Percutaneous coronary intervention at centers with and without on-site surgery: a meta-analysis.
Percutaneous coronary interventions are performed at centers without onsite surgery, despite current guidelines discouraging this. To assess literature comparing rates of in-hospital mortality and emergency coronary artery bypass grafting surgery at centers with and without on-site surgery. A systematic search of studies published between January 1990 and May 2010 was conducted using MEDLINE, EMBASE, and Cochrane Review databases. English-language studies of percutaneous coronary intervention performed at centers with and without on-site surgery providing data on in-hospital mortality and emergency bypass were identified. Two study authors independently reviewed the 1029 articles originally identified and selected 40 for analysis. Study title, time period, indication for angioplasty, and outcomes were extracted manually from all selected studies, and quality of each study was assessed using the strengthening the reporting of observational studies in epidemiology (STROBE) checklist. High-quality studies of percutaneous coronary interventions performed at centers with and without on-site surgery were included. Pooled-effect estimates were calculated with random-effects models. Analyses of primary percutaneous coronary intervention for ST-segment elevation myocardial infarction of 124,074 patients demonstrated no increase in in-hospital mortality (no on-site surgery vs on-site surgery: observed risk, 4.6% vs 7.2%; odds ratio [OR], 0.96; 95% CI, 0.88-1.05; I(2) = 0%) or emergency bypass (observed risk, 0.22% vs 1.03%; OR, 0.53; 95% CI, 0.35-0.79; I(2) = 20%) at centers without on-site surgery. For nonprimary percutaneous coronary interventions (elective and urgent, n = 914,288), the rates of in-hospital mortality (observed risk, 1.4% vs 2.1%; OR, 1.15; 95% CI, 0.93-1.41; I(2) = 46%) and emergency bypass (observed risk, 0.17% vs 0.29%; OR, 1.21; 95% CI, 0.52-2.85; I(2) = 5%) were not significantly different at centers without or with on-site surgery. Percutaneous coronary interventions performed at centers without on-site surgery, compared with centers with on-site surgery, were not associated with a higher incidence of in-hospital mortality or emergency bypass surgery.


Sphingosine 1-phosphate, a bioactive sphingolipid abundantly stored in platelets, is a normal constituent of human plasma and serum.
Although sphingosine 1-phosphate (Sph-1-P) is reportedly involved in diverse cellular processes and the physiological roles of this bioactive sphingolipid have been strongly suggested, few studies have revealed the presence of Sph-1-P in human samples, including body fluids and cells, under physiological conditions. In this study, we identified Sph-1-P as a normal constituent of human plasma and serum. The Sph-1-P levels in plasma and serum were 191+/-79 and 484+/-82 pmol/ml (mean+/-SD, n=8), respectively. Furthermore, when Sph-1-P was measured in paired plasma and serum samples obtained from 6 healthy adults, the serum Sph-1-P/plasma Sph-1-P ratio was found to be 2.65+/-1.26 (mean+/-SD). It is most likely that the source of discharged Sph-1-P during blood clotting is platelets, because platelets abundantly store Sph-1-P compared with other blood cells, and release part of their stored Sph-1-P extracellularly upon stimulation. We also studied Sph-1-P-related metabolism in plasma. [3H]Sph was stable and not metabolized at all in plasma, but was rapidly incorporated into platelets and metabolized mainly to Sph-1-P in platelet-rich plasma. [3H]Sph-1-P was found to be unchanged in plasma, revealing that plasma does not contain the enzymes needed for Sph-1-P degradation. In summary, platelets can convert Sph into Sph-1-P, and are storage sites for the latter in the blood. In view of the diverse biological effects of Sph-1-P, the release of Sph-1-P from activated platelets may be involved in a variety of physiological and pathophysiological processes, including thrombosis, hemostasis, atherosclerosis and wound healing.


Enhanced liver progenitor cell survival and differentiation in vivo by spheroid implantation in a vascularized tissue engineering chamber.
Liver tissue engineering is hampered by poor implanted cell survival due to inadequate vascularization and cell-cell/cell-matrix interactions. Here, we use liver progenitor cell (LPC) spheroids to enhance cell-cell/cell-matrix interactions, with implantation into an angiogenic in vivo mouse chamber. Spheroids were generated in vitro in methylcellulose medium. Day 2 spheroids were optimal for implantation (22,407 +/-645 cells/spheroid), demonstrating maximal proliferation (Ki67 immunolabeling) and minimal apoptosis (caspase-3 immunolabelling). In vivo chambers established bilaterally on epigastric vessels of immunodeficient mice were implanted with equivalent numbers of LPCs as a cell suspension (200,000 cells), or spheroids (9 spheroids). At day 14, a trend of increased LPC survival was observed in spheroid-implanted chambers [pan-cytokeratin (panCK+) cells, p = 0.38, 2.4 fold increase)], with significantly increased differentiation [cytokeratin 18 (CK18+) cells, p < 0.002, 5.1 fold increase)] compared to cell suspension-implanted chambers. At day 45, both measures were significantly increased in spheroid-implanted chambers (panCK, p < 0.006, 16 fold increase) (CK18, p < 0.019, 6 fold increase). Hepatic acini/plates of CK18 + cells expressed hepatocyte nuclear factor 4-α and β-catenin, indicating ongoing hepatic differentiation. Spheroid cell-delivery significantly increased LPC survival and differentiation compared to conventional cell suspensions. This LPC spheroid/vascularized chamber model has clinical potential to generate three-dimensional vascularized liver tissue for liver replacement.


Inference of population structure using multilocus genotype data.
We describe a model-based clustering method for using multilocus genotype data to infer population structure and assign individuals to populations. We assume a model in which there are K populations (where K may be unknown), each of which is characterized by a set of allele frequencies at each locus. Individuals in the sample are assigned (probabilistically) to populations, or jointly to two or more populations if their genotypes indicate that they are admixed. Our model does not assume a particular mutation process, and it can be applied to most of the commonly used genetic markers, provided that they are not closely linked. Applications of our method include demonstrating the presence of population structure, assigning individuals to populations, studying hybrid zones, and identifying migrants and admixed individuals. We show that the method can produce highly accurate assignments using modest numbers of loci-e.g. , seven microsatellite loci in an example using genotype data from an endangered bird species. The software used for this article is available from http://www.stats.ox.ac.uk/ approximately pritch/home. html.


Genome-wide characterization of pancreatic adenocarcinoma patients using next generation sequencing.
Pancreatic adenocarcinoma (PAC) is among the most lethal malignancies. While research has implicated multiple genes in disease pathogenesis, identification of therapeutic leads has been difficult and the majority of currently available therapies provide only marginal benefit. To address this issue, our goal was to genomically characterize individual PAC patients to understand the range of aberrations that are occurring in each tumor. Because our understanding of PAC tumorigenesis is limited, evaluation of separate cases may reveal aberrations, that are less common but may provide relevant information on the disease, or that may represent viable therapeutic targets for the patient. We used next generation sequencing to assess global somatic events across 3 PAC patients to characterize each patient and to identify potential targets. This study is the first to report whole genome sequencing (WGS) findings in paired tumor/normal samples collected from 3 separate PAC patients. We generated on average 132 billion mappable bases across all patients using WGS, and identified 142 somatic coding events including point mutations, insertion/deletions, and chromosomal copy number variants. We did not identify any significant somatic translocation events. We also performed RNA sequencing on 2 of these patients' tumors for which tumor RNA was available to evaluate expression changes that may be associated with somatic events, and generated over 100 million mapped reads for each patient. We further performed pathway analysis of all sequencing data to identify processes that may be the most heavily impacted from somatic and expression alterations. As expected, the KRAS signaling pathway was the most heavily impacted pathway (P<0.05), along with tumor-stroma interactions and tumor suppressive pathways. While sequencing of more patients is needed, the high resolution genomic and transcriptomic information we have acquired here provides valuable information on the molecular composition of PAC and helps to establish a foundation for improved therapeutic selection.


