Kaposi's sarcoma: a model of both malignancy and chronic inflammation.
Kaposi's sarcoma (KS) is a complex cancer characterized by angioproliferative multifocal tumors of the skin, mucosa and viscera. KS lesions are comprised of both distinctive spindle cells of endothelial origin and a variable inflammatory infiltrate. There are four different epidemiological forms of KS: classic (sporadic), African (endemic), AIDS-associated (epidemic), and immunosupression-associated (iatrogenic). Although these various forms of KS have different environmental and immunological components, the development of each depends upon infection with Kaposi's sarcoma herpesvirus/human herpesvirus-8 (KSHV/HHV8). KSHV encodes an arsenal of gene products that induce cellular proliferation, transformation, cell signaling, cytokine production, immune evasion, antiapoptosis and angiogenesis. Yet, KSHV alone is insufficient to give rise to KS. The exact origin of the tumor cell (spindle cell), which is generally agreed to be a type of endothelial cell, remains elusive. Current evidence supports their derivation from lymphatic endothelium. However, both lymphatic and vascular endothelial cell types can be infected by KSHV in vitro, and recent studies suggest that this virus may reprogram the target cell, thus masking the cell's true origin. It is also possible that the original target cell is an uncommitted progenitor. In addition to the potentially neoplastic spindle cells, the KS lesion also contains dendritic cells, macrophages, plasma cells and lymphocytes. The presence of this admixed immune infiltrate has led to the suggestion that KS may result from reactive hyperproliferation induced by chronic inflammation, and that it is therefore not a true neoplasm. This review details the data that support KS as a model of both oncogenesis and chronic inflammation.


Longitudinal field study on bovine Babesia spp. and Anaplasma phagocytophilum infections during a grazing season in Belgium.
Anaplasmosis and babesiosis are major tick-borne diseases with a high economic impact but are also a public health concern. Blood samples collected in the spring, summer, and autumn of 2010 from 65 cows in seven different farms in Belgium were monitored with an indirect immunofluorescence antibody test to assess seroprevalence against these pathogens. Seroprevalences to Babesia spp. were measured as 10.7%, 20%, and 12.3% in spring, summer, and autumn, respectively, whereas seroprevalences to Anaplasma phagocytophilum were 30.8%, 77%, and 56.9%, respectively. A total of 805 Ixodes ricinus ticks were collected at the same time from both cattle (feeding ticks) and grazed pastures (questing ticks). The infection level of ticks, assessed by PCR assay, for Babesia spp. DNA was 14.6% and 7.9% in feeding and questing ticks, respectively, whereas 21.7% and 3% of feeding and questing ticks were found be positive for A. phagocytophilum cDNA. Fifty-five PCR-positive samples were identified by sequencing as Babesia sp. EU1, of which five from feeding ticks were positive for both A. phagocytophilum and Babesia sp. EU1. The high density of wild cervids in the study area could explain these observations, as deer are considered to be the main hosts for adults of I. ricinus. However, the absence of Babesia divergens both in feeding and questing ticks is surprising, as the study area is known to be endemic for cattle babesiosis. Increasing cervid populations and comorbidity could play an import role in the epidemiology of these tick-borne diseases.


Hepatocyte growth factor in normal and diseased bone and joint tissues.
Hepatocyte Growth Factor (HGF) is a multifunctional growth factor which, like its receptor c-Met, is widely expressed in osteoarticular tissues. HGF has profound effects on cell motility and differentiation and tissue morphogenesis and angiogenesis. HGF plays an important role in normal bone and cartilage turnover. Changes in HGF/c-Met have also been linked to pathophysiological changes in several bone and joint disorders. HGF has been implicated in the pathogenesis of inflammatory changes in rheumatoid synovium and in degenerative changes in osteoarthritis. HGF also influences bone remodelling and has significant effects on the proliferation and differentiation of osteoclast precursors, osteoclast activity and survival. A therapeutic role of HGF also has been proposed in the regeneration of osteoarticular tissues.


Alzheimer's disease cell bank.
The seventh sentence of the first paragraph of the letter from P. W. Anderson, E. Abrahams, and R. Laughlin that appeared in the issue of 1 March (pp. 1005-1006) was printed incorrectly. It should have read, "Others, such as the ;anyon' proponents, a group at Bell laboratories and Rutgers, and another at Princeton, are sure that this system is not a Fermi liquid."


Comparison of spinal manipulation methods and usual medical care for acute and subacute low back pain: a randomized clinical trial.
Randomized controlled trial with follow-up to 6 months. This was a comparative effectiveness trial of manual-thrust manipulation (MTM) versus mechanical-assisted manipulation (MAM); and manipulation versus usual medical care (UMC). Low back pain (LBP) is one of the most common conditions seen in primary care and physical medicine practice. MTM is a common treatment for LBP. Claims that MAM is an effective alternative to MTM have yet to be substantiated. There is also question about the effectiveness of manipulation in acute and subacute LBP compared with UMC. A total of 107 adults with onset of LBP within the past 12 weeks were randomized to 1 of 3 treatment groups: MTM, MAM, or UMC. Outcome measures included the Oswestry LBP Disability Index (0-100 scale) and numeric pain rating (0-10 scale). Participants in the manipulation groups were treated twice weekly during 4 weeks; subjects in UMC were seen for 3 visits during this time. Outcome measures were captured at baseline, 4 weeks, 3 months, and 6 months. Linear regression showed a statistically significant advantage of MTM at 4 weeks compared with MAM (disability = -8.1, P = 0.009; pain = -1.4, P = 0.002) and UMC (disability = -6.5, P = 0.032; pain = -1.7, P < 0.001). Responder analysis, defined as 30% and 50% reductions in Oswestry LBP Disability Index scores revealed a significantly greater proportion of responders at 4 weeks in MTM (76%; 50%) compared with MAM (50%; 16%) and UMC (48%; 39%). Similar between-group results were found for pain: MTM (94%; 76%); MAM (69%; 47%); and UMC (56%; 41%). No statistically significant group differences were found between MAM and UMC, and for any comparison at 3 or 6 months. MTM provides greater short-term reductions in self-reported disability and pain scores compared with UMC or MAM. 2.


Genomic data assimilation for estimating hybrid functional Petri net from time-course gene expression data.
We propose an automatic construction method of the hybrid functional Petri net as a simulation model of biological pathways. The problems we consider are how we choose the values of parameters and how we set the network structure. Usually, we tune these unknown factors empirically so that the simulation results are consistent with biological knowledge. Obviously, this approach has the limitation in the size of network of interest. To extend the capability of the simulation model, we propose the use of data assimilation approach that was originally established in the field of geophysical simulation science. We provide genomic data assimilation framework that establishes a link between our simulation model and observed data like microarray gene expression data by using a nonlinear state space model. A key idea of our genomic data assimilation is that the unknown parameters in simulation model are converted as the parameter of the state space model and the estimates are obtained as the maximum a posteriori estimators. In the parameter estimation process, the simulation model is used to generate the system model in the state space model. Such a formulation enables us to handle both the model construction and the parameter tuning within a framework of the Bayesian statistical inferences. In particular, the Bayesian approach provides us a way of controlling overfitting during the parameter estimations that is essential for constructing a reliable biological pathway. We demonstrate the effectiveness of our approach using synthetic data. As a result, parameter estimation using genomic data assimilation works very well and the network structure is suitably selected.


Characteristics and outcome of patients with newly diagnosed advanced or metastatic lung cancer admitted to intensive care units (ICUs).
Although patients with advanced or metastatic lung cancer have poor prognosis, admission to the ICU for management of life-threatening complications has increased over the years. Patients with newly diagnosed lung cancer appear as good candidates for ICU admission, but more robust information to assist decisions is lacking. The aim of our study was to evaluate the prognosis of newly diagnosed unresectable lung cancer patients. A retrospective multicentric study analyzed the outcome of patients admitted to the ICU with a newly diagnosed lung cancer (diagnosis within the month) between 2010 and 2013. Out of the 100 patients, 30 had small cell lung cancer (SCLC) and 70 had non-small cell lung cancer. (Thirty patients had already been treated with oncologic treatments.) Mechanical ventilation (MV) was performed for 81 patients. Seventeen patients received emergency chemotherapy during their ICU stay. ICU, hospital, 3- and 6-month mortality were, respectively, 47, 60, 67 and 71%. Hospital mortality was 60% when invasive MV was used alone, 71% when MV and vasopressors were needed and 83% when MV, vasopressors and hemodialysis were required. In multivariate analysis, hospital mortality was associated with metastatic disease (OR 4.22 [1.4-12.4]; p = 0.008), need for invasive MV (OR 4.20 [1.11-16.2]; p = 0.030), while chemotherapy in ICU was associated with survival (OR 0.23, [0.07-0.81]; p = 0.020). This study shows that ICU management can be appropriate for selected newly diagnosed patients with advanced lung cancer, and chemotherapy might improve outcome for patients with SCLC admitted for cancer-related complications. Nevertheless, tumors' characteristics, numbers and types of organ dysfunction should be taken into account in the decisional process before admitting these patients in ICU.


Molecular genetics in myelodysplastic syndromes.
Myelodysplastic syndromes (MDS) are diagnosed by a combination of cytomorphology and cytogenetics. Fluorescence in situ hybridisation (FISH) can accompany cytogenetic results or can in some cases also be performed instead of chromosome banding analysis. In recent years also immunophenotyping added important information for the diagnosis of MDS. So far, diagnosis however still depends on cytomorphology of peripheral blood and bone marrow smears. The prognostication is done according to the IPSS or very recently to the revised IPSS by a combination of cytopenia, morphologic features according to the WHO classification (2008) and cytogenetic results. In addition, also molecular markers have been shown to contribute important information for diagnosis and also for prognosis in patients with MDS. These markers are in some cases found by next generation sequencing including whole exome sequencing of patients with MDS. Prospective analysis will show the best combination of methods to diagnose patients with MDS or to define their respective prognosis. Without doubt, mutations in newly depicted genes, including genes involved in the spliceosome, will be included in the management of MDS patients.


