Effects of Citral on Lipopolysaccharide-Induced Inflammation in Human Umbilical Vein Endothelial Cells.
Citral is an active compound of lemongrass oil which has been reported to have anti-inflammatory effects. In this study, we investigated the effects of citral on lipopolysaccharide (LPS)-induced inflammatory response in a rat model of peritonitis and human umbilical vein endothelial cells (HUVECs). LPS was intraperitoneally injected into rats to establish a peritonitis model. The HUVECs were treated with citral for 12 h before exposure to LPS. The levels of TNF-α and IL-8 were measured using ELISA. Western blotting was used to detect the expression of VCAM-1, ICAM-1, NF-κB, and PPAR-γ. The results showed that citral had a protective effect against LPS-induced peritonitis. Citral decreased the levels of WBCs and inflammatory cytokines TNF-α and IL-6. Citral also inhibited LPS-induced myeloperoxidase (MPO) activity in the peritoneal tissue. Treatment of HUVECs with citral significantly inhibited TNF-α and IL-8 expression induced by LPS. LPS-induced VCAM-1 and ICAM-1 expression were also suppressed by citral. Meanwhile, we found that citral inhibited LPS-induced NF-κB activation in HUVECs. Furthermore, we found that citral activated PPAR-γ and the anti-inflammatory effects of citral can be reversed by PPAR-γ antagonist GW9662. In conclusion, citral inhibits LPS-induced inflammatory response via activating PPAR-γ which attenuates NF-κB activation and inflammatory mediator production.


COVID-19 and the ageing workforce: global perspectives on needs and solutions across 15 countries.
COVID-19 has a direct impact on the employment of older people. This adds to the challenge of ageism. The World Health Organization has started a worldwide campaign to combat ageism and has called for more research and evidence-based strategies that have the potential to be scaled up. This study specifically aims to identify solutions to combat the adverse effects of COVID-19 on the global ageing workforce. We present 15 case studies from different countries and report on what those countries are doing or not doing to address the impact of COVID-19 on ageing workers. We provide examples of how COVID-19 influences older people's ability to work and stay healthy, and offer case studies of what governments, organizations or individuals can do to help ensure older people can obtain, maintain and, potentially, expand their current work. Case studies come from Australia, Austria, Canada, China, Germany, Israel, Japan, Nigeria, Romania, Singapore, Sweden, South Korea, Thailand, United Kingdom (UK), and the United States (US). Across the countries, the impact of COVID-19 on older workers is shown as widening inequalities. A particular challenge has arisen because of a large proportion of older people, often with limited education and working in the informal sector within rural areas, e.g. in Nigeria, Thailand and China. Remedies to the particular disadvantage experienced by older workers in the context of COVID are presented. These range from funding support to encouraging business continuity, innovative product and service developments, community action, new business models and localized, national and international actions. The case studies can be seen as frequently fitting within strategies that have been proven to work in reducing ageism within the workplace. They include policy and laws that have increased benefits to workers during lockdowns (most countries); educational activities such as coaching seniorpreneurship (e,g, Australia); intergenerational contact interventions such as younger Thai people who moved back to rural areas and sharing their digital knowledge with older people and where older people reciprocate by teaching the younger people farming knowledge. Global sharing of this knowledge among international, national and local governments and organizations, businesses, policy makers and health and human resources experts will further understanding of the issues that are faced by older workers. This will facilitate the replication or scalability of solutions as called for in the WHO call to combat ageism in 2021. We suggest that policy makers, business owners, researchers and international organisations build on the case studies by investing in evidence-based strategies to create inclusive workplaces. Such action will thus help to challenge ageism, reduce inequity, improve business continuity and add to the quality of life of older workers.


Aldose reductase functions as a detoxification system for lipid peroxidation products in vasculitis.
Giant cell arteritis (GCA) is a systemic vasculitis preferentially affecting large and medium-sized arteries. Inflammatory infiltrates in the arterial wall induce luminal occlusion with subsequent ischemia and degradation of the elastic membranes, allowing aneurysm formation. To identify pathways relevant to the disease process, differential display-PCR was used. The enzyme aldose reductase (AR), which is implicated in the regulation of tissue osmolarity, was found to be upregulated in the arteritic lesions. Upregulated AR expression was limited to areas of tissue destruction in inflamed arteries, where it was detected in T cells, macrophages, and smooth muscle cells. The production of AR was highly correlated with the presence of 4-hydroxynonenal (HNE), a toxic aldehyde and downstream product of lipid peroxidation. In vitro exposure of mononuclear cells to HNE was sufficient to induce AR production. The in vivo relationship of AR and HNE was explored by treating human GCA temporal artery-severe combined immunodeficiency (SCID) mouse chimeras with the AR inhibitors Sorbinil and Zopolrestat. Inhibition of AR increased HNE adducts twofold and the number of apoptotic cells in the arterial wall threefold. These data demonstrate that AR has a tissue-protective function by preventing damage from lipid peroxidation. We propose that AR is an oxidative defense mechanism able to neutralize the toxic effects of lipid peroxidation and has a role in limiting the arterial wall injury mediated by reactive oxygen species.


Novel Activities of Select NSAID R-Enantiomers against Rac1 and Cdc42 GTPases.
Rho family GTPases (including Rac, Rho and Cdc42) collectively control cell proliferation, adhesion and migration and are of interest as functional therapeutic targets in numerous epithelial cancers. Based on high throughput screening of the Prestwick Chemical Library® and cheminformatics we identified the R-enantiomers of two approved drugs (naproxen and ketorolac) as inhibitors of Rac1 and Cdc42. The corresponding S-enantiomers are considered the active component in racemic drug formulations, acting as non-steroidal anti-inflammatory drugs (NSAIDs) with selective activity against cyclooxygenases. Here, we show that the S-enantiomers of naproxen and ketorolac are inactive against the GTPases. Additionally, more than twenty other NSAIDs lacked inhibitory action against the GTPases, establishing the selectivity of the two identified NSAIDs. R-naproxen was first identified as a lead compound and tested in parallel with its S-enantiomer and the non-chiral 6-methoxy-naphthalene acetic acid (active metabolite of nabumetone, another NSAID) as a structural series. Cheminformatics-based substructure analyses-using the rotationally constrained carboxylate in R-naproxen-led to identification of racemic [R/S] ketorolac as a suitable FDA-approved candidate. Cell based measurement of GTPase activity (in animal and human cell lines) demonstrated that the R-enantiomers specifically inhibit epidermal growth factor stimulated Rac1 and Cdc42 activation. The GTPase inhibitory effects of the R-enantiomers in cells largely mimic those of established Rac1 (NSC23766) and Cdc42 (CID2950007/ML141) specific inhibitors. Docking predicts that rotational constraints position the carboxylate moieties of the R-enantiomers to preferentially coordinate the magnesium ion, thereby destabilizing nucleotide binding to Rac1 and Cdc42. The S-enantiomers can be docked but are less favorably positioned in proximity to the magnesium. R-naproxen and R-ketorolac have potential for rapid translation and efficacy in the treatment of several epithelial cancer types on account of established human toxicity profiles and novel activities against Rho-family GTPases.


Acute pyelonephritis in pregnancy.
To examine the incidence of pyelonephritis and the incidence of risk factors, microbial pathogens, and obstetric complications in women with acute antepartum pyelonephritis. For 2 years, information on pregnant women with acute pyelonephritis was collected in a longitudinal study. All women were admitted to the hospital and treated with intravenous antimicrobial agents. We compared the pregnancy outcomes of these women with those of the general obstetric population received at our hospital during the same time period. Four hundred forty cases of acute antepartum pyelonephritis were identified during the study period (incidence 1.4%). Although there were no significant differences in ethnicity, pyelonephritis was associated with nulliparity (44% versus 37%, P = .003) and young age (P = .003). Thirteen percent of the women had a known risk factor for pyelonephritis. Acute pyelonephritis occurred more often in the second trimester (53%), and the predominant uropathogens were Escherichia coli (70%) and gram-positive organisms, including group B beta Streptococcus (10%). Complications included anemia (23%), septicemia (17%), transient renal dysfunction (2%), and pulmonary insufficiency (7%). The incidence of pyelonephritis has remained low in the era of routine prenatal screening for asymptomatic bacteriuria. First-trimester pyelonephritis accounts for over 1 in 5 antepartum cases. Gram-positive uropathogens are found more commonly as pregnancy progresses. Maternal complications continue, but poor obstetrical outcomes are rare.


Diabetes mellitus in patients with schizophrenia in West-Bank, Palestine.
The main aims of the study were to investigate the prevalence of pre-diabetes and diabetes mellitus (DM) in patients with schizophrenia, to compare it with those published in the general population, and to assess significant associations with dysglycemia defined as having either pre-DM or DM. A cross-sectional study carried out in 4 governmental primary psychiatric healthcare centers in Northern West-Bank, Palestine. Fasting blood glucose (FBG) and glycated hemoglobin (HbA1c) were measured. The World Health Organization (WHO) criteria for defining pre-DM and DM were used. Dysglycemia was defined as FBG >110mg/dl. Based on WHO criteria, 27 patients (10.8%) had diabetes and 34 (13.6%) had pre-diabetes. The prevalence of DM in patients with schizophrenia was not significantly higher than that reported in the general population of Palestine. However, the prevalence of pre-DM was significantly higher than that reported in the general population of Palestine. Regression analysis showed that advancing age and abnormal waist circumference were significant predictors of dysglycemia in patients with schizophrenia. This study confirmed the high prevalence of dysglycemia in patients with schizophrenia, supporting the need for monitoring of blood glucose in this category of patients. The presence of primary risk factors is more important in the development of dysglycemia in patients with schizophrenia than exposure to antipsychotic drugs.