Sclerotherapy for intractable ganglion cyst of the hallux.
We devised a method of sclerotherapy using OK432. The present study comprised a retrospective followup of sclerotherapy outcomes. Eighteen feet in 18 consecutive patients (seven men, 11 women; mean age, 55 years) were treated with sclerotherapy. Previous surgery had been performed one to four times for seven feet. After aspirating the contents of the ganglion cysts, 0.2 to 0.3 ml of suspension of OK432 (lyophilized strep pyogenes) was injected. The volume of fluid aspirated was from 0.2 to 2.5 ml, with an average of 0.9 ml. Mean duration of followup was 3 years 6 months. Clinical evaluation was performed using the AOFAS hallux scale. All ganglion cysts disappeared after sclerotherapy. However, recurrences were observed in eight feet. Mean duration until recurrence was 13 months. Sclerotherapy was again performed for all patients with recurrence. Re-recurrence occurred in three feet. A third sclerotherapy was performed for all three patients. All ganglion cysts had disappeared by final followup. Mean AOFAS score improved from 75 points before therapy to 95 points at followup. Six patients had complications with local redness and pain for 1 to 6 days after injection. Sclerotherapy using OK432 is a minimally invasive treatment of symptomatic ganglion cysts of the hallux. Recurrence is common but complications are infrequent and self-limited.


Repair characteristics and differentiation propensity of long-term cultures of epidermal keratinocytes derived from normal and NER-deficient mice.
Epidermal keratinocytes constitute the most relevant cellular system in terms of DNA damage because of their continuous exposure to UV light and genotoxic chemicals from the environment. Here, we describe the establishment of long-term keratinocyte cultures from the skin of wild-type and nucleotide excision repair (NER) deficient mouse mutants. The use of media with a lowered calcium concentration and the inclusion of keratinocyte growth factor (KGF) permitted repeated passaging of the cultures and resulted in the generation of stable cell lines that proliferated efficiently. The cells retained their normal ability to engage into terminal differentiation when triggered with high calcium concentrations or after suspension in semi-solid medium. The cultures reflected the cellular characteristics (i.e. repair and transcription profiles) of the Xpa(-/-), Xpc(-/-), Csb(-/-) and Xpd(TTD) mouse models from which they were derived. For instance, in line with earlier in vivo results, Xpd(TTD) keratinocytes were disturbed in their ability to terminally differentiate in vitro. This was concluded from a delay in calcium-induced stratification and by reduced transcription of both early (keratin 10) and late (loricrin) terminal differentiation marker genes. UDS measurements in wild-type cells committed to terminal differentiation did not reveal any reduction in global DNA repair that could be indicative of differentiation associated repair (DAR) as found in neurons. UV sensitivity data revealed that in keratinocytes global genome repair contributes more to cell survival than previously concluded from fibroblast studies. It is inferred that these fully controllable in vitro cultures will be a valuable tool to assess critical parameters of genome care-taking systems in cell proliferation and differentiation.


Global Gene Expression Profiling in Omental Adipose Tissue of Morbidly Obese Diabetic African Americans.
Adipose tissues play important role in the pathophysiology of obesity-related diseases including type 2 diabetes (T2D). To describe gene expression patterns and functional pathways in obesity-related T2D, we performed global transcript profiling of omental adipose tissue (OAT) in morbidly obese individuals with or without T2D. Twenty morbidly obese (mean BMI: about 54 kg/m2) subjects were studied, including 14 morbidly obese individuals with T2D (cases) and 6 morbidly obese individuals without T2D (reference group). Gene expression profiling was performed using the Affymetrix U133 Plus 2.0 human genome expression array. Analysis of covariance was performed to identify differentially expressed genes (DEGs). Bioinformatics tools including PANTHER and Ingenuity Pathway Analysis (IPA) were applied to the DEGs to determine biological functions, networks and canonical pathways that were overrepresented in these individuals. At an absolute fold-change threshold of 2 and false discovery rate (FDR) < 0.05, 68 DEGs were identified in cases compared to the reference group. Myosin X (MYO10) and transforming growth factor beta regulator 1 (TBRG1) were upregulated. MYO10 encodes for an actin-based motor protein that has been associated with T2D. Telomere extension by telomerase (HNRNPA1, TNKS2), D-myo-inositol (1, 4, 5)-trisphosphate biosynthesis (PIP5K1A, PIP4K2A), and regulation of actin-based motility by Rho (ARPC3) were the most significant canonical pathways and overlay with T2D signaling pathway. Upstream regulator analysis predicted 5 miRNAs (miR-320b, miR-381-3p, miR-3679-3p, miR-494-3p, and miR-141-3p,) as regulators of the expression changes identified. This study identified a number of transcripts and miRNAs in OAT as candidate novel players in the pathophysiology of T2D in African Americans.


A clinically useful and biologically informative genomic classifier for papillary thyroid cancer.
Clinical management of papillary thyroid cancer depends on estimations of prognosis. Standard care, which relies on prognostication based on clinicopathologic features, is inaccurate. We applied a machine learning algorithm (HighLifeR) to 502 cases annotated by The Cancer Genome Atlas Project to derive an accurate molecular prognostic classifier. Unsupervised analysis of the 82 genes that were most closely associated with recurrence after surgery enabled the identification of three unique molecular subtypes. One subtype had a high recurrence rate, an immunosuppressed microenvironment, and enrichment of the EZH2-HOTAIR pathway. Two other unique molecular subtypes with a lower rate of recurrence were identified, including one subtype with a paucity of BRAFV600E mutations and a high rate of RAS mutations. The genomic risk classifier, in addition to tumor size and lymph node status, enabled effective prognostication that outperformed the American Thyroid Association clinical risk stratification. The genomic classifier we derived can potentially be applied preoperatively to direct clinical decision-making. Distinct biological features of molecular subtypes also have implications regarding sensitivity to radioactive iodine, EZH2 inhibitors, and immune checkpoint inhibitors.


Verification of the biomarker candidates for non-small-cell lung cancer using a targeted proteomics approach.
Lung cancer, with its high metastatic potential and high mortality rate, is the worldwide leading cause of cancer-related deaths. High-throughput "omics"-based platforms have accelerated the discovery of biomarkers for lung cancer, and the resulting candidates are to be evaluated for their diagnostic potential as noninvasive biomarkers. The evaluation of the biomarker candidates involves the quantitative measurement of large numbers of proteins in bodily fluids using advanced mass spectrometric techniques. In this study, a robust pipeline based on targeted proteomics was developed for biomarker verification in plasma samples and applied to verifying lung cancer biomarker candidates. Highly multiplexed liquid chromatrography-selected reaction monitoring (LC-SRM) assays for 95 potential tumor markers for non-small-cell lung cancer (NSCLC) were generated to screen plasma samples obtained from 72, early to late stage, patients. A total of 17 proteins were verified as potent tumor markers detectable in plasma and, where available, verified by enzyme-linked immunosorbent assays (ELISAs). A novel plasma-based biomarker, zyxin, fulfilled the criteria for a potential early diagnostic marker for NSCLC.


Concomitant tricuspid valve surgery during implantation of continuous-flow left ventricular assist devices: a Society of Thoracic Surgeons database analysis.
Performing concomitant tricuspid valve procedures (TVPs) in left ventricular assist device (LVAD) patients with significant pre-operative tricuspid regurgitation (TR) is controversial, and no studies have been large enough to definitively guide therapy. Between January 2006 and September 2012, 2,196 patients with moderate to severe pre-operative TR from 115 institutions underwent implantation of a continuous-flow left ventricular assist device (LVAD) as reported by The Society of Thoracic Surgeons National Database. Of these, 588 (27%) underwent a concomitant TVP. Inverse probability weighting based on propensity score was used to adjust for differences between the LVAD alone and LVAD+TVP groups, and outcomes were compared. Most patients in the LVAD+TVP group underwent an annuloplasty alone (81.1%). Concomitant TVP did not affect risk of post-operative right VAD insertion (risk ratio [RR], 0.81; 95% confidence interval [CI], 0.49-1.36; p = 0.4310) or death (RR, 0.95; 95% CI, 0.68-1.33; p = 0.7658). However, TVP was associated with an increased risk for post-operative renal failure (RR, 1.53; 95% CI, 1.13-2.08; p = 0.0061), dialysis (RR, 1.49; 95% CI, 1.03-2.15; p = 0.0339), reoperation (RR, 1.24; 95% CI, 1.07-1.45; p = 0.0056), greater total transfusion requirement (RR, 1.03; 95% CI, 1.01-1.05; p = 0.0013), and hospital length of stay > 21 days (RR, 1.29; 95% CI, 1.16-1.43; p < 0.0001). Time on the ventilator and intensive care unit length of stay were also significantly prolonged for the LVAD+TVP group. Performing a concomitant TVP for continuous-flow LVAD patients with moderate to severe TR did not reduce early death or right VAD requirement and was associated with worse early post-operative outcomes. These data caution against routine concomitant TVP based solely on degree of pre-operative TR and suggest that additional selection criteria are needed to identify those patients in whom concomitant TVP may prevent post-operative right ventricular failure.