A qualitative study of GP, NP and patient views about the use of rapid streptococcal antigen detection tests (RADTs) in primary care: 'swamped with sore throats?'.
To explore patient and healthcare professionals' (HCP) views of clinical scores and rapid streptococcal antigen detection tests (RADTs) for acute sore throat. Qualitative semistructured interview study. UK primary care. General practitioners (GPs), nurse practitioners (NPs) and patients from general practices across Hampshire, Oxfordshire and the West Midlands who were participating in the Primary Care Streptococcal Management (PRISM) study. Semistructured, face-to-face and phone interviews were conducted with GPs, NPs and patients from general practices across Hampshire, Oxfordshire and the West Midlands. 51 participants took part in the study. Of these, 42 were HCPs (29 GPs and 13 NPs) and 9 were patients. HCPs could see a positive role for RADTs in terms of reassurance, as an educational tool for patients, and for aiding inexperienced practitioners, but also had major concerns about RADT use in clinical practice. Particular concerns included the validity of the tests (the role of other bacteria, and carrier states), the tension and possible disconnect with clinical assessment and intuition, the issues of time and resource use and the potential for medicalisation of self-limiting illness. In contrast, however, experience of using RADTs over time seemed to make some participants more positive about using the tests. Moreover, patients were much more positive about the place of RADTs in providing reassurance and in limiting their antibiotic use. It is unlikely that RADTs will have a (comfortable) place in clinical practice in the near future until health professionals' concerns are met, and they have direct experience of using them. The routine use of clinical scoring systems for acute upper respiratory illness also face important barriers related to clinicians' perceptions of their utility in the face of clinician experience and intuition.


Mortality effects of timing alternatives for hip fracture surgery.
The appropriate timing of hip fracture surgery remains a matter of debate. We sought to estimate the effect of changes in timing policy and the proportion of deaths attributable to surgical delay. We obtained discharge abstracts from the Canadian Institute for Health Information for hip fracture surgery in Canada (excluding Quebec) between 2004 and 2012. We estimated the expected population-average risks of inpatient death within 30 days if patients were surgically treated on day of admission, inpatient day 2, day 3 or after day 3. We weighted observations with the inverse propensity score of surgical timing according to confounders selected from a causal diagram. Of 139 119 medically stable patients with hip fracture who were aged 65 years or older, 32 120 (23.1%) underwent surgery on admission day, 60 505 (43.5%) on inpatient day 2, 29 236 (21.0%) on day 3 and 17 258 (12.4%) after day 3. Cumulative 30-day in-hospital mortality was 4.9% among patients who were surgically treated on admission day, increasing to 6.9% for surgery done after day 3. We projected an additional 10.9 (95% confidence interval [CI] 6.8 to 15.1) deaths per 1000 surgeries if all surgeries were done after inpatient day 3 instead of admission day. The attributable proportion of deaths for delays beyond inpatient day 2 was 16.5% (95% CI 12.0% to 21.0%). Surgery on admission day or the following day was estimated to reduce postoperative mortality among medically stable patients with hip fracture. Hospitals should expedite operating room access for patients whose surgery has already been delayed for nonmedical reasons.


[Prevalence of microbiologically-confirmed influenza in patients with influenza-like illness in primary care and clinical and epidemiological characteristics].
We evaluated the prevalence of microbiologically-confirmed influenza infection among patients with influenza-like symptoms and compared the clinical and epidemiological characteristics of patients with and without influenza infection. Retrospective study of a cohort of patients with influenza-like symptoms from 2016 to 2018 who participated in a clinical trial in thirteen urban primary centres in Catalonia. Different epidemiological data were collected. Patients rated the different symptoms and signs on a Likert scale (absent, little problem, moderate problem and severe problem) and self-reported the measure of health status with the EuroQol visual analogue scale. A nasopharyngeal swab was taken for microbiological isolation of influenza and other microorganisms. A total of 427 patients were included. Microbiologically confirmed influenza was found in 240 patients (56.2%). The percentage of patients with moderate-to-severe cough, muscle aches, tiredness and dizziness was greater among patients with microbiologically confirmed influenza. The self-reported health status was significantly lower among patients with true flu infection (mean of 36.3 ± 18.2 vs 41.7 ± 17.8 in patients without influenza; p<0.001). Clinical findings are not particularly useful for confirming or excluding the diagnosis of influenza when intensity is not considered. However, the presence of moderate-to-severe cough, myalgias, tiredness and dizziness along with a poor health status is more common in patients with confirmed flu infection.


ERβ-Dependent Direct Suppression of Human and Murine Th17 Cells and Treatment of Established Central Nervous System Autoimmunity by a Neurosteroid.
Multiple sclerosis (MS), an autoimmune disease of the CNS, is mediated by autoreactive Th cells. A previous study showed that the neurosteroid dehydroepiandrosterone (DHEA), when administered preclinically, could suppress progression of relapsing-remitting experimental autoimmune encephalomyelitis (EAE). However, the effects of DHEA on human or murine pathogenic immune cells, such as Th17, were unknown. In addition, effects of this neurosteroid on symptomatic disease, as well as the receptors involved, had not been investigated. In this study, we show that DHEA suppressed peripheral responses from patients with MS and reversed established paralysis and CNS inflammation in four different EAE models, including the 2D2 TCR-transgenic mouse model. DHEA directly inhibited human and murine Th17 cells, inducing IL-10-producing regulatory T cells. Administration of DHEA in symptomatic mice induced regulatory CD4(+) T cells that were suppressive in an IL-10-dependent manner. Expression of the estrogen receptor β by CD4(+) T cells was necessary for DHEA-mediated EAE amelioration, as well as for direct downregulation of Th17 responses. TGF-β1 as well as aryl hydrocarbon receptor activation was necessary for the expansion of IL-10-producing T cells by DHEA. Thus, our studies demonstrate that compounds that inhibit pathogenic Th17 responses and expand functional regulatory cells could serve as therapeutic agents for autoimmune diseases, such as MS.


Reference intervals and physiologic alterations in hematologic and biochemical values of free-ranging desert tortoises in the Mojave Desert.
Desert tortoise (Gopherus agassizii) populations have experienced precipitous declines resulting from the cumulative impact of habitat loss, and human and disease-related mortality. Evaluation of hematologic and biochemical responses of desert tortoises to physiologic and environmental factors can facilitate the assessment of stress and disease in tortoises and contribute to management decisions and population recovery. The goal of this study was to obtain and analyze clinical laboratory data from free-ranging desert tortoises at three sites in the Mojave Desert (California, USA) between October 1990 and October 1995, to establish reference intervals, and to develop guidelines for the interpretation of laboratory data under a variety of environmental and physiologic conditions. Body weight, carapace length, and venous blood samples for a complete blood count and clinical chemistry profile were obtained from 98 clinically healthy adult desert tortoises of both sexes at the Desert Tortoise Research Natural area (western Mojave), Goffs (eastern Mojave) and Ivanpah Valley (northeastern Mojave). Samples were obtained four times per year, in winter (February/March), spring (May/June), summer (July/August), and fall (October). Years of near-, above- and below-average rainfall were represented in the 5 yr period. Minimum, maximum and median values, and central 95 percentiles were used as reference intervals and measures of central tendency for tortoises at each site and/or season. Data were analyzed using repeated measures analysis of variance for significant (P < 0.01) variation on the basis of sex, site, season, and interactions between these variables. Significant sex differences were observed for packed cell volume, hemoglobin concentration, aspartate transaminase activity, and cholesterol, triglyceride, calcium, and phosphorus concentrations. Marked seasonal variation was observed in most parameters in conjunction with reproductive cycle, hibernation, or seasonal rainfall. Year-to-year differences and long-term alterations primarily reflected winter rainfall amounts. Site differences were minimal, and largely reflected geographic differences in precipitation patterns, such that results from these studies can be applied to other tortoise populations in environments with known rainfall and forage availability patterns.


From map reading to geometric intuitions.
The origins and development of our geometric intuitions have been debated for millennia. The present study links children's developing intuitions about the properties of planar triangles to their developing abilities to read purely geometric maps. Six-year-old children are limited when navigating by maps that depict only the sides of a triangle in an environment composed of only the triangle's corners and vice versa. Six-year-old children also incorrectly judge how the angle size of the third corner of a triangle varies with changes to the other two corners. These limitations in map reading and in judgments about triangles are attenuated, respectively, by 10 and 12 years of age. Moreover, as children get older, their map reading predicts their geometric judgments on the triangle task. Map reading thus undergoes developmental changes that parallel an emerging capacity to reason explicitly about the distance and angle relations essential to euclidean geometry. (PsycINFO Database Record


Demographic and Clinical Profile of Invasive Staphylococcal Infections in Children Admitted to Pediatric Intensive Care Unit: A Retrospective Study.
Staphylococcal infections are common cause of morbidity and mortality in pediatric intensive care unit (PICU). The objective of this study was to describe the clinical and microbial features, and outcome of patients with invasive staphylococcal infection. We conducted a retrospective chart review of the children admitted to PICU with invasive staphylococcal infections. Invasive staphylococcal infection was defined as clinical infection with isolation of Staphylococcus aureus from a normally sterile body site. A total of 50 children (1 month to 16 years) were identified with staphylococcal infections during the study period. There was male preponderance (75%) with high prevalence in school going children. Among these children, 36% (18) were coagulase-negative (CONS), which were excluded. Of the remaining, 64% (32) were coagulase-positive Staphylococcus aureus, 54% (27) were methicillin-resistant Staphylococcus aureus (MRSA), and 10% (5) were methicillin-susceptible Staphylococcus aureus (MSSA). Community-acquired staphylococcal infections were present in 24 children (CA-MRSA). Pneumonia with empyema was the most common 20 (62%) site of primary staphylococcal infection, followed by blood stream infection 9 (28%) and skin and soft tissue infection 3 (9%). Of the soft tissue infection, three were MRSA, with two had pyopericardium with infective endocarditis. Resistance in MSSA was found to be maximum to penicillin, erythromycin, and ciprofloxacin with no resistance with vancomycin. There is an increase incidence of MRSA among community-acquired staphylococcal infections requiring intensive care management. A larger study on clinical profile of Staphylococcus infection in pediatrics is urgently needed to define the exact magnitude of the problem. Lalitha AV, Rebello G, Chettri S, Reddy M. Demographic and Clinical Profile of Invasive Staphylococcal Infections in Children Admitted to Pediatric Intensive Care Unit: A Retrospective Study. Indian J Crit Care Med 2020;24(9):890-891.