Gut permeability and food allergies.
Intestinal permeability is a critical feature of the gastrointestinal epithelium as it must allow an efficient passage of nutrients and restrict the entry of larger molecules, such as protein antigen, in order to facilitate appropriate immune responses towards food antigens. The proper regulation of the epithelial barrier relies on multiple, intricate physiological and immunologic mechanisms, in terms of which recent progresses regarding the cellular and molecular components have been unravelled. In genetically predisposed individuals, breakdown of oral tolerance can occur, leading to the inadequate production of allergen-specific IgE and the recruitment of mast cells in the gastrointestinal mucosa. Under such conditions, the intestinal permeability towards allergen is altered via different mechanisms, with IgE-CD23-mediated transport across the mucosa playing an important amplification role. Additionally, during the effector phase of the allergic reaction, when mast cells degranulate, a series of inflammatory mediators, such as proteases and cytokines, are released and further affects intestinal permeability. This leads to an increase in the passage of allergens and hence contributes to perpetuate the inflammatory reaction. In this review, we describe the importance of properly balanced intestinal permeability in oral tolerance induction and address the processes involved in damaging the intestinal barrier in the sensitized epithelium and during allergic reactions. We conclude by speculating on the effect of increased intestinal permeability on the onset of sensitization towards dietary antigens.


Renal Denervation Prevents Immune Cell Activation and Renal Inflammation in Angiotensin II-Induced Hypertension.
Inflammation and adaptive immunity play a crucial role in the development of hypertension. Angiotensin II and probably other hypertensive stimuli activate the central nervous system and promote T-cell activation and end-organ damage in peripheral tissues. To determine if renal sympathetic nerves mediate renal inflammation and T-cell activation in hypertension. Bilateral renal denervation using phenol application to the renal arteries reduced renal norepinephrine levels and blunted angiotensin II-induced hypertension. Bilateral renal denervation also reduced inflammation, as reflected by decreased accumulation of total leukocytes, T cells, and both CD4+ and CD8+ T cells in the kidney. This was associated with a marked reduction in renal fibrosis, albuminuria, and nephrinuria. Unilateral renal denervation, which partly attenuated blood pressure, only reduced inflammation in the denervated kidney, suggesting that this effect is pressure independent. Angiotensin II also increased immunogenic isoketal-protein adducts in renal dendritic cells (DCs) and increased surface expression of costimulation markers and production of interleukin (IL)-1α, IL-1β, and IL-6 from splenic DCs. Norepinephrine also dose dependently stimulated isoketal formation in cultured DCs. Adoptive transfer of splenic DCs from angiotensin II-treated mice primed T-cell activation and hypertension in recipient mice. Renal denervation prevented these effects of hypertension on DCs. In contrast to these beneficial effects of ablating all renal nerves, renal afferent disruption with capsaicin had no effect on blood pressure or renal inflammation. Renal sympathetic nerves contribute to DC activation, subsequent T-cell infiltration and end-organ damage in the kidney in the development of hypertension.


Neighborhood characteristics and disability in older adults.
To characterize the influence of the residential neighborhood of older adults on the prevalence of disability. We combined Census data on disability in older adults living in New York City with environmental information from a comprehensive geospatial database. We used factor analysis to derive dimensions of compositional and physical neighborhood characteristics and linear regression to model their association with levels of disability. Measures of neighborhood collective efficacy were added to these models to explore the impact of the social environment. Low neighborhood socioeconomic status, residential instability, living in areas with low proportions of foreign born and high proportions of Black residents, and negative street characteristics were associated with higher prevalence of both "physical" disability and "going outside the home" disability. High crime levels were additionally associated with physical disability, although this relationship disappeared when misdemeanor arrests were removed from the crime variable. Low levels of collective efficacy were associated with more going-outside-the-home disability, with racial/ethnic composition dropping out of this model to be replaced by an interaction term. The urban environment may have a substantial impact on whether an older adult with a given level of functional impairment is able to age actively and remain independent.


Comparison of molecularly imprinted solid-phase extraction (MISPE) with classical solid-phase extraction (SPE) for the detection of benzodiazepines in post-mortem hair samples.
This preliminary study compares the benzodiazepine results for 10 post-mortem scalp hair samples using a classical solid-phase extraction (SPE) and a molecularly imprinted solid-phase extraction (MISPE) system. The hair samples selected for testing were from drug-related deaths where a positive benzodiazepine blood result was obtained. Samples were decontaminated with 0.1% sodium dodecyl sulfate, distilled water and dichloromethane, incubated overnight in methanol/25% aqueous ammonium hydroxide (20:1), extracted by SPE or MISPE and subsequently analysed by liquid chromatography-tandem mass spectrometry (LC-MS-MS). Both extraction methods detected diazepam, nordiazepam, oxazepam, temazepam and nitrazepam in the samples. Diazepam was detected in a greater number of samples using MISPE due to both its lower limit of detection (LOD) and higher extraction recovery as a result of excellent molecular recognition of the template (diazepam) imparted by the imprinting process. The selective recognition of two diazepam analogues, nordiazepam and oxazepam, was demonstrated using MISPE since they were also detected in a greater number of samples. In contrast, another diazepam analogue, temazepam, was detected in a greater number of samples using SPE since the LOD using this extraction was lower than with MISPE. Nitrazepam was detected in one sample using both extraction methods. Overall the MISPE and SPE hair results were in good qualitative agreement. For the samples, where both extraction methods detected nordiazepam, temazepam and oxazepam, the concentrations were always higher for SPE. This is probably due to the MIP procedure producing extracts with fewer matrix interferences than the extracts produced using the classical SPE method. MISPE could be used as a complementary method to classical SPE for the analysis of benzodiazepine positive hair samples collected from chronic users.


The Texas Training Initiative for Emergency Response (T-TIER): an effective learning strategy to prepare the broader audience of health professionals.
Recognizing the need to prepare the broader workforce of responders to plan and respond to the consequences of public health emergencies, the School of Rural Public Health at Texas A&M University Health Science Center launched a self-supporting, continuing education initiative in March 2003, designed to offer training to individuals throughout Texas with responsibility for emergency planning, preparedness, and response. The Texas Training Initiative for Emergency Response (T-TIER) fosters the integration and collaboration of key organizations and disciplines, using the Centers for Disease Control and Prevention-identified competencies by focus area. T-TIER is designed as a three-module training initiative that builds upon the knowledge, skills, and abilities that participants acquire in each preceding module. To increase efficacy, T-TIER uses multiple training methodologies, including live presentations, hands-on practical activities, tabletop exercises, and on-site or televideo conference technology. This unique, multidisciplinary approach enhances respect and collaboration among the various disciplines, limiting unilateral emergency preparedness planning and response at the national, state, and local levels. The next step in disseminating this training curriculum is the adaptation of materials using distance education technologies to reach a broader audience, both in Texas and other states across the nation.


Lifetime estrogen exposure and cognition in late life: the Cache County Study.
Prevalence of Alzheimer's disease (AD) is higher for women, possibly influenced by sex-dependent effects of the estrogen. We examined the association between estrogen and cognitive decline in over 2,000 older adult women in a 12-year population-based study in Cache County, Utah. The baseline sample included 2,114 women (mean age = 74.94 y, SD = 6.71) who were dementia-free at baseline and completed a women's health questionnaire, asking questions regarding reproductive history and hormone therapy (HT). Endogenous estrogen exposure (EEE) was calculated taking the reproductive window (age at menarche to age at menopause), adjusted for pregnancy and breastfeeding. HT variables included duration of use, HT type (unopposed; opposed), and time of HT initiation. A modified version of the Mini-Mental State Examination (3MS) was administered at four triennial waves to assess cognitive status. Linear mixed-effects models examined the relationship between estrogen exposure and 3MS score over time. EEE was positively associated with cognitive status (β = 0.03, P = 0.054). In addition, longer duration of HT use was positively associated with cognitive status (β = 0.02, P = 0.046) and interacted with age; older women had greater benefit compared with younger women. The timing of HT initiation was significantly associated with 3MS (β = 0.55, P = 0.048), with higher scores for women who initiated HT within 5 years of menopause compared with those initiating HT 6-or-more years later. Our results suggest that longer EEE and HT use, especially in older women, are associated with higher cognitive status in late life.


Tissue Engineering of Cartilage; Can Cannabinoids Help?
This review discusses the role of the cannabinoid system in cartilage tissue and endeavors to establish if targeting the cannabinoid system has potential in mesenchymal stem cell based tissue-engineered cartilage repair strategies. The review discusses the potential of cannabinoids to protect against the degradation of cartilage in inflamed arthritic joints and the influence of cannabinoids on the chondrocyte precursors, mesenchymal stem cells (MSCs). We provide experimental evidence to show that activation of the cannabinoid system enhances the survival, migration and chondrogenic differentiation of MSCs, which are three major tenets behind the success of a cell-based tissue-engineered cartilage repair strategy. These findings highlight the potential for cannabinoids to provide a dual function by acting as anti-inflammatory agents as well as regulators of MSC biology in order to enhance tissue engineering strategies aimed at cartilage repair.


Nosocomial infection of the urinary tract: pattern of antibiotic use and drug resistance.
Nosocomial infection of the urinary tract is a long standing problem that pre-dates the antibiotic era. Hospitals have remained veritable reservoirs of bacteria with increased numbers and types resistant to antibiotic treatment. Most hospitals have epidemiologists and infection control manuals but unfortunately most hospital staff do not follow infection control protocols. Whenever a new class of antibiotics become available, enthusiastic physicians rush to use them discarding the older and slightly less potent ones which are subsequently regarded as obsolete. Some individuals claim that "good medicine is supposed to be practiced by those physicians who give their patients the most up to date drugs available". However, the resistance and sensitivity pattern of bacteria have changed and continue to do so, varying widely even among facilities within the same community. Furthermore, within several years of each antibiotic advancement, a parallel increase in the resistant strains of previously sensitive bacteria has been observed. The problem of resistant pathogens has become particularly important within the context of nosocomial infection of the urinary tract. Reduced hospital stay and avoidance of bacterial resistance by rational and selective use of antibiotics for preoperative prophylaxis and definitive therapy and strict enforcement of the hospital disease control protocols must be encouraged.