Patterns of Local Community Composition Are Linked to Large-Scale Diversification and Dispersal of Clades.
At any location, a group of organisms may be represented by several clades. What determines which clades will dominate local communities in terms of their species richness? Here, this relatively neglected question is addressed by analyzing 166 local assemblages of snakes distributed globally. For most regions, local assemblages are dominated by clades with higher global-scale diversification rates and more frequent dispersal into each region, and not by clades that have been present in that region longer. This result contrasts with many other studies of local richness (in other organisms), which show strong impacts of regional colonization time on overall local species richness of clades. Furthermore, even though local assemblages are assembled independently on different continents, most regions have converged on similar patterns of proportional richness. Specifically, a few rapidly diversifying clades dominate most communities around the world. The high diversification rates of these clades are then linked to their high dispersal rates. Similar patterns may occur in many groups, such as plants, frogs, salamanders, birds, and mammals.


WiFi Related Radiofrequency Electromagnetic Fields Promote Transposable Element Dysregulation and Genomic Instability in Drosophila melanogaster.
Exposure to artificial radio frequency electromagnetic fields (RF-EMFs) has greatly increased in recent years, thus promoting a growing scientific and social interest in deepening the biological impact of EMFs on living organisms. The current legislation governing the exposure to RF-EMFs is based exclusively on their thermal effects, without considering the possible non-thermal adverse health effects from long term exposure to EMFs. In this study we investigated the biological non-thermal effects of low-level indoor exposure to RF-EMFs produced by WiFi wireless technologies, using Drosophila melanogaster as the model system. Flies were exposed to 2.4 GHz radiofrequency in a Transverse Electromagnetic (TEM) cell device to ensure homogenous controlled fields. Signals were continuously monitored during the experiments and regulated at non thermal levels. The results of this study demonstrate that WiFi electromagnetic radiation causes extensive heterochromatin decondensation and thus a general loss of transposable elements epigenetic silencing in both germinal and neural tissues. Moreover, our findings provide evidence that WiFi related radiofrequency electromagnetic fields can induce reactive oxygen species (ROS) accumulation, genomic instability, and behavioural abnormalities. Finally, we demonstrate that WiFi radiation can synergize with RasV12 to drive tumor progression and invasion. All together, these data indicate that radiofrequency radiation emitted from WiFi devices could exert genotoxic effects in Drosophila and set the stage to further explore the biological effects of WiFi electromagnetic radiation on living organisms.


Mechanisms of Cellular Avidity Regulation in CD2-CD58-Mediated T Cell Adhesion.
The CD2 receptor on T lymphocytes is essential for T cell adhesion and stimulation by antigen presenting cells (APCs). Blockade of CD2 function is immunosuppressive in both model systems and humans, indicating the importance of CD2 for the cellular immune response. Although the affinity of the molecular interaction between CD2 and its counter-receptor, CD58, is relatively low when measured in solution, this interaction mediates tight adhesion within the 2D cell-cell interface. To understand the mechanisms responsible for regulating the avidity of the CD2-CD58 interaction, we measured the number, affinity, and lateral mobility of CD2 molecules on resting and activated T cells. Cell activation caused a 1.5-fold increase in the number of CD2 sites on the cell surface, and the 2D affinity of CD2 for CD58 increased by 2.5-fold. The combination of T cell activation and CD2 ligation to CD58 decreased the laterally mobile fraction of the ligated CD2. Together, these changes would substantially enhance CD2 avidity and strengthen T cell-APC adhesion. The change in CD2 mobile fraction suggests that the cell uses cytoskeletal regulators to immobilize the receptor selectively at the site of contact with surfaces expressing CD58. Our observations are consistent with a model in which T cell activation initially induces increased CD2 2D affinity, cell surface receptor expression, and lateral mobility, allowing the CD2 molecules to diffuse to sites of contact with CD58-bearing APCs. Subsequently, T cell activation causes the CD58-bound CD2 to be recognized and immobilized at sites of cell-cell contact, thereby strengthening T cell-APC adhesion.


Rituximab treatment for recurrence of nephrotic syndrome in a pediatric patient after renal transplantation for congenital nephrotic syndrome of Finnish type.
Congenital nephrotic syndrome (CNS) of the Finnish type due to mutation in the NPHS-1 gene results in massive proteinuria due to structural abnormality in the glomerular slit diaphragm, and is usually refractory to immunosuppressive therapy. Patients eventually require bilateral nephrectomy and renal replacement therapy, with transplantation being the ultimate goal. Post-transplant recurrence of nephrotic syndrome occurs in about 25% of children and is thought to be immune-mediated secondary to antibodies formed against the nephrin protein in renal allograft. Conventional therapy with calcineurin inhibitors (CNI), cyclophosphamide and corticosteroids with or without plasmapheresis often fails to achieve remission resulting in graft loss in 12-16%. There is limited experience with use of rituximab (RTX) in pediatric organ transplant recipients. We report the first case of post-transplant recurrence of nephrotic syndrome in a 4-yr-old child with CNS due to NPHS-1 mutation in whom CNI, corticosteroid and cyclophosphamide therapy was unsuccessful, but who achieved remission after depletion of B cells with RTX, associated with a decrease in the level of anti-nephrin antibodies. The child remains in remission 5 yr following treatment. Our experience suggests that activated B cells may play a pivotal role in the recurrence of nephrosis after renal transplantation in children with CNS.


Mechanistic modeling of a capsule filling process.
Filling a dosator nozzle moving into a powder bed was investigated using the Discrete Element Method (DEM). Various particle diameters and contact properties were modeled. The simulations qualitatively showed the influence of powder properties on the amount of dosed powder. Two factors that influence the dosed mass were observed. First, the ratio between the particle and dosator diameters affects the packing of particles inside the dosator chamber. Second, the flow behavior of the powder significantly modifies its filling and compression behavior. Cohesive powders pack less densely inside the powder bed, which could lead to a lower amount of dosed powder. In contrast, cohesive powders are compressed more during dosing and the density inside the dosator chamber increases during the dosing process. Since the simulation of fine cohesive powders is numerically impossible due to a high number of particles and small simulation time steps, we applied a simple method for particle scaling to acquire a qualitative understanding of the filling behavior of coarse and fine powders.


Autophagy contributes to inflammation in patients with TNFR-associated periodic syndrome (TRAPS).
Tumour necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) is caused by TNFRSF1A mutations, known to induce intracellular retention of the TNFα receptor 1 (TNFR1) protein, defective TNFα-induced apoptosis, and production of reactive oxygen species. As downregulation of autophagy, the main cellular pathway involved in insoluble aggregate elimination, has been observed to increase the inflammatory response, we investigated whether it plays a role in TRAPS pathogenesis. The possible link between TNFRSF1A mutations and inflammation in TRAPS was studied in HEK-293T cells, transfected with expression constructs for wild-type and mutant TNFR1 proteins, and in monocytes derived from patients with TRAPS, by investigating autophagy function, NF-κB activation and interleukin (IL)-1β secretion. We found that autophagy is responsible for clearance of wild-type TNFR1, but when TNFR1 is mutated, the autophagy process is defective, probably accounting for mutant TNFR1 accumulation as well as TRAPS-associated induction of NF-κB activity and excessive IL-1β secretion, leading to chronic inflammation. Autophagy inhibition due to TNFR1 mutant proteins can be reversed, as demonstrated by the effects of the antibiotic geldanamycin, which was found to rescue the membrane localisation of mutant TNFR1 proteins, reduce their accumulation and counteract the increased inflammation by decreasing IL-1β secretion. Autophagy appears to be an important mechanism in the pathogenesis of TRAPS, an observation that provides a rationale for the most effective therapy in this autoinflammatory disorder. Our findings also suggest that autophagy could be proposed as a novel therapeutic target for TRAPS and possibly other similar diseases.


Beyond widowhood: Do prior discovered themes that describe the experiences of older Australian widowed women persist over time?
In previous cross-sectional studies researchers have explored the experiences of widowed women in the 1921-1926 cohort of the Australian Longitudinal Study on Women's Health and identified three major themes: health, social relationships and support, and financial and structural issues. In the current study the authors examine longitudinal data collected over 15 years to assess whether these themes persisted and/or evolved over time. The sample included 162 widowed women aged 70-90 years. Thematic analysis was used with a constant comparison method. Many women reported good health despite managing comorbidities. Social relationships frequently shifted from friends to family to more formal support. Most financial and structural issues related to managing increasing health costs as women aged. These results confirmed that the three major themes previously reported persisted over time, and underscore the importance of continuing to support women, and their changing needs, well beyond the initial period of bereavement.