Zinc-bearing zeolite clinoptilolite improves tissue zinc accumulation in laying hens by enhancing zinc transporter gene mRNA abundance.
A study was conducted to investigate effects of zinc-bearing zeolite clinoptilolite (ZnCP), as an alternative for zinc sulfate (ZnSO4), on laying performance, tissue Zn accumulation and Zn transporter genes expression in laying hens. Hy-Line Brown laying hens were allocated to three treatments, each of which had six replicates with 15 hens per replicate, receiving basal diet supplemented with ZnSO4 (control, 80 mg Zn/kg diet), 0.23% ZnCP (40.25 mg Zn/kg diet) and 0.46% ZnCP (80.50 mg Zn/kg diet) for 8 weeks, respectively. Compared with control, hens fed diet containing 0.23% ZnCP had similar Zn content in measured tissues (P > 0.05). A higher ZnCP inclusion (0.46%) enhanced Zn accumulation in liver (P < 0.05) and pancreas (P < 0.05). In addition, ZnCP inclusion increased blood iron (Fe) content (P < 0.05). ZnCP supplementation enhanced jejunal metallothionein-4 (MT-4) messenger RNA (mRNA) abundance (P < 0.05). ZnCP inclusion at a higher level (0.46%) increased mRNA expression of MT-4 in pancreas (P < 0.05) and zinc transporter-1 (ZnT-1) in jejunum (P < 0.05). The highest ZnT-2 mRNA abundance in jejunum was found in hens fed 0.23% ZnCP inclusion diet (P < 0.05). The results indicated that ZnCP reached a higher bioavailability as compared with ZnSO4 as evidenced by enhanced tissue Zn accumulation and Zn transporter genes expression.


Neural mechanisms of attending to items in working memory.
Working memory, the ability to keep recently accessed information available for immediate manipulation, has been proposed to rely on two mechanisms that appear difficult to reconcile: self-sustained neural firing, or the opposite-activity-silent synaptic traces. Here we review and contrast models of these two mechanisms, and then show that both phenomena can co-exist within a unified system in which neurons hold information in both activity and synapses. Rapid plasticity in flexibly-coding neurons allows features to be bound together into objects, with an important emergent property being the focus of attention. One memory item is held by persistent activity in an attended or "focused" state, and is thus remembered better than other items. Other, previously attended items can remain in memory but in the background, encoded in activity-silent synaptic traces. This dual functional architecture provides a unified common mechanism accounting for a diversity of perplexing attention and memory effects that have been hitherto difficult to explain in a single theoretical framework.


A novel unsupervised method to identify genes important in the anti-viral response: application to interferon/ribavirin in hepatitis C patients.
Treating hepatitis C with interferon/ribavirin results in a varied response in terms of decrease in viral titer and ultimate outcome. Marked responders have a sharp decline in viral titer within a few days of treatment initiation, whereas in other patients there is no effect on the virus (poor responders). Previous studies have shown that combination therapy modifies expression of hundreds of genes in vitro and in vivo. However, identifying which, if any, of these genes have a role in viral clearance remains challenging. The goal of this paper is to link viral levels with gene expression and thereby identify genes that may be responsible for early decrease in viral titer. Microarrays were performed on RNA isolated from PBMC of patients undergoing interferon/ribavirin therapy. Samples were collected at pre-treatment (day 0), and 1, 2, 7, 14 and 28 days after initiating treatment. A novel method was applied to identify genes that are linked to a decrease in viral titer during interferon/ribavirin treatment. The method uses the relationship between inter-patient gene expression based proximities and inter-patient viral titer based proximities to define the association between microarray gene expression measurements of each gene and viral-titer measurements. We detected 36 unique genes whose expressions provide a clustering of patients that resembles viral titer based clustering of patients. These genes include IRF7, MX1, OASL and OAS2, viperin and many ISG's of unknown function. The genes identified by this method appear to play a major role in the reduction of hepatitis C virus during the early phase of treatment. The method has broad utility and can be used to analyze response to any group of factors influencing biological outcome such as antiviral drugs or anti-cancer agents where microarray data are available.


An atrial peptide is a potent renal vasodilator substance.
Renal intra-arterial administration of rat atrial extracts elicits a concentration dependent renal vasodilation (independent of prostaglandin or dopamine release) in anesthetized rats. The atrial extracts do not alter skeletal musculature (hindlimb) vascular resistance or systemic arterial blood pressure. The high molecular weight peptide fraction of atrial extracts obtained by gel filtration, reduces renal resistance intra-arterially only after proteolytic activation (in vitro) or following intravenous (i.e., systemic in vivo activation) administration. The low molecular weight peptide fraction of the atrial extract which is active intra-arterially as a renal vasodilator has been further purified to yield two major peptides. The 21 amino acid peptide, designated atriopeptin I, was previously demonstrated to be natriuretic and to relax intestinal but not vascular smooth muscle strips. This peptide exerted little or no intra-arterial effect on renal resistance. The 23 amino acid peptide (the phenylalanine-arginine C terminal extension of atriopeptin I), designated atriopeptin II, was natriuretic and spasmolytic (in vitro) on both intestinal and vascular strips and was a potent renal vasodilator in vivo. Thus, the renal vasodilator activity present in cardiac atrial extracts appears to derive from a proteolytic process which selectively generates the 23 amino acid peptide, atriopeptin II. Further cleavage with the loss of phenylalanine-arginine C-terminal, as occurs with atriopeptin I, markedly suppresses the renal vasodilation.


Reduced Access to Liver Transplantation in Women: Role of Height, MELD Exception Scores, and Renal Function Underestimation.
Sex-based disparities in liver transplantation (LT) are incompletely understood. We assessed the role of height, Model for End-Stage Liver Disease (MELD), MELD-Na, and exception points in the disparate access to LT. Adults waitlisted for LT at Organ Procurement and Transplantation Network between 2002 and 2013 were included. Covariates associated with likelihood of LT were analyzed by Cox proportional model. In a separate cohort of waitlisted adults with glomerular filtration rate measurement by iothalamate clearance (n = 611), we determined the number of creatinine-derived MELD points in men versus women, across all ranges of glomerular filtration rate. The impact of correcting the MELD score deficit in women on LT was modeled. Among 90 720 Organ Procurement and Transplantation Network registrants, women had higher mortality than men (4 years after listing: 22% vs 18%, P < 0.0001), and lower likelihood of LT (49% vs 58%, P < 0.0001); women were 20% less likely to be transplanted (hazard ratio, 0.80; 95% confidence interval, 0.78-0.81). Differences in height and MELD exception scores accounted for most of the LT deficit in women (hazard ratio, 0.91; 95% confidence interval, 0.89-0.94). Women received between 1 and 2.4 fewer creatinine-derived MELD points than men with similar renal dysfunction. MELD-Na worsened the gender disparity. Addition of 1 or 2 MELD points to women significantly impacted LT access. Differences in height and MELD exception points explained most of the sex-based disparity in LT. Additionally, MELD score underestimated disease severity in women by up to 2.4 points and MELD Na exacerbated this disparity. The degree of underestimation based on MELD had significant impact on allocation.


Effects of barbiturates and ethanol on the physical properties of brain membranes.
Synaptic plasma membranes (SPM) and myelin were prepared from mouse brain and their physical properties evaluated by fluorescence probes. 1,6,-Diphenyl-1,3,5-hexatriene (DPH) was used as a probe of the membrane core and endogenous tryptophan as a probe of membrane proteins. In vitro addition of pentobarbital or ethanol decreased the fluorescence polarization of DPH in SPM. These decreases were not due to changes in fluorescence lifetime and indicate that both drugs increased the rotation mobility of the probe in the membrane core. This action was shared by other barbiturates and their potencies were correlated with their lipid solubility. In contrast to the effect on SPM, pentobarbital increased the fluorescence polarization of DPH in SPM phospholipids but had little effect on the fluorescence polarization of DPH in a total lipid extract from SPM. Pentobarbital did not affect fluorescence polarization of DPH in myelin. Analysis of the temperature dependence of pentobarbital effects indicated that the initial rigidity of the membranes was one factor determining whether the drug decreased, increased or did not change the membrane fluidity. Pentobarbital decreased the fluorescence intensity of SPM tryptophan, but did not affect the fluorescence of free tryptophan. Ethanol did not alter tryptophan fluorescence. Thus, pentobarbital, but not ethanol, produced a detectable perturbation of synaptic proteins. These results indicate that both pentobarbital and ethanol fluidized the hydrophobic core of the membrane, but pentobarbital differed from ethanol in its action on very fluid lipid domains and on membrane proteins.


A genetic contribution from the Far East into Ashkenazi Jews via the ancient Silk Road.
Contemporary Jews retain a genetic imprint from their Near Eastern ancestry, but obtained substantial genetic components from their neighboring populations during their history. Whether they received any genetic contribution from the Far East remains unknown, but frequent communication with the Chinese has been observed since the Silk Road period. To address this issue, mitochondrial DNA (mtDNA) variation from 55,595 Eurasians are analyzed. The existence of some eastern Eurasian haplotypes in eastern Ashkenazi Jews supports an East Asian genetic contribution, likely from Chinese. Further evidence indicates that this connection can be attributed to a gene flow event that occurred less than 1.4 kilo-years ago (kya), which falls within the time frame of the Silk Road scenario and fits well with historical records and archaeological discoveries. This observed genetic contribution from Chinese to Ashkenazi Jews demonstrates that the historical exchange between Ashkenazim and the Far East was not confined to the cultural sphere but also extended to an exchange of genes.


Prevalence and correlates of self-reported state of teeth among schoolchildren in Kerala, India.
Oral health status in India is traditionally evaluated using clinical indices. There is growing interest to know how subjective measures relate to outcomes of oral health. The aims of the study were to assess the prevalence and correlates of self-reported state of teeth in 12-year-old schoolchildren in Kerala, India. Cross-sectional survey data were used. The sample consisted of 838 12-year-old schoolchildren. Data was collected using clinical examination and questionnaire. The clinical oral health status was recorded using Decayed, Missing and Filled Teeth (DMFT) and Oral Hygiene Index-Simplified (OHI-S). The questionnaire included questions on sociodemographics, self reports of behaviour, knowledge and oral problems and a single-item measuring self-reported state and satisfaction with appearance of teeth. The Kappa values for test-retest of the questionnaire ranged from 0.55 to 0.97. Twenty-three per cent of the schoolchildren reported the state of teeth as bad. Multivariate logistic regression showed significant associations between schoolchildren who reported to have bad teeth and poor school performance (Odds Ratio (OR) = 2.5), having bad breath (OR = 2.4), food impaction (OR = 1.7) dental visits (OR = 1.6), being dissatisfied with appearance of teeth (OR = 4.2) and caries experience (OR = 1.7). The explained variance was highest when the variables dental visits, bleeding gums, bad breath, food impaction and satisfaction with appearance were introduced into the model (19%). A quarter of 12-year-olds reported having bad teeth. The self-reported bad state of teeth was associated with poor school performance, having bad breath and food impaction, having visited a dentist, being dissatisfied with teeth appearance and having caries experience. Information from self-reports of children might help in planning effective strategies to promote oral health.


