus formation, is the major cause of acute coronary syndromes and cardiovascular deaths. It is the leading cause of morbidity and mortality in the industrialized world. Plaque composition, rather than luminal stenosis, is recognized as the major determinant of this disease. Since tissue factor is found within atheroma and also in the bloodstream of atherosclerotic patients, it likely plays a key role in determining both plaque and blood thrombogenicity. Ongoing clinical and preclinical studies are evaluating the therapeutic possibilities of specific inhibition of the tissue factor pathway. Here, we will review the role of tissue factor in atherothrombosis.


Sustained vortex-like waves in normal isolated ventricular muscle.
Sustained reentrant excitation may be initiated in small (20 x 20 x less than 0.6 mm) preparations of normal ventricular muscle. A single appropriately timed premature electrical stimulus applied perpendicularly to the wake of a propagating quasiplanar wavefront gives rise to circulation of self-sustaining excitation waves, which pivot at high frequency (5-7 Hz) around a relatively small "phaseless" region. Such a region develops only very low amplitude depolarizations. Once initiated, most episodes of reentrant activity last indefinitely but can be interrupted by the application of an appropriately timed electrical stimulus. The entire course of the electrical activity is visualized with high temporal and spatial resolution, as well as high signal-to-noise ratio, using voltage-sensitive dyes and optical mapping. Two- and three-dimensional graphics of the fluorescence changes recorded by a 10 x 10 photodiode array from a surface of 12 x 12 mm provide sequential images (every msec) of voltage distribution during a reentrant vortex. The results suggest that two-dimensional vortex-like reentry in cardiac muscle is analogous to spiral waves in other biological and chemical excitable media.


Newer Diagnostic and Cost-Effective Ways to Identify Asymptomatic Atrial Fibrillation for the Prevention of Stroke.
Atrial fibrillation (Afib) is the most common and underestimated cardiac arrhythmia with a lifetime risk of >35% after the age of 55 years and the risk continues to rise exponentially. Afib leads to stasis of blood within the atria allowing clot formation and increasing the risk for systemic embolization leading to strokes. Outcomes due to Afib can improve significantly with appropriate treatment. Thus, the need for convenient, well-tolerated, cost-effective cardiac monitoring for Afib is needed. The study aims to evaluate the various newer devices and compare them with traditional Holter monitoring, keeping diagnostic yield, cost-effectiveness, and patients' convenience in mind. Though Holter monitoring is simple and non-expensive, it has major limitations including limited recording capacity, inability for real-time recordings, and inconvenience to patients. Zio Patch (iRhythm Technologies, Inc; San Francisco, CA) and other loop recording devices are patient-friendly, inexpensive, and can offer real-time data for longer days. More prospective studies are needed to evaluate the sensitivity, specificity, and the actual number of patients getting benefits from newer devices by diagnosing Afib sooner and start early prevention therapy.


Expression of CMV protein pp65 in cutaneous malignant melanoma.
Human cytomegalovirus (CVM) has been detected by immunohistochemistry (IHC) in brain tumours; however, whether CMV antigen is seen in melanomas has not yet been elucidated. Applying IHC, melanoma tissue was assessed for the expression of pp65, a tegument protein of CMV. Two cohorts were available, cohort-I and II, the latter included also related metastasis. In addition to IHC, in situ hybridisation (ISH) was carried out to assess whether CMV related genetic sequences were detectable in a subset of cases. Seventy per cent of the 142 cases in cohort-I and 50% of the 37 cases in cohort-II displayed immunoreactivity (IR). In both cohorts, the IHC outcome correlated with T-stage (Cohort I: Spearman 0.22, p = 0.01, Cohort II: Fisher exact text 0.04). In 30 of cohort-II cases, when IHC staining was carried out on both the primary tumour and the corresponding metastasis, no change in IR was noted in 53%; in 20%, the IR was lower and in 27% higher in the metastasis when compared with the primary tumour. These results were significant (Fisher exact test 0.03). Applying ISH technique on four tumour cases with detectable pp65 protein, CMV related genetic sequence was not detected. Here, we demonstrate, congruent with observations published for brain tumours, that the protein pp65 is indeed observed in substantial number of melanoma cases with IHC; however, no signal was detected with ISH technique. These findings are in line with previously reported studies, demonstrating that the role of CMV in tumours is still debatable.