Heme: emergent roles of heme in signal transduction, functional regulation and as catalytic centres.
Protoporphyrin IX iron complex (heme) is an important cofactor for oxygen transfer, oxygen storage, oxygen activation, and electron transfer when bound to the heme proteins hemoglobin, myoglobin, cytochrome P450 and cytochrome c, respectively. In addition to these prototypical heme proteins, there are emergent, critical roles of exchangeable/labile heme in signal transduction. Specifically, it has been shown that association/dissociation of heme to/from heme-responsive sensors regulates numerous functions, including transcription, DNA binding, microRNA splicing, translation, protein kinase activity, protein degradation, heme degradation, K+ channel function, two-component signal transduction, and many other functions. In this review, we provide a comprehensive overview of structure-function relationships of heme-responsive sensors and describe new, additional roles of exchangeable/labile heme as functional inhibitors and activators. In order to complete the description of the various roles of heme in heme-bound proteins, we also mention heme as a novel chemical reaction centre for aldoxime dehydratase, cis-trans isomerase, N-N bond formation, hydrazine formation and S-S formation, and other functions. These unprecedented functions of exchangeable/labile heme and heme proteins should be of interest to biological chemists. Insight into underlying molecular mechanisms is essential for understanding the new role of heme in important physiological and pathological processes.


Association between single nucleotide polymorphisms in AKT1 and the risk of prostate cancer in the Chinese Han population.
AKT1, also known as v-akt murine thymoma viral oncogene homolog 1, is involved in the regulation of cell-survival and anti-apoptotic activities, which may affect the pathogenesis of various cancers. However, the association between genetic variants of AKT1 and the risk of developing prostate cancer has not been investigated before. This study investigated the associations between three polymorphisms (rs1130214, rs3730358, and rs2494732) in AKT1 and the risk of development of prostate cancer in the Chinese Han population. Sequenom MassARRAY & iPLEX technology were used to genotype these polymorphisms in 493 Chinese Han patients with prostate cancer and 309 age-matched healthy individuals. Compared to the CC genotype of the rs3730358 polymorphism, the CT genotype of the same polymorphism was strongly associated with a decreased risk of prostate cancer (OR = 0.617, 95%CI = 0.390-0.976, P = 0.037). However, there was no significant difference between the allele frequency of the rs3730358 polymorphism and those of the other two polymorphisms (P > 0.05). Moreover, no significant difference was found in the haplotype analysis (P > 0.05). Our study found that the variant genotype CT of rs3730358 of AKT1 was associated with a decreased risk of prostate cancer, which suggested that this polymorphism could play an important role in the development of the disease.


Cellular basis of hypocotyl growth in Arabidopsis thaliana.
The Arabidopsis thaliana hypocotyl is widely used to study the effects of light and plant growth factors on cell elongation. To provide a framework for the molecular-genetic analysis of cell elongation in this organ, here we describe, at the cellular level, its morphology and growth and identify a number of characteristic, developmental differences between light-grown and dark-grown hypocotyls. First, in the light epidermal cells show a characteristic differentiation that is not observed in the dark. Second, elongation growth of this organ does not involve significant cortical or epidermal cell divisions. However, endoreduplication occurs, as revealed by the presence of 4C and 8C nuclei. In addition, 16C nuclei were found specifically in dark-grown seedlings. Third, in the dark epidermal cells elongate along a steep, acropetal spatial and temporal gradient along the hypocotyl. In contrast, in the light all epidermal cells elongated continuously during the entire growth period. These morphological and physiological differences, in combination with previously reported genetic data (T. Desnos, V. Orbovic, C. Bellini, J. Kronenberger, M. Caboche, J. Traas, H. Höfte [1996] Development 122: 683-693), illustrate that light does not simply inhibit hypocotyl growth in a cell-autonomous fashion, but that the observed growth response to light is a part of an integrated developmental change throughout the elongating organ.


Nomograms for predicting survival of patients with newly diagnosed glioblastoma: prognostic factor analysis of EORTC and NCIC trial 26981-22981/CE.3.
A randomised trial published by the European Organisation for Research and Treatment of Cancer (EORTC) and the National Cancer Institute of Canada (NCIC) Clinical Trials Group (trial 26981-22981/CE.3) showed that addition of temozolomide to radiotherapy in the treatment of patients with newly diagnosed glioblastoma significantly improved survival. We aimed to undertake an exploratory subanalysis of the EORTC and NCIC data to confirm or identify new prognostic factors for survival in adult patients with glioblastoma, derive nomograms that predict an individual patient's prognosis, and suggest stratification factors for future trials. Data from 573 patients with newly diagnosed glioblastoma who were randomly assigned to radiotherapy alone or to the same radiotherapy plus temozolomide in the EORTC and NCIC trial were included in this subanalysis. Survival modelling was done in three patient populations: intention-to-treat population of all randomised patients (population 1); patients assigned temozolomide and radiotherapy (population 2, n=287); and patients assigned temozolomide and radiotherapy who had assessment of MGMT promoter methylation status and who had undergone tumour resection (population 3, n=103). Cox proportional hazards models were fitted with and without O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status. Nomograms were developed to predict an individual patient's median and 2-year survival probabilities. No nomogram was developed in the radiotherapy-alone group because combined treatment is now the new standard of care. Independent of the MGMT promoter methylation status, analysis in all randomised patients (population 1) identified combined treatment with temozolomide, more extensive tumour resection, younger age, Mini-Mental State Examination (MMSE) score of 27 or higher, and no corticosteroid treatment at baseline as independent prognostic factors correlated with improved survival outcome. In patients assigned temozolomide and radiotherapy (population 2), younger age, better performance status, more extensive tumour resection, and MMSE score of 27 or higher were associated with better survival. In patients who had tumours resected, who were assigned temozolomide and radiotherapy, and who had available MGMT promoter methylation status (population 3), methylated MGMT, better performance status, and MMSE score of 27 or higher were associated with improved survival. Nomograms were developed and are available at http://www.eortc.be/tools/gbmcalculator. MGMT promoter methylation status, age, performance status, extent of resection, and MMSE are suggested as eligibility or stratification factors for future trials in patients with newly diagnosed glioblastoma. Stratifying by MGMT promoter methylation status should be mandatory in all glioblastoma trials that use alkylating chemotherapy. Nomograms can be used to predict an individual patient's prognosis, and they integrate pertinent molecular information that is consistent with a paradigm shift towards individualised patient management.


Evaluation of corrosion and scaling tendency indices in a drinking water distribution system: a case study of Bandar Abbas city, Iran.
Corrosion and scaling is a major problem in water distribution systems, thus evaluation of water corrosivity properties is a routine test in water networks. To evaluate water stability in the Bandar Abbas water distribution system, the network was divided into 15 clusters and 45 samples were taken. Langelier, Ryznar, Puckorius, Larson-Skold (LS) and Aggressive indices were determined and compared to the marble test. The mean parameters included were pH (7.8 ± 0.1), electrical conductivity (1,083.9 ± 108.7 μS/cm), total dissolved solids (595.7 ± 54.7 mg/L), Cl (203.5 ± 18.7 mg/L), SO₄(174.7 ± 16.0 mg/L), alkalinity (134.5 ± 9.7 mg/L), total hardness (156.5 ± 9.3 mg/L), HCO₃(137.4 ± 13.0 mg/L) and calcium hardness (71.8 ± 4.3 mg/L). According to the Ryznar, Puckorius and Aggressive Indices, all samples were stable; based on the Langelier Index, 73% of samples were slightly corrosive and the rest were scale forming; according to the LS index, all samples were corrosive. Marble test results showed tested water of all 15 clusters tended to scale formation. Water in Bandar Abbas is slightly scale forming. The most appropriate indices for the network conditions are the Aggressive, Puckorius and Ryznar indices that were consistent with the marble test.


Configurational entropy and effective temperature in systems of active Brownian particles.
We propose a method to determine the effective density of states and configurational entropy in systems of active Brownian particles by measuring the probability distribution function of potential energy at varying temperatures. Assuming that the entropy is a continuous and monotonically increasing function of energy, we provide support that two-dimensional systems of purely repulsive active Brownian spheres can be mapped onto an equilibrium system with a Boltzmann-like distribution and an effective temperature. We find that the effective temperature depends even for a large number of particles on system size, suggesting that active systems are non-extensive. In addition, the effective Helmholtz free energy can be derived from the configurational entropy. We verify our results regarding the configurational entropy by using thermodynamic integration of the effective Helmholtz free energy with respect to temperature.


A neurobehavioral model of affiliative bonding: implications for conceptualizing a human trait of affiliation.
Because little is known about the human trait of affiliation, we provide a novel neurobehavioral model of affiliative bonding. Discussion is organized around processes of reward and memory formation that occur during approach and consummatory phases of affiliation. Appetitive and consummatory reward processes are mediated independently by the activity of the ventral tegmental area (VTA) dopamine (DA)-nucleus accumbens shell (NAS) pathway and the central corticolimbic projections of the u-opiate system of the medial basal arcuate nucleus, respectively, although these two projection systems functionally interact across time. We next explicate the manner in which DA and glutamate interact in both the VTA and NAS to form incentive-encoded contextual memory ensembles that are predictive of reward derived from affiliative objects. Affiliative stimuli, in particular, are incorporated within contextual ensembles predictive of affiliative reward via: (a) the binding of affiliative stimuli in the rostral circuit of the medial extended amygdala and subsequent transmission to the NAS shell; (b) affiliative stimulus-induced opiate potentiation of DA processes in the VTA and NAS; and (c) permissive or facilitatory effects of gonadal steroids, oxytocin (in interaction with DA), and vasopressin on (i) sensory, perceptual, and attentional processing of affiliative stimuli and (ii) formation of social memories. Among these various processes, we propose that the capacity to experience affiliative reward via opiate functioning has a disproportionate weight in determining individual differences in affiliation. We delineate sources of these individual differences, and provide the first human data that support an association between opiate functioning and variation in trait affiliation.