Assessing evidence for a pervasive alteration in tropical tree communities.
In Amazonian tropical forests, recent studies have reported increases in aboveground biomass and in primary productivity, as well as shifts in plant species composition favouring fast-growing species over slow-growing ones. This pervasive alteration of mature tropical forests was attributed to global environmental change, such as an increase in atmospheric CO2 concentration, nutrient deposition, temperature, drought frequency, and/or irradiance. We used standardized, repeated measurements of over 2 million trees in ten large (16-52 ha each) forest plots on three continents to evaluate the generality of these findings across tropical forests. Aboveground biomass increased at seven of our ten plots, significantly so at four plots, and showed a large decrease at a single plot. Carbon accumulation pooled across sites was significant (+0.24 MgC ha(-1) y(-1), 95% confidence intervals [0.07, 0.39] MgC ha(-1) y(-1)), but lower than reported previously for Amazonia. At three sites for which we had data for multiple census intervals, we found no concerted increase in biomass gain, in conflict with the increased productivity hypothesis. Over all ten plots, the fastest-growing quartile of species gained biomass (+0.33 [0.09, 0.55] % y(-1)) compared with the tree community as a whole (+0.15 % y(-1)); however, this significant trend was due to a single plot. Biomass of slow-growing species increased significantly when calculated over all plots (+0.21 [0.02, 0.37] % y(-1)), and in half of our plots when calculated individually. Our results do not support the hypothesis that fast-growing species are consistently increasing in dominance in tropical tree communities. Instead, they suggest that our plots may be simultaneously recovering from past disturbances and affected by changes in resource availability. More long-term studies are necessary to clarify the contribution of global change to the functioning of tropical forests.


Improved diagnostic performance of the circulating antigen assay in human schistosomiasis by parallel testing for circulating anodic and cathodic antigens in serum and urine.
Serum and urine levels of two Schistosoma circulating antigens, the circulating anodic antigen (CAA) and the circulating cathodic antigen (CCA), were determined by monoclonal antibody-based enzyme-linked immunosorbent assays in 56 Egyptian patients infected with S. mansoni and in 12 patients infected with both S. mansoni and S. haematobium. Both CAA and CCA could be specifically demonstrated in 82% and 88% of the serum samples and in 88% and 87% of the urine samples, respectively. While complete specificity was maintained, sensitivity was increased to a range of 91-98% by parallel use of the two circulating antigen assays, i.e., an individual with a positive titer for at least one of the assays was considered to be infected. A combination of CAA and CCA determinations in urine samples only resulted in a sensitivity of 94%. However, the highest sensitivity was achieved when the serum-CCA assay was combined with the urine-CCA assay (98%) or with the urine-CAA assay (97%). Sensitivity could not be increased further by combining more than two tests. A significant correlation was demonstrated between the level of circulating antigen and the number of parasite eggs in feces in each of the four assays. In addition, the levels of CAA and CCA in serum and urine were significantly correlated with each other. Our results indicate that diagnosis of schistosome infections by detection of circulating antigens can be significantly improved by parallel testing for multiple antigens.


How do gastroenterologists assess overall activity of eosinophilic esophagitis in adult patients?
There is no "gold standard" for assessing disease activity in patients with eosinophilic esophagitis (EoE). We aimed to compare physicians' judgment of EoE activity with patients' judgment of symptom severity. We also aimed to examine the relative contribution of symptoms as well as endoscopic and histologic findings in shaping physicians' judgment of EoE activity. Six gastroenterologists (all EoE experts) assessed EoE-associated symptoms in adult patients. Patients completed a symptom instrument and provided global assessment of EoE symptom severity (PatGA) (Likert scale: 0 (inactive) to 10 (most active)). Following esophagogastroduodenoscopy with biopsy sampling, gastroenterologists provided a global assessment of EoE activity (PhysGA) (Likert scale from 0 to 10) based on patient history and endoscopic and histologic findings. Linear regression and analysis of variance was used to quantify the extent to which variations in severity of EoE symptoms and endoscopic and histologic findings explain variations in PhysGA. A total of 149 EoE patients were prospectively included (71.8% male, median age at inclusion 38 years, 71.8% with concomitant allergies). A moderate positive correlation between PhysGA and PatGA (rho=0.442, P<0.001) was observed and the mean difference in the Bland-Altman plot was 1.77. Variations in severity of endoscopic findings, symptoms, and histologic findings alone explained 53%, 49%, and 30%, of the variability in PhysGA, respectively. Together, these findings explained 75% of variability in PhysGA. Gastroenterologists rate EoE activity mainly on the basis of endoscopic findings and symptoms and, to a lesser extent, on histologic findings.


Phylogenetic analysis of Harmonin homology domains.
Harmonin Homogy Domains (HHD) are recently identified orphan domains of about 70 residues folded in a compact five alpha-helix bundle that proved to be versatile in terms of function, allowing for direct binding to a partner as well as regulating the affinity and specificity of adjacent domains for their own targets. Adding their small size and rather simple fold, HHDs appear as convenient modules to regulate protein-protein interactions in various biological contexts. Surprisingly, only nine HHDs have been detected in six proteins, mainly expressed in sensory neurons. Here, we built a profile Hidden Markov Model to screen the entire UniProtKB for new HHD-containing proteins. Every hit was manually annotated, using a clustering approach, confirming that only a few proteins contain HHDs. We report the phylogenetic coverage of each protein and build a phylogenetic tree to trace the evolution of HHDs. We suggest that a HHD ancestor is shared with Paired Amphipathic Helices (PAH) domains, a four-helix bundle partially sharing fold and functional properties. We characterized amino-acid sequences of the various HHDs using pairwise BLASTP scoring coupled with community clustering and manually assessed sequence features among each individual family. These sequence features were analyzed using reported structures as well as homology models to highlight structural motifs underlying HHDs fold. We show that functional divergence is carried out by subtle differences in sequences that automatized approaches failed to detect. We provide the first HHD databases, including sequences and conservation, phylogenic trees and a list of HHD variants found in the auditory system, which are available for the community. This case study highlights surprising phylogenetic properties found in orphan domains and will assist further studies of HHDs. We unveil the implication of HHDs in their various binding interfaces using conservation across families and a new protein-protein surface predictor. Finally, we discussed the functional consequences of three identified pathogenic HHD variants involved in Hoyeraal-Hreidarsson syndrome and of three newly reported pathogenic variants identified in patients suffering from Usher Syndrome.


Schisandra fructus extract ameliorates doxorubicin-induce cytotoxicity in cardiomyocytes: altered gene expression for detoxification enzymes.
The effect of Schisandra fructus extract (SFE) on doxorubicin (Dox)-induced cardiotoxicity was investigated in H9c2 cardiomyocytes. Dox, which is an antineoplastic drug known to induce cardiomyopathy possibly through production of reactive oxygen species, induced significant cytotoxicity, intracellular reactive oxygen species (ROS), and lipid peroxidation. SFE treatment significantly increased cell survival up to 25%, inhibited intracellular ROS production in a time- and dose-dependent manner, and inhibited lipid peroxidation induced by Dox. In addition, SFE treatment induced expression of cellular glutathione S-transferases (GSTs), which function in the detoxification of xenobiotics, and endogenous toxicants including lipid peoxides. Analyses of 31,100 genes using Affymetrix cDNA microarrays showed that SFE treatment up-regulated expression of genes involved in glutathione metabolism and detoxification [GST theta 1, mu 1, and alpha type 2, heme oxygenase 1 (HO-1), and microsomal epoxide hydrolase (mEH)] and energy metabolism [carnitine palmitoyltransferase-1 (CPT-1), transaldolase, and transketolase]. These data indicated that SFE might increase the resistance to cardiac cell injury by Dox, at least partly, together with altering gene expression, especially induction of phase II detoxification enzymes.


JAK mutations in high-risk childhood acute lymphoblastic leukemia.
Pediatric acute lymphoblastic leukemia (ALL) is a heterogeneous disease consisting of distinct clinical and biological subtypes that are characterized by specific chromosomal abnormalities or gene mutations. Mutation of genes encoding tyrosine kinases is uncommon in ALL, with the exception of Philadelphia chromosome-positive ALL, where the t(9,22)(q34;q11) translocation encodes the constitutively active BCR-ABL1 tyrosine kinase. We recently identified a poor prognostic subgroup of pediatric BCR-ABL1-negative ALL patients characterized by deletion of IKZF1 (encoding the lymphoid transcription factor IKAROS) and a gene expression signature similar to BCR-ABL1-positive ALL, raising the possibility of activated tyrosine kinase signaling within this leukemia subtype. Here, we report activating mutations in the Janus kinases JAK1 (n = 3), JAK2 (n = 16), and JAK3 (n = 1) in 20 (10.7%) of 187 BCR-ABL1-negative, high-risk pediatric ALL cases. The JAK1 and JAK2 mutations involved highly conserved residues in the kinase and pseudokinase domains and resulted in constitutive JAK-STAT activation and growth factor independence of Ba/F3-EpoR cells. The presence of JAK mutations was significantly associated with alteration of IKZF1 (70% of all JAK-mutated cases and 87.5% of cases with JAK2 mutations; P = 0.001) and deletion of CDKN2A/B (70% of all JAK-mutated cases and 68.9% of JAK2-mutated cases). The JAK-mutated cases had a gene expression signature similar to BCR-ABL1 pediatric ALL, and they had a poor outcome. These results suggest that inhibition of JAK signaling is a logical target for therapeutic intervention in JAK mutated ALL.