Hypoglycemic effects of brassinosteroid in diet-induced obese mice.
The prevalence of obesity is increasing globally, and obesity is a major risk factor for metabolic diseases such as type 2 diabetes. Previously, we reported that oral administration of homobrassinolide (HB) to healthy rats triggered a selective anabolic response that was associated with lower blood glucose. Therefore, the aim of this study was to evaluate the effects of HB administration on glucose metabolism, insulin sensitivity, body composition, and gluconeogenic gene expression profiles in liver of C57BL/6J high-fat diet-induced obese mice. Acute oral administration of 50-300 mg/kg HB to obese mice resulted in a dose-dependent decrease in fasting blood glucose within 3 h of treatment. Daily chronic administration of HB (50 mg/kg for 8 wk) ameliorated hyperglycemia and improved oral glucose tolerance associated with obesity without significantly affecting body weight or body composition. These changes were accompanied by lower expression of two key gluconeogenic enzymes, phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G-6-Pase), and increased phosphorylation of AMP-activated protein kinase in the liver and muscle tissue. In vitro, HB treatment (1-15 μM) inhibited cyclic AMP-stimulated but not dexamethasone-stimulated upregulation of PEPCK and G-6-Pase mRNA levels in H4IIE rat hepatoma cells. Among a series of brassinosteroid analogs related to HB, only homocastasterone decreased glucose production in cell culture significantly. These results indicate the antidiabetic effects of brassinosteroids and begin to elucidate their putative cellular targets both in vitro and in vivo.


Disease Pandemics and Major Epidemics Arising from New Encounters between Indigenous Viruses and Introduced Crops.
Virus disease pandemics and epidemics that occur in the world's staple food crops pose a major threat to global food security, especially in developing countries with tropical or subtropical climates. Moreover, this threat is escalating rapidly due to increasing difficulties in controlling virus diseases as climate change accelerates and the need to feed the burgeoning global population escalates. One of the main causes of these pandemics and epidemics is the introduction to a new continent of food crops domesticated elsewhere, and their subsequent invasion by damaging virus diseases they never encountered before. This review focusses on providing historical and up-to-date information about pandemics and major epidemics initiated by spillover of indigenous viruses from infected alternative hosts into introduced crops. This spillover requires new encounters at the managed and natural vegetation interface. The principal virus disease pandemic examples described are two (cassava mosaic, cassava brown streak) that threaten food security in sub-Saharan Africa (SSA), and one (tomato yellow leaf curl) doing so globally. A further example describes a virus disease pandemic threatening a major plantation crop producing a vital food export for West Africa (cacao swollen shoot). Also described are two examples of major virus disease epidemics that threaten SSA's food security (rice yellow mottle, groundnut rosette). In addition, brief accounts are provided of two major maize virus disease epidemics (maize streak in SSA, maize rough dwarf in Mediterranean and Middle Eastern regions), a major rice disease epidemic (rice hoja blanca in the Americas), and damaging tomato tospovirus and begomovirus disease epidemics of tomato that impair food security in different world regions. For each pandemic or major epidemic, the factors involved in driving its initial emergence, and its subsequent increase in importance and geographical distribution, are explained. Finally, clarification is provided over what needs to be done globally to achieve effective management of severe virus disease pandemics and epidemics initiated by spillover events.


Evolving concepts of pathogenesis in atopic dermatitis and other eczemas.
The eczemas represent a common and diverse group of inflammatory skin diseases whose definitions and pathogenic mechanisms have often been confused and controversial. Since the millennium, fresh approaches are providing better insight. Research has focused much more upon the epidermis and the very relevant signaling pathways that contribute to spongiosis, proliferation, generation of proinflammatory factors, and differentiation to form an effective stratum corneum barrier. A major step in understanding has come from the solidly confirmed association between filaggrin null mutations of ichthyosis vulgaris and atopic dermatitis. Similar associations relating to protease and lipid defects have highlighted the role of barrier disruption that allows greater access of environmental toxins, microbes, and allergens. Animal models are beginning to predict mechanisms in which such direct perturbation of keratinocytes may initiate inflammation and condition immune responses in irritant contact dermatitis and atopic dermatitis. These conceptual shifts are nurturing more balanced approaches to understanding eczema and hold the hope for better prevention efforts and more specific molecular targeting for therapy.