Electroacupuncture is Beneficial for Primary Dysmenorrhea: The Evidence from Meta-Analysis of Randomized Controlled Trials.
Electroacupuncture (EA) is considered to be a promising alternative therapy to relieve the menstrual pain for primary dysmenorrhea (PD), but the conclusion is controversial. Here, we conducted a systematic review and meta-analysis specifically to evaluate the clinical efficacy from randomized controlled trials (RCTs) on the use of EA in patients with PD. PubMed, Embase, ISI Web of Science, CENTRAL, CNKI, and Wanfang were searched to identify RCTs that evaluated the effectiveness of EA for PD. The outcome measurements included visual analogue scale (VAS), verbal rating scale (VRS), COX retrospective symptom scale (RSS), and the curative rate. Nine RCTs with high risk of bias were included for meta-analysis. The combined VAS 30 minutes after the completion of intervention favoured EA at SP6 when compared with EA at GB39, nonacupoints, and waiting-list groups. EA was superior to pharmacological treatment when the treatment duration lasted for three menstrual cycles, evidenced by significantly higher curative rate. No statistically significant differences between EA at SP6 and control groups were found regarding the VRS, RSS-COX1, and RSS-COX2. The findings of our study suggested that EA can provide considerable immediate analgesia effect for PD. Additional studies with rigorous design and larger sample sizes are needed.


Periadolescent ethanol vapor exposure persistently reduces measures of hippocampal neurogenesis that are associated with behavioral outcomes in adulthood.
Excessive alcohol consumption is prevalent among adolescents and may result in lasting neurobehavioral consequences. The use of animal models to study adolescent alcohol exposure has the advantage of allowing for the control necessary in order to evaluate the effects of ethanol on the brain and separate such effects from genetic background and other environmental insults. In the present study the effects of moderate ethanol vapor exposure, during adolescence, on measures of neurogenesis and behavioral measures were evaluated at two different times following ethanol withdrawal, in adulthood. The two groups of Wistar rats were both exposed to intermittent ethanol vapor (14 h on/10h off/day) for 35-36 days from PD 23 to PD 58 (average blood ethanol concentration: 163 mg%). In the first group, after rats were withdrawn from vapor they were subsequently assessed for locomotor activity, conflict behavior in the open field, and behaviors in the forced swim test (FST) and then sacrificed at 72 days of age. The second group of rats were withdrawn from vapor and injected for 5 days with Bromo-deoxy-Uridine (BrdU). Over the next 8 weeks they were also assessed for locomotor activity, conflict behavior in the open field, and behaviors in the FST and then sacrificed at 113/114 days of age. All rats were perfused for histochemical analyses. Ethanol vapor-exposed rats displayed hypoactivity in tests of locomotion and less anxiety-like and/or more "disinhibitory" behavior in the open field conflict. Quantitative analyses of immunoreactivity revealed a significant reduction in measures of neurogenesis, progenitor proliferation, as indexed by doublecortin (DCX), Ki67, and increased markers of cell death as indexed by cleaved caspase-3, and Fluoro-Jade at 72 days, and decreases in DCX, and increases in cleaved caspase-3 at 114 days in the ethanol vapor-exposed rats. Progenitor survival, as assessed by BrdU+, was reduced in the vapor-exposed animals that were sacrificed at 114 days. The reduction seen in DCX labeled in cell counts was significantly correlated with hypoactivity at 24h after withdrawal as well as less anxiety-like and/or more "disinhibitory" behavior in the open field conflict test at 2 and 8 weeks following termination of vapor exposure. These studies demonstrate that behavioral measures of disinhibitory behavior correlated with decreases in neurogenesis are all significantly and persistently impacted by periadolescent ethanol exposure and withdrawal in Wistar rats.


Structural and experiential neighborhood contexts, developmental stage, and antisocial behavior among urban adolescents in poverty.
This study explored the effects of structural and experiential neighborhood factors and developmental stage on antisocial behavior, among a sample of poor urban adolescents in New York City. Conceptually and empirically distinct profiles of neighborhood experience were derived from the data, based on measures of perceived neighborhood cohesion, poverty-related hassles, and involvement in neighborhood organizations and activities. Both the profiles of neighborhood experience and a measure of census-tract-level neighborhood hazard (poverty and violence) showed relationships to antisocial behavior. Contrary to expectation, higher levels of antisocial behavior were reported among adolescents residing in moderate-structural-risk neighborhoods than those in high-structural-risk neighborhoods. This effect held only for teens in middle (not early) adolescence and was stronger for teens perceiving their neighborhoods as hassling than for those who did not. Implications for future research and preventive intervention are discussed.


Effect of alendronate on HIV-associated osteoporosis: a randomized, double-blind, placebo-controlled, 96-week trial (ANRS 120).
Low bone mineral density (BMD) is common in HIV-infected patients. Bisphosphonates such as alendronate potently inhibit bone resorption and are effective against osteoporosis. The aim of the ANRS 120 Fosivir trial was to evaluate the effect of alendronate on low BMD in HIV-infected patients. HIV-1-infected adults with a t-score≤-2.5 at the lumbar spine and/or total hip, as assessed by dual x-ray absorptiometry, and no other known risk factors for low BMD, were randomized to receive either extended-release alendronate 70 mg weekly or placebo for 96 weeks, with stratification for gender. All the patients also received daily calcium carbonate (500 mg) and vitamin D (400 U). The primary endpoint for efficacy was the percentage change in BMD at the site with a t-score≤-2.5. Forty-four antiretroviral-treated patients (42 men, 2 women) were enrolled. The median age was 45 years, the median CD4 cell count was 422/mm(3), and viral load was <400 copies/ml in 84% of patients. Baseline characteristics were well balanced between the alendronate (n=20) and placebo (n=24) groups. At baseline, 15 patients (75%) in the alendronate group and 17 patients (71%) in the placebo group had a t-score≤-2.5 at the lumbar spine. In the main analysis, BMD at the site with a t-score≤-2.5 increased by 7.1% and 1.0%, respectively, in the alendronate (n=14) and placebo (n=20) groups at week 96 [mean difference, 6.1% (95% CI 2.8 to 9.3); p=0.0003]. Alendronate 70 mg weekly for 96 weeks improves BMD in HIV-1-infected patients on antiretroviral therapy.


The recognition and emergency management of suspected stroke and transient ischaemic attack.
In April 2006, the National Pre-hospital Guidelines Group produced suspected stroke and transient ischaemic attack guidelines to complement the National clinical guidelines for stroke. These concise guidelines contain recommendations from the group and the Intercollegiate Working Party for Stroke. This article serves as an introduction to the guidelines for healthcare staff working in emergency care.


Ferritin nanocage with intrinsically disordered proteins and affibody: A platform for tumor targeting with extended pharmacokinetics.
Ferritin nanocages are of particular interest as a novel platform for drug and vaccine delivery, diagnosis, biomineralization scaffold and more, due to their perfect and complex symmetry, ideal physical properties, high biocompatibility, low toxicity profiles as well as easy manipulation by genetic or chemical strategies. However, a short half-life is still a hurdle for the translation of ferritin-based nanomedicines into the clinic. Here, we developed a series of rationally designed long circulating ferritin nanocages (LCFNs) with 'Intrinsically Disordered Proteins (IDP)' as a stealth layer for extending the half-life of ferritin nanocages. Through predictions with 3D modelling, the LCFNs were designed, generated and their pharmacokinetic parameters including half-life, clearance rate, mean residence time, and more, were evaluated by qualitative and quantitative analysis. LCFNs have a tenfold increased half-life and overall improved pharmacokinetic parameters compared to wild-type ferritin nanocages (wtFN), corresponding to the low binding against bone marrow-derived macrophages (BMDMs) and endothelial cells. Subsequently, a tumor targeting moiety, epidermal growth factor receptor (EGFR)-targeting affibody peptide, was fused to LCFNs for evaluating their potential as a theragnostic platform. The tumor targeting-LCFNs successfully accumulated to the tumor tissue, by efficient targeting via active and passive properties, and also the shielding effect of IDP in vivo. This strategy can be applied to other protein-based nanocages for further progressing their use in the field of nanomedicine.


Unambiguous identification of miRNA:target site interactions by different types of ligation reactions.
To exert regulatory function, miRNAs guide Argonaute (AGO) proteins to partially complementary sites on target RNAs. Crosslinking and immunoprecipitation (CLIP) assays are state-of-the-art to map AGO binding sites, but assigning the targeting miRNA to these sites relies on bioinformatics predictions and is therefore indirect. To directly and unambiguously identify miRNA:target site interactions, we modified our CLIP methodology in C. elegans to experimentally ligate miRNAs to their target sites. Unexpectedly, ligation reactions also occurred in the absence of the exogenous ligase. Our in vivo data set and reanalysis of published mammalian AGO-CLIP data for miRNA-chimeras yielded ∼17,000 miRNA:target site interactions. Analysis of interactions and extensive experimental validation of chimera-discovered targets of viral miRNAs suggest that our strategy identifies canonical, noncanonical, and nonconserved miRNA:targets. About 80% of miRNA interactions have perfect or partial seed complementarity. In summary, analysis of miRNA:target chimeras enables the systematic, context-specific, in vivo discovery of miRNA binding.


Structure and function of S-adenosylmethionine synthetase: crystal structures of S-adenosylmethionine synthetase with ADP, BrADP, and PPi at 28 angstroms resolution.
S-Adenosylmethionine synthetase (MAT,ATP:L-methionine S-adenosltransferase, EC 126.96.36.199) plays a central metabolic role in all organisms. MAT catalyzes the two-step reaction which synthesizes S-adenosylmethionine (AdoMet), pyrophosphate (PPi), and orthophosphate (Pi) from ATP and L-methionine. AdoMet is the primary methyl group donor in biological systems. The first crystal structure of MAT from Escherichia coli has recently been determined [Takusagawa et al. (1995) J. Biol. Chem. 271, 136-147]. In order to elucidate the active site and possible catalytic reaction mechanism, the MAT structures in the crystals grown with the substrate ATP (and BrATP) and the product PPi have been determined (space group P6(2)22; unit cell a = b = 128.9 Angstroms, c= 139.8 Angstroms, resolution limit 2.8 Angstroms; R O.19; Rfree 0.26). The enzyme consists of four identical subunits; two subunits form a spherical dimer, and pairs of these tightly bound dimers form a tetrameric enzyme. Each dimer has two active sites which are located between the subunits. Each subunit consists of three domains related to each other by a pseudo 3-fold symmetry. The crystal structures showed that the ATP molecules were hydrolyzed to ADP and Pi by the enzyme. Those products were found at the active site along with the essential metal ions (K+ and Mg2+). This rather unexpected finding was first confirmed by the structure of the complex with PPi and later by an HPLC analysis. The enzyme hydrolyzed ATP to ADP and Pi in 72 h under the same conditions as the crystallization of the enzyme. In the active site, the diphosphate moiety of ADP and Pi interacts extensively with amino acid residues from the two subunits of the enzyme, whereas the adenine and ribose moieties have little interaction with the enzyme. The enzyme structure is little changed upon binding ADP. All amino acid residues involved in the active site are found to be conserved in the 14 reported sequences of MAT from a wide range of organisms. Thus the structure determined in this study can be utilized as a model for other members of the MAT family. On the basis of the crystal structures, the catalytic reaction mechanisms of AdoMet formation and hydrolysis of tripolyphosphate are proposed.