Comparison of the binding behavior of FCCP with HSA and HTF as determined by spectroscopic and molecular modeling techniques.
The interaction of carbonylcyanide p-(trifluoromethoxy) phenylhydrazone (FCCP) with human serum albumin (HSA) and human transferrin (HTF) was investigated using multiple spectroscopy, molecular modeling, zeta-potential and conductometry measurements of aqueous solutions at pH 7.4. The fluorescence, UV/vis and polarization fluorescence spectroscopy data disclosed that the drug-protein complex formation occurred through a remarkable static quenching. Based on the fluorescence quenching, two sets of binding sites with distinct affinities for FCCP existed in the two proteins. Steady-state and polarization fluorescence analysis showed that there were more affinities between FCCP and HSA than HTF. Far UV-CD and synchronous fluorescence studies indicated that FCCP induced more structural changes on HSA. The resonance light scattering (RLS) and zeta-potential measurements suggested that HTF had a greater resistance to drug aggregation, whereas conductometry measurements expressed the presence of free ions improving the resistance of HSA to aggregation. Thermodynamic measurements implied that a combination of electrostatic and hydrophobic forces was involved in the interaction between FCCP with both proteins. The phase diagram plots indicated that the presence of second binding site on HSA and HTF was due to the existence of intermediate structures. Site marker competitive experiments demonstrated that FCCP had two distinct binding sites in HSA which were located in sub-domains IIA and IIIA and one binding site in the C-lobe of HTF as confirmed by molecular modeling. The obtained results suggested that both proteins could act as drug carriers, but that the HSA potentially had a higher capacity for delivering FCCP to cancerous tissues.


Physician-assisted deaths under the euthanasia law in Belgium: a population-based survey.
Legalization of euthanasia and physician-assisted suicide has been heavily debated in many countries. To help inform this debate, we describe the practices of euthanasia and assisted suicide, and the use of life-ending drugs without an explicit request from the patient, in Flanders, Belgium, where euthanasia is legal. We mailed a questionnaire regarding the use of life-ending drugs with or without explicit patient request to physicians who certified a representative sample (n = 6927) of death certificates of patients who died in Flanders between June and November 2007. The response rate was 58.4%. Overall, 208 deaths involving the use of life-ending drugs were reported: 142 (weighted prevalence 2.0%) were with an explicit patient request (euthanasia or assisted suicide) and 66 (weighted prevalence 1.8%) were without an explicit request. Euthanasia and assisted suicide mostly involved patients less than 80 years of age, those with cancer and those dying at home. Use of life-ending drugs without an explicit request mostly involved patients 80 years of older, those with a disease other than cancer and those in hospital. Of the deaths without an explicit request, the decision was not discussed with the patient in 77.9% of cases. Compared with assisted deaths with the patient's explicit request, those without an explicit request were more likely to have a shorter length of treatment of the terminal illness, to have cure as a goal of treatment in the last week, to have a shorter estimated time by which life was shortened and to involve the administration of opioids. Physician-assisted deaths with an explicit patient request (euthanasia and assisted suicide) and without an explicit request occurred in different patient groups and under different circumstances. Cases without an explicit request often involved patients whose diseases had unpredictable end-of-life trajectories. Although opioids were used in most of these cases, misconceptions seem to persist about their actual life-shortening effects.


Hypoxic heterogeneity in human tumors: EF5 binding, vasculature, necrosis, and proliferation.
We evaluated the levels and distribution of hypoxia in 31 human tumors using fluorescent immunohistochemical detection of binding by the 2-nitroimidazole, EF5. Hypoxia was found to be a heterogeneous property of human tumors. Necrosis was usually found adjacent to the highest level of binding in an individual patient's tumor. However, hypoxia often occurred without necrosis. In the group of tumors studied, the most common relationship between blood vessels (PECAM/CD31) and EF5 staining was consistent with diffusion-limited hypoxia; acute hypoxia occurred infrequently. Within a given patient's tumor, there was an inverse correlation between regions of proliferation (Ki-67) and regions of hypoxia. Again, however, when these parameters were examined in a group of patients, the absence of proliferation did not predict the presence of hypoxia. The relationships between hypoxia and other biologic endpoints are complex, but, within a given tumor's spatial relationships, they are in accord with known physiologic principles. Thus, our data emphasize that the relationships between hypoxia and other biologic parameters vary between patients. Necrosis, proliferation, and blood vessel distribution cannot predict the level or presence of hypoxia in an individual patient's tumor.


Operative and nonoperative adverse events in the management of traumatic fractures of the thoracolumbar spine: a systematic review.
Thoracolumbar spine injuries are commonly encountered in patients with trauma, accounting for almost 90% of all spinal fractures. Thoracolumbar burst fractures comprise a high percentage of these traumatic fractures (45%), and approximately half of the patients with this injury pattern are neurologically intact. However, a debate over complication rates associated with operative versus nonoperative management of various thoracolumbar fracture morphologies is ongoing, particularly concerning those patients presenting without a neurological deficit. A MEDLINE search for pertinent literature published between 1966 and December 2013 was conducted by 2 authors (G.G. and R.D.), who used 2 broad search terms to maximize the initial pool of manuscripts for screening. These terms were "operative lumbar spine adverse events" and "nonoperative lumbar spine adverse events." In an advanced MEDLINE search of the term "operative lumbar spine adverse events" on January 8, 2014, 1459 results were obtained. In a search of "nonoperative lumbar spine adverse events," 150 results were obtained. After a review of all abstracts for relevance to traumatic thoracolumbar spinal injuries, 62 abstracts were reviewed for the "operative" group and 21 abstracts were reviewed for the "nonoperative" group. A total of 14 manuscripts that met inclusion criteria for the operative group and 5 manuscripts that met criteria for the nonoperative group were included. There were a total of 919 and 436 patients in the operative and nonoperative treatment groups, respectively. There were no statistically significant differences between the groups with respect to age, sex, and length of stay. The mean ages were 43.17 years in the operative and 34.68 years in the nonoperative groups. The majority of patients in both groups were Frankel Grade E (342 and 319 in operative and nonoperative groups, respectively). Among the studies that reported the data, the mean length of stay was 14 days in the operative group and 20.75 in the nonoperative group. The incidence of all complications in the operative and nonoperative groups was 300 (32.6%) and 21 (4.8%), respectively (p = 0.1065). There was no significant difference between the 2 groups with respect to the incidence of pulmonary, thromboembolic, cardiac, and gastrointestinal complications. However, the incidence of infections (pneumonia, urinary tract infection, wound infection, and sepsis) was significantly higher in the operative group (p = 0.000875). The incidence of instrumentation failure and need for revision surgery was 4.35% (40 of 919), a significant morbidity, and an event unique to the operative category (p = 0.00396). Due to the limited number of high-quality studies, conclusions related to complication rates of operative and nonoperative management of thoracolumbar traumatic injuries cannot be definitively made. Further prospective, randomized studies of operative versus nonoperative management of thoracolumbar and lumbar spine trauma, with standardized definitions of complications and matched patient cohorts, will aid in properly defining the risk-benefit ratio of surgery for thoracolumbar spine fractures.


Reference intervals from birth to adulthood for serum thyroxine (T4), triiodothyronine (T3), free T3, free T4, thyroxine binding globulin (TBG) and thyrotropin (TSH).
Disorders in thyroid function can impair normal development in children. Therefore it was our aim to establish reference intervals for serum triiodothyronine (T3), free T3 (fT3), thyroxine (T4), free T4 (fT4), thyroxine binding globulin (TBG) and thyrotropin (TSH) which are applicable from birth to adulthood by using the non-isotopic automated chemiluminescence immunoassay system, Immulite (DPC Los Angeles, USA). Serum samples from 762 euthyroid newborns, children and adolescents (369 female, 393 male; age 1 day to 19 years) were examined; of these, 381 were classified as pubertal. Due to non-normal distribution, the 2.5th, 50th and 97.5th percentiles (the central 95% interval) were calculated for each group. The median concentrations of T4, fT4 and TSH were up to 3.2-fold higher during the first 2 weeks, while T4 increased during the first month of life. The concentrations in all age groups showed no sex differences. From 1 year onwards, the concentration of all parameters tended to decrease until adult age, with the exception of TBG which increased by >60% (p<0.02) and reached a maximum at approximately 5 years of age. The findings underscore the fact that thyroid hormones are not associated with sexual development, except for TBG, which decreased slightly (p<0.04) between Tanner stages 1 and 5. However, the reference intervals established here demonstrate that marked changes occur in concentrations of thyroid hormones after the neonatal period. Our findings complement these of earlier studies. The developed reference intervals can be used to assess the thyroid status of patients, particularly if the measurements are done on the Immulite/Immulite 2000 system.


HIV Care Continuum Interventions for Transgender Women: A Topical Review.
Transgender women experience a disproportionate prevalence of HIV and barriers to linkage to care, retention in care, medication adherence, and viral suppression. As part of a national cooperative agreement funded by the Health Resources and Services Administration's HIV/AIDS Bureau, we searched the literature from January 1, 2010, through June 1, 2020, for English-language articles on interventions designed to improve at least 1 HIV care continuum outcome or address 1 barrier to achieving HIV care continuum outcomes among transgender women diagnosed with HIV in the United States. To be included, articles needed to identify transgender women as a priority population for the intervention. We found 22 interventions, of which 15 reported quantitative or qualitative outcomes and 7 reported study protocols. Recent interventions have incorporated a range of strategies that show promise for addressing pervasive structural and individual barriers rooted in societal and cultural stigma and discrimination against transgender people. Cross-cutting themes found among the interventions included meaningful community participation in the design and implementation of the interventions; culturally affirming programs that serve as a gateway to HIV care and combine gender-affirming care and social services with HIV care; interventions to improve behavioral health outcomes; peer-led counseling, education, and navigation; and technology-based interventions to increase access to care management and online social support. Ongoing studies will further elucidate the efficacy and effectiveness of these interventions, with the goal of reducing disparities in the HIV care continuum and bringing us closer to ending the HIV epidemic among transgender women in the United States.