The skeletal phenotype of "negritos" from the Andaman Islands and Philippines relative to global variation among hunter-gatherers.
The "negrito hypothesis" suggests that populations of small-bodied foragers in South and Southeast Asia who share common phenotypic characteristics may also share a common, ancient origin. The key defining characteristics of the "negrito" phenotype, small body size, dark skin, and tightly curled hair, have been interpreted as linking these populations to sub-Saharan Africans. The underlying assumption of this interpretation is that the observed phenotypic similarities likely reflect shared ancestry rather than phenotypic convergence. Current genetic evidence is inconclusive, as it both demonstrates that negrito populations have genetic affinities with neighboring populations but also rare and ancient variation that suggests considerable isolation. This study investigates the skeletal phenotype of Andaman Islanders and Aeta foragers from the Philippines in the context of the phenotypic variation among other hunter-gatherers globally, to test whether they show a common, unique physique apart from small body size. Particular emphasis is placed on the comparison of negrito phenotypes to African, Asian, and Australian hunter-gatherer diversity to investigate phenotypic similarities to other populations globally. The results demonstrate that despite sharing small adult stature, the Andaman Islanders and Aeta show variation in body dimensions. In particular, the Andaman Islanders share a pattern of narrow bi-iliac breadth and short upper limbs with the Khoisan (Later Stone Age Southern Africans), whereas the Aeta and Efé show broader bi-iliac breadths relative to lower limb lengths. Although general similarities in size and proportions remain between the Andamanese and Aeta, differences in humero-femoral indices and arm length between these groups and the Efé demonstrate that there is not a generic "pygmy" phenotype. Our interpretations of negrito origins and adaptation must account for this phenotypic variation.


Treatment of Plasmodium chabaudi Parasites with Curcumin in Combination with Antimalarial Drugs: Drug Interactions and Implications on the Ubiquitin/Proteasome System.
Antimalarial drug resistance remains a major obstacle in malaria control. Evidence from Southeast Asia shows that resistance to artemisinin combination therapy (ACT) is inevitable. Ethnopharmacological studies have confirmed the efficacy of curcumin against Plasmodium spp. Drug interaction assays between curcumin/piperine/chloroquine and curcumin/piperine/artemisinin combinations and the potential of drug treatment to interfere with the ubiquitin proteasome system (UPS) were analyzed. In vivo efficacy of curcumin was studied in BALB/c mice infected with Plasmodium chabaudi clones resistant to chloroquine and artemisinin, and drug interactions were analyzed by isobolograms. Subtherapeutic doses of curcumin, chloroquine, and artemisinin were administered to mice, and mRNA was collected following treatment for RT-PCR analysis of genes encoding deubiquitylating enzymes (DUBs). Curcumin was found be nontoxic in BALB/c mice. The combination of curcumin/chloroquine/piperine reduced parasitemia to 37% seven days after treatment versus the control group's 65%, and an additive interaction was revealed. Curcumin/piperine/artemisinin combination did not show a favorable drug interaction in this murine model of malaria. Treatment of mice with subtherapeutic doses of the drugs resulted in a transient increase in genes encoding DUBs indicating UPS interference. If curcumin is to join the arsenal of available antimalarial drugs, future studies exploring suitable drug partners would be of interest.


Integrated and patient-centred management of Parkinson's disease: a network model for reshaping chronic neurological care.
Chronic neurological diseases are the leading cause of disability globally. Yet, our health-care systems are not designed to meet the needs of many patients with chronic neurological conditions. Care is fragmented with poor interdisciplinary collaboration and lack of timely access to services and therapies. Furthermore, care is typically reactive, and complex problems are managed inadequately because of a scarcity of disease-specific expertise and insufficient use of non-pharmacological interventions. Treatment plans tend to focus on the disease rather than the individual living with it, and patients are often not involved in clinical decision making. By use of Parkinson's disease as a model condition, we show an integrated care concept with a patient-centred perspective that includes evidence-based solutions to improve health-care delivery for people with chronic neurological conditions. We anticipate that this integrated care model will improve the quality of life for patients, create a positive working environment for health-care professionals, and be affordable.


Validation of human papillomavirus genotyping by signature DNA sequence analysis.
Screening with combined cytologic and HPV testing has led to the highest number of excessive colposcopic referrals due to high false positive rates of the current HPV testing in the USA. How best to capitalize on the enhanced sensitivity of HPV DNA testing while minimizing false-positive results from its lower specificity is an important task for the clinical pathologists. The HPV L1 gene DNA in liquid-based Pap cytology specimens was initially amplified by the degenerate MY09/MY11 PCR primers and then re-amplified by the nested GP5+/GP6+ primers, or the heminested GP6/MY11, heminested GP5/MY09 primers or their modified equivalent without sample purification or DNA extraction. The nested PCR products were used for direct automated DNA sequencing. A 34- to 50-base sequence including the GP5+ priming site was selected as the signature sequence for routine genotyping by online BLAST sequence alignment algorithms. Of 3,222 specimens, 352 were found to contain HPV DNA, with 92% of the positive samples infected by only 1 of the 35 HPV genotypes detected and 8% by more than 1 HPV genotype. The most common genotype was HPV-16 (68 isolates), followed by HPV-52 (25 isolates). More than half (53.7%) of the total number of HPV isolates relied on a nested PCR for detection although the majority of HPV-16, -18, -31, -33 -35 and -58 isolates were detected by a single MY09/MY11 PCR. Alignment of a 34-base sequence downstream of the GP5+ site failed to distinguish some isolates of HPV-16, -31 and -33. Novel variants of HPV with less than "100% identities" signature sequence match with those stored in the Genbank database were also detected by signature DNA sequencing in this rural and suburban population of the United States. Laboratory staff must be familiar with the limitations of the consensus PCR primers, the locations of the signature sequence in the L1 gene for some HPV genotypes, and HPV genotype sequence variants in order to perform accurate HPV genotyping.


Colloidal jamming at interfaces: a route to fluid-bicontinuous gels.
Colloidal particles or nanoparticles, with equal affinity for two fluids, are known to adsorb irreversibly to the fluid-fluid interface. We present large-scale computer simulations of the demixing of a binary solvent containing such particles. The newly formed interface sequesters the colloidal particles; as the interface coarsens, the particles are forced into close contact by interfacial tension. Coarsening is markedly curtailed, and the jammed colloidal layer seemingly enters a glassy state, creating a multiply connected, solidlike film in three dimensions. The resulting gel contains percolating domains of both fluids, with possible uses as, for example, a microreaction medium.


Insulin secretion is controlled by mGlu5 metabotropic glutamate receptors.
Recent evidence suggests that metabotropic glutamate (mGlu) receptors are involved in the regulation of hormone secretion in the endocrine pancreas. We report here that endogenous activation of mGlu5 receptors is required for an optimal insulin response to glucose both in clonal beta-cells and in mice. In clonal beta-cells, mGlu5 receptors were expressed at the cell surface and were also found in purified insulin-containing granules. These cells did not respond to a battery of mGlu5 receptor agonists that act extracellularly, but instead responded to a cell-permeant analog of glutamate with an increase in [Ca2+]i and insulin secretion. Both effects were largely attenuated by the mGlu5 receptor antagonist, 2-methyl-6-(phenylethynyl)-pyridine (MPEP). MPEP and its structural analog, (E)-2-methyl-6-styryl-pyridine (SIB-1893), reduced the increase in [Ca2+]i and insulin secretion induced by glucose in clonal beta-cells, whereas a mGlu1 receptor antagonist was inactive. mGlu5 knockout mice showed a defective insulin response at all times after a glucose pulse (1.5 g/kg, i.p.), whereas wild-type mice treated with MPEP (10 mg/kg, i.p.) showed a selective impairment in the late phase of insulin secretion in response to glucose challenge. Mice injected with MPEP or lacking mGlu5 receptors also showed a blunted glucagon response to an insulin challenge. We conclude that insulin secretion is under the control of mGlu5 receptors both in clonal beta-cells and in vivo. Drugs that modulate the function of mGlu5 receptors might affect glucose homeostasis by altering the secretion of pancreatic hormones.