The disposition of intravenous potassium in normal man: the role of insulin.
1. Potassium infusion causes an increase in immunoreactive insulin levels in dogs, but either a small (30%) or no increase in humans. Since insulin stimulates the uptake of K+ by cells, a regulatory role for K+-induced insulin release has been postulated. To study the role of insulin in regulating cellular K+ uptake, six fasting normal volunteer subjects underwent two K+ infusions on separate days. Both infusions delivered 0.6 mmol h-1 kg-1 for 3 h. In one subject glucose was simultaneously infused at 0.67 mmol h-1 kg-1 (a rate known to increase peripheral insulin levels by 40-100%); the other infusion contained no glucose. 2. Plasma insulin levels did not increase during the glucose-free infusions. During glucose-containing infusions, insulin levels were 40% higher than those during glucose-free infusions. Despite this, neither urinary potassium excretion nor the increment in plasma K+ concentration or the calculated cellular K+ uptake differed significantly during the 3 h of glucose-free and glucose-containing infusions respectively. 3. These data do not support the view that potassium-induced insulin secretion regulates cellular potassium uptake within the physiological range of plasma K+ concentration.


Monoclonal antibodies to Cryptococcus neoformans capsular polysaccharide modify the course of intravenous infection in mice.
Immunoglobulin G1 (IgG1) monoclonal antibodies (MAbs) to the capsular glucuronoxylomannan (GXM) were studied for their ability to modify the course of intravenous Cryptococcus neoformans infection in mice. A/J mice were given intraperitoneal injection of 1.0 mg of either a GXM-binding IgG1 MAb (2H1 or 2D10 gamma 1) or the irrelevant isotype-matched control MAb 36-65 prior to intravenous infection. Parameters used to study antibody efficacy were lung and brain tissue fungal burden, lung and brain weights, serum GXM levels, and histopathological examination of lung, brain, heart, kidney, and spleen tissues. Mice given GXM-binding MAb had significantly reduced lung tissue fungal burden as measured by CFU. In contrast to the reduction in lung tissue burden, the reduction in brain tissue burden was small and did not achieve statistical significance. Serum GXM levels were reduced in mice receiving GXM-binding MAb. Histopathological examination revealed reduced numbers of granulomas and C. neoformans organisms in the lungs, brains, and kidneys of MAb 2H1-treated mice relative to control mice. The lungs and brains of mice receiving GXM-binding MAb weighed significantly less than those of control animals, consistent with the reduced inflammation noted histologically. Subendocardial inflammation and kidney cortical infarctions were present in control infected mice but not in MAb 2H1-treated mice. Immunocytochemical staining for polysaccharide antigen revealed a marked reduction in the amount of tissue polysaccharide in mice treated with MAb 2H1 relative to control mice. The results support an useful role for passive antibody administration in C. neoformans infections.


Allelic loss on chromosome 13q in human prostate carcinoma.
To clarify the role in prostate tumorigenesis played by loss of the three known or putative tumor suppressor loci on the centromeric portion of chromosome 13q, we examined 80 clinically localized and 15 advanced prostate carcinomas for allelic loss at microsatellite markers mapped to this region, including markers tightly linked to the BRCA-2, retinoblastoma (Rb), and DBM (deleted in B-cell malignancy) loci. Among the 80 clinically localized cases, 24 showed allelic loss at one or more 13q loci. In all cases with loss, the Rb and/or DBM loci were lost. No cases were found with loss of Rb without loss of DBM or loss of DBM without loss of Rb, implying a role for both the Rb and DBM loci in clinically localized prostate cancer. Loss of the BRCA-2 locus was less common (4 of 55 informative cases) and was always associated with loss of Rb and/or DBM loci. Thus, the BRCA-2 locus does not appear to play as important a role in clinically localized prostate cancer as the Rb and/or DBM loci. Allelic loss on 13q was extremely common in the clinically advanced cases; it was present in 14 of the 15 cases. The rate of allelic loss at each of the three tumor suppressor loci was increased significantly in the advanced cases (P < 0.01, Fisher's exact test). Thus, loss of heterozygosity on 13q is very common in prostate cancer and occurs at all three known or putative tumor suppressor loci on the centromeric portion of chromosome 13q.


Evaluation of the "Cellscreen" system for proliferation studies on liver progenitor cells.
Proliferation studies on mammalian cells have been disadvantaged by the limited availability of non-invasive assays as the majority of approaches are based on chemical treatment, sampling or staining of cells removed from culture. In this study, we utilised the Cellscreen system (Innovatis AG, Bielefeld, Germany), a non-invasive automated technique for measuring proliferation of adherent and suspension cells over time. We have evaluated the ability of the Cellscreen system to monitor and quantify growth of adherent liver progenitor cells over time and tested several applications, (i) serum reduction or (ii) treatment with a cytokine. Our results demonstrate that the Cellscreen system reproducibly documents pro- and anti-proliferative effects of cytokines and growth factors and quantifies changes by providing cell-doubling times for control and test cultures. However, we found that for the conversion of cell density values into absolute cell numbers different conversion factors, which better suit the individual growth phases, need to be established. Collectively, these findings reveal that the Cellscreen system is applicable for the determination of cell proliferation of adherent and suspension cells in response to a variety of (growth) factors. It minimises operator participation and thus enables more rapid and larger screens and, being non-invasive, permits multiple assays on the same culture of cells. Hence, this technique proves superior to the common proliferation assays opening up new dimensions of proliferation studies in cell biology.


Screening for prostate cancer: an update of the evidence for the U.S. Preventive Services Task Force.
In U.S. men, prostate cancer is the most common noncutaneous cancer and the second leading cause of cancer death. Screening for prostate cancer is controversial. To examine for the U.S. Preventive Services Task Force the evidence of benefits and harms of screening and earlier treatment. MEDLINE and the Cochrane Library, experts, and bibliographies of reviews. Researchers developed eight questions representing a logical chain between screening and reduced mortality, along with eligibility criteria for admissible evidence for each question. Admissible evidence was obtained by searching the data sources. Two reviewers abstracted relevant information using standardized abstraction forms and graded article quality according to Task Force criteria. No conclusive direct evidence shows that screening reduces prostate cancer mortality. Some screening tests can detect prostate cancer at an earlier stage than clinical detection. One study provides good evidence that radical prostatectomy reduces disease-specific mortality for men with localized prostate cancer detected clinically. No study has examined the additional benefit of earlier treatment after detection by screening. Men with a life expectancy of fewer than 10 years are unlikely to benefit from screening even under favorable assumptions. Each treatment is associated with several well-documented potential harms. Although potential harms of screening for prostate cancer can be established, the presence or magnitude of potential benefits cannot. Therefore, the net benefit of screening cannot be determined.


How useful are the SF-36 sub-scales in older people? Mokken scaling of data from the HALCyon programme.
To evaluate two psychometric properties of SF-36, namely unidimensionality and reliability. The data are from three cohorts in the HALCyon collaborative research programme into healthy ageing: Aberdeen Birth Cohort 1936 (n = 428), Hertfordshire Ageing Study (n = 358) and Hertfordshire Cohort Study (n = 3,216). The Mokken scaling model was applied to each sub-scale of SF-36 to evaluate unidimensionality as indicated by scalability. The lower bound for internal consistency reliability was determined by Cronbach's alpha. All six sub-scales of SF-36, with the exception of general health (GH) and mental health (MH), demonstrated strong scalability (0.5 ≤ H < 1). The results were consistent across all 3 cohorts. Both GH and MH showed medium scalability (0.4 ≤ H <0.55), although individual items 'sick easier..', 'as healthy as..' and 'expect to get worse' of the GH sub-scale and 'nervous', 'happy' in the MH sub-scale had low scalability (H < 0.4) in the oldest cohort (aged 73-83). Cronbach's alphas for all sub-scales were between 0.70 and 0.92. The unidimensionality and reliability of the sub-scales of SF-36 are sufficient to make this a useful measure of health-related quality of life in older people. Caution is needed when interpreting the results for GH and MH in the oldest cohort due to the poor unidimensionality.


Psychological distress in adult survivors of childhood cancer: the Swiss Childhood Cancer Survivor study.
To evaluate the degree of psychological distress in adult childhood cancer survivors in Switzerland and to characterize survivors with significant distress. Childhood cancer survivors who were age younger than 16 years when diagnosed between 1976 and 2003, had survived more than 5 years, and were currently age 20 years or older received a postal questionnaire. Psychological distress was assessed using the Brief Symptom Inventory (BSI). Raw scores were transformed into T scores according to the German norm sample, and the proportion of participants being at increased risk for psychological distress was calculated (case rule: T > or = 63). t tests and univariable and multivariable logistic regressions were used for statistical analyses. One thousand seventy-six survivors (63.% of eligible survivors, 71.9% of contacted survivors) returned the questionnaire, 987 with complete data on BSI. Comparison with the norm populations showed lower T scores (T < 50) in the Global Severity Index (GSI; T = 46.2), somatization (T = 47.6), obsessive-compulsive tendencies (T = 46.9), and anxiety (T = 48.4). However, more childhood cancer survivors (especially women) had increased distress for GSI (14.4%), interpersonal sensitivity (16.5%), depression (13.4%), aggression (16.9%), and psychotic tendencies (15.6%) than the expected 10% from the norm population. Caseness was associated with female sex, being a single child, older age at study, and self-reported late effects, especially psychological problems. Results show that childhood cancer survivors, on average, have less psychological distress than a norm population but that the proportion of survivors at risk for high psychological distress is disproportionally large. Monitoring psychological distress in childhood cancer survivors may be desirable during routine follow-up, and psychological support should be offered as needed.