Sleeping ribosomes: Bacterial signaling triggers RaiA mediated persistence to aminoglycosides.
Indole is a molecule proposed to be involved in bacterial signaling. We find that indole secretion is induced by sublethal tobramycin concentrations and increases persistence to aminoglycosides in V. cholerae. Indole transcriptomics showed increased expression of raiA, a ribosome associated factor. Deletion of raiA abolishes the appearance of indole dependent persisters to aminoglycosides, although its overexpression leads to 100-fold increase of persisters, and a reduction in lag phase, evocative of increased active 70S ribosome content, confirmed by sucrose gradient analysis. We propose that, under stress conditions, RaiA-bound inactive 70S ribosomes are stored as "sleeping ribosomes", and are rapidly reactivated upon stress relief. Our results point to an active process of persister formation through ribosome protection during translational stress (e.g., aminoglycoside treatment) and reactivation upon antibiotic removal. Translation is a universal process, and these results could help elucidate a mechanism of persistence formation in a controlled, thus inducible way.


Thermal ablation combined with high ligation of sapheno-femoral junction for lower limb primary varicosity.
For long time the traditional surgical treatment for lower limb varicose veins has been high ligation of sapheno-femoral junction and stripping of great saphenous vein. Surgery, however, has been frustrated by postoperative pains, discomfort and recurrences so that it has been challenged by minimally invasive endovenous techniques such as laser treatment and radiofrequency ablation. The aim of the article is to assess the feasibility of a combined approach to greater saphenous vein reflux: high ligation of sapheno-femoral junction and thermal treatment of the great saphenous vein. A retrospective analysis on 95 patients treated with high ligation and thermal ablation at our institution was performed, assessing duration of surgery, post-operative pain and analgesics requirements, early complications and resumption of activities. Two patients (5,4%), in the laser group experienced skin burns in the course of the GSV. Moderate ecchymosis, by laser fibre-Romainduced perforation of the vein wall, were observed in another two patients (5.4%). Four limbs (10.8%) in the EVLT group developed transient paraesthesias. Analgesic requirement on POD 3 was nil for RFA group; conversely half of the EVLT patients did take analgesics, either 2 or 3 tabs were required. On POD 7, the patients of RFA group continued to not ask for any analgesics, but the same half of the patients in EVLT group still needed 1-2 tabs to carry out their normal activities smoothly. On POD 15, no patient did require analgesics. Resumption of routine activities was earlier for RFA group patients than for those in the EVLT group. The RFA group resumed their activities within 3 days, whereas EVLT group in 8-9 days. High ligation of the SFJ didn't add too much time or morbidities. High ligation of saphenous femoral arc combined with catheter delivered thermal energies for saphenous ablation, even when combined with high ligation of saphenous femoral arc, demonstrated to be minimally invasive, easy to learn and easy to perform, with early resumption and return to normal activity. EVLT achieved similar results to RFA and both techniques were considered equally effective and safe; the results we obtained were not statistically significant but RFA showed less pain, ecchymosis and haematomas, as well as provided better short-term quality of life.


A prospective study of floor surface, shoes, floor cleaning and slipping in US limited-service restaurant workers.
Slips and falls are a leading cause of injury at work. Few studies, however, have systematically examined risk factors of slipping outside the laboratory environment. This study examined the association between floor surface characteristics, slip-resistant shoes, floor cleaning frequency and the risk of slipping in limited-service restaurant workers. 475 workers from 36 limited-service restaurants from three major chains in six states in the USA were recruited to participate in a prospective cohort study of workplace slipping. Kitchen floor surface roughness and coefficient of friction (COF) were measured in eight working areas and then averaged within each restaurant. The use of slip-resistant shoes was determined by examining the participant's shoes and noting the presence of a 'slip-resistant' marking on the sole. Restaurant managers reported the frequency of daily kitchen floor cleaning. Participants reported their slip experience and work hours weekly for up to 12 weeks. The survey materials were made available in three languages: English, Spanish and Portuguese. The associations between rate of slipping and risk factors were assessed using a multivariable negative binomial generalised estimating equation model. The mean of individual slipping rate varied among the restaurants from 0.02 to 2.49 slips per 40 work hours. After adjusting for age, gender, BMI, education, primary language, job tenure and restaurant chain, the use of slip-resistant shoes was associated with a 54% reduction in the reported rate of slipping (95% CI 37% to 64%), and the rate of slipping decreased by 21% (95% CI 5% to 34%) for each 0.1 increase in the mean kitchen COF. Increasing floor cleaning frequency was significantly associated with a decreasing rate of slipping when considered in isolation but not after statistical adjustment for other factors. These results provide support for the use of slip-resistant shoes and measures to increase COF as preventive interventions to reduce slips, falls and injuries.


A meta-analysis of EMG biofeedback treatment of temporomandibular disorders.
Outcome evaluations of treatments incorporating electromyographic (EMG) biofeedback for temporomandibular disorders (TMD) have been conducted for more than 2 decades. The purpose of this study was to review the available literature to determine the efficacy of biofeedback-based treatments and to estimate treatment effect sizes. A literature search located 13 studies of EMG biofeedback treatment for TMD, including 6 controlled, 4 comparative treatment, and 3 uncontrolled trials. Three types of outcome were examined: patient pain reports, clinical exam findings, and ratings of global improvement. Five of the 6 controlled trials found EMG biofeedback treatments to be superior to no treatment or psychologic placebo controls for at least 1 of the 3 types of outcome. Data from 12 studies contributed to a meta-analysis that compared pre- to posttreatment effect sizes for EMG biofeedback treatments to effect sizes for control conditions. Mean effect sizes for both reported pain and clinical exam outcomes were substantially larger for biofeedback treatments than for control conditions. In addition, 69% of patients who received EMG biofeedback treatments were rated as symptom-free or significantly improved, compared with 35% of patients treated with a variety of placebo interventions. Follow-up outcomes for EMG biofeedback treatments showed no deterioration from posttreatment levels. Although limited in extent, the available data support the efficacy of EMG biofeedback treatments for TMD.


Phenotypic presentation of chronic cough in children.
Chronic cough in children is increasingly defined as a cough that lasts more than four weeks. It is recognized as a different entity than cough in adults. As a result, the diagnostic approach and management of chronic cough in children are no longer extrapolated from adult guidelines. These differences are attributed to the various characteristics of the respiratory tract, immunological system and nervous system in children. Specific paediatric guidelines and algorithms for chronic cough are now widely applied. Post-infectious cough, asthma, bronchiectasis, malacia and protracted bacterial bronchitis (PBB) appear to be the major causes of cough in young children. By adolescence, the causes of cough are more likely to be similar to those in adults, namely, gastroesophageal reflux, asthma, and upper airway syndrome. In a primary setting, it is essential to investigate the underlying disease entity that initiates and sustains chronic cough. The use of cough management protocols or algorithms improves clinical outcomes and should differ depending on the associated characteristics of the cough and the child's clinical history. Performing a thorough history and physical examination is crucial to starting an individualised approach. A correct interpretation of the phenotypic presentation can be translated into guidance for workup. This approach will be helpful for adequate management without the risk of inappropriate investigations or inadequate treatment.


Calculating hospital length of stay using the Hospital Episode Statistics; a comparison of methodologies.
Accurate calculation of hospital length of stay (LOS) from the English Hospital Episode Statistics (HES) is important for a wide range of audit and research purposes. The two methodologies which are commonly used to achieve this differ in their accuracy and complexity. We compare these methods and make recommendations on when each is most appropriate. We calculated LOS using continuous inpatient spells (CIPS), which link care spanning across multiple hospitals, and spells, which do not, for six conditions with short (dyspepsia or other stomach function, ENT infection), medium (dehydration and gastroenteritis, perforated or bleeding ulcer), and long (stroke, fractured proximal femur) average LOS. We examined how inter-area comparisons (i.e. benchmarking) and temporal trends differed. We defined a classification system for spells and explored the causes of differences. Stroke LOS was 16.5 days using CIPS but 24% (95% CI: 23, 24) lower, at 12.6 days, using spells. Smaller differences existed for shorter-LOS conditions including dehydration and gastroenteritis (4.5 vs. 4.2 days) and ENT infection (0.9 vs. 0.8 days). Typical patient pathways differed markedly between areas and have evolved over time. One area had the third shortest stroke LOS (out of 151) using spells but the fourth longest using CIPS. These issues were most profound for stroke and fractured proximal femur, as patients were frequently transferred to a separate hospital for rehabilitation, however important disparities also existed for conditions with simpler secondary care pathways (e.g. ENT infections, dehydration and gastroenteritis). Spell-based LOS is widely used by researchers and national reporting organisations, including the Health and Social Care Information Centre, however it can substantially underestimate the time patients spend in hospital. A widespread shift to a CIPS methodology is required to improve the quality of LOS estimates and the robustness of research and benchmarking findings. This is vital when investigating clinical areas with typically long, complex patient pathways. Researchers should ensure that their LOS calculation methodology is fully described and explicitly acknowledge weaknesses when appropriate.


Journey of vulnerability: a mixed-methods study to understand intrapartum transfers in Tanzania and Zambia.
Timely intrapartum referral between facilities is pivotal in reducing maternal/neonatal mortality and morbidity but is distressing to women, resource-intensive and likely to cause delays in care provision. We explored the complexities around referrals to gain understanding of the characteristics, experiences and outcomes of those being transferred. We used a mixed-method parallel convergent design, in Tanzania and Zambia. Quantitative data were collected from a consecutive, retrospective case-note review (target, n = 2000); intrapartum transfers and stillbirths were the outcomes of interest. A grounded theory approach was adopted for the qualitative element; data were collected from semi-structured interviews (n = 85) with women, partners and health providers. Observations (n = 33) of transfer were also conducted. Quantitative data were analysed descriptively, followed by binary logistic regression models, with multiple imputation for missing data. Qualitative data were analysed using Strauss's constant comparative approach. Intrapartum transfer rates were 11% (111/998; 2 unknown) in Tanzania and 37% (373/996; 1 unknown) in Zambia. Main reasons for transfer were prolonged/obstructed labour and pre-eclampsia/eclampsia. Women most likely to be transferred were from Zambia (as opposed to Tanzania), HIV positive, attended antenatal clinic < 4 times and living > 30 min away from the referral hospital. Differences were observed between countries. Of those transferred, delays in care were common and an increase in poor outcomes was observed. Qualitative findings identified three categories: social threats to successful transfer, barriers to timely intrapartum care and reparative interventions which were linked to a core category: journey of vulnerability. Although intrapartum transfers are inevitable, modifiable factors exist with the potential to improve the experience and outcomes for women. Effective transfers rely on adequate resources, effective transport infrastructures, social support and appropriate decision-making. However, women's (and families) vulnerability can be reduced by empathic communication, timely assessment and a positive birth outcome; this can improve women's resilience and influence positive decision-making, for the index and future pregnancy.