Effect of Segmental Thoracic Epidural Block on Pancreatitisinduced Organ Dysfunction: A Preliminary Study.
This preliminary randomized controlled study evaluated effect of thoracic epidural block (TEB) on progression of acute pancreatitis induced organ dysfunction/failure. Patients with predicted severe acute pancreatitis, without contraindication to TEB were randomized to receive (group TE) or not receive a TEB (group NTE) (n = 16 each). For group TE, TEB was performed at T8-9 or T9-10 vertebral level, with infusion of ropivacaine (0.2%) along with fentanyl 2 µg/mL; in group NTE, intravenous morphine was used instead, both interventions titrated to NRS of <4. SOFA score was assessed daily till discharge from ICU, and aggregate SOFA calculated by summing worst scores for each of organ system during ICU stay as primary outcome measure. Other surrogate measures of patient outcome were recorded as secondary objectives. Aggregate SOFA score was statistically similar between both groups (group NTE: 3 [2 - 4]; group TE: 5 [2 - 6]) (P = 0.379); but there was trend of improvement in SOFA score in group TE versus a worsening in group NTE. Duration of hospital stay, and number of patients requiring mechanical ventilation were statistically similar; mortality was insignificantly lesser for group TE (12.5% versus 6.6%; p = 1.000). Fall in serum procalcitonin was significantly greater for group TE. Thoracic epidural was associated with insignificant clinical trend towards better organ functions and lesser mortality; along with significantly greater fall in serum procalcitonin. These are encouraging results that could guide future use of thoracic epidural in acute pancreatitis for its non-analgesic benefits. Tyagi A, Gupta YR et al. Effect of Segmental Thoracic Epidural Block on Pancreatitis Induced Organ Dysfunction: A Preliminary Study. Indian J of Crit Care Med 2019;23(2):89-94.


Complementary and alternative medicine (CAM) use in advanced cancer: a systematic review.
This systematic review synthesizes knowledge about the use of complementary and alternative medicine (CAM) among advanced cancer patients. EBSCO and Ovid databases were searched using core concepts, including advanced cancer, CAM, integrative medicine, and decision-making. Articles included in the final review were analyzed using narrative synthesis methods, including thematic analysis, concept mapping, and critical reflection on the synthesis process. Results demonstrate that advanced cancer patients who are younger, female, more educated, have longer duration of disease, and have previously used CAM are more likely to use CAM during this stage of illness. Key themes identified include patterns of and reasons for use; and barriers and facilitators to informed CAM decision-making. Knowledge regarding the use of CAM in advanced cancer remains in its nascent stages. Findings suggest a need for more research on understanding the dynamic process of CAM decision-making in the advanced cancer population from the patients' perspective.


Multiple factors contribute to outcrossing in a tropical emergent Dipterocarpus tempehes, including a new pollen-tube guidance mechanism for self-incompatibility.
The self-rejection system of Dipterocarpus tempehes (Dipterocarpaceae), an emergent tree of the lowland tropical forests of Borneo, were studied by means of pollination experiments, fluorescence microscopy of pollen tubes, and monitoring of ovary maturation patterns. Fruit set was higher in cross-pollinated flowers than in control and self-pollinated flowers, indicating the existence of pollen limitation and a self-rejection system. Although the adhesion and the germination of self-pollen and the growth of self-pollen tubes were not inhibited, the proportion of cross-pollen tubes that entered the style was 1.7-2.3 times higher than that of self-pollen tubes, indicating a partial self-incompatibility that inhibits self-pollen tubes from entering the style hollow. These results suggest, for the first time, that self-incompatibility is caused by a defect of pollen-tube guidance. We also suggest a threshold effect in number of pollen tubes or late-acting self-incompatibility to fully explain the drastic and uniform selection against self-pollinated flowers before ovary swelling. After that, maternal selection and/or inbreeding depression caused the abortion and delayed maturation of self-pollinated flowers. The advantages of the self-rejection process composed of partial early-acting self-incompatibility and relatively strong delayed abortion is discussed with respect to the general-flowering phenomenon in lowland dipterocarp forests.


Pleuroscopy: our initial experience in Hong Kong.
To report our preliminary experience using pleuroscopy for patients with pleural diseases. Prospective cohort study. Tertiary referral hospital with service input from respiratory physicians and cardiothoracic surgeons in Hong Kong. Between April and November 2007, patients with undiagnosed exudative pleural effusions and proven malignant pleural effusions were recruited for diagnostic evaluations and therapeutic interventions, respectively. Pleuroscopy with a semi-rigid thoracoscope performed under local anaesthesia and conscious sedation. A total of 20 patients (16 males and 4 females; mean age, 63 years) underwent the procedure and were followed up for a mean of 19 weeks. For the 14 patients having diagnostic pleuroscopy, the yield was 79% (11 patients). The 3-month success rate for the six patients undergoing pleurodesis was 83% (five patients). Complications were mild and included self-limiting fever (20%, four patients) and localised subcutaneous emphysema (20%, four patients). No major complications or mortality were noted. Pleuroscopy using a semi-rigid instrument is a safe and efficacious procedure for the management of pleural diseases in suitable patients.


Th2-predominant inflammation and blockade of IFN-gamma signaling induce aneurysms in allografted aortas.
Abdominal aortic aneurysms (AAAs) cause death due to complications related to expansion and rupture. The underlying mechanisms that drive AAA development remain largely unknown. We recently described evidence for a shift toward T helper type 2 (Th2) cell responses in human AAAs compared with stenotic atheromas. To evaluate putative pathways in AAA formation, we induced Th1- or Th2-predominant cytokine environments in an inflammatory aortic lesion using murine aortic transplantation into WT hosts or those lacking the receptors for the hallmark Th1 cytokine IFN-gamma, respectively. Allografts in WT recipients developed intimal hyperplasia, whereas allografts in IFN-gamma receptor-deficient (GRKO) hosts developed severe AAA formation associated with markedly increased levels of MMP-9 and MMP-12. Allografts in GRKO recipients treated with anti-IL-4 antibody to block the characteristic IL-4 Th2 cytokine or allografts in GRKO hosts also congenitally deficient in IL-4 did not develop AAA and likewise exhibited attenuated collagenolytic and elastolytic activities. These observations demonstrate an important dichotomy between cellular immune responses that induce IFN-gamma- or IL-4-dominated cytokine environments. The findings establish important regulatory roles for a Th1/Th2 cytokine balance in modulating matrix remodeling and have important implications for the pathophysiology of AAAs and arteriosclerosis.


Individual mice can be distinguished by the period of their islet calcium oscillations: is there an intrinsic islet period that is imprinted in vivo?
Pulsatile insulin secretion in vivo is believed to be derived, in part, from the intrinsic glucose-dependent intracellular calcium concentration ([Ca2+]i) pulsatility of individual islets. In isolation, islets display fast, slow, or mixtures of fast and slow [Ca2+]i oscillations. We show that the period of islet [Ca2+]i oscillations is unique to each mouse, with the islets from an individual mouse demonstrating similar rhythms to one another. Based on their rhythmic period, mice were broadly classified as being either fast (0.65 +/- 0.1 min; n = 6 mice) or slow (4.7 +/- 0.2 min; n = 15 mice). To ensure this phenomenon was not an artifact of islet-to-islet communication, we confirmed that islets cultured in isolation (period: 2.9 +/- 0.1 min) were not statistically different from islets cultured together from the same mouse (3.1 +/- 0.1 min, P > 0.52, n = 5 mice). We also compared pulsatile insulin patterns measured in vivo with islet [Ca2+]i patterns measured in vitro from six mice. Mice with faster insulin pulse periods corresponded to faster islet [Ca2+]i patterns, whereas slower insulin patterns corresponded to slower [Ca2+]i patterns, suggesting that the insulin rhythm of each mouse is preserved to some degree by its islets in vitro. We propose that individual mice have characteristic oscillatory [Ca2+]i patterns, which are imprinted in vivo through an unknown mechanism.


Role of Laparoscopic Surgery in the Current Management of Mirizzi Syndrome.
Mirizzi syndrome (MS) is an uncommon complication of cholelithiasis caused by extrinsic biliary compression by stones in the gallbladder infundibulum or cystic duct. The purpose of this study was to evaluate the outcomes associated with a laparoscopic approach to this disease process. This is a 10-year, retrospective study conducted at two academic medical centers with established acute care surgery practices. Patients with a diagnosis of MS confirmed intraoperatively were included. Eighty-eight patients with MS were identified with 55 (62.5%) being type 1. Twenty six (29.5%) patients, all type 1, underwent successful laparoscopic cholecystectomy. Of the 62 patients that underwent open cholecystectomy, 27.3 per cent had a laparoscopy converted to open procedure. There was no significant difference in overall complications (19.2 vs 29%) among those undergoing laparoscopic versus open cholecystectomy. Length of stay was lower in patients that had a laparoscopic approach (P = 0.001). Laparoscopic cholecystectomy can safely be attempted in type 1 MS and seems to be associated with fewer overall complications and shorter length of stay compared with an open approach.