Regulation of mating and filamentation genes by two distinct Ste12 complexes in Saccharomyces cerevisiae.
The Saccharomyces cerevisiae transcription factor Ste12 controls two distinct developmental programs of mating and filamentation. Ste12 activity is regulated by Fus3 and Kss1 mitogen-activated protein kinases through two Ste12 inhibitors, Dig1 and Dig2. Mating genes are regulated by Ste12 through Ste12 binding sites (pheromone response elements [PREs]), whereas filamentation genes are supposedly regulated by the cooperative binding of Ste12 and Tec1 on a PRE adjacent to a Tec1-binding site (TCS), termed filamentous responsive element (FRE). However, most filamentation genes do not contain an FRE; instead, they all have a TCS. By immunoprecipitation, we show that Ste12 forms two distinct complexes, Ste12/Dig1/Dig2 and Tec1/Ste12/Dig1, both in vivo and in vitro. The two complexes are formed by the competitive binding of Tec1 and Dig2 with Ste12, as Tec1 can compete off Dig2 from Ste12 in vitro and in vivo. In the Tec1/Ste12/Dig1 complex, Tec1 binds to the N terminus of Ste12 and to Dig1 indirectly through Ste12. Tec1 has low basal activity, and its transcriptional activation is provided by the associated Ste12, which is under Dig1 inhibition. Filamentation genes are bound by the Tec1/Ste12/Dig1 complex, whereas mating genes are occupied by mostly Ste12/Dig1/Dig2 with some Tec1/Ste12/Dig1. We suggest that Tec1 tethers Ste12 to TCS elements upstream of filamentation genes and defines the filamentation genes as a subset of Ste12-regulated genes.


The multi-vessel and diffuse coronary spasm is a risk factor for persistent angina in patients received anti-angina medication.
Coronary artery spasm (CAS) is known to be a risk factor for cardiovascular events. However, there is limited data whether the multi-vessel and diffuse spasm (MVDS) is related to more adverse clinical outcomes compared to the Non-MVDS. The aim of this study is to evaluate the impact of the MVDS on clinical outcomes during a 3-year clinical follow-up period.A total 2797 patients underwent coronary angiography (CAG) with acetylcholine (ACH) provocation test from Nov 2004 to Oct 2010 were enrolled. It is a single-center, observational, prospective, all-comers registry designed to reflect the "real world" practic. The patients were divided into the 3 groups; the negative spasm (NS) group (n = 1188), the Non-MVDS group (n = 1081), and the MVDS group (n = 528). The incidence of major adverse cardiac events (MACE) and recurrent angina was evaluated up to 3 years. To minimize confounding factors, multivariable Cox-proportional hazards regression analysis was performed.In the 3-year clinical follow-up, the incidence of total death, myocardial infarction, de novo percutaneous coronary intervention (PCI), cerebrovascular accident and MACE were similar among the 3 groups. However, recurrent angina occurred more frequently in the MVDS group than in the NS group (hazard ratio [HR], 1.96; 95% confidence interval [CI], 1.27-3.02; P = .002). Recurrence angina between the MVDS group and the Non-MVDS group was not statistically significant (HR, 1.36; 95% CI, 0.91-2.03; P = .129).In this study, although the incidence of major adverse cardiovascular events were not different regardless of spasm type, the MVDS was associated with higher incidence of recurrent chest pain requiring repeat CAG during the 3-year follow-up period, suggesting more intensive optimal medical therapy with close clinical follow up would be necessary for this particular subset of patients.


Long-term trend and spatial pattern of PM2.5 induced premature mortality in China.
With rapid economic growth, China has witnessed increasingly frequent and severe haze and smog episodes over the past decade, posing serious health impacts to the Chinese population, especially those in densely populated city clusters. Quantification of the spatial and temporal variation of health impacts attributable to ambient fine particulate matter (PM2.5) has important implications for China's policies on air pollution control. In this study, we evaluated the spatial distribution of premature deaths in China between 2000 and 2010 attributable to ambient PM2.5 in accord with the Global Burden of Disease based on a high resolution population density map of China, satellite retrieved PM2.5 concentrations, and provincial health data. Our results suggest that China's anthropogenic ambient PM2.5 led to 1,255,400 premature deaths in 2010, 42% higher than the level in 2000. Besides increased PM2.5 concentration, rapid urbanization has attracted large population migration into the more developed eastern coastal urban areas, intensifying the overall health impact. In addition, our analysis implies that health burdens were exacerbated in some developing inner provinces with high population density (e.g. Henan, Anhui, Sichuan) because of the relocation of more polluting and resource-intensive industries into these regions. In order to avoid such national level environmental inequities, China's regulations on PM2.5 should not be loosened in inner provinces. Furthermore policies should create incentive mechanisms that can promote transfer of advanced production and emissions control technologies from the coastal regions to the interior regions.


Microbial diversity in saliva of oral squamous cell carcinoma.
In the oral cavity, chronic inflammation has been observed at various stages of oral squamous cell carcinomas (OSCC). Such inflammation could result from persistent mucosal or epithelial cell colonization by microorganisms. There is increasing evidence of the involvement of oral bacteria in inflammation, warranting further studies on the association of bacteria with the progression of OSCC. The objective of this study was to evaluate the diversity and relative abundance of bacteria in the saliva of subjects with OSCC. Using 454 parallel DNA sequencing, ∼58,000 PCR amplicons that span the V4-V5 hypervariable region of rRNAs from five subjects were sequenced. Members of eight phyla (divisions) of bacteria were detected. The majority of classified sequences belonged to the phyla Firmicutes (45%) and Bacteroidetes (25%). Further, 52 different genera containing approximately 860 (16.51%) known species were identified and 1077 (67%) sequences belonging to various uncultured bacteria or unclassified groups. The species diversity estimates obtained with abundance-based coverage estimators and Chao1 were greater than published analyses of other microbial profiles from the oral cavity. Fifteen unique phylotypes were present in all three OSCC subjects.


Consensus statement on current and emerging methods for the diagnosis and evaluation of cerebrovascular disease.
Cerebrovascular disease (CVD) remains a leading cause of death and the leading cause of adult disability in most developed countries. This work summarizes state-of-the-art, and possible future, diagnostic and evaluation approaches in multiple stages of CVD, including (i) visualization of sub-clinical disease processes, (ii) acute stroke theranostics, and (iii) characterization of post-stroke recovery mechanisms. Underlying pathophysiology as it relates to large vessel steno-occlusive disease and the impact of this macrovascular disease on tissue-level viability, hemodynamics (cerebral blood flow, cerebral blood volume, and mean transit time), and metabolism (cerebral metabolic rate of oxygen consumption and pH) are also discussed in the context of emerging neuroimaging protocols with sensitivity to these factors. The overall purpose is to highlight advancements in stroke care and diagnostics and to provide a general overview of emerging research topics that have potential for reducing morbidity in multiple areas of CVD.


A highly versatile optical fibre vacuum feed-through.
Coupling light into a vacuum system is a non-trivial problem, requiring the use of a specialized feed-through. This feed-through must be both leak tight and offer a low optical loss if it is to be suitable for general use. In this paper, we report on the development of an extremely simple yet versatile, low cost, demountable optical fiber vacuum feed-through based on the modification of a standard optical fiber bulkhead connector. The modified connector was found to have a leak rate of 6.6 ± 2.1 × 10(-6) mbar l/s and an optical loss of -0.41 ± 0.28 dB, making it suitable for use in high vacuum applications.


Translating research into policy: lessons learned from eclampsia treatment and malaria control in three southern African countries.
Little is known about the process of knowledge translation in low- and middle-income countries. We studied policymaking processes in Mozambique, South Africa and Zimbabwe to understand the factors affecting the use of research evidence in national policy development, with a particular focus on the findings from randomized control trials (RCTs). We examined two cases: the use of magnesium sulphate (MgSO(4)) in the treatment of eclampsia in pregnancy (a clinical case); and the use of insecticide treated bed nets and indoor residual household spraying for malaria vector control (a public health case). We used a qualitative case-study methodology to explore the policy making process. We carried out key informants interviews with a range of research and policy stakeholders in each country, reviewed documents and developed timelines of key events. Using an iterative approach, we undertook a thematic analysis of the data. Prior experience of particular interventions, local champions, stakeholders and international networks, and the involvement of researchers in policy development were important in knowledge translation for both case studies. Key differences across the two case studies included the nature of the evidence, with clear evidence of efficacy for MgSO(4 )and ongoing debate regarding the efficacy of bed nets compared with spraying; local researcher involvement in international evidence production, which was stronger for MgSO(4 )than for malaria vector control; and a long-standing culture of evidence-based health care within obstetrics. Other differences were the importance of bureaucratic processes for clinical regulatory approval of MgSO(4), and regional networks and political interests for malaria control. In contrast to treatment policies for eclampsia, a diverse group of stakeholders with varied interests, differing in their use and interpretation of evidence, was involved in malaria policy decisions in the three countries. Translating research knowledge into policy is a complex and context sensitive process. Researchers aiming to enhance knowledge translation need to be aware of factors influencing the demand for different types of research; interact and work closely with key policy stakeholders, networks and local champions; and acknowledge the roles of important interest groups.


Development of a Chinese medicine assessment measure: an interdisciplinary approach using the delphi method.
The diagnostic framework and clinical reasoning process in Chinese medicine emphasizes the contextual and qualitative nature of a patient's illness. Chinese medicine assessment data may help interpret clinical outcomes. As part of a study aimed at assessing the validity and improving the inter-rater reliability of the Chinese diagnostic process, a structured assessment instrument was developed for use in clinical trials of acupuncture and other Chinese medical therapies. To foster collaboration and maximize resources and information, an interdisciplinary advisory team was assembled. Under the guidance of two group process facilitators, and in order to establish whether the assessment instrument was consistent with accepted Chinese medicine diagnostic categories (face validity) and included the full range of each concept's meaning (content validity), a panel of Traditional Chinese Medicine (TCM) expert clinicians was convened and their responses were organized using the Delphi process, an iterative, anonymous, idea-generating and consensus-building process. An aggregate rating measure was obtained by taking the mean of mean ratings for each question across all 10 experts. Over three rounds, the overall rating increased from 7.4 (SD = 1.3) in Round 1 to 9.1 (SD = 0.5) in Round 3. The level of agreement among clinicians was measured by a decrease in SD. The final instrument TEAMSI-TCM (Traditional East Asian Medicine Structured Interview, TCM version) uses the pattern differentiation model characteristic of TCM. This modular, dynamic version was specifically designed to assess women, with a focus on gynecologic conditions; with modifications it can be adapted for use with other populations and conditions. TEAMSI-TCM is a prescriptive instrument that guides clinicians to use the proper indicators, combine them in a systematic manner, and generate conclusions. In conjunction with treatment manualization and training it may serve to increase inter-rater reliability and inter-trial reproducibility in Chinese medicine clinical trials. Testing of the validity and reliability of this instrument currently is underway.