An alternative sampling algorithm for use in liquid chromatography/tandem mass spectrometry experiments.
In liquid chromatography/tandem mass spectrometry (LC/MS/MS) analyses of complex peptide mixtures, dynamic exclusion functions are used to minimize repeat selections of identical precursors for collision induced dissociation (CID). We describe a new algorithm for the dynamic exclusion of m/z values during LC/MS/MS. Full-scan based peak exclusion (Fulspec) uses a simplified model of chromatographic peak formation to detect and exclude contaminants present throughout the run or that lead to broad peaks. Therefore, instead of excluding peptides from fragment analysis according to a rigidly predefined time window, the chromatographic properties of the detected analytes are used. The algorithm was tested on two datasets derived from previously published experiments. Fulspec achieves a distribution of CID spectra with minimal tailing on the retention time axis, without resorting to rigid exclusion of m/z values. The procedure further excludes intensities with a bias towards low-quality CID spectra. This combination frees up valuable analytical capacity. The underlying intensity vs. quality analyses challenge the assumption that abundant precursors automatically give the best identifications. Further validation of the algorithm will require its incorporation by equipment manufacturers into the instrument control programs.


Calcium absorption and bone mineral density in celiacs after long term treatment with gluten-free diet and adequate calcium intake.
Calcium malabsorption, hypocalcemia and skeletal demineralization are well-recognized features of untreated celiac disease. This study investigates calcium absorption and bone mineral density (BMD) after a prolonged, over 4 years, treatment with a gluten-free diet. Twenty-four adult females with treated celiac disease and twenty age- and sex-matched control subjects were studied. Mean body mass index (MBI), energy intake, serum calcium, and serum 25(OH)D concentrations in treated celiacs did not differ from controls. However, while both dietary calcium and protein intake were significantly higher in celiacs (P<0.012), fractional calcium absorption was lower (mean percentage+/-SD; treated 39.8+/-12 versus controls 52.3+/-10, P<0.001). Thus, after adjusting for calcium intake, the estimated amount of calcium absorbed daily was similar in both groups. Whole body, spine and trochanter BMD were significantly lower in treated celiac patients compared with controls (P<0.05). There were significant inverse correlations between: serum parathyroid hormone (PTH) and femoral neck or total body BMD (P<0.01), PTH and duration of gluten-free diet (P=0.05), and fractional calcium absorption and alkaline phosphatase (P=0.022). Increased calcium intake could potentially compensate for the reduced fractional calcium absorption in treated adult celiac patients, but may not normalize the BMD. In addition, the inverse correlation between PTH and time following treatment is suggestive of a continuing long-term benefit of gluten withdrawal on bone metabolism in celiac patients.


Splash!: a prospective birth cohort study of the impact of environmental, social and family-level influences on child oral health and obesity related risk factors and outcomes.
Dental caries (decay) is the most prevalent disease of childhood. It is often left untreated and can impact negatively on general health, and physical, developmental, social and learning outcomes. Similar to other health issues, the greatest burden of dental caries is seen in those of low socio-economic position. In addition, a number of diet-related risk factors for dental caries are shared risk factors for the development of childhood obesity. These include high and frequent consumption of refined carbohydrates (predominately sugars), and soft drinks and other sweetened beverages, and low intake of (fluoridated) water. The prevalence of childhood obesity is also at a concerning level in most countries and there is an opportunity to determine interventions for addressing both of these largely preventable conditions through sustainable and equitable solutions. This study aims to prospectively examine the impact of drink choices on child obesity risk and oral health status. This is a two-stage study using a mixed methods research approach. The first stage involves qualitative interviews of a sub-sample of recruited parents to develop an understanding of the processes involved in drink choice, and inform the development of the Discrete Choice Experiment analysis and the measurement instruments to be used in the second stage. The second stage involves the establishment of a prospective birth cohort of 500 children from disadvantaged communities in rural and regional Victoria, Australia (with and without water fluoridation). This longitudinal design allows measurement of changes in the child's diet over time, exposure to fluoride sources including water, dental caries progression, and the risk of childhood obesity. This research will provide a unique contribution to integrated health, education and social policy and program directions, by providing clearer policy relevant evidence on strategies to counter social and environmental factors which predispose infants and children to poor health, wellbeing and social outcomes; and evidence-based strategies to promote health and prevent disease through the adoption of healthier lifestyles and diet. Further, given the absence of evidence on the processes and effectiveness of contemporary policy implementation, such as community water fluoridation in rural and regional communities it's approach and findings will be extremely informative.


A comparative synthetic, magnetic and theoretical study of functional M₄Cl₄ cubane-type Co(II) and Ni(II) complexes.
We describe the synthesis, structures, and magnetochemistry of new M4Cl4 cubane-type cobalt(II) and nickel(II) complexes with the formula [M(μ3-Cl)Cl(HL·S)]4 (1: M = Co; 2: M = Ni), where HL·S represents a pyridyl-alcohol-type ligand with a thioether functional group, introduced to allow subsequent binding to Au surfaces. Dc and ac magnetic susceptibility data of 1 and 2 were modeled with a full spin Hamiltonian implemented in the computational framework CONDON 2.0. Although both coordination clusters 1 and 2 are isostructural, with each of their transition metal ions in a pseudo-octahedral coordination environment of four Cl atoms and N,O-donor atoms of one chelating HL·S ligand, the substantially different ligand field effects of Co(II) and Ni(II) results in stark differences in their magnetism. In contrast to compound 1 which exhibits a dominant antiferromagnetic intramolecular coupling (J = -0.14 cm(-1)), 2 is characterised by a ferromagnetic coupling (J = +10.6 cm(-1)) and is considered to be a single-molecule magnet (SMM), a feature of special interest for future surface deposition studies. An analysis based on density functional theory (DFT) was performed to explore possible magnetostructural correlations in these compounds. Using a two-J model Hamiltonian, it revealed that compound 1 has four positive and two (small) negative J(Co···Co) isotropic interactions leading to a S(HS) = 6 ground state. Taking into account the magnetic anisotropy, one would recover a M(S) = 0 ground state since D > 0 from computations. In 2, all the J constants are positive and, in this framework, the zero-field splitting energy characterising the axial anisotropy was estimated to be negative (D = -0.44 cm(-1)). The computational results are consistent with compound 2 being an SMM.


Marine anoxia and delayed Earth system recovery after the end-Permian extinction.
Delayed Earth system recovery following the end-Permian mass extinction is often attributed to severe ocean anoxia. However, the extent and duration of Early Triassic anoxia remains poorly constrained. Here we use paired records of uranium concentrations ([U]) and (238)U/(235)U isotopic compositions (δ(238)U) of Upper Permian-Upper Triassic marine limestones from China and Turkey to quantify variations in global seafloor redox conditions. We observe abrupt decreases in [U] and δ(238)U across the end-Permian extinction horizon, from ∼3 ppm and -0.15‰ to ∼0.3 ppm and -0.77‰, followed by a gradual return to preextinction values over the subsequent 5 million years. These trends imply a factor of 100 increase in the extent of seafloor anoxia and suggest the presence of a shallow oxygen minimum zone (OMZ) that inhibited the recovery of benthic animal diversity and marine ecosystem function. We hypothesize that in the Early Triassic oceans-characterized by prolonged shallow anoxia that may have impinged onto continental shelves-global biogeochemical cycles and marine ecosystem structure became more sensitive to variation in the position of the OMZ. Under this hypothesis, the Middle Triassic decline in bottom water anoxia, stabilization of biogeochemical cycles, and diversification of marine animals together reflect the development of a deeper and less extensive OMZ, which regulated Earth system recovery following the end-Permian catastrophe.


Downregulation of S100 Calcium Binding Protein A9 in Esophageal Squamous Cell Carcinoma.
The development of esophageal squamous cell carcinoma (ESCC) is poorly understood and the major regulatory molecules involved in the process of tumorigenesis have not yet been identified. We had previously employed a quantitative proteomic approach to identify differentially expressed proteins in ESCC tumors. A total of 238 differentially expressed proteins were identified in that study including S100 calcium binding protein A9 (S100A9) as one of the major downregulated proteins. In the present study, we carried out immunohistochemical validation of S100A9 in a large cohort of ESCC patients to determine the expression and subcellular localization of S100A9 in tumors and adjacent normal esophageal epithelia. Downregulation of S100A9 was observed in 67% (n = 192) of 288 different ESCC tumors, with the most dramatic downregulation observed in the poorly differentiated tumors (99/111). Expression of S100A9 was restricted to the prickle and functional layers of normal esophageal mucosa and localized predominantly in the cytoplasm and nucleus whereas virtually no expression was observed in the tumor and stromal cells. This suggests the important role that S100A9 plays in maintaining the differentiated state of epithelium and suggests that its downregulation may be associated with increased susceptibility to tumor formation.