Artificial neural networks and gene filtering distinguish between global gene expression profiles of Barrett's esophagus and esophageal cancer.
cDNAmicroarrays, combined with bioinformatics analyses, are becomingincreasingly used in current medical research. Existing analytic methods,particularly those that are unsupervised, often have difficulty recognizing subtle differences among predefined subgroups. In contrast, supervised methods, such as Artificial Neural Networks (ANNs), are able to recognize subtly different biological entities. We applied ANNs in a proof-of-principle study of cDNA microarray data in esophageal cancer (CA) and premalignancy. cDNA microarrays, each containing 8064 clones, were hybridized to RNAs from 22 esophageal lesions, including 14 Barrett's esophagus (BA) metaplasias and 8 esophageal carcinomas (3 squamous cell carcinomas and 5 adenocarcinomas). Scanned cDNA microarray data were analyzed using the bioinformatics software Cluster/TreeView, Significance Analysis of Microarrays (SAM), and ANNs. Cluster analysis based on all 8064 clones on the microarrays was unable to correctly distinguish BA specimens from CA specimens. SAM then selected 160 differentially expressed genes between Barrett's and cancer. Cluster analysis based on this reduced set still misclassified 2 Barrett's as cancers. The ANN was trained on 12 samples and tested against the remaining 10 samples. Using the 160 selected genes, the ANN correctly diagnosed all 10 samples in the test set. Finally, the 160 genes selected by SAM may merit further study as biomarkers of neoplastic progression in the esophagus, as well as in elucidating pathological mechanisms underlying BA and CA.


Can chronic disease be managed through integrated care cost-effectively? Evidence from a systematic review.
The increase in demand for integrated care models to manage chronic disease is a challenge for the Irish health system, which is traditionally organised around the acute hospital services. Implementing integrated care programmes requires significant investment, and thus, their economic impact requires consideration. This paper updates the previous evidence on the cost-effectiveness of integrated care programmes to support the development of a cost-effective integrated care programme for chronic disease management. A systematic review of economic evaluations of integrated care programmes for chronic diseases (respiratory, cardiovascular, diabetes and musculoskeletal diseases) was performed using methods guided by the principles of conducting systematic reviews. The evidence was combined and summarised using a narrative synthesis. A meta-analysis of the evidence was not performed due to the heterogeneity of interventions and associated outcomes. Six studies met the inclusion criteria; no study considered an integrated model of care that dealt with more than one chronic illness. Four chronic conditions were examined: stroke, diabetes, cardiovascular disease and COPD. Three studies were full economic evaluations, and three were partial economic evaluations. The economic evidence, examined within this review, suggests that integrated care programmes have the potential to be cost-effective, achieving greater health benefits and are less expensive than usual care. Across all the interventions considered, the reduction in inpatient and outpatient admissions was the main contributor to reducing costs.


Long-Term (1-Year) Safety and Efficacy of a Single 6-mL Injection of Hylan G-F 20 in Indian Patients with Symptomatic Knee Osteoarthritis.
The prevalence of symptomatic knee osteoarthritis (OA) among Asians ≥65 years is estimated to double by 2040. This study was designed to evaluate the safety and efficacy of a single, 6-mL intra-articular injection of hylan G-F 20 in Indian patients with knee OA at 26 weeks through to 52 weeks. This study was an open-label, multicentre, phase 4 clinical trial. Enrolled patients (N=394) were ≥30 years old with Kellgren-Lawrence grade 1-3 OA; all patients received hylan G-F 20. WOMAC, SF-12, PTGA, and COGA scores, and OA medication use were evaluated at weeks 1, 4, 12, 26, 39, and 52 (initial treatment phase). At 26, 39, or 52 weeks, eligible patients could participate in a repeat treatment phase. McNemar-Bowkers, paired t-tests and ANOVA analyses were performed (alpha=0.05). At 26 weeks, statistically significant changes from baseline were observed in all efficacy parameters, including the primary efficacy endpoint of WOMAC A1 (p<0.0001). Improvements continued for 52 weeks. No significant changes occurred in concomitant medication use. Eleven patients (2.8%) were re-injected at week 26 or 52. After repeat injection, statistically significant decreases were observed in WOMAC A1, WOMAC C and PTGA scores (p≤0.028). Twenty-three (5.8%) patients reported 26 local target knee AEs. Among Indian patients within this study, a 6-mL hylan G-F 20 injection was well tolerated and effective in treating symptomatic knee OA with significant long-term (1 year) improvement of outcomes. When needed, repeat treatment was safe and efficacious for 4 weeks. Clinical Trial Registry of India (CTRI/2010/091/000052) www.ctri.nic.in/Clinicaltrials/login.php.


Drug use as boundary play: a qualitative exploration of gay circuit parties.
Research findings have revealed that gay circuit parties may be locations that are disproportionately responsible for the increasing rates of many STIs/HIV among gay/bisexual men. Theories have been put forth that this may be the case because circuit parties are locales of prevalent drug use and unsafe sex. To explore the relationship between these two phenomena, in-depth qualitative interviews were undertaken with 17 men who (1) have sex with other men, (2) attended gay circuit parties in Montréal, Canada, in 2007. These revealed that drugs (including alcohol) were used intentionally to engage in unsafe sex, and then to justify this behavior after the fact. This process we called boundary play.


Quantitative Microbial Risk Analysis to evaluate health effects of interventions in the urban water system of Accra, Ghana.
A quantitative microbial risk assessment was applied to evaluate the microbial risks of the Accra Urban Water System (AUWS). The exposure assessment was based on the count of indicator organisms in waste water from open roadside drains and in water and sand samples from the beach. The predicted total disease burden generated in a representative catchment of the AUWS (Odaw Catchment) was 36,329 Disability Adjusted Life Years (DALYs) per year, of which 12 and 88% are caused by, respectively, shortcomings in the water supply system and inappropriate sanitation. The DALYs per person per year were above the WHO reference value. The open roadside drain had the highest contribution to the disease burden. Of four possible interventions evaluated for health risk reduction, the highest efficiency in terms of DALYs averted per euro invested would be achieved by providing covers for the open roadside drains.


The diverse older HIV-positive population: a national profile of economic circumstances, social support, and quality of life.
The objectives of this study were to provide a national profile of socioeconomic circumstances of the middle-aged and older population living with HIV and to evaluate variations in social support and quality of life (QOL) across age and socioeconomic subgroups, controlling for indicators of disease progression. The design used was a cross-sectional analysis of nationally representative interview data on HIV-infected individuals collected in the HIV Cost and Services Utilization Study. Multiple measures of social support and QOL were used. Bivariate comparisons of outcomes across categories of age and exposure category were performed; multivariate analyses to isolate the effect of older age on outcomes within exposure categories were performed, controlling for socioeconomic and clinical co-variates. Study results indicate that older gay men with HIV/AIDS are a predominantly white population and more likely to have health insurance than their younger counterparts; 38% were employed and 48% reported incomes of more than $25,000. Older injection drug users (IDUs) with HIV/AIDS are a predominantly black population with a particularly high concentration of disadvantages; only 11% were employed and 74% reported incomes of less than $10,000. Older IDUs reported especially low levels of physical functioning and emotional support in comparison with their younger counterparts, whereas older gay men did not significantly differ from younger gay men in these respects. The authors conclude that characteristics and care needs of the older HIV-positive population are very diverse and vary sharply by exposure route. Interventions need to be tailored to the needs of these distinct subpopulations, with an emphasis on development of supportive care interventions for older IDUs.


Re-emergence of Chikungunya and O'nyong-nyong viruses: evidence for distinct geographical lineages and distant evolutionary relationships.
Chikungunya (CHIK) virus is a member of the genus Alphavirus in the family TOGAVIRIDAE: Serologically, it is most closely related to o'nyong-nyong (ONN) virus and is a member of the Semliki Forest antigenic complex. CHIK virus is believed to be enzootic throughout much of Africa and historical evidence indicates that it spread to other parts of the world from this origin. Strains from Africa and Asia are reported to differ biologically, indicating that distinct lineages may exist. To examine the relatedness of CHIK and ONN viruses using genetic data, we conducted phylogenetic studies on isolates obtained throughout Africa and Southeast Asia. Analyses revealed that ONN virus is indeed distinct from CHIK viruses, and these viruses probably diverged thousands of years ago. Two distinct CHIK virus lineages were delineated, one containing all isolates from western Africa and the second comprising all southern and East African strains, as well as isolates from Asia. Phylogenetic trees corroborated historical evidence that CHIK virus originated in Africa and subsequently was introduced into Asia. Within the eastern Africa and southern Africa/Asia lineage, Asian strains grouped together in a genotype distinct from the African groups. These different geographical genotypes exhibit differences in their transmission cycles: in Asia, the virus appears to be maintained in an urban cycle with Aedes aegypti mosquito vectors, while CHIK virus transmission in Africa involves a sylvatic cycle, primarily with AE: furcifer and AE: africanus mosquitoes.