CLIMB (the Cloud Infrastructure for Microbial Bioinformatics): an online resource for the medical microbiology community.
The increasing availability and decreasing cost of high-throughput sequencing has transformed academic medical microbiology, delivering an explosion in available genomes while also driving advances in bioinformatics. However, many microbiologists are unable to exploit the resulting large genomics datasets because they do not have access to relevant computational resources and to an appropriate bioinformatics infrastructure. Here, we present the Cloud Infrastructure for Microbial Bioinformatics (CLIMB) facility, a shared computing infrastructure that has been designed from the ground up to provide an environment where microbiologists can share and reuse methods and data.


Effects of N-n-propylnorapomorphine enantiomers on single unit activity of substantia nigra pars compacta and ventral tegmental area dopamine neurons.
Prompted by conflicting reports of both agonist and antagonist properties of the S-(+)-enantiomer of the potent dopamine agonist R-(-)-N-n-propylnorapomorphine (NPA), we carried out extracellular, single unit recording studies to compare the effects of both enantiomers on substantia nigra and ventral tegmental area (VTA) dopamine neurons in male rats anesthetized with chloral hydrate. Like the classic dopamine agonist apomorphine, R-(-)-NPA inhibited cell firing in both populations. Mean cumulative doses to inhibit firing by 50% (ID50) were 0.53 micrograms/kg for nigral and 0.50 micrograms/kg for VTA dopamine cells, respectively, reflecting a potency for R-(-)-NPA 10-fold greater than that of apomorphine for inhibition of nigral dopamine cells (ID50 5.3 micrograms/kg). Inhibitions elicited by R-(-)-NPA could be fully reversed by i.v. haloperidol (0.2 mg/kg) but not by S-(+)-NPA in doses up to 0.9 mg/kg. Interestingly, S-(+)-NPA also exhibited agonist activity in both cell groups but with a much lower potency than R-(-)-NPA. In addition, VTA dopamine cells displayed a significantly greater sensitivity to the drug: ID50 values of 149 micrograms/kg vs. 514 micrograms/kg for VTA and substantia nigra neurons, respectively (P less than .01). Prior administration of haloperidol (0.1 mg/kg) consistently and fully prevented the inhibitory effects of S-(+)-NPA on all cells tested, although subsequent administration of haloperidol (up to 1.6 mg/kg) did not reverse completely S-(+)-NPA-induced inhibitions in all cases.(ABSTRACT TRUNCATED AT 250 WORDS)


Evaluations of diapers containing absorbent gelling material with conventional disposable diapers in newborn infants.
We evaluated 149 infants diapered in either conventional cellulose core disposable diapers or diapers containing cellulose core with absorbent gelling material. The infants were evaluated from 1 day of age to 14 weeks of age for the prevalence and severity of diaper dermatitis. We identified a low prevalence of diaper dermatitis throughout the study period. At 14 weeks of age, we noted that infants in diapers containing absorbent gelling material had significantly less diaper dermatitis than those in conventional disposable diapers. Despite the overall low prevalence of diaper dermatitis in the newborn period, 7 of 204 infants evaluated had small skin erosions in the diaper area noted within the first 4 days of age. Both diaper types were associated with infants with erosions. This surprisingly high incidence of erosions in newborn infants suggests previously undocumented increased skin fragility of full-term infants.


Metabolic regulation analysis of an ethanologenic Escherichia coli strain based on RT-PCR and enzymatic activities.
A metabolic regulation study was performed, based upon measurements of enzymatic activities, fermentation performance, and RT-PCR analysis of pathways related to central carbon metabolism, in an ethanologenic Escherichia coli strain (CCE14) derived from lineage C. In comparison with previous engineered strains, this E coli derivative has a higher ethanol production rate in mineral medium, as a result of the elevated heterologous expression of the chromosomally integrated genes encoding PDCZm and ADHZm (pyruvate decarboxylase and alcohol dehydrogenase from Zymomonas mobilis). It is suggested that this behavior might be due to lineage differences between E. coli W and C. This study demonstrated that the glycolytic flux is controlled, in this case, by reactions outside glycolysis, i.e., the fermentative pathways. Changes in ethanol production rate in this ethanologenic strain result in low organic acid production rates, and high glycolytic and ethanologenic fluxes, that correlate with enhanced transcription and enzymatic activity levels of PDCZm and ADHZm. Furthermore, a higher ethanol yield (90% of the theoretical) in glucose-mineral media was obtained with CCE14 in comparison with previous engineered E. coli strains, such as KO11, that produces a 70% yield under the same conditions. Results suggest that a higher ethanol formation rate, caused by ahigher PDCZm and ADHZm activities induces a metabolic state that cells compensate through enhanced glucose transport, ATP synthesis, and NAD-NADH+H turnover rates. These results show that glycolytic enzymatic activities, present in E. coli W and C under fermentative conditions, are sufficient to contend with increases in glucose consumption and product formation rates.


Site-Directed Mutagenesis of Modular Polyketide Synthase Ketoreductase Domains for Altered Stereochemical Control.
Bacterial modular type I polyketide synthases (PKSs) are complex multidomain assembly line proteins that produce a range of pharmaceutically relevant molecules with a high degree of stereochemical control. Due to their colinear properties, they have been considerable targets for rational biosynthetic pathway engineering. Among the domains harbored within these complex assembly lines, ketoreductase (KR) domains have been extensively studied with the goal of altering their stereoselectivity by site-directed mutagenesis, as they confer much of the stereochemical complexity present in pharmaceutically active reduced polyketide scaffolds. Here we review all efforts to date to perform site-directed mutagenesis on PKS KRs, most of which have been done in the context of excised KR domains on model diffusible substrates such as β-keto N-acetyl cysteamine thioesters. We also discuss the challenges around translating the findings of these studies to alter stereocontrol in the context of a complex multidomain enzymatic assembly line.


Dietary abundance distributions: Dominance and diversity in vertebrate diets.
Diet composition is among the most important yet least understood dimensions of animal ecology. Inspired by the study of species abundance distributions (SADs), we tested for generalities in the structure of vertebrate diets by characterising them as dietary abundance distributions (DADs). We compiled data on 1167 population-level diets, representing >500 species from six vertebrate classes, spanning all continents and oceans. DADs near-universally (92.5%) followed a hollow-curve shape, with scant support for other plausible rank-abundance-distribution shapes. This strong generality is inherently related to, yet incompletely explained by, the SADs of available food taxa. By quantifying dietary generalisation as the half-saturation point of the cumulative distribution of dietary abundance (sp50, minimum number of foods required to account for 50% of diet), we found that vertebrate populations are surprisingly specialised: in most populations, fewer than three foods accounted for at least half the diet. Variation in sp50 was strongly associated with consumer type, with carnivores being more specialised than herbivores or omnivores. Other methodological (sampling method and effort, taxonomic resolution), biological (body mass, frugivory) and biogeographic (latitude) factors influenced sp50 to varying degrees. Future challenges include identifying the mechanisms underpinning the hollow-curve DAD, its generality beyond vertebrates, and the biological determinants of dietary generalisation.


Ecstasy--long-term effects on the human central nervous system revealed by positron emission tomography.
The main psychotropic agent of the popular illicit drug ecstasy is 3,4-methylenedioxymethamphetamine (MDMA). In the light of animal studies and examinations of human cerebrospinal fluid, MDMA is suspected of causing neurotoxic lesions to the serotonergic system. To postulate a relationship between ecstasy use and lasting alterations to the cerebral glucose metabolic rate. Positron emission tomography (PET) with 2-[18F]-fluoro-2-deoxy-D-glucose (FDG) was performed on seven ecstasy users and seven subjects without any known history of illicit drug use. Data were compared for a limited number of brain regions. By comparison with the control group, the glucose metabolic uptake of the ecstasy user group was altered within the amygdala, hippocampus and Brodmann's area II. The results suggest the possibility that ecstasy use has lasting effects on central neuronal activity in humans.


Essential role of NK cells in IgG therapy for experimental autoimmune encephalomyelitis.
Intravenous immunoglobulin has long been used in treating autoimmune diseases, although mechanisms remain uncertain. Activating Fcγ receptors are receptors of IgG and reported to be essential in intravenous immunoglobulin (IVIG) therapy. Therefore, we hypothesized natural killer (NK) cells, which express abundant activating Fcγ receptors, are the potential cellular target. In experimental autoimmune encephalomyelitis (EAE), we demonstrated that IgG suppressed disease development in intact, but not in NK cell depleted mice. Adoptive transfer of IgG-treated NK cell could protect mice against EAE, and suppressed interferon γ and interleukin 17 production. The percentage of CD4(+)Foxp3(+) regulatory T cells was significantly increased. The increase of regulatory T cells was also observed in IgG-treated EAE mice but not in NK cell depleted mice. In vitro experiments confirmed that IgG-treated NK cells enhanced regulatory T cell induction from naïve CD4(+) T cells. Interestingly, cells from draining lymph nodes produced more interleukin 2 after the adoptive transfer of IgG-treated NK cells. We neutralized interleukin 2 and the induction of CD4(+)Foxp3(+) T cells by IgG-treated NK cells was significantly reduced. To our knowledge, we identified for the first time the critical role of NK cells in the mechanism of IgG-induced induction of Treg cells in treatment of autoimmunity.


Dynamic cyanobacterial response to hydration and dehydration in a desert biological soil crust.
Biological soil crusts (BSCs) cover extensive portions of the earth's deserts. In order to survive desiccation cycles and utilize short periods of activity during infrequent precipitation, crust microorganisms must rely on the unique capabilities of vegetative cells to enter a dormant state and be poised for rapid resuscitation upon wetting. To elucidate the key events involved in the exit from dormancy, we performed a wetting experiment of a BSC and followed the response of the dominant cyanobacterium, Microcoleus vaginatus, in situ using a whole-genome transcriptional time course that included two diel cycles. Immediate, but transient, induction of DNA repair and regulatory genes signaled the hydration event. Recovery of photosynthesis occurred within 1 h, accompanied by upregulation of anabolic pathways. Onset of desiccation was characterized by the induction of genes for oxidative and photo-oxidative stress responses, osmotic stress response and the synthesis of C and N storage polymers. Early expression of genes for the production of exopolysaccharides, additional storage molecules and genes for membrane unsaturation occurred before drying and hints at preparedness for desiccation. We also observed signatures of preparation for future precipitation, notably the expression of genes for anaplerotic reactions in drying crusts, and the stable maintenance of mRNA through dormancy. These data shed light on possible synchronization between this cyanobacterium and its environment, and provides key mechanistic insights into its metabolism in situ that may be used to predict its response to climate, and or, land-use driven perturbations.