[A meta-analysis on acupuncture treatment of polycystic ovary syndrome].
To evaluate the effect and safety of acupuncture treatment of polycystic ovary syndrome (PCOS) by using systematic review in view of evidence-based medicine (EBM). Original articles about acupuncture treatment of PCOS published from the database-established year to November of 2013 were searched from the Chinese National Knowledge Infrastructure Database (CNKI), Chongqing VIP Chinese Science and Technology Periodical Database (VIP), Chinese Biomedical Library (CBM), Wanfang Data, PubMed, and the Cochrane Library and the associated references-indicated papers by using keywords of polycystic ovary syndrome, randomization, acupoint, acupuncture, acupuncture plus moxibustion, acupuncture plus acupoint-embedment of catgut, and acupuncture plus otopoint application. Those articles about treatment of PCOS with simple abdominal acupuncture, simple acupoint-embedment of catgut, simple otopoint-pellet-pressure, and simple moxibustion treatment, and simple abstracts were excluded. If the articles re-published in both Chinese and English and in academic conferences and journals, one of them with higher quality was included. Two independent reviewers extracted data from located articles in a pre-defined structured way, and the Meta-analysis was conducted using software RevMan 5.2, otherwise using the qualitative analysis. A total of 31 articles (28 in Chinese, 3 in English) containing 2,321 cases of PCOS patients met the included criteria. Meta-analysis showed that the clinical efficacy of simple acupuncture was the same as that of western medicine, and the efficacy of acupuncture combined with Chinese herbal medicine interventions was obviously higher than that of western medicine (P < 0.05). In addition, simple acupuncture intervention and acupuncture combined with Chinese herbal medicines or with moxibustion treatment have advantages in reducing serum luteinizing hormone/follicle-stimulating hormone (LH/FSH), insulin resistance (IR), testosterone (T), and body mass index (BMI). However, the quality of the collected articles is generally lower due to unclear bias, no sample quantity estimation, incorrect randomization methods, no follow-up survey, etc. Acupuncture therapy may be effective for PCOS, but needs to be confirmed further by larger sample randomized controlled trials.


Collaborative care to improve the management of depressive disorders: a community guide systematic review and meta-analysis.
To improve the quality of depression management, collaborative care models have been developed from the Chronic Care Model over the past 20 years. Collaborative care is a multicomponent, healthcare system-level intervention that uses case managers to link primary care providers, patients, and mental health specialists. In addition to case management support, primary care providers receive consultation and decision support from mental health specialists (i.e., psychiatrists and psychologists). This collaboration is designed to (1) improve routine screening and diagnosis of depressive disorders; (2) increase provider use of evidence-based protocols for the proactive management of diagnosed depressive disorders; and (3) improve clinical and community support for active client/patient engagement in treatment goal-setting and self-management. A team of subject matter experts in mental health, representing various agencies and institutions, conceptualized and conducted a systematic review and meta-analysis on collaborative care for improving the management of depressive disorders. This team worked under the guidance of the Community Preventive Services Task Force, a nonfederal, independent, volunteer body of public health and prevention experts. Community Guide systematic review methods were used to identify, evaluate, and analyze available evidence. An earlier systematic review with 37 RCTs of collaborative care studies published through 2004 found evidence of effectiveness of these models in improving depression outcomes. An additional 32 studies of collaborative care models conducted between 2004 and 2009 were found for this current review and analyzed. The results from the meta-analyses suggest robust evidence of effectiveness of collaborative care in improving depression symptoms (standardized mean difference [SMD]=0.34); adherence to treatment (OR=2.22); response to treatment (OR=1.78); remission of symptoms (OR=1.74); recovery from symptoms (OR=1.75); quality of life/functional status (SMD=0.12); and satisfaction with care (SMD=0.39) for patients diagnosed with depression (all effect estimates were significant). Collaborative care models are effective in achieving clinically meaningful improvements in depression outcomes and public health benefits in a wide range of populations, settings, and organizations. Collaborative care interventions provide a supportive network of professionals and peers for patients with depression, especially at the primary care level.


Diet and diabetes: lines and dots.
Diabetes, particularly type 2 diabetes, is epidemic in the United States among adults and children alike, and increasingly prevalent around the world. On its current trajectory, the increasing incidence of diabetes has the potential to ravage both public health and economies. There has, however, been evidence for decades that lifestyle has enormous potential to prevent chronic disease, diabetes included. Studies suggest that the combination of tobacco avoidance, routine physical activity, optimal dietary pattern, and weight control could eliminate as much as 80% of all chronic disease, and 90% of cases of diabetes specifically. None of these factors is necessarily easily achieved, but most are simple. Diet, on the other hand, is complex, and arguments abound for competing diets and related health benefits. From an expansive review of relevant literature, the case emerges that the overall theme of optimal eating for human beings is very well established, whereas the case for any given variation on that theme is substantially less so. Once the theme of healthful eating is acknowledged, the challenge shifts to getting there from here. Although much effort focuses on the wholesale conversion of dietary patterns, the introduction or removal of highly nutritious foods can have direct health effects, and potentially reverberate through the diet as well, shifting the quality of the diet and related health effects. Studies demonstrating favorable effects of daily walnut ingestion in diabetes and insulin resistance are profiled as an illustration, and an ongoing study examining the implications of daily walnut ingestion on diet quality and various biometric variables is described. The line between dietary pattern and the epidemiology of diabetes is indelibly established; we must work to connect the dots between here and there.


Phototactic behavior of the Armand pine bark weevil, Pissodes punctatus.
The Armand pine bark weevil, Pissodes punctatus Langor et Zhang (Coleoptera: Curculionidae) is a destructive bark weevil on the Armand pine, Pinus armandii Franch (Pinales: Pinaceae), an important timbering tree in southern China. This study examined the phototactic behavior ïéP. punctatus through observation of behavioral characteristics, response to nine monochromatic lights (ranging from 340 nm to 689 nm with about 40-nm step), and response to five intensities (ranging from 1 lux to 200 lux) of the most attractive light. The results demonstrated that P. punctatus was most active in the day, and kept still at night (or in a dark room). P. punctatus could be attracted to eight of nine monochromatic lights, the exception being red light (649 nm), which implied broad sensitivity to the spectrum of light. P. punctatus was most sensitive to violet (415 nm), ultraviolet (340 nm), and green (504 nm) light, suggesting there might be at least three types of photoreceptors in the compound eyes of this weevil. Furthermore, low intensities elicited an increased phototactic response, and high intensities a decreased phototactic response, under both violet and UV light. Thus, P. punctatus were found to be phototactic insects, and the phototactic behavior of P. punctatus is both a color and intensity preference. The information provided here provides a basis for the improvement of trapping devices for detection and survey of P. punctatus, as well as a basis for the development of alternate control strategies for this important pest of Armand pine and other pine trees.


Implementing early warning messages on emerging health technologies.
The purpose of this study was to determine how horizon-scanning organizations can encourage the implementation of recommendations contained in their early warning messages about emerging health technologies. We reviewed the conclusions of the EUR-ASSESS Project Subgroup report on dissemination and impact, an overview of systematic reviews of interventions to promote implementation of research findings by health care professionals, and various Cochrane Effective Practice and Organisation of Care Group protocols and reviews. The evidence on the effectiveness of different implementation strategies aimed at distinct target groups is of variable quality. There is some evidence from rigorous study designs on the effectiveness of strategies designed to influence the behavior of health care professionals; the quality of the evidence relating to policy makers and the general public is more limited. Horizon-scanning organizations can improve the likelihood of their recommendations being acted upon by developing active implementation strategies based on the best available evidence, establishing links with key groups, and directing early warning messages at specific target audiences. Given the relative lack of good quality evidence, it is important that implementation strategies be rigorously evaluated to determine their effectiveness.


Computation of accommodation coefficients and the use of velocity correlation profiles in molecular dynamics simulations.
For understanding the behavior of a gas close to a channel wall it is important to model the gas-wall interactions as detailed as possible. When using molecular dynamics simulations these interactions can be modeled explicitly, but the computations are time consuming. Replacing the explicit wall with a wall model reduces the computational time but the same characteristics should still remain. Elaborate wall models, such as the Maxwell-Yamamoto model or the Cercignani-Lampis model need a phenomenological parameter (the accommodation coefficient) for the description of the gas-wall interaction as an input. Therefore, computing these accommodation coefficients in a reliable way is very important. In this paper, two systems (platinum walls with either argon or xenon gas confined between them) are investigated and are used for comparison of the accommodation coefficients for the wall models and the explicit molecular dynamics simulations. Velocity correlations between incoming and outgoing particles colliding with the wall have been used to compare explicit simulations and wall models even further. Furthermore, based on these velocity correlations, a method to compute the accommodation coefficients is presented, and these newly computed accommodation coefficients are used to show improved correlation behavior for the wall models.


Labour turnover in the British National Health Service: a local labour market analysis.
This study uses regression analyses to examine the relationship between staff turnover in the British National Health Service (NHS) and a range of labour market, job and worker characteristics. Data relating to nine staff groups in up to 103 District Health Authority areas, and covering over 300,000 employees, form the basis for the analysis. In the regression analysis, two variables consistently emerge as significantly related to turnover across a range of staff groups: the size of the private nursing homes, and the pay of the staff group relative to the local average for comparable workers. The results suggest that staff groups of different skill levels each have distinct labour markets, and this needs to be recognised in the future design of human resources management policies.


Multiple metastases of thyroid cancer in the cranium and pituitary gland in two dogs.
Two dogs, a 14-year-old, female American Eskimo dog and a 14-year-old, male Maltese dog, were presented with thalamic syndromes, including lowered levels of consciousness, poor postural responses and presence of masses in the neck region. In both dogs, magnetic resonance imaging revealed multiple masses inside the cranium, including the pituitary gland. One dog died from status epilepticus two days after magnetic resonance imaging and the other died two months after magnetic resonance imaging from respiratory failure. These dogs were histopathologically diagnosed with multiple metastases of thyroid cancer occurring inside the cranium, including the pituitary gland. To the authors' knowledge, this is the first time this tumour pattern has been reported in dogs, but it is possible that it is not uncommon.