Cytoprotective and anti-inflammatory actions of carbon monoxide in organ injury and sepsis models.
Carbon monoxide (CO) can exert potent anti-inflammatory effects in animal and cell culture models of sepsis, despite well-known lethal effects at high concentration. Endogenous biological CO arises from the enzymatic degradation of haem, mainly from haemoglobin turnover, catalysed by haem oxygenases (HO). The inducible form of HO, haem oxygenase 1 (HO-1) participates in endogenous cellular defence against oxidative stress. HO-1 confers cytoprotection in many models of organ and tissue injury where inflammatory processes are implicated, including sepsis. When applied exogenously at low concentration, CO mimics the cytoprotective potential of HO-1 induction in these models. CO confers protection against endotoxin shock in vitro and in vivo by inhibiting the production of pro-inflammatory cytokines, in a mechanism involving the modulation of p38 mitogen activated protein kinase. CO protection against vascular injury may involve both anti-inflammatory and antiproliferative effects. The protection afforded by CO against liver failure and inflammatory lung injury was associated with the modulation of inducible nitric oxide synthase. Recent in vitro studies indicate that CO inhibits proinflammatory signalling by differentially inhibiting the trafficking of toll-like receptors (TLRs) to lipid rafts. Additional candidate mechanisms in anti-inflammatory effects of CO include the increased expression of heat shock proteins and the tumour suppressor protein caveolin 1.


Learning about the history of landscape use for the future: consequences for ecological and social systems in Swedish Bergslagen.
Barriers and bridges to implement policies about sustainable development and sustainability commonly depend on the past development of social-ecological systems. Production of metals required integration of use of ore, streams for energy, and wood for bioenergy and construction, as well as of multiple societal actors. Focusing on the Swedish Bergslagen region as a case study we (1) describe the phases of natural resource use triggered by metallurgy, (2) the location and spatial extent of 22 definitions of Bergslagen divided into four zones as a proxy of cumulative pressure on landscapes, and (3) analyze the consequences for natural capital and society. We found clear gradients in industrial activity, stream alteration, and amount of natural forest from the core to the periphery of Bergslagen. Additionally, the legacy of top-down governance is linked to today's poorly diversified business sector and thus municipal vulnerability. Comparing the Bergslagen case study with other similar regions in Russia and Germany, we discuss the usefulness of multiple case studies.


Rumination and modes of processing around meal times in women with anorexia nervosa: qualitative and quantitative results from a pilot study.
The primary aim of this exploratory study was to examine qualitatively and quantitatively the effects of rumination, mindful breathing, and distraction on processing styles and the meal time experience in women with a history of anorexia nervosa (AN). A quasi-experimental within-participant design was employed. Thirty-seven women with history of AN and all experiencing current eating disorder psychopathology listened to a single rumination, mindful breathing and distraction exercise before a meal time. Qualitative and quantitative analyses were employed. Specific themes were extracted for each exercise including avoidance, being in the moment and rumination. The rumination exercise led to significantly greater analytical self-focus. Mindful breathing led to significantly greater experiential self-focus compared with distraction in partially weight-restored AN participants. In AN, self-material is processed in a ruminative way and avoidance is valued. It is difficult to shift individuals with AN out of a rumination around meal times using brief mindful breathing. Future research should investigate at what stage of AN illness mindful-based and acceptance-based strategies are useful and how these strategies could be incorporated in treatment.


Enhancing plant regeneration in tissue culture: a molecular approach through manipulation of cytokinin sensitivity.
Micropropagation is used for commercial purposes worldwide, but the capacity to undergo somatic organogenesis and plant regeneration varies greatly among species. The plant hormones auxin and cytokinin are critical for plant regeneration in tissue culture, with cytokinin playing an instrumental role in shoot organogenesis. Type-B response regulators govern the transcriptional output in response to cytokinin and are required for plant regeneration. In our paper published in Plant Physiology, we explored the functional redundancy among the 11 type-B Arabidopsis response regulators (ARRs). Interestingly, we discovered that the enhanced expression of one family member, ARR10, induced hypersensitivity to cytokinin in multiple assays, including callus greening and shoot induction of explants. Here we 1) discuss the hormone dependence for in vitro plant regeneration, 2) how manipulation of the cytokinin response has been used to enhance plant regeneration, and 3) the potential of the ARR10 transgene as a tool to increase the regeneration capacity of agriculturally important crop plants. The efficacy of ARR10 for enhancing plant regeneration likely arises from its ability to transcriptionally regulate key cytokinin responsive genes combined with an enhanced protein stability of ARR10 compared with other type-B ARRs. By increasing the capacity of key tissues and cell types to respond to cytokinin, ARR10, or other type-B response regulators with similar properties, could be used as a tool to combat the recalcitrance of some crop species to tissue culture techniques.


Behavioral and demographic risk factors for transmission of human immunodeficiency virus type 1 in heterosexual couples: report from the Heterosexual HIV Transmission Study.
We compared 224 heterosexual couples who were discordant for human immunodeficiency virus (HIV) type 1 infection (one partner HIV infected) with 78 HIV-concordant couples (both partners HIV infected) to identify demographic and behavioral risk factors for HIV transmission. Among the 229 couples whose male partner was first infected, HIV-concordant couples had engaged in anal sex more frequently before and after knowing that the male was infected than had HIV-discordant couples. Pap smears of grade 2 or higher (inflammation) were more prevalent among the second-infected female partners in HIV-concordant couples than among uninfected women in discordant couples (58% vs. 23%; P < .001). Anal sex and unprotected vaginal sex after knowledge of a male partner's infection were significant correlates of concordance in a multivariate logistic model, as were ethnicity, marital status, and antiviral therapy. Ethnicity strongly predicted concordance, even after controlling for sexual risk behaviors and stage of disease.


The transmembrane heparan sulphate proteoglycan syndecan-4 is involved in establishment of the lamellar structure of the annulus fibrosus of the intervertebral disc.
The annulus fibrosus of the intervertebral disc unites adjacent vertebral bodies along the length of the spine and provides tensile resistance towards compressive, twisting and bending movements arising through gait. It consists of a nested series of oriented collagenous lamellae, arranged in cross-ply circumferentially around the nucleus pulposus. The organisation of oriented collagen in the annulus is established during foetal development by an identical arrangement of oriented fibroblasts that are precisely organised into cell sheets, or laminae. These provide a template for ordered deposition of extracellular matrix material on cell surfaces, by means of a poorly understood mechanism involving the actin cytoskeleton. In this study, we investigate the role of two cell surface heparan sulphate proteoglycans (HSPGs), glypican-6 and syndecan-4, in the matrix assembly process in the developmental rat intervertebral disc. We compare their expression patterns with those of heparan sulphate and the interactive, cell-surface adhesive glycoprotein, fibronectin, and relate these to the stage-specific collagenous architectures present within the annulus at both light and electron microscopic levels. We show that both proteoglycans are strongly associated with the development, growth and aging of the intervertebral disc. Furthermore, the immunohistochemical labelling patterns suggest that syndecan-4, in particular, plays a potentially-significant role in annulus formation. We propose that this HSPG mediates interaction between the actin cytoskeleton and nascent extracellular matrix in the lamellar organisation of annulus tissue. These data add considerably towards an understanding of how cells organise and maintain complex, oriented extracellular matrices and has particular clinical relevance to the fields of tissue engineering and repair.


Color categories only affect post-perceptual processes when same- and different-category colors are equally discriminable.
Prior claims that color categories affect color perception are confounded by inequalities in the color space used to equate same- and different-category colors. Here, we equate same- and different-category colors in the number of just-noticeable differences, and measure event-related potentials (ERPs) to these colors on a visual oddball task to establish if color categories affect perceptual or post-perceptual stages of processing. Category effects were found from 200 ms after color presentation, only in ERP components that reflect post-perceptual processes (e.g., N2, P3). The findings suggest that color categories affect post-perceptual processing, but do not affect the perceptual representation of color.


Sonographic prediction of outcome of vacuum deliveries: a multicenter, prospective cohort study.
Safe management of the second stage of labor is of great importance. Unnecessary interventions should be avoided and correct timing of interventions should be focused. Ultrasound assessment of fetal position and station has a potential to improve the precision in diagnosing and managing prolonged or arrested labors. The decision to perform vacuum delivery is traditionally based on subjective assessment by digital vaginal examination and clinical expertise and there is currently no method of objectively quantifying the likelihood of successful delivery. Prolonged attempts at vacuum delivery are associated with neonatal morbidity and maternal trauma, especially so if the procedure is unsuccessful and a cesarean is performed. The aim of the study was to assess if ultrasound measurements of fetal position and station can predict duration of vacuum extractions, mode of delivery, and fetal outcome in nulliparous women with prolonged second stage of labor. We performed a prospective cohort study in nulliparous women at term with prolonged second stage of labor in 7 European maternity units from 2013 through 2016. Fetal head position and station were determined using transabdominal and transperineal ultrasound, respectively. Our preliminary clinical experience assessing head-perineum distance prior to vacuum delivery suggested that we should set 25 mm for the power calculation, a level corresponding roughly to +2 below the ischial spines. The main outcome was duration of vacuum extraction in relation to ultrasound measured head-perineum distance with a predefined cut-off of 25 mm, and 220 women were needed to discriminate between groups using a hazard ratio of 1.5 with 80% power and alpha 5%. Secondary outcomes were delivery mode and umbilical artery cord blood samples after birth. The time interval was evaluated using survival analyses, and the outcomes of delivery were evaluated using receiver operating characteristic curves and descriptive statistics. Results were analyzed according to intention to treat. The study population comprised 222 women. The duration of vacuum extraction was shorter in women with head-perineum distance ≤25 mm (log rank test <0.01). The estimated median duration in women with head-perineum distance ≤25 mm was 6.0 (95% confidence interval, 5.2-6.8) minutes vs 8.0 (95% confidence interval, 7.1-8.9) minutes in women with head-perineum distance >25 mm. The head-perineum distance was associated with spontaneous delivery with area under the curve 83% (95% confidence interval, 77-89%) and associated with cesarean with area under the curve 83% (95% confidence interval, 74-92%). In women with head-perineum distance ≤35 mm, 7/181 (3.9%) were delivered by cesarean vs 9/41 (22.0%) in women with head-perineum distance >35 mm (P <.01). Ultrasound-assessed position was occiput anterior in 73%. Only 3/138 (2.2%) fetuses in occiput anterior position and head-perineum distance ≤35 mm vs 6/17 (35.3%) with nonocciput anterior position and head-perineum distance >35 mm were delivered by cesarean. Umbilical cord arterial pH <7.10 occurred in 2/144 (1.4%) women with head-perineum distance ≤35 mm compared to 8/40 (20.0%) with head-perineum distance >35 mm (P < .01). Ultrasound has the potential to predict labor outcome in women with prolonged second stage of labor. The information obtained could guide whether vacuum delivery should be attempted or if cesarean is preferable, whether senior staff should be in attendance, and if the vacuum attempt should be performed in the operating theater.