Statistical learning in songbirds: from self-tutoring to song culture.
At the onset of vocal development, both songbirds and humans produce variable vocal babbling with broadly distributed acoustic features. Over development, these vocalizations differentiate into the well-defined, categorical signals that characterize adult vocal behaviour. A broadly distributed signal is ideal for vocal exploration, that is, for matching vocal production to the statistics of the sensory input. The developmental transition to categorical signals is a gradual process during which the vocal output becomes differentiated and stable. But does it require categorical input? We trained juvenile zebra finches with playbacks of their own developing song, produced just a few moments earlier, updated continuously over development. Although the vocalizations of these self-tutored (ST) birds were initially broadly distributed, birds quickly developed categorical signals, as fast as birds that were trained with a categorical, adult song template. By contrast, siblings of those birds that received no training (isolates) developed phonological categories much more slowly and never reached the same level of category differentiation as their ST brothers. Therefore, instead of simply mirroring the statistical properties of their sensory input, songbirds actively transform it into distinct categories. We suggest that the early self-generation of phonological categories facilitates the establishment of vocal culture by making the song easier to transmit at the micro level, while promoting stability of shared vocabulary at the group level over generations.This article is part of the themed issue 'New frontiers for statistical learning in the cognitive sciences'.


Retrospective study of technical aspects and complications of endoscopic submucosal dissection for laterally spreading tumors of the colorectum.
Laterally spreading tumors - non granular type (LST-NG) are more often considered candidates for endoscopic submucosal dissection (ESD) than laterally spreading tumors - granular type (LST-G), because of their higher potential for submucosal invasion. However, ESD for LST-NG can be technically difficult. The aim of our study was to compare our ESD results for LST-NG and for LST-G. Ninety-nine LST-NG and 169 LST-G measuring 20 mm in size or more were removed by ESD. We retrospectively evaluated the clinicopathological features of the tumors and treatment results (en bloc resection rate, procedure time and speed, rate of use of ancillary devices, and complication and recurrence rates). Histopathology revealed that there were more submucosally invasive lesions in the LST-NG than in the LST-G group (28 % vs. 9 %; P < 0.0001). The en bloc resection rate, en bloc R0 resection rate, and en bloc curative resection rate of LST-NG were similar to those of LST-G (LST-NG: 99 %, 98 %, and 88 %; LST-G: 99 %, 98 %, and 91 %). In LST-NG, the median procedure time tended to be longer (LST-NG: 69 min; LST-G: 60 min) and the median procedure speed was slower (LST-NG: 0.15 cm (2)/min; LST-G: 0.25 cm (2)/min; P < 0.0001). Use of ancillary devices was higher for LST-NG (38 % vs. 15 % for LST-G; P < 0.0001), as was the perforation rate (5.1 % vs. 0.6 % for LST-G; P = 0.027). No recurrence was seen in either group. ESD was an effective treatment method for both LST-NG and LST-G. However, the degree of technical difficulty appears higher for LST-NG than for LST-G lesions, as shown by the lower dissection speed and higher perforation rate. ESD for LST-NG should probably be performed by those with significant experience of colorectal ESD.


[Omega-3 and omega-6 fatty acids in the treatment of children and adolescents with ADHD].
Background There is a growing trend towards the use of alternative forms of treatment for attention deficit hyperactivity disorder (adhd), such as the food supplements omega-3 and omega-6 fatty acids. To study biochemical aspects, important hypotheses regarding the role of these fatty acids in brain development, the mode of operation and research results concerning the effectiveness of treating adhd with these supplements. A Medline search was performed using the Mesh-term 'fatty acids' and the search terms 'omega-3 and omega-6 fatty acids' and 'attention deficit hyperactivity disorder'. results Some rct's (randomised controlled trails) involving children with adhd didn't show any improvement after treatment with omega-3 and omega-6 fatty acids. Some other rct's, however, did show a reduction in adhd symptoms and learning difficulties, but the children concerned had not been officially diagnosed with adhd. A recent rct showed a substantial reduction in adhd symptoms in children with the inattentive type of adhd and in children with adhd and comorbid problems. There are indications that there is a theoretical rationale for the effectiveness of fatty acids in the treatment of adhd; research is ongoing. At the moment, however, treatment of adhd with omega-3 and omega-6 fatty acids is not recommended because it does not qualify as being evidence-based.


Synthesis, physico-chemical properties and biological analysis of newly obtained copper(II) complexes with pyrazole derivatives.
Three new copper(II) complexes containing two different pyrazole bound ligands (1, 2) have been synthesized and characterized by IR, LSI-MS (liquid secondary ion mass spectrometry) and elemental analysis. (1)H NMR spectra of the organic ligands have been recorded. We describe the influence of these complexes on particular cancer cell lines and DNA structure by MTT-assay [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide], APA (acid phosphatase activity)-assay or CD-spectroscopy and agarose gel electrophoresis methods, together with their physico-chemical properties such as lipophilicity and stability in aqueous solution. The cytotoxic effect on HUVEC (endothelial cells) for the most active complex 4 has been also investigated. Moreover, the ability of these complexes to induce apoptosis in cancer cells has been assessed by using fluorescence microscopy. Our results indicate that dichloridobis{1-[amino(thioxo)methyl]-5-hydroxy-3-phenyl-1H-pyrazole-κN2}copper(II) is the most potent complex among the tested complexes.


Controlled bacterial lysis for electron tomography of native cell membranes.
Cryo-electron tomography (cryoET) has become a powerful tool for direct visualization of 3D structures of native biological specimens at molecular resolution, but its application is limited to thin specimens (<300 nm). Recently, vitreous sectioning and cryoFIB milling technologies were developed to physically reduce the specimen thickness; however, cryoET analysis of membrane protein complexes within native cell membranes remains a great challenge. Here, we use phage ΦX174 lysis gene E to rapidly produce native, intact, bacterial cell membranes for high resolution cryoET. We characterized E gene-induced cell lysis using FIB/SEM and cryoEM and showed that the bacteria cytoplasm was largely depleted through spot lesion, producing ghosts with the cell membranes intact. We further demonstrated the utility of E-gene-induced lysis for cryoET using the bacterial chemotaxis receptor signaling complex array. The described method should have a broad application for structural and functional studies of native, intact cell membranes and membrane protein complexes.


Central osmotic regulation of sympathetic nerve activity.
In this review, we will focus on the central neural mechanisms that couple osmotic perturbations to changes in sympathetic nerve discharge, and the possible impact these actions have in cardiovascular diseases such as arterial hypertension and congestive heart failure. Changes in extracellular fluid osmolality lead to specific regulatory responses in defence of body fluid and cardiovascular homeostasis. Systemic hyperosmolality is well known to stimulate thirst and the release of antidiuretic hormone. These responses are largely due to osmosensing neurones in the forebrain lamina terminalis and hypothalamus and are critical elements in a control system that operates to restore body fluid osmolality. An equally important, but less characterized, target of central osmoregulatory processes is the sympathetic nervous system. Understanding the neurobiology of sympathetic responses to changes in osmolality has important implications for body fluid and cardiovascular physiology. By stabilizing osmolality, vascular volume is preserved and thereby relatively normal levels of cardiac output and arterial pressure are maintained.


Synergistic antitumor effects of immunotherapy with recombinant interleukin-2 and recombinant tumor necrosis factor-alpha.
The antitumor activity of combination therapy with recombinant tumor necrosis-alpha (rhTNF-alpha) and recombinant interleukin-2 (rhIL-2) was assessed against established immunogenic (MCA-106) and nonimmunogenic (MCA-102) sarcomas at both s.c. and visceral (hepatic) sites. C57BL/6 (B6) mice were treated with a single i.v. dose of rhTNF-alpha (2, 4, 6, or 8 micrograms) followed by rhIL-2 (25,000 U) i.p. thrice daily for 5 consecutive days. Synergistic effects as measured by regression of tumor, prolongation of survival, and improved cure rates were found using the combination of rhTNF-alpha plus rhIL-2 compared to rhTNF-alpha alone or rhIL-2 alone in the treatment of the immunogenic sarcoma MCA-106. No significant antitumor effects were observed against the nonimmunogenic MCA-102 sarcoma. These findings were similar for both s.c. and large single hepatic tumor models. The effect of the timing of rhIL-2 injections in relation to rhTNF-alpha administration (concurrent, 2, 4, or 6 days post single rhTNF-alpha dose) was also evaluated. Substantial tumor regression and increased survival times were seen in mice with s.c. tumors when rhIL-2 therapy was delayed as much as 48 h after rhTNF-alpha administration. No antitumor response was noted with the combination compared to rhTNF-alpha alone when rhIL-2 was delayed for greater than 4 days. No increase in lethal toxicity during treatment course of the combination of rhTNF-alpha and rhIL-2 was noted at any schedule compared to single agent rhTNF-alpha therapy. A possible role of rhTNF-alpha in regulation of IL-2-dependent antitumor activity in vivo is discussed.