Coherently-enabled environmental control of optics and energy transfer pathways of hybrid quantum dot-metallic nanoparticle systems.
It is well-known that optical properties of semiconductor quantum dots can be controlled using optical cavities or near fields of localized surface plasmon resonances (LSPRs) of metallic nanoparticles. In this paper we study the optics, energy transfer pathways, and exciton states of quantum dots when they are influenced by the near fields associated with plasmonic meta-resonances. Such resonances are formed via coherent coupling of excitons and LSPRs when the quantum dots are close to metallic nanorods and driven by a laser beam. Our results suggest an unprecedented sensitivity to the refractive index of the environment, causing significant spectral changes in the Förster resonance energy transfer from the quantum dots to the nanorods and in exciton transition energies. We demonstrate that when a quantum dot-metallic nanorod system is close to its plasmonic meta-resonance, we can adjust the refractive index to: (i) control the frequency range where the energy transfer from the quantum dot to the metallic nanorod is inhibited, (ii) manipulate the exciton transition energy shift of the quantum dot, and (iii) disengage the quantum dot from the metallic nanoparticle and laser field. Our results show that near meta-resonances the spectral forms of energy transfer and exciton energy shifts are strongly correlated to each other.


Multi-Scale Procedural Animations of Microtubule Dynamics Based on Measured Data.
Biologists often use computer graphics to visualize structures, which due to physical limitations are not possible to image with a microscope. One example for such structures are microtubules, which are present in every eukaryotic cell. They are part of the cytoskeleton maintaining the shape of the cell and playing a key role in the cell division. In this paper, we propose a scientifically-accurate multi-scale procedural model of microtubule dynamics as a novel application scenario for procedural animation, which can generate visualizations of their overall shape, molecular structure, as well as animations of the dynamic behaviour of their growth and disassembly. The model is spanning from tens of micrometers down to atomic resolution. All the aspects of the model are driven by scientific data. The advantage over a traditional, manual animation approach is that when the underlying data change, for instance due to new evidence, the model can be recreated immediately. The procedural animation concept is presented in its generic form, with several novel extensions, facilitating an easy translation to other domains with emergent multi-scale behavior.


Simplified intraoperative sentinel-node detection performed by the urologist accurately determines lymph-node stage in prostate cancer.
The reference standard for lymph-node staging in prostate cancer is currently an extended pelvic lymph-node dissection (ePLND), which detects most, but not all, regional lymph-node metastases. As an alternative to ePLND, sentinel-node dissection with preoperative isotope injection and imaging has been reported. The objective was to determine whether intraoperative sentinel-node detection with a simplified protocol can accurately determine lymph-node stage in prostate cancer patients. Patients with biopsy-verified high-risk prostate cancer with tumour stage T2-3 were included in the study. All patients underwent both ePLND and sentinel-node detection. (99m)Tc-marked nanocolloid was injected peritumourally by the operating urologist after induction of anaesthesia just before surgery. Sentinel nodes were detected both in vivo and ex vivo intraoperatively using a gamma probe. Sentinel nodes and metastases and their locations were recorded. Sensitivity and specificity were calculated. At least one sentinel node was detected in 72 (87%) of the 83 patients. In 13 (18%) of these 72 patients sentinel nodes were detected outside the ePLND template. In six of these 13 patients, the Sentinel nodes from outside the template contained metastases, which proved to be the only metastases in two. For 12 patients the only metastatic deposit found was a micrometastasis (≤2 mm) in a sentinel node. In the 72 patients with detectable sentinel nodes, pathological analysis of the sentinel node correctly categorized 71 and ePLND 70 patients. This protocol yielded results comparable to the commonly used technique of sentinel-node detection, but with more cases of non-detection.


Hydration of cellobial by exo- and endo-type cellulases: evidence for catalytic flexibility of glycosylases.
New insight has been obtained into the catalytic capabilities of cellulase. Essentially homogeneous preparations of exo- (or Avicelase-) type and endo- (or CMCase-) type cellulases from Irpex lacteus and Aspergillus niger, respectively, were shown to hydrate the enolic bond of cellobial to form 2-deoxycellobiose. The A. niger enzyme also synthesized a small amount of a 2-deoxycellobiosyl-transfer product from cellobial. By use of digests conducted in deuterated buffer and 1H NMR spectra for product analysis, both cellulases were found to protonate (deuterate) the double bond of cellobial from below the si face of the D-glucal moiety, i.e., from a direction opposite that assumed for protonation of the beta-D-glycosidic linkages of cellulose and cellodextrins. The exo enzyme, which hydrolyzes the latter substrates primarily to cellobiose, rapidly catalyzed cellobial hydration to produce the beta-anomer of beta-D-glucopyranosyl(1----4)-2-deoxy-D-glucose-2(e)-d. The A. niger cellulase produced the same 2-deoxycellobiose-d from cellobial, though too slowly for its configuration to be determined. However, evidence was obtained for the formation of a beta-2-deoxycellobiosyl-d-D-glucose-transfer product by the enzyme. Thus, it is likely that all of the observed reactions with cellobial represent trans additions at the double bond. In any case, the anomeric configuration of products is created de novo. Separate mechanisms are described for the reaction of cellobial hydration and for the stereochemically different reaction of cellulose hydrolysis catalyzed by the present enzymes, assuming an arrangement of their catalytic groups analogous to that found in lysozyme.(ABSTRACT TRUNCATED AT 250 WORDS)


The effect of APOE genotype on brain levels of oxysterols in young and old human APOE epsilon2, epsilon3 and epsilon4 knock-in mice.
Despite apolipoprotein E's important role in cholesterol transport and metabolism in the brain as well as its influence on Alzheimer's disease, the impact of the human APOE genotype on cholesterol metabolism in brain has not been fully examined. This study was carried out to investigate APOE genotype effects on oxysterols measured. In this study the measurement of cholesterol and several oxysterols in the brains of human APOE epsilon2, epsilon3 and epsilon4 knock-in mice at 8 weeks and 1 year of age using gas chromatography mass spectrometry (GC-MS) demonstrated no APOE genotype or age effect on total brain cholesterol and the oxysterol 24-hydroxycholesterol. The level of 27-hydroxycholesterol was elevated in 1 year old animals for all APOE genotypes. Interestingly, lathosterol an indicator of cholesterol synthesis was significantly reduced in the 1 year old animals for all APOE genotypes. APOE epsilon4 expressing mice exhibited statistically lower levels of lathosterol compared to APOE epsilon2 in both the young and old mice. Oxidized cholesterol metabolites were significantly lower in APOE epsilon2 mice compared to other genotypes at 8 weeks old. Although minimal differences were observed between APOE E3 and E4 knock-in (KI) mice, these findings indicate that there are some clear APOE genotype specific effects on brain cholesterol synthesis and associated metabolic pathways, particularly in APOE epsilon2 KI mice.


The Alexander Technique and musicians: a systematic review of controlled trials.
Musculoskeletal disorders, stress and performance anxiety are common in musicians. Therefore, some use the Alexander Technique (AT), a psycho-physical method that helps to release unnecessary muscle tension and re-educates non-beneficial movement patterns through intentional inhibition of unwanted habitual behaviours. According to a recent review AT sessions may be effective for chronic back pain. This review aimed to evaluate the evidence for the effectiveness of AT sessions on musicians' performance, anxiety, respiratory function and posture. The following electronic databases were searched up to February 2014 for relevant publications: PUBMED, Google Scholar, CINAHL, EMBASE, AMED, PsycINFO and RILM. The search criteria were "Alexander Technique" AND "music*". References were searched, and experts and societies of AT or musicians' medicine contacted for further publications. 237 citations were assessed. 12 studies were included for further analysis, 5 of which were randomised controlled trials (RCTs), 5 controlled but not randomised (CTs), and 2 mixed methods studies. Main outcome measures in RCTs and CTs were music performance, respiratory function, performance anxiety, body use and posture. Music performance was judged by external experts and found to be improved by AT in 1 of 3 RCTs; in 1 RCT comparing neurofeedback (NF) to AT, only NF caused improvements. Respiratory function was investigated in 2 RCTs, but not improved by AT training. Performance anxiety was mostly assessed by questionnaires and decreased by AT in 2 of 2 RCTs and in 2 of 2 CTs. A variety of outcome measures has been used to investigate the effectiveness of AT sessions in musicians. Evidence from RCTs and CTs suggests that AT sessions may improve performance anxiety in musicians. Effects on music performance, respiratory function and posture yet remain inconclusive. Future trials with well-established study designs are warranted to further and more reliably explore the potential of AT in the interest of musicians.


The mediating effect of social relationships on the association between socioeconomic status and subjective health - results from the Heinz Nixdorf Recall cohort study.
Socioeconomic status (SES) is an important determinant of population health. Explanatory approaches on how SES determines health have so far included numerous factors, amongst them psychosocial factors such as social relationships. However, it is unclear whether social relationships can help explain socioeconomic differences in general subjective health. Do different aspects of social relationships contribute differently to the explanation? Based on a cohort study of middle and older aged residents (45 to 75 years) from the Ruhr Area in Germany our study tries to clarify the matter. For the analyses data from the population-based prospective Heinz Nixdorf Recall (HNR) Study is used. As indicators of SES education, equivalent household income and occupational status were employed. Social relations were assessed by including structural as well as functional aspects. Structural aspects were estimated by the Social Integration Index (SII) and functional aspects were measured by availability of emotional and instrumental support. Data on general subjective health status was available for both baseline examination (2000-2003) and a 5-year follow-up (2006-2008). The sample consists of 4,146 men and women. Four logistic regression models were calculated: in the first model we controlled for age and subjective health at baseline, while in models 2 and 3, either functional or structural aspects of social relationships were introduced separately. Model 4 then included all variables. As former studies indicated different health effects of SES and social relations in men and women, analyses were conducted with the overall sample as well as for each gender alone. Prospective associations of SES and subjective health were reduced after introducing social relationships into the regression models. Percentage reductions between 2% and 30% were observed in the overall sample when all aspects of social relations were included. The percentage reductions were strongest in the lowest SES group. Gender specific analyses revealed mediating effects of social relationships in women and men. The magnitude of mediating effects varied depending on the indicators of SES and social relations. Social relationships substantially contribute to the explanation of SES differences in subjective health. Interventions for improving social relations which especially focus on socially deprived groups are likely to help reducing socioeconomic disparities in health.