Nitric oxide is a mediator of hypoxic coronary vasodilatation. Relation to adenosine and cyclooxygenase-derived metabolites.
Hypoxia is a potent coronary-vasodilating signal; its mechanisms are still controversial. We have assessed the possible role of nitric oxide (NO) in hypoxic coronary vasodilatation (HCVD) in isolated guinea pig hearts perfused at constant pressure. HCVD was elicited by a 1-minute 100% N2 exposure; coronary flow doubled within 1 minute of hypoxia (early phase) and returned to baseline within 40 seconds after reoxygenation (late phase). The early phase of HCVD was associated with a rapid approximately eightfold increase in cGMP overflow, an indication of NO release. The specific NO synthase inhibitor N omega-methyl-L-arginine (NMA, 0.1-1 mM) antagonized HCVD and the associated increase in cGMP spillover (maximum inhibition, approximately 65%); excess arginine (1.2 mM) prevented both effects. The late phase of HCVD was associated with an increase in adenosine overflow and was attenuated by the adenosine receptor antagonist BW A1433 (1 microM; maximum inhibition, approximately 45%). Indomethacin (10 microM) inhibited HCVD in spontaneously beating hearts by approximately 35% but had no effect in hearts paced at faster rates. NMA and BW A1433 were more effective in combination than alone (maximum inhibition, approximately 72%). However, irrespective of the concentrations used, there was no synergism among the anti-HCVD effects of NMA, BW A1433, and indomethacin, nor was HCVD completely inhibited by the antagonists, whether alone or in combination. Our findings indicate that NO is an important mediator of the early phase of HCVD, whereas additional mechanisms and/or factors, including adenosine and vasodilatatory prostaglandins, contribute to the late phase.


Race, clinical factors and pre-term birth in a low-income urban setting.
While infant mortality rates have declined for both White and African-American populations, the perennial two-fold excess in risk for African Americans remains unchanged, and indeed, may have increased since 1985. One potential explanation for the excess risk in African Americans might be racial differences in maternal clinical risk factors, such as prior pregnancy history and pregnancy complications. This paper examines the contributions of such clinical indicators to racial differences in pre-term delivery in a study sample of urban, low-income women, aged 18 to 43 years. Study participants were enrolled during their first prenatal care visit at one of four hospital-based, prenatal care clinics in Baltimore City. Medical history and pregnancy outcome data were abstracted from clinical records. Multiple logistic regression models were used to assess the independent relationship between race and pre-term birth, after controlling for clinical factors. Without adjustment for clinical risk factors, African-American women were 1.8 times more likely than White women to have a pre-term birth outcome (95% confidence interval 1.20-2.78). After statistical adjustment for the clinical variables, however, the association between race and pre-term birth was diminished (OR = 1.64, 95% confidence interval: 0.99-2.72). Moreover, the associations between certain clinical risks and pre-term birth were stronger for African-American than White women. These results suggest that attention to clinical risk factors among African-American women may be an important avenue for reducing Black/White racial disparities in pre-term birth.


Interactive effects of plant species diversity and elevated CO2 on soil biota and nutrient cycling.
Terrestrial ecosystems consist of mutually dependent producer and decomposer subsystems, but not much is known on how their interactions are modified by plant diversity and elevated atmospheric CO2 concentrations. Factorially manipulating grassland plant species diversity and atmospheric CO2 concentrations for five years, we tested whether high diversity or elevated CO2 sustain larger or more active soil communities, affect soil aggregation, water dynamics, or nutrient cycling, and whether plant diversity and elevated CO2 interact. Nitrogen (N) and phosphorus (P) pools, symbiotic N2 fixation, plant litter quality, soil moisture, soil physical structure, soil nematode, collembola and acari communities, soil microbial biomass and microflora community structure (phospholipid fatty acid [PLFA] profiles), soil enzyme activities, and rates of C fluxes to soils were measured. No increases in soil C fluxes or the biomass, number, or activity of soil organisms were detected at high plant diversity; soil H2O and aggregation remained unaltered. Elevated CO2 affected the ecosystem primarily by improving plant and soil water status by reducing leaf conductance, whereas changes in C cycling appeared to be of subordinate importance. Slowed-down soil drying cycles resulted in lower soil aggregation under elevated CO2. Collembola benefited from extra soil moisture under elevated CO2, whereas other faunal groups did not respond. Diversity effects and interactions with elevated CO2 may have been absent because soil responses were mainly driven by community-level processes such as rates of organic C input and water use; these drivers were not changed by plant diversity manipulations, possibly because our species diversity gradient did not extend below five species and because functional type composition remained unaltered. Our findings demonstrate that global change can affect soil aggregation, and we advocate that soil aggregation should be considered as a dynamic property that may respond to environmental changes and feed back on other ecosystem functions.


Memory improvement with treatment of hypothyroidism.
The consequences of inadequate thyroid hormone availability to the brain and treatment effects of levothyroxine on cognitive function are still poorly understood. This study prospectively assessed the effects of thyroid replacement therapy on cognitive function in patients suffering from biochemical evidenced, untreated hypothyroidism. Significant effects between the untreated hypothyroid group and control group were limited to verbal memory retrieval. When assessing the effects of 3-month treatment, results revealed that the treated hypothyroid group had significant increased verbal memory retrieval. Results suggest that specific memory retrieval deficits associated with hypothyroidism can resolve after replacement therapy with levothyroxine.


Co-delivery of PLK1-specific shRNA and doxorubicin via core-crosslinked pH-sensitive and redox ultra-sensitive micelles for glioma therapy.
Anticancer drug delivery encounters many biological barriers, including mucosal barriers, nonspecific uptake and intracellular drug resistance. Consequently, efficient delivery of therapeutic agents with nanocarriers to the target cell and controlled intracellular release of encapsulated drugs are key to achieving high therapeutic efficiency. In this study, we develop a tumor microenvironment-sensitive polymer micelle system from a pH- and glutathione (GSH) dual-responsive copolymer with each repeating unit containing a disulfide bond. To prevent premature drug release within the blood circulation, the core region was chemically crosslinked via UV light irradiation. In tumor cells, the micelles are able to escape from the acidic lysosome into the cytoplasm via a prompt expansion due to the "proton sponge effect". Subsequently, ultra-sensitive redox responsiveness is realized since the abundant disulfide bonds of the micellar matrix can be cleaved by a high level of GSH, leading to a rapid intracellular release of encapsulated doxorubicin (DOX) and PLK1-specific shRNA. The antitumor activity in U87 glioma tumor-bearing mice reveals that this novel system possesses a high therapeutic efficacy against solid tumors with negligible side effects on normal tissues. Therefore, this micellar nanoplatform has great potential in delivering drugs for enhanced glioma therapy.


Modified liver-free multivisceral transplantation for a metastatic small bowel neuroendocrine tumor: a case report.
Neuroendocrine tumors originating from the small bowel frequently metastasize to the lymph nodes and/or liver. Although surgical extirpation of the primary tumor and locoregional metastases epitomizes the management of patients with such tumors, this is not always possible with conventional surgical techniques. Nonresectable, slow-growing tumors involving the mesenteric root represent a generally accepted indication for deceased donor intestinal and multivisceral transplantation. Furthermore, vascularized sentinel forearm flaps offer opportunities for monitoring graft rejection and tailoring immunosuppression regimens. Here, we report the first documented case of modified liver-free multivisceral transplantation preceded by neoadjuvant 177-lutetium peptide receptor radionuclide therapy in a patient with a small bowel neuroendocrine tumor and extensive lymph node metastases in the mesenterium. At a follow-up of 21 months the patient is biochemically and radiologically disease-free.