Broadening perspectives on trauma and recovery: a socio-interpersonal view of PTSD.
Posttraumatic stress disorder (PTSD) is one of the very few mental disorders that requires by definition an environmental context-a traumatic event or events-as a precondition for diagnosis. Both trauma sequelae and recovery always occur in the context of social-interpersonal contexts, for example, in interaction with a partner, family, the community, and the society. The present paper elaborates and extends the social-interpersonal framework model of PTSD. This was developed to complement other intrapersonally focused models of PTSD, which emphasize alterations in an individual's memory, cognitions, or neurobiology. Four primary reasons for broadening the perspective from the individual to the interpersonal-societal contexts are discussed. The three layers of the model (social affects, close relationships, and culture and society) are outlined. We further discuss additional insights and benefits of the social-interpersonal perspective for the growing field of research regarding resilience after traumatic experiences. The paper closes with an outlook on therapy approaches and interventions considering this broader social-interpersonal perspective on PTSD.


A deep convolutional neural network for classification of red blood cells in sickle cell anemia.
Sickle cell disease (SCD) is a hematological disorder leading to blood vessel occlusion accompanied by painful episodes and even death. Red blood cells (RBCs) of SCD patients have diverse shapes that reveal important biomechanical and bio-rheological characteristics, e.g. their density, fragility, adhesive properties, etc. Hence, having an objective and effective way of RBC shape quantification and classification will lead to better insights and eventual better prognosis of the disease. To this end, we have developed an automated, high-throughput, ex-vivo RBC shape classification framework that consists of three stages. First, we present an automatic hierarchical RBC extraction method to detect the RBC region (ROI) from the background, and then separate touching RBCs in the ROI images by applying an improved random walk method based on automatic seed generation. Second, we apply a mask-based RBC patch-size normalization method to normalize the variant size of segmented single RBC patches into uniform size. Third, we employ deep convolutional neural networks (CNNs) to realize RBC classification; the alternating convolution and pooling operations can deal with non-linear and complex patterns. Furthermore, we investigate the specific shape factor quantification for the classified RBC image data in order to develop a general multiscale shape analysis. We perform several experiments on raw microscopy image datasets from 8 SCD patients (over 7,000 single RBC images) through a 5-fold cross validation method both for oxygenated and deoxygenated RBCs. We demonstrate that the proposed framework can successfully classify sickle shape RBCs in an automated manner with high accuracy, and we also provide the corresponding shape factor analysis, which can be used synergistically with the CNN analysis for more robust predictions. Moreover, the trained deep CNN exhibits good performance even for a deoxygenated dataset and distinguishes the subtle differences in texture alteration inside the oxygenated and deoxygenated RBCs.


Ethnobotanical study on medicinal plants used by local Hoklos people on Hainan Island, China.
The aim of this study is to collect information on the use of medicinal plants by the local Hoklos people on Hainan Island, and compare medicinal traditions in the study area with Li medicines (LM) and traditional Chinese medicines (TCM). Ethnobotanical data were collected by 3 means: semi-structured interviews, personal conversation and guided field trips. There were 27 informants from 9 towns and 14 villages who were visited. Quantitative indices (Informant Consensus Factor - FIC, Use Value - UV, and Fidelity Level - FL) were calculated. In the present study, 264 species from 92 families and 233 genera were recorded, with Compositae (20 species), Leguminosae (19 species), Rubiaceae (12 species) and Gramineae (11 species) as predominate families. Leaves were the most frequently used parts in the preparation of local medicines. The most common preparation method was decoction (452 mentions). The plant with the highest values was Eclipta prostrata (0.46). The 6 plant species with the maximum FL (100%) were Atalantia buxifolia (Poir.) Oliv., Garcinia oblongifolia Champ. ex Benth., Hypericum japonicum Thunb. ex Murray, Imperata cylindrica (L.) Beauv., Microcos paniculata L., and Psidium guajava L. In addition, 120 investigated human ailments were grouped into 10 categories, within which symptoms and signs (184 mentions), diseases of the skin and subcutaneous tissue (139 mentions) and diseases of the digestive system (94 mentions) were the most mentioned in our investigation. The informant consensus about using medicinal plants ranged from 0.27 to 0.48, which showed a high level of agreement among the informants on symptoms and signs (0.48) and certain infectious and parasitic diseases (0.43). In comparison with TCM and LM, the results reflected a closer connection between local medicine and TCM. The information reported by Hoklos people is of great value to ethnic medicinal culture. However, this precious medicinal knowledge is at risk of being lost due to rapid degradation of the environment. It is essential that more people engage in in-depth studies on local medicinal plants and relevant organizations address this serious problem before the damage is irreversible.


Multiple sclerosis.
Multiple sclerosis is the prototype inflammatory autoimmune disorder of the central nervous system and, with a lifetime risk of one in 400, potentially the most common cause of neurological disability in young adults. As with all complex traits, the disorder results from an interplay between as yet unidentified environmental factors and susceptibility genes. Together, these factors trigger a cascade of events, involving engagement of the immune system, acute inflammatory injury of axons and glia, recovery of function and structural repair, post-inflammatory gliosis, and neurodegeneration. The sequential involvement of these processes underlies the clinical course characterised by episodes with recovery, episodes leaving persistent deficits, and secondary progression. The aim of treatment is to reduce the frequency, and limit the lasting effects, of relapses, relieve symptoms, prevent disability arising from disease progression, and promote tissue repair. Despite limited success in each of these categories, everyone touched by multiple sclerosis looks for a better dividend from applying an improved understanding of the pathogenesis to clinical management.


Caffeoylquinic Acid-Rich Extract of Aster glehni F. Schmidt Ameliorates Nonalcoholic Fatty Liver through the Regulation of PPARδ and Adiponectin in ApoE KO Mice.
Aster glehni is well known for its therapeutic properties. This study was performed to investigate the effects of A. glehni on nonalcoholic fatty liver disease (NAFLD) in atherosclerotic condition, by determining the levels of biomarkers related to lipid metabolism and inflammation in serum, liver, and adipose tissue. Body and abdominal adipose tissue weights and serum triglyceride level decreased in all groups treated with A. glehni. Serum adiponectin concentration and protein levels of peroxisome proliferator-activated receptor δ, 5' adenosine monophosphate-activated protein kinase, acetyl-CoA carboxylase, superoxide dismutase, and PPARγ coactivator 1-alpha in liver tissues increased in the groups treated with A. glehni. Conversely, protein levels of ATP citrate lyase, fatty acid synthase, tumor necrosis factor α, and 3-hydroxy-3-methylglutaryl-CoA reductase and the concentrations of interleukin 6 and reactive oxygen species decreased upon A. glehni. Triglyceride concentration in the liver was lower in mice treated with A. glehni than in control mice. Lipid accumulation in HepG2 and 3T3-L1 cells decreased upon A. glehni treatment; this effect was suppressed in the presence of the PPARδ antagonist, GSK0660. Our findings suggest that A. glehni extracts may ameliorate NAFLD through regulation of PPARδ, adiponectin, and the related subgenes.


Broad spectrum of coreceptor usage and rapid disease progression in HIV-1-infected individuals from Central African Republic.
To study the progression of HIV-1 infection and coreceptor usages in Central African Republic, clinical data, plasma viral load, and coreceptor usage of sequential HIV-1 isolates were analyzed in a seroincident prospective cohort (PRIMOCA). Twenty-three HIV-1 infected individuals from the Central African Armed Forces were followed from 1995 to 2000. Viruses were isolated from 17 patients at various time points after seroconversion and their coreceptor usage was examined using GHOST cells expressing CD4 and one of the HIV-1 chemokine coreceptors CCR5, CXCR4, BOB/GPR15, and Bonzo/STRL33/CXCR6. Eleven patients died from AIDS. Eight of them died between 2 and 5 years after seroconversion, after a brief symptomatic stage. Patients who rapidly progressed to AIDS and death displayed the highest viral loads after seroconversion. All isolates obtained soon after seroconversion used CCR5, albeit, in some cases, CXCR4, BOB, or Bonzo were also used. Most isolates remained R5 (59 out of 61 isolates), although viruses using CXCR4 appeared in some cases of progression to AIDS. In several cases, a broad tropism was observed during the course of infection, with a frequent usage of BOB and Bonzo in addition to CCR5. Rapid progression to disease and short survival time among Central African HIV-1 patients appear more frequent than those reported in industrialized countries. Viral coreceptor used was mainly CCR5, but, interestingly, a large part of isolates also used BOB and Bonzo. However, there was no strict correlation between the clinical outcome and extended viral tropism.


[Food consumption Brazilian children by 6 to 59 months of age].
The aim of this study was to assess food consumption in Brazilian children 6 to 59 months of age by region of the country and area of residence. This was a descriptive cross-sectional study of 4,322 children in the National Demographic and Health Survey (2006-2007). The data showed low daily consumption of leafy vegetables (12.7%), vegetables (21.8%), and meat (24.6%) and high consumption (1-3 times a week) of soft drinks (40.5%), fried foods (39.4%), salty snacks (39.4%), and sweets (37.8%). Comparing the regions of Brazil, children in the South, Southeast, and Central-West consumed more rice, bread, potatoes, beans, greens, vegetables, and meat, but they also ate more foods not recommended for their age, like sweets and soft drinks (soda). Rural children showed lower consumption of foods recommended for their age and also those not recommended for their age, as compared to their urban counterparts. According to this study, food consumption in these young children fails to meet the recommendations for healthy eating in this age bracket.