Circadian disruption induced by light-at-night accelerates aging and promotes tumorigenesis in rats.
We evaluated the effect of various light/dark regimens on the survival, life span and tumorigenesis in rats. Two hundred eight male and 203 females LIO rats were subdivided into 4 groups and kept at various light/dark regimens: standard 12:12 light/dark (LD); natural lighting of the North-West of Russia (NL); constant light (LL), and constant darkness (DD) since the age of 25 days until natural death. We found that exposure to NL and LL regimens accelerated development of metabolic syndrome and spontaneous tumorigenesis, shortened life span both in male and females rats as compared to the standard LD regimen. We conclude that circadian disruption induced by light-at-night accelerates aging and promotes tumorigenesis in rats. This observation supports the conclusion of the International Agency Research on Cancer that shift-work that involves circadian disruption is probably carcinogenic to humans.


Plan-library supported automated replanning for online-adaptive intensity-modulated proton therapy of cervical cancer.
Background: Intensity-modulated proton therapy is sensitive to inter-fraction variations, including density changes along the pencil-beam paths and variations in organ-shape and location. Large day-to-day variations are seen for cervical cancer patients. The purpose of this study was to develop and evaluate a novel method for online selection of a plan from a patient-specific library of prior plans for different anatomies, and adapt it for the daily anatomy. Material and methods: The patient-specific library of prior plans accounting for altered target geometries was generated using a pretreatment established target motion model. Each fraction, the best fitting prior plan was selected. This prior plan was adapted using (1) a restoration of spot-positions (Bragg peaks) by adapting the energies to the new water equivalent path lengths; and (2) a spot addition to fully cover the target of the day, followed by a fast optimization of the spot-weights with the reference point method (RPM) to obtain a Pareto-optimal plan for the daily anatomy. Spot addition and spot-weight optimization could be repeated iteratively. The patient cohort consisted of six patients with in total 23 repeat-CT scans, with a prescribed dose of 45 Gy(RBE) to the primary tumor and the nodal CTV. Using a 1-plan-library (one prior plan based on all motion in the motion model) was compared to choosing from a 2-plan-library (two prior plans based on part of the motion). Results: Applying the prior-plan adaptation method with one iteration of adding spots resulted in clinically acceptable target coverage ( V95%≥95% and V107%≤2% ) for 37/46 plans using the 1-plan-library and 41/46 plans for the 2-plan-library. When adding spots twice, the 2-plan-library approach could obtain acceptable coverage for all scans, while the 1-plan-library approach showed V107%>2% for 3/46 plans. Similar OAR results were obtained. Conclusion: The automated prior-plan adaptation method can successfully adapt for the large day-to-day variations observed in cervical cancer patients.


Trachynilysin mediates SNARE-dependent release of catecholamines from chromaffin cells via external and stored Ca2+.
Trachynilysin, a 159 kDa dimeric protein purified from stonefish (Synanceia trachynis) venom, dramatically increases spontaneous quantal transmitter release at the frog neuromuscular junction, depleting small clear synaptic vesicles, whilst not affecting large dense core vesicles. The basis of this insensitivity of large dense core vesicles exocytosis was examined using a fluorimetric assay to determine whether the toxin could elicit catecholamine release from bovine chromaffin cells. Unlike the case of the motor nerve endings, nanomolar concentrations of trachynilysin evoked sustained Soluble N-ethylmaleimide-sensitive fusion protein Attachment Protein REceptor-dependent exocytosis of large dense core vesicles, but only in the presence of extracellular Ca2+. However, this response to trachynilysin does not rely on Ca2+ influx through voltage-activated Ca2+ channels because the secretion was only slightly affected by blockers of L, N and P/Q types. Instead, trachynilysin elicited a localized increase in intracellular fluorescence monitored with fluo-3/AM, that precisely co-localized with the increase of fluorescence resulting from caffeine-induced release of Ca2+ from intracellular stores. Moreover, depletion of the latter stores inhibited trachynilysin-induced exocytosis. Thus, the observed requirement of external Ca2+ for stimulation of large dense core vesicles exocytosis from chromaffin cells implicates plasma membrane channels that signal efflux of Ca2+ from intracellular stores. This study also suggests that the bases of exocytosis of large dense core vesicles from motor nerve terminals and neuroendocrine cells are distinct.


Role of Hsp70 ATPase domain intrinsic dynamics and sequence evolution in enabling its functional interactions with NEFs.
Catalysis of ADP-ATP exchange by nucleotide exchange factors (NEFs) is central to the activity of Hsp70 molecular chaperones. Yet, the mechanism of interaction of this family of chaperones with NEFs is not well understood in the context of the sequence evolution and structural dynamics of Hsp70 ATPase domains. We studied the interactions of Hsp70 ATPase domains with four different NEFs on the basis of the evolutionary trace and co-evolution of the ATPase domain sequence, combined with elastic network modeling of the collective dynamics of the complexes. Our study reveals a subtle balance between the intrinsic (to the ATPase domain) and specific (to interactions with NEFs) mechanisms shared by the four complexes. Two classes of key residues are distinguished in the Hsp70 ATPase domain: (i) highly conserved residues, involved in nucleotide binding, which mediate, via a global hinge-bending, the ATPase domain opening irrespective of NEF binding, and (ii) not-conserved but co-evolved and highly mobile residues, engaged in specific interactions with NEFs (e.g., N57, R258, R262, E283, D285). The observed interplay between these respective intrinsic (pre-existing, structure-encoded) and specific (co-evolved, sequence-dependent) interactions provides us with insights into the allosteric dynamics and functional evolution of the modular Hsp70 ATPase domain.


Prenatal exposures to persistent and non-persistent organic compounds and effects on immune system development.
Immune system development, particularly in the prenatal period, has far-reaching consequences for health during early childhood, as well as throughout life. Environmental disturbance of the complex balances of Th1 and Th2 response mechanisms can alter that normal development. Dysregulation of this process or an aberrant trajectory or timing of events can result in atopy, asthma, a compromised ability to ward off infection, or other auto-immune disease. A wide range of chemical, physical and biological agents appear to be capable of disrupting immune development. This MiniReview briefly reviews developmental milestones of the immune system in the prenatal period and early life, and then presents examples of environmentally induced alterations in immune markers. The first example involves a birth cohort study linked to an extensive programme of air pollution monitoring; the analysis shows prenatal ambient polycyclic aromatic hydrocarbons (PAH) and fine particle (PM2.5) exposures to be associated with altered lymphocyte immunophenotypic distributions in cord blood and possible changes in cord serum immunoglobulin E levels. The second example is a study of prenatal-polychlorinated biphenyl (PCB) exposures and the foetal development of the thymus, the organ responsible for lymphocyte maturation. Mothers with higher serum concentrations of PCBs gave birth to neonates having smaller indices of thymus size. Finally, this report underscores the tight connection between development of the immune system and that of the central nervous system, and the plausibility that disruption of critical events in immune development may play a role in neurobehavioural disorders.


Excess deaths associated with the Iranian COVID-19 epidemic: A province-level analysis.
There has been no province-level data on the number of coronavirus disease 2019 (COVID-19)-related deaths in Iran since the start of the pandemic. This study was performed to estimate the number of COVID-19 deaths and population-level exposure per province using seasonal all-cause mortality data. Time-series data were collected from the National Organization for Civil Registration on the seasonal all-cause mortality from spring 2015 to summer 2020 (from March 21, 2015 to September 21, 2020), in accordance with the Solar Hijri (SH) calendar, to estimate the expected number of seasonal deaths for each province using a piecewise linear regression model. A population-weighted infection fatality ratio was then applied to estimate the level of exposure per province during this period. From the start of winter to the end of summer (from December 22, 2019 to September 21, 2020), there were a total of 58 900 (95% confidence interval 46 900-69 500) excess deaths across all 31 provinces, with 27% (95% confidence interval 20-34%) estimated nationwide exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In particular, Qom and Golestan were among the hardest-hit provinces, with nearly 57% exposure, while another 27 provinces showed significant levels of excess mortality in at least one season with >20% population-level exposure to the virus. Unexpectedly high levels of excess mortality were also detected during fall 2019 (from September 23 to December 21, 2019) across 18 provinces, unrelated and prior to the start of the COVID-19 pandemic. This study quantified the pattern of spread of COVID-19 across the country and identified areas with the largest epidemic growth requiring the most immediate interventions.


Phase I and pharmacokinetic study of intraperitoneal thioTEPA in patients with ovarian cancer.
A total of 15 patients with residual ovarian cancer confined to the peritoneal cavity after first-line systemic chemotherapy were treated with triethylene-thiophosphoramide (thioTEPA) in a phase I study. A total of 50 courses of thioTEPA were given intraperitoneally in doses ranging from 30 to 80 mg/m2. The dose limiting toxicity was myelosuppression, which occurred at 80 mg/m2 and was frequently prolonged. Short-lived nausea and vomiting was easily controlled, and there was no local toxicity. Three patients remain free of disease progression at 6, 6 and 12 months. ThioTEPA concentrations were measured by gas chromatography. Peritoneal fluid concentrations declined rapidly in a first-order fashion, with a half-life of 0.96 +/- 0.1 h. A mean of 93% of the drug was absorbed during the 4-h dwell time. Peak plasma levels were achieved 30-60 min after drug instillation and were substantially lower than corresponding peritoneal levels. A pharmacokinetic advantage for intraperitoneal delivery was detected for peak drug concentration (24.9 +/- 8.5) and AUC (9.2 +/- 4.8). Based on this study, the recommended dose for intraperitoneal thioTEPA is 60 mg/m2 every 3-4 weeks. However, the rapid absorption of this drug from the peritoneum, secondary to thioTEPA's small molecular weight and lipophilic nature, suggests that it has only a limited role in intraperitoneal therapy.