Australia in 2030: what is our path to health for all?
CHAPTER 1: HOW AUSTRALIA IMPROVED HEALTH EQUITY THROUGH ACTION ON THE SOCIAL DETERMINANTS OF HEALTH: Do not think that the social determinants of health equity are old hat. In reality, Australia is very far away from addressing the societal level drivers of health inequity. There is little progressive policy that touches on the conditions of daily life that matter for health, and action to redress inequities in power, money and resources is almost non-existent. In this chapter we ask you to pause this reality and come on a fantastic journey where we envisage how COVID-19 was a great disruptor and accelerator of positive progressive action. We offer glimmers of what life could be like if there was committed and real policy action on the social determinants of health equity. It is vital that the health sector assists in convening the multisectoral stakeholders necessary to turn this fantasy into reality. CHAPTER 2: ABORIGINAL AND TORRES STRAIT ISLANDER CONNECTION TO CULTURE: BUILDING STRONGER INDIVIDUAL AND COLLECTIVE WELLBEING: Aboriginal and Torres Strait Islander peoples have long maintained that culture (ie, practising, maintaining and reclaiming it) is vital to good health and wellbeing. However, this knowledge and understanding has been dismissed or described as anecdotal or intangible by Western research methods and science. As a result, Aboriginal and Torres Strait Islander culture is a poorly acknowledged determinant of health and wellbeing, despite its significant role in shaping individuals, communities and societies. By extension, the cultural determinants of health have been poorly defined until recently. However, an increasing amount of scientific evidence supports what Aboriginal and Torres Strait Islander people have always said - that strong culture plays a significant and positive role in improved health and wellbeing. Owing to known gaps in knowledge, we aim to define the cultural determinants of health and describe their relationship with the social determinants of health, to provide a full understanding of Aboriginal and Torres Strait Islander wellbeing. We provide examples of evidence on cultural determinants of health and links to improved Aboriginal and Torres Strait Islander health and wellbeing. We also discuss future research directions that will enable a deeper understanding of the cultural determinants of health for Aboriginal and Torres Strait Islander people. CHAPTER 3: PHYSICAL DETERMINANTS OF HEALTH: HEALTHY, LIVEABLE AND SUSTAINABLE COMMUNITIES: Good city planning is essential for protecting and improving human and planetary health. Until recently, however, collaboration between city planners and the public health sector has languished. We review the evidence on the health benefits of good city planning and propose an agenda for public health advocacy relating to health-promoting city planning for all by 2030. Over the next 10 years, there is an urgent need for public health leaders to collaborate with city planners - to advocate for evidence-informed policy, and to evaluate the health effects of city planning efforts. Importantly, we need integrated planning across and between all levels of government and sectors, to create healthy, liveable and sustainable cities for all. CHAPTER 4: HEALTH PROMOTION IN THE ANTHROPOCENE: THE ECOLOGICAL DETERMINANTS OF HEALTH: Human health is inextricably linked to the health of the natural environment. In this chapter, we focus on ecological determinants of health, including the urgent and critical threats to the natural environment, and opportunities for health promotion arising from the human health co-benefits of actions to protect the health of the planet. We characterise ecological determinants in the Anthropocene and provide a sobering snapshot of planetary health science, particularly the momentous climate change health impacts in Australia. We highlight Australia's position as a major fossil fuel producer and exporter, and a country lacking cohesive and timely emissions reduction policy. We offer a roadmap for action, with four priority directions, and point to a scaffold of guiding approaches - planetary health, Indigenous people's knowledge systems, ecological economics, health co-benefits and climate-resilient development. Our situation requires a paradigm shift, and this demands a recalibration of health promotion education, research and practice in Australia over the coming decade. CHAPTER 5: DISRUPTING THE COMMERCIAL DETERMINANTS OF HEALTH: Our vision for 2030 is an Australian economy that promotes optimal human and planetary health for current and future generations. To achieve this, current patterns of corporate practice and consumption of harmful commodities and services need to change. In this chapter, we suggest ways forward for Australia, focusing on pragmatic actions that can be taken now to redress the power imbalances between corporations and Australian governments and citizens. We begin by exploring how the terms of health policy making must change to protect it from conflicted commercial interests. We also examine how marketing unhealthy products and services can be more effectively regulated, and how healthier business practices can be incentivised. Finally, we make recommendations on how various public health stakeholders can hold corporations to account, to ensure that people come before profits in a healthy and prosperous future Australia. CHAPTER 6: DIGITAL DETERMINANTS OF HEALTH: THE DIGITAL TRANSFORMATION: We live in an age of rapid and exponential technological change. Extraordinary digital advancements and the fusion of technologies, such as artificial intelligence, robotics, the Internet of Things and quantum computing constitute what is often referred to as the digital revolution or the Fourth Industrial Revolution (Industry 4.0). Reflections on the future of public health and health promotion require thorough consideration of the role of digital technologies and the systems they influence. Just how the digital revolution will unfold is unknown, but it is clear that advancements and integrations of technologies will fundamentally influence our health and wellbeing in the future. The public health response must be proactive, involving many stakeholders, and thoughtfully considered to ensure equitable and ethical applications and use. CHAPTER 7: GOVERNANCE FOR HEALTH AND EQUITY: A VISION FOR OUR FUTURE: Coronavirus disease 2019 has caused many people and communities to take stock on Australia's direction in relation to health, community, jobs, environmental sustainability, income and wealth. A desire for change is in the air. This chapter imagines how changes in the way we govern our lives and what we value as a society could solve many of the issues Australia is facing - most pressingly, the climate crisis and growing economic and health inequities. We present an imagined future for 2030 where governance structures are designed to ensure transparent and fair behaviour from those in power and to increase the involvement of citizens in these decisions, including a constitutional voice for Indigenous peoples. We imagine that these changes were made by measuring social progress in new ways, ensuring taxation for public good, enshrining human rights (including to health) in legislation, and protecting and encouraging an independent media. Measures to overcome the climate crisis were adopted and democratic processes introduced in the provision of housing, education and community development.


Predictive models for water sources with high susceptibility for bromine-containing disinfection by-product formation: implications for water treatment.
This study examines a matrix of synthetic water samples designed to include conditions that favour brominated disinfection by-product (Br-DBP) formation, in order to provide predictive models suitable for high Br-DBP forming waters such as salinity-impacted waters. Br-DBPs are known to be more toxic than their chlorinated analogues, in general, and their formation may be favoured by routine water treatment practices such as coagulation/flocculation under specific conditions; therefore, circumstances surrounding their formation must be understood. The chosen factors were bromide concentration, mineral alkalinity, bromide to dissolved organic carbon (Br/DOC) ratio and Suwannee River natural organic matter concentration. The relationships between these parameters and DBP formation were evaluated by response surface modelling of data generated using a face-centred central composite experimental design. Predictive models for ten brominated and/or chlorinated DBPs are presented, as well as models for total trihalomethanes (tTHMs) and total dihaloacetonitriles (tDHANs), and bromide substitution factors for the THMs and DHANs classes. The relationships described revealed that increasing alkalinity and increasing Br/DOC ratio were associated with increasing bromination of THMs and DHANs, suggesting that DOC lowering treatment methods that do not also remove bromide such as enhanced coagulation may create optimal conditions for Br-DBP formation in waters in which bromide is present.


Trema orientalis Linn. Blume: A potential for prospecting for drugs for various uses.
Medicinal plants are used by traditional practitioners to treat several ailments. Ethnomedicinal studies on Trema orientalis Linn. Blume (Ulmaceae) have shown that it is used in the treatment of diabetes mellitus, respiratory diseases, oliguria, and malaria. This article is aimed at providing comprehensive information on the medicinal uses, biology, phytochemical constituents, and pharmacological data available on T. orientalis. This has been done to explore its therapeutic potential for future research opportunities. This review was compiled with information obtained from databases such as Medline, Elsevier, Springer, Science Direct, Pubmed, Google Scholar, and a library search for articles published in peer-reviewed journals. Compounds present in the plant include tannins, saponins, flavanoids, triterpenes, phytosterols, and several constituents of xanthones. Some pharmacological research done on the plant has focused on, hypoglycemic activity, analgesic, anti-inflammatory activities, anti-plasmodial activity, diuretic activity, laxativity effect, anti-convulsant activity, anti-helmintic activity, anti-sickling effect, anti-oxidant, and anti-bacterial activity. This compilation strongly supports the view that T. orientalis has beneficial therapeutic properties, and indicates its potential as an effective herbal remedy for several diseases. The promising results from several research works could be further substantiated by clinical trials.


Concentration estimation from differential absorption lidar using nonstationary Wiener filtering.
An approach is presented for smoothing and differentiating path-integrated concentration estimates provided by range-resolved differential absorption lidar that is based on a nonstationary implementation of the Wiener-Kolmogorov filtering theory. The primary advantage of the method lies in its ability to provide filtered estimates that are smoothed relative to the local uncertainty in the input data. The approach is derived and illustrated on both synthetic and actual lidar data.


Global and regional patterns in cardiovascular mortality from 1990 to 2013.
There is a global commitment to reduce premature cardiovascular diseases (CVDs) 25% by 2025. CVD mortality rates have declined dramatically over the past 2 decades, yet the number of life years lost to premature CVD deaths is increasing in low- and middle-income regions. Ischemic heart disease and stroke remain the leading causes of premature death in the world; however, there is wide regional variation in these patterns. Some regions, led by Central Asia, face particularly high rates of premature death from ischemic heart disease. Sub-Saharan Africa and Asia suffer disproportionately from death from stroke. The purpose of the present report is to (1) describe global trends and regional variation in premature mortality attributable to CVD, (2) review past and current approaches to the measurement of these trends, and (3) describe the limitations of existing models of epidemiological transitions for explaining the observed distribution and trends of CVD mortality. We describe extensive variation both between and within regions even while CVD remains a dominant cause of death. Policies and health interventions will need to be tailored and scaled for a broad range of local conditions to achieve global goals for the improvement of cardiovascular health.


High Cholesterol Diet-Induced Changes in Oxysterol and Scavenger Receptor Levels in Heart Tissue.
Involvement of high cholesterol and oxidative stress in cardiovascular diseases is well studied, as it can be hypothesized that various products originated from lipid peroxidation, such as oxysterols, or affected protein expression might lead to cardiomyocyte damage followed by the pathological modifications. Although oxidation of excessive cholesterol to oxysterols in elevated stress conditions is identified by a number of studies, the role of a high cholesterol diet in regulating fatty acid and oxysterol accumulation, together with scavenger receptor mRNA levels, in the heart remains little investigated. Our study provides a detailed analysis of the changes in fatty acid, oxysterol, and scavenger receptor profiles and its relation with histological alterations in the heart tissue. We evaluated alterations of fatty acid composition, by the GC-MS method, while 4β-, 25-, and 27-hydroxycholesterol and 7-ketocholesterol levels by means of LC-MS/MS in high cholesterol diet-fed rabbits. Additionally, a number of proteins related to lipid metabolism and scavenger receptor mRNA expressions were evaluated by Western blotting and RT-PCR. According to our in vivo results, a high cholesterol diet enhances a number of unsaturated fatty acids, oxysterols, and LXRα, in addition to CD36, CD68, CD204, and SR-F1 expressions while α-tocopherol supplementation decreases LXRα and SR expressions together with an increase in 27-hydroxycholesterol and ABCA1 levels. Our results indicated that the high cholesterol diet modulates proteins related to lipid metabolism, which might result in the malfunction of the heart and α-tocopherol shows its beneficial effects. We believe that this work will lead the generation of different theories in the development of heart diseases.


Temporal expression of the staphylococcal enterotoxin D gene under NaCl stress conditions.
Staphylococcus aureus is one of the most osmotolerant food-borne pathogens. While its growth is repressed by competing bacteria, the organism exhibits a growth advantage at increased salt concentrations. Staphylococcal enterotoxin D leads to vomiting and diarrhea upon ingestion. To date, the effect of NaCl on both sed expression and its regulatory control are unclear. We determined the impact of NaCl stress on sed expression and the influence of agr, sarA and sigB on sed expression under NaCl stress. The temporal expression of sed in LB and LB with 4.5% NaCl was compared, as well as sed expression of wild-type (wt) strains and isogenic Δagr, ΔsarA and ΔsigB mutants. In general, NaCl stress led to decreased sed expression. However, one strain exhibited a trend towards increased sed expression under NaCl stress. No significant effect of agr on sed expression was detected and only one ΔsigB mutant showed a significant decrease in sed expression in the early stationary phase under NaCl stress. One ΔsarA mutant showed decreased sed expression in the early stationary and another increased sed expression in the stationary growth phase under NaCl stress. These findings suggest high strain-specific variation in sed expression and its regulation under NaCl stress.