The Use of Endotoxin Adsorption in Extracorporeal Blood Purification Techniques. A Case Report.
Sepsis and septic shock are major healthcare problems, resulting in high morbidity and mortality. The Surviving Sepsis Campaign (SSC), which standardised the approach to sepsis, was recently updated. Strategies to decrease the systemic inflammatory response have been proposed to modulate organ dysfunctions. Endotoxin, derived from the membrane of Gram-negative bacteria, is considered a major factor in the pathogenesis of sepsis. Endotoxin adsorption, if effective, has the potential to reduce the biological cascade of Gram-negative sepsis. We present a case of a 64-year-old man with severe Gram-negative sepsis, following purulent peritonitis secondary to rectosigmoid adenocarcinoma. To reduce the amplitude of the general effects of endotoxins we used a novel device, the Alteco® LPS Adsorber (Alteco Medical AB, Lund, Sweden), for lipopolysaccharide (LPS) adsorption. The efficacy markers were: the overall haemodynamic profile, translated into decreased vasopressor requirements, the normalisation of the cardiac index, the systemic vascular resistance index combined with the lactate level and the reduction in procalcitonin (PCT) levels. A decrease in the sequential organ failure assessment (SOFA) score at twenty-four hours was demonstrated. The clinical course following treatment was favourable for the days immediately following the treatment.This was attributed to the removal of endotoxin from the systemic circulation. The patient died one week after the endotoxin removal session, developing an ischemic bowel perforation with subsequent multiple organ failures.


Number estimates of neuronal phenotypes in layer II of the medial entorhinal cortex of rat and mouse.
Modelling entorhinal function or evaluating the consequences of neuronal losses which accompany neurodegenerative disorders requires detailed information on the quantitative cellular composition of the normal entorhinal cortex. Using design-based stereological methods, we estimated the numbers, proportions, densities and sectional areas of layer II cells in the medial entorhinal area (MEA), and its constituent caudal entorhinal (CE) and medial entorhinal (ME) fields, in the rat and mouse. We estimated layer II of the MEA to contain approximately 58,000 neurons in the rat and approximately 24,000 neurons in the mouse. Field CE accounted for more than three-quarters of the total neuron population in both species. In the rat, layer II of the MEA is comprised of 38% ovoid stellate cells, 29% polygonal stellate cells and 17% pyramidal cells. The remainder is comprised of much smaller populations of horizontal bipolar, tripolar, oblique pyramidal and small round cells. In the mouse, MEA layer II is comprised of 52% ovoid stellate cells, 22% polygonal stellate cells and 14% pyramidal cells. Significant species differences in the proportions of ovoid and polygonal stellate cells suggest differences in physiological and functional properties. The majority of MEA layer II cells contribute to the entorhinal-hippocampal pathways. The degree of divergence from MEA layer II cells to the dentate granule cells was similar in the rat and mouse. In both rat and mouse, the only dorsoventral difference we observed is a gradient in polygonal stellate cell sectional area, which may relate to the dorsoventral increase in the size and spacing of individual neuronal firing fields. In summary, we found species-specific cellular compositions of MEA layer II, while, within a species, quantitative parameters other than cell size are stable along the dorsoventral and mediolateral axis of the MEA.


Genetic Determinants of the Gut Microbiome in UK Twins.
Studies in mice and humans have revealed intriguing associations between host genetics and the microbiome. Here we report a 16S rRNA-based analysis of the gut microbiome in 1,126 twin pairs, a subset of which was previously reported. Tripling the sample narrowed the confidence intervals around heritability estimates and uncovered additional heritable taxa, some of which are validated in other studies. Repeat sampling of subjects showed heritable taxa to be temporally stable. A candidate gene approach uncovered associations between heritable taxa and genes related to diet, metabolism, and olfaction. We replicate an association between Bifidobacterium and the lactase (LCT) gene locus and identify an association between the host gene ALDH1L1 and the bacteria SHA-98, suggesting a link between formate production and blood pressure. Additional genes detected are involved in barrier defense and self/non-self recognition. Our results indicate that diet-sensing, metabolism, and immune defense are important drivers of human-microbiome co-evolution.


Evidence for the early onset of aberrant promoter methylation in urothelial carcinoma.
There is evidence that carcinoma in situ (CIS) is the precursor of invasive urothelial carcinoma, a tumour characterized by frequent gene promoter methylation. The timing of altered DNA methylation is unknown in this pathway. Here we investigate gene methylation in 196 consecutive samples of normal urothelium, CIS, and tumours from 104 patients with both CIS and invasive urothelial carcinoma using quantitative methyl-sensitive polymerase chain reaction for six genes (p16, p14, E-cadherin, RARbeta2, RASSF1a, and GSTP1). Control normal urothelial samples from 15 patients with no history of urothelial carcinoma were also analysed. Immunohistochemistry established the expression of well-characterized CIS markers p53 and cytokeratin 20. Promoter methylation occurred frequently in both normal urothelium and CIS samples from patients with urothelial carcinoma, and increased with progression from normal to invasive urothelial carcinoma, at both specific loci (chi2 test: E-cadherin, p=0.0001; RASSF1a, p=0.003, RARbeta2, p=0.007, p16, p=0.024) and in general (methylation indices [t-test, p<0.0001]). Methylation was associated with cytokeratin 20 expression (t-test, p=0.004) and poor prognosis, and with increased progression to tumour death in patients whose CIS samples showed methylation, in comparison with those without methylation (log rank p<0.03). Promoter methylation occurs early in the urothelial carcinogenic pathway and appears to be a good biomarker of the invasive urothelial carcinoma phenotype.


Public health emergency preparedness and response communications with health care providers: a literature review.
Health care providers (HCPs) play an important role in public health emergency preparedness and response (PHEPR) so need to be aware of public health threats and emergencies. To inform HCPs, public health issues PHEPR messages that provide guidelines and updates, and facilitate surveillance so HCPs will recognize and control communicable diseases, prevent excess deaths and mitigate suffering. Public health agencies need to know that the PHEPR messages sent to HCPs reach their target audience and are effective and informative. Public health agencies need to know that the PHEPR messages sent to HCPs reach their target audience and are effective and informative. We conducted a literature review to investigate the systems and tools used by public health to generate PHEPR communications to HCPs, and to identify specific characteristics of message delivery mechanisms and formats that may be associated with effective PHEPR communications. A systematic review of peer- and non-peer-reviewed literature focused on the following questions: 1) What public health systems exist for communicating PHEPR messages from public health agencies to HCPs? 2) Have these systems been evaluated and, if yes, what criteria were used to evaluate these systems? 3) What have these evaluations discovered about characterizations of the most effective ways for public health agencies to communicate PHEPR messages to HCPs? We identified 25 systems or tools for communicating PHEPR messages from public health agencies to HCPs. Few articles assessed PHEPR communication systems or messaging methods or outcomes. Only one study compared the effectiveness of the delivery format, device or message itself. We also discovered that the potential is high for HCPs to experience "message overload" given redundancy of PHEPR messaging in multiple formats and/or through different delivery systems. We found that detailed descriptions of PHEPR messaging from public health to HCPs are scarce in the literature and, even when available are rarely evaluated in any systematic fashion. To meet present-day and future information needs for emergency preparedness, more attention needs to be given to evaluating the effectiveness of these systems in a scientifically rigorous manner.


Feasibility and effectiveness of cotrimoxazole prophylaxis for HIV-1-infected adults attending an HIV/AIDS clinic in Uganda.
Cotrimoxazole is recommended for prevention of opportunistic infections in symptomatic HIV patients in sub-Saharan Africa. We examined the feasibility and effectiveness of daily cotrimoxazole prophylaxis in a well-established cohort of HIV-infected adults attending clinics in Entebbe, Uganda. We compared mortality and morbidity rates for 12 months before and after the introduction of cotrimoxazole. Between August 2000 and February 2002, 94% of cohort members were enrolled onto cotrimoxazole prophylaxis. Revisits were scheduled every 