Measurement of activities of daily living in patients with COPD: a systematic review.
The objectives of this systematic review were to synthesize the literature on measures of activities of daily living (ADLs) that have been used in individuals with COPD and to provide an overview of the psychometric properties of the identified measures and describe the relationship of the disease-specific instruments with other relevant outcome measures for individuals with COPD and health-care use. Studies that included a measure of ADLs in individuals with COPD were identified using electronic and hand searches. Two investigators performed the literature search. One investigator reviewed the study title, abstract, and full text of the articles to determine study eligibility and performed the data extraction and tabulation. In cases of uncertainty, a second reviewer was consulted. A total of 679 articles were identified. Of those, 116 met the inclusion criteria. Twenty-seven ADLs instruments were identified, of which 11 instruments were respiratory disease-specific, whereas 16 were generic. Most instruments combined instrumental ADLs (IADLs) with basic ADLs (BADLs). The majority of the instruments were self-reported; only three instruments were performance based. Twenty-one studies assessed psychometric properties of 16 ADLs instruments in patients with COPD. Although several ADLs instruments were identified, psychometric properties have only been reported in a few. Selection of the most appropriate measure should focus on the target construct (BADLs or IADLs or both), type of test (disease-specific vs generic and self-reported vs performance-based), depth of information obtained, and psychometric properties of the instruments. Given the relevance of ADLs to the lives of patients with COPD, its assessment should be more frequently incorporated as a clinical outcome in their management.


Constitutively-active androgen receptor variants function independently of the HSP90 chaperone but do not confer resistance to HSP90 inhibitors.
The development of lethal, castration resistant prostate cancer is associated with adaptive changes to the androgen receptor (AR), including the emergence of mutant receptors and truncated, constitutively active AR variants. AR relies on the molecular chaperone HSP90 for its function in both normal and malignant prostate cells, but the requirement for HSP90 in environments with aberrant AR expression is largely unknown. Here, we investigated the efficacy of three HSP90 inhibitors, 17-AAG, HSP990 and AUY922, against clinically-relevant AR missense mutants and truncated variants. HSP90 inhibition effectively suppressed the signaling of wild-type AR and all AR missense mutants tested. By contrast, two truncated AR variants, AR-V7 and ARv567es, exhibited marked resistance to HSP90 inhibitors. Supporting this observation, nuclear localization of the truncated AR variants was not affected by HSP90 inhibition and AR variant:HSP90 complexes could not be detected in prostate cancer cells. Interestingly, HSP90 inhibition resulted in accumulation of AR-V7 and ARv567es in both cell lines and human tumor explants. Despite the apparent independence of AR variants from HSP90 and their treatment-associated induction, the growth of cell lines with endogenous or enforced expression of AR-V7 or ARv567es remained highly sensitive to AUY922. This study demonstrates that functional AR variant signaling does not confer resistance to HSP90 inhibition, yields insight into the interaction between AR and HSP90 and provides further impetus for the clinical application of HSP90 inhibitors in advanced prostate cancer.


An investigation of the impact of the Force Sensing Array pressure mapping system on the clinical judgement of occupational therapists.
To examine the impact of pressure mapping technology on the clinical decisions of occupational therapists and to examine the role of the Braden Scale in assisting with the selection of pressure-reducing cushions. Case studies. Community. Forty clients. Clients were pressure mapped on their current seating surface and on four pre-selected cushions by the principal researcher. An occupational therapist completed the Braden Scale and a decision tree to assist in recommending a suitable pressure-reducing cushion. Interface pressure maps, Braden Scale, and the cushion recommended, using a decision tree to guide clinical judgement. Thirty per cent (12) of the 40 cushions recommended were changed when the pressure maps from the Force Sensing Array (FSA) system were viewed. In 70% (26) of cases, the maps supported the cushion recommended. In 25% (10) of the cases, the maps showed that the client's current seating surface was unsuitable. After viewing the pressure maps, a surface other than the client's current surface was recommended in 47% (19) of the cases. There was a lack of agreement between the risk level of the clients as identified by the Braden Scale score, and the risk level of the clients as identified by the occupational therapist using a decision tree and the FSA maps. Pressure mapping technology has a positive impact on clinical decisions regarding the provision of pressure-reducing cushions. Future research should examine the predictive validity of this technology. The Braden Scale may underpredict the risk level of the clients.


Bluetongue virus genome remains stable throughout prolonged infection of cattle.
Infection of three calves with a highly plaque-purified strain of bluetongue virus (BTV) resulted in prolonged infections, during which virus and neutralizing antibodies co-circulated in peripheral blood. Oligonucleotide fingerprint analyses of the original challenge virus and of the final virus isolate obtained from each calf demonstrated the BTV genome to remain stable throughout prolonged infection as no differences in fingerprint patterns were detected. Six neutralizing monoclonal antibodies (MAbs), and a polyclonal rabbit antiserum, were produced against the challenge virus. This panel of MAbs recognized at least two distinct neutralizing epitopes as demonstrated by immune precipitation. Neutralizing epitopes remained stable through the prolonged infections, as all MAbs and the polyclonal rabbit antiserum neutralized the challenge virus and the final calf isolates to equivalent titres. These results suggest that antigenic drift is not the mechanism by which BTV is able to persist in cattle in spite of a strong humoral immune response.


lncRNA-H19 in Fibroblasts Promotes Wound Healing in Diabetes.
Cutaneous wound healing in diabetes is impaired and would develop into nonhealing ulcerations. However, the molecular mechanism underlying the wound-healing process remains largely obscure. Here, we found that cutaneous PDGFRα+ fibroblast-expressing lncRNA-H19 (lncH19) accelerates the wound-healing process via promoting dermal fibroblast proliferation and macrophage infiltration in injured skin. PDGFRα+ cell-derived lncH19, which is lower in contents in the wound-healing cutaneous tissue of patients and mice with type 2 diabetes, is required for wound healing through promoting proliferative capacity of dermis fibroblasts as well as macrophage recruitments. Mechanistically, lncH19 relieves the cell cycle arrest of fibroblasts and increases macrophage infiltration in injured tissues via inhibiting p53 activity and GDF15 releasement. Furthermore, exosomes derived from adipocyte progenitor cells efficiently restore the impaired diabetic wound healing via delivering lncH19 to injured tissue. Therefore, our study reveals a new role for lncRNA in regulating cutaneous tissue repair and provides a novel promising insight for developing clinical treatment of diabetes.


Revision of tuberculous lesions in the Bácsalmás-Oalmás series--preliminary morphological and biomolecular studies.
Previous investigations carried out in some parts of the 16th-17th century AD series of Bácsalmás-Oalmás (southern Hungary) have already provided interesting paleopathological cases of tuberculosis (e.g. Molnár & Pálfi 1994). These studies were essentially based on macromorphological analysis, biomolecular methods were used only in a few cases (e.g. Haas et al. 2000). From a macromorphological point of view, former investigations have only considered 'classical' tuberculosis (TB) alterations (advanced-stage lesions in common skeletal locations). However, due to the recent development of diagnostic criteria in the field of the paleopathology of infectious diseases, new approaches have been introduced in the identification of skeletal TB lesions (Pálfi et al. 1999, Maczel 2003). Molecular methods for the detection of mycobacterial aDNA have also been developed considerably in the last few years (e.g. Donoghue 2008, Donoghue 2011). The good state of preservation of the material, the important chronological period of the series and the relative high prevalence of TB reported in preliminary studies encouraged us to carry out a revision of TB-related lesions in the complete Bácsalmás-Oalmás series. A five year international research program--including both macroscopic and biomolecular studies of the series--was recently started. The present paper summarizes the results ofa pilot project conducted to optimize the further systematic paleopathological and paleomicrobial studies. Skeletal material of 205 individuals was chosen forthe macromorphological test-investigation, which was focused both on classical/advanced stage skeletal TB alterations (tuberculous spondylitis, tuberculous arthritis) and atypical/early-stage TB lesions (rib lesions, superficial vertebral changes, endocranial alterations, early-stage spondylodiscitis). In addition, the association of possible stress factors (long bone periostitis, cribra orbitalia, cribra cranii) were also considered. Paleomicrobiological analysis was used to study the presence of Mycobacterium tuberculosis ancient DNA (aDNA) in morphologically positive and negative cases. A comparative paleomicrobial analysis was carried out on different samples, to test the presence of MTB DNA in different skeletal regions.


Cross-species investigation of Helicoverpa armigera microsatellites as potential markers for other related species in the Helicoverpa--Heliothis complex.
Primers previously designed to amplify microsatellite DNA markers in the Old World bollworm, Helicoverpa armigera, larvae were tested in three closely related species: the corn earworm, Helicoverpa zea, tobacco budworm, Heliothis virescens, and Heliothis subflexa. Of the fourteen loci surveyed, only four loci (HaB60, HaC14, HaC87, HarSSR1) consistently demonstrated scorable single-copy microsatellite bands. Of these four, length polymorphism was identified only in the HaB60 marker (160 bp, 140 bp) of the H. virescens and H. subflexa sampled laboratory populations. Partial DNA sequences of all the identified single-copy microsatellites are presented as well as alignments to their respective H. armigera microsatellite.


Review of nutritional assessment and clinical outcomes in pediatric surgical patients: does preoperative nutritional assessment impact clinical outcomes?
Malnourished adult patients who undergo surgical procedures tend to have worse clinical outcomes compared to well-nourished patients. In the pediatric surgical patient, nutritional assessment is considered a critical aspect of the initial evaluation, but a correlation between preoperative malnutrition and poor surgical outcomes is not clear. We hypothesized that an evidence-based review would reveal that measures of nutritional assessment in children would not correlate pre-operative malnutrition with poor surgical outcomes. A search of major English language medical databases (Medline, Cochrane, SCOPUS) was conducted for the key words nutritional assessment, pediatric, children, surgery, and outcomes. All methods of nutritional assessment in pediatric surgery were evaluated for their relevance and relation to outcomes after surgery. The Oxford Center for Evidence Based Medicine (CEBM) classification for levels of evidence was used to develop grades of clinical recommendation for each variable studied. 35 articles were evaluated after an exhaustive literature search, of which six met inclusion criteria for this review. There is a paucity of high quality evidence correlating preoperative malnutrition in pediatric surgical patients with clinical outcomes. Factors contributing to the low level of evidence include a lack of high quality randomized controlled trials, a lack of consensus in study design and methods, and utilization of incongruous methods of nutritional assessment, including methods that may be unproven in the study population. Larger multi center randomized studies are needed to offer higher level of evidence to support nutritional intervention prior to major elective pediatric surgery.


The role of nutraceutical medications in men with non bacterial chronic prostatitis and chronic pelvic pain syndrome: A prospective non blinded study utilizing flower pollen extracts versus bioflavonoids.
Chronic prostatitis (CP)/chronic pelvic pain syndrome (CPPS) represents a challenge for the urologist, since the therapeutic efficacy does not always result in a satisfactory quality of life for the patients. Often the side effects of the medications used (antiinflammatories, antibiotics, alpha blockers) far outweighs the benefits gained with their admission. The choice of nutraceutical medications is preferred for their effectiveness, that has been accepted and proven by the scientific community, and for the low incidence of side effects. The objective of this study to compare the therapeutic efficacy of the flower pollen extracts (Deprox®) versus Bioflavonoids in terms of reduction of symptoms, and in the average waiting time of the variation of the National Institute of Health Chronic Prostatitis Symptom Index (NIH-CPSI), and to evaluate the quality of life improvement of the patients affected by CP/CPPS. Among the 68 patients presented with prostatic symptoms to the Hospital "Umberto I" in Rome, Italy between March 2016 and June 2016, 54 patients met the clinical diagnosis of CP/CPPS (class IIIa or IIIb according to the NIH classification). The patients were assigned to either treatment with Deprox® or quercetin based on a randomization scheme previously determined.The NIH- CPSI, IPSS, QoL questionnaires were administered. Every patient underwent bacterial cultures and trans-rectal ultrasound. There was a statistically significant improvement of the NIH-CPSI score and QoL in the Deprox® group (p = < 0.0001 and p = 0.003 respectively). The average waiting time of the variation of the National Institute of Health Chronic Prostatitis Symptom Index (NIH-CPSI) was statistically significant (p = 0.0019). In the absence of efficacy of the "conventional" medications, which also carries significant side effects, the dietary supplements may represent a valid alternative. DEPROX® has demonstrated a significant improvement of the symptoms and quality of life of patients diagnosed with by CP/CPPS. Furthermore, there was a statistical difference in the average waiting time of the variation of the NIH-CPSI) score without side effects as compared to the bioflavonoids complex with quercetin.


Leptin increases energy expenditure of a marsupial by inhibition of daily torpor.
Leptin plays an important role in regulating body fat stores of placental mammals, but the contribution of changes in energy expenditure to this adjustment remains controversial. We were interested in how recombinant murine leptin would affect metabolic rate (MR) and body temperature (Tb) of a marsupial mammal (Sminthopsis macroura, 25 g) known to display daily torpor but lacking thermogenetically active brown adipose tissue. In a group of eight animals deprived of food for 1 day at 18 degreesC, leptin treatment halved the duration of torpor bouts (time at Tb < 30 degreesC) and raised the average daily minimum Tb by 4.5 degreesC and minimum MR by 2.2-fold. Leptin treatment thus increased daily energy expenditure by 9%, although MR and Tb during the activity phase were not raised. Body mass was also not affected. These findings in a marsupial suggest that the adjustment of thermoregulatory energy expenditure during the rest phase in accordance with energy availability is a phylogenetically old function of leptin.


Higher alkyl sulfatase activity required by microbial inhabitants to remove anionic surfactants in the contaminated surface waters.
Biodegradation of anionic surfactants, like sodium dodecyl sulfate (SDS) are challenged by some bacteria through the function of the enzyme alkyl sulfatases. Therefore, identifying and characterizing bacteria capable of degrading SDS with high alkyl sulfatase enzyme activity are pivotal. In this study, bacteria isolated from surfactant contaminated river water were screened for their potential to degrade SDS. Primary screening carried out by the conventional enrichment culture technique and assessment of SDS-degrading ability through methylene blue active substance assay revealed 12, out of 290, SDS-degrading surface water bacteria with maximum SDS degrading abilities of 46-94% in 24-54 h. The isolates exhibited optimum growth at SDS concentration of 1 g/L, but tolerated up to 15-75 g/L. Eleven isolates were identified as the species of Pseudomonas and one isolate was identified as Aeromonas through 16S rRNA sequencing. Proteolytic activity of alkyl sulfatases in the identified isolates was shown by using native-PAGE analysis. The determined enzyme activities changed in between 1.32 and 2.90 U/mg in the crude extracts. Preliminary experiments showed that the isolates with the alkyl sulfatase enzyme activities ≥2.50 U/mg were strong gratuitous degraders. However, their relative importance in soil, sewage, and wastewater treatment plants remains to be assessed.


Association between SNPs in the promoter region in cathepsin S and risk of asthma in Chinese Han population.
Cathepsin S (CTSS) is a lysosomal cysteine protease and is predominantly expressed in antigen-presenting cells, which plays an important role in the allergic response. In this study, we explored the association between single nucleotide polymorphisms (SNPs) in the promotor regions in CTSS and risk of asthma. A total of 591 cases and 621 controls were recruited for this study. Five SNPs in the CTSS were selected including rs7534124, rs16827671, rs34495036, rs3754212, and rs1136774. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was employed for genotyping. Logistic regression analysis showed that rs7534124 CT and CT + CC genotypes had significantly decreased risk of asthma (CT vs. 0.576, 95% CI: 0.425-0.780, p < 0.001; CT + CC vs. 0.638, 95% CI: 0.479-0.849, p < 0.001; respectively) compared to TT genotype. Similarly, the rs1136774 AG and AG + GG genotypes (AG vs. 0.581, 95% CI: 0.426-0.793, p = 0.001; AG + GG vs. 0.647, 95% CI: 0.483-0.867, p = 0.004, respectively) were also associated with a decreased risk of asthma. However, there was no significant association between genotypes of the remaining SNPs and the risk of asthma (p > 0.006). Moreover, the alleles in all SNPs are also not associated with the risk of asthma. Our study provided strong evidence that polymorphism of rs7534124 and rs1136774 in CTSS promoter may decrease the susceptibility of asthma in a Chinese Han population.


Proficiency and Control in Verbal Fluency Performance across the Lifespan for Monolinguals and Bilinguals.
The verbal fluency task is a widely used neuropsychological test of word retrieval efficiency. Both category fluency (e.g., list animals) and letter fluency (e.g., list words that begin with F) place demands on semantic memory and executive control functions. However letter fluency places greater demands on executive control than category fluency, making this task well-suited to investigating potential bilingual advantages in word retrieval. Here we report analyses on category and letter fluency for bilinguals and monolinguals at four ages, namely, 7-year-olds, 10-year-olds, young adults, and older adults. Three main findings emerged: 1) verbal fluency performance improved from childhood to young adulthood and remained relatively stable in late adulthood; 2) beginning at 10-years-old, the executive control requirements for letter fluency were less effortful for bilinguals than monolinguals, with a robust bilingual advantage on this task emerging in adulthood; 3) an interaction among factors showed that category fluency performance was influenced by both age and vocabulary knowledge but letter fluency performance was influenced by bilingual status.


Regulation of noradrenergic and serotonergic systems by cannabinoids: relevance to cannabinoid-induced effects.
The cannabinoid system is composed of Gi/o protein-coupled cannabinoid type 1 receptor (CB1) and cannabinoid type 2 (CB2) receptor and endogenous compounds. The CB1 receptor is widely distributed in the central nervous system (CNS) and it is involved in the regulation of common physiological functions. At the neuronal level, the CB1 receptor is mainly placed at GABAergic and glutamatergic axon terminals, where it modulates excitatory and inhibitory synapses. To date, the involvement of CB2 receptor in the regulation of neurotransmission in the CNS has not been clearly shown. The majority of noradrenergic (NA) cells in mammalian tissues are located in the locus coeruleus (LC) while serotonergic (5-HT) cells are mainly distributed in the raphe nuclei including the dorsal raphe nucleus (DRN). In the CNS, NA and 5-HT systems play a crucial role in the control of pain, mood, arousal, sleep-wake cycle, learning/memory, anxiety, and rewarding behaviour. This review summarizes the electrophysiological, neurochemical and behavioural evidences for modulation of the NA/5-HT systems by cannabinoids and the CB1 receptor. Cannabinoids regulate the neuronal activity of NA and 5-HT cells and the release of NA and 5-HT by direct and indirect mechanisms. The interaction between cannabinoid and NA/5-HT systems may underlie several behavioural changes induced by cannabis such as anxiolytic and antidepressant effects or side effects (e.g. disruption of attention). Further research is needed to better understand different aspects of NA and 5-HT systems regulation by cannabinoids, which would be relevant for their use in therapeutics.


Application of glycoproteomics for the discovery of biomarkers in lung cancer.
Lung cancer is the leading cause of cancer-related deaths in the United States. Approximately 40-60% of lung cancer patients present with locally advanced or metastatic disease at the time of diagnosis. Lung cancer development and progression are a multistep process that is characterized by abnormal gene and protein expressions ultimately leading to phenotypic change. Glycoproteins have long been recognized to play fundamental roles in many physiological and pathological processes, particularly in cancer genesis and progression. In order to improve the survival rate of lung cancer patients, the discovery of early diagnostic and prognostic biomarkers is urgently needed. Herein, we reviewed the recent technological developments of glycoproteomics and published data in the field of glycoprotein biomarkers in lung cancer, and discussed their utility and limitations for the discovery of potential biomarkers in lung cancer. Although numerous papers have already acknowledged the importance of the discovery of cancer biomarkers, the systemic study of glycoproteins in lung cancer using glycoproteomic approaches is still suboptimal. Recent development in the glycoproteomics will provide new platforms for identification of potential protein biomarkers in lung cancers.


Treatment of mycoplasma pneumonia: a systematic review.
Children with community-acquired lower respiratory tract infection (CA-LRTI) commonly receive antibiotics for Mycoplasma pneumoniae. The objective was to evaluate the effect of treating M. pneumoniae in children with CA-LRTI. PubMed, Cochrane Central Register of Controlled Trials, and bibliography review. A search was conducted by using Medical Subject Headings terms related to CA-LRTI and M. pneumoniae and was not restricted by language. Eligible studies included randomized controlled trials (RCTs) and observational studies of children #17 years old with confirmed M. pneumoniae and a diagnosis of CA-LRTI; each must have also compared treatment regimens with and without spectrum of activity against M. pneumoniae. Data extraction and quality assessment were completed independently by multiple reviewers before arriving at a consensus. Data were pooled using a random effects model. Sixteen articles detailing 17 studies were included. The most commonly selected primary outcome was symptomatic improvement. Nine studies examined M. pneumoniae treatment in CA-LRTI secondary to M. pneumoniae, and 5 RCTs met criteria for meta-analysis. The suggested pooled risk difference of 0.12 (95% confidence interval, 20.04 to 0.20) favoring treatment was not significantly different and demonstrated significant heterogeneity. Limitations included substantial bias and subjective outcomes within the individual studies, difficulty interpreting testing modalities, and the inability to correct for mixed infections or timing of intervention. We identified insufficient evidence to support or refute treatment of M. pneumoniae in CA-LRTI. These data highlight the need for well-designed, prospective RCTs assessing the effect of treating M. pneumoniae in CA-LRTI.


Recurrent Malignancy-Associated Atypical Neutrophilic Dermatosis With Noninfectious Shock.
Sweet syndrome (SS) or acute febrile neutrophilic dermatosis presents with the sudden onset of fever, leukocytosis and tender, erythematous, edematous, well-demarcated papules and plaques that histopathologically demonstrate a dense neutrophilic infiltrate. A total of 20% of patients with SS have malignancy-associated disease that can present with bullous or atypical skin lesions that mimic pyoderma gangrenosum, another neutrophilic dermatosis. Both entities exist on a spectrum, and in the context of underlying malignancy, these neutrophilic diseases become less clinically distinct. The literature also describes life-threatening cases of neutrophilic dermatoses that mimic severe sepsis. We present a fatal case of a patient with chronic eosinophilic leukemia with recurrent episodes of malignancy-associated atypical neutrophilic dermatosis characterized by necrotic skin lesions, pulmonary infiltrates and noninfectious shock and we also summarize the clinical presentations of an additional 10 patients reported in the literature. We conducted a PubMed search of articles published up to and in 2015, focusing on the English and Spanish literature with SS cross-referenced with the following search terms: neutrophilic dermatosis, pyoderma gangrenosum, shock, multiorgan failure and systemic inflammatory response syndrome. The articles were reviewed and the patients׳ clinical and laboratory findings were summarized. Cases of atypical neutrophilic dermatosis presenting with noninfectious shock syndrome are likely underrecognized clinically and underreported in the literature. Patients with malignancy-associated atypical neutrophilic dermatoses associated with noninfectious shock syndrome typically have multisystem disease characterized by recurrent episodes and typically have poor prognoses.


Dynamic diffuse optical tomography imaging of peripheral arterial disease.
Peripheral arterial disease (PAD) is the narrowing of arteries due to plaque accumulation in the vascular walls. This leads to insufficient blood supply to the extremities and can ultimately cause cell death. Currently available methods are ineffective in diagnosing PAD in patients with calcified arteries, such as those with diabetes. In this paper we investigate the potential of dynamic diffuse optical tomography (DDOT) as an alternative way to assess PAD in the lower extremities. DDOT is a non-invasive, non-ionizing imaging modality that uses near-infrared light to create spatio-temporal maps of oxy- and deoxy-hemoglobin in tissue. We present three case studies in which we used DDOT to visualize vascular perfusion of a healthy volunteer, a PAD patient and a diabetic PAD patient with calcified arteries. These preliminary results show significant differences in DDOT time-traces and images between all three cases, underscoring the potential of DDOT as a new diagnostic tool.


A phase 2 randomized, double-masked, placebo-controlled study of a novel integrin antagonist (SAR 1118) for the treatment of dry eye.
To investigate the efficacy and safety of an investigational integrin antagonist (SAR 1118) ophthalmic solution compared to placebo (vehicle) in subjects with dry eye disease. Multicenter, prospective, double-masked, placebo-controlled trial. A total of 230 dry eye subjects selected with use of a controlled adverse environment were randomized 1:1:1:1 to receive SAR 1118 (0.1%, 1.0%, 5.0%) or placebo eye drops twice daily for 84 days. Principal eligibility criteria included exacerbation in corneal staining and ocular symptoms with controlled adverse environment exposure, no active lid margin disease, and Schirmer test (mm/5 min) >1 and <10. Ocular signs and symptoms (Ocular Surface Disease Index, OSDI) were assessed at day 14, 42, and 84. No supplemental artificial tears were allowed. Primary outcome measure was inferior corneal staining score at day 84. A dose response for the corneal staining score (P = .0566) was observed for SAR 1118 at day 84 compared to placebo. Mean change from baseline to day 84 showed significant improvements (P < .05) in corneal staining score, total OSDI, and visual-related function OSDI scores for SAR 1118 compared to placebo; improvements in tear production and symptoms were observed as early as day 14 (P < .05). Adverse events were mild and transient in nature with no serious ocular adverse events. SAR 1118 5.0% showed increased instillation site adverse events relative to placebo but were limited to the initial dose. SAR 1118 demonstrated improvements in signs and symptoms of dry eye compared to placebo and appears safe when administered over 84 days.


Enhanced vascular effects of cyclic GMP in septic rat aorta.
The modulation of vascular function by guanosine 3',5'-cyclic monophosphate (cGMP) in sepsis was examined in isolated rat aortas. Basal cGMP content was similar in aortas from sham-operated [3.6 +/- 0.8 (SE) pmol cGMP/mg protein] and from septic (3.2 +/- 1.0) rats. Acetylcholine-induced increases in cGMP content were significantly greater in aortas from sham (109.7 +/- 31.1) than aortas from septic rats (42.1 +/- 10.6). Maximal contractile performance by aortas from septic rats was impaired whether contractions were induced by the alpha 1-receptor agonist norepinephrine (497 +/- 49 mg tension/mg tissue vs. sham 749 +/- 43) or by KCl depolarization (265 +/- 31 vs. sham 613 +/- 79). Aortas from septic rats also exhibited a rightward-shifted dose response to norepinephrine. Inhibition of endogenous cGMP production by myoglobin or methylene blue treatment disproportionally improved responses by aortas from septic rats to both norepinephrine and KCl. In contrast, exposure of aortas to exogenous 8-bromo-cGMP engaged exaggerated vasodilatory responses in tissue from septic animals. Aortas from sham and septic rats contracted equally to stimulation by phorbol 12,13-dibutyrate. These findings indicate that reduced vascular contraction in sepsis is not mediated by altered cGMP levels, but rather that enhanced sensitivity to effects of cGMP may contribute to the disorder.


Cyclosporin A prodrugs: design, synthesis and biophysical properties.
The cyclic undecapeptide cyclosporin A (CsA) has a remarkable spectrum of diverse biological activities, including anti-inflammatory, antifungal, antiparasitic as well as immunosuppressive activities. However, the low water solubility of this drug is a serious problem causing undesirable pharmacological properties such as erratic oral absorption. In order to overcome this problem, the design and synthesis of water-soluble prodrugs of CsA are described. Using the OH-MeBmt-1-group as attachment site, we investigate dipeptide systems exhibiting differential tendencies for intramolecular cyclization [diketopiperazine (DKP) formation] for tailoring the chemoreversible release of the parent CsA. In modulating the chemical and structural features of the dipeptide esters (N-alkylation, side chains, C-terminal Pro), we find conversion rates at physiological conditions ranging from minutes to several days. Together with their thermodynamic stability in the solid state and strongly enhanced solubility in water, these chemoreversible CsA prodrugs represent versatile candidates for therapeutical use.


Initiation of periovulatory events in gonadotrophin-stimulated macaques with varying doses of recombinant human chorionic gonadotrophin.
During in-vitro fertilization (IVF) cycles, a large bolus of human chorionic gonadotrophin (HCG) is used to induce periovulatory events, but the efficacy of lower doses is undefined. Following follicular stimulation in rhesus monkeys, oocyte nuclear maturation, IVF, granulosa cell luteinization and corpus luteum function were compared after injection of 100, 300 or 1000 IU recombinant HCG or 1000 IU urinary HCG. Bioactive HCG rose to peak concentrations within 2 h that were proportional to the dose administered (100 < 300 < 1000 IU, recombinant HCG = urinary HCG). The duration of surge values (>100 ng/ml) was also dose-dependent (0 h, 100 IU; 24 h, 300 IU; >48 h, 1000 IU, recombinant and urinary HCG). While the proportions of oocytes resuming meiosis and undergoing IVF were similar among groups, fewer animals yielded fertilizable oocytes following 100 and 300 IU (five of nine) compared to 1000 IU recombinant and urinary HCG (nine of 10). Peak values of serum progesterone in the luteal phase were similar, but declined 2 days earlier after 100 and 300 IU relative to 1000 IU recombinant and urinary HCG. Thus, 3-10 fold lower doses of HCG elicit low amplitude surges of short duration that induce periovulatory events such as re-initiation of oocyte meiosis and granulosa cell luteinization. However, oocyte fertilization and luteal function may optimally require surges of higher amplitude and longer duration similar to those produced by standard doses of 1000 IU recombinant or urinary HCG.


Spatial variability in sustainable development trajectories in South Africa: provincial level safe and just operating spaces.
The Sustainable Development Goals (SDGs) represents the first globally agreed framework to address human development and environmental stewardship in an integrated way. One approach to summarising national SDG status is our "barometer for inclusive sustainable development in South Africa". The barometer downscales global social and planetary boundaries to provide status and trends for 20 critical indicators of environmental stress and social deprivation. In this paper, we explore the sub-national heterogeneity in sustainable development indicators by creating barometers defining the 'safe and just operating space' for South Africa's nine provinces. Our results show that environmental stress varies significantly and provinces need to focus on quite different issues. Although generally environmental stress is increasing, there are areas where it is decreasing, most notably, marine harvesting. Social deprivation results show more of a pattern with high levels of deprivation in employment, income and safety across the provinces, and historically disadvantaged provinces showing the most deprivation overall. Although deprivation is generally decreasing, there are notable exceptions such as food security in six provinces. Our provincial barometers and trend plots are novel in that they present comparable environmental and social data on key indicators over time for all South Africa's provinces. They are visual tools that communicate the range of key challenges and risks that provincial governments face, and are non-specialist and accessible to a range of audiences. In addition, the paper provides a critical case study of spatial disaggregation of national data that is required for the SDGs implementation.


mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt.
Stimulation of the insulin and insulin-like growth factor I (IGF-I) receptor activates the phosphoinositide-3-kinase/Akt/mTOR pathway causing pleiotropic cellular effects including an mTOR-dependent loss in insulin receptor substrate-1 expression leading to feedback down-regulation of signaling through the pathway. In model systems, tumors exhibiting mutational activation of phosphoinositide-3-kinase/Akt kinase, a common event in cancers, are hypersensitive to mTOR inhibitors, including rapamycin. Despite the activity in model systems, in patients, mTOR inhibitors exhibit more modest antitumor activity. We now show that mTOR inhibition induces insulin receptor substrate-1 expression and abrogates feedback inhibition of the pathway, resulting in Akt activation both in cancer cell lines and in patient tumors treated with the rapamycin derivative, RAD001. IGF-I receptor inhibition prevents rapamycin-induced Akt activation and sensitizes tumor cells to inhibition of mTOR. In contrast, IGF-I reverses the antiproliferative effects of rapamycin in serum-free medium. The data suggest that feedback down-regulation of receptor tyrosine kinase signaling is a frequent event in tumor cells with constitutive mTOR activation. Reversal of this feedback loop by rapamycin may attenuate its therapeutic effects, whereas combination therapy that ablates mTOR function and prevents Akt activation may have improved antitumor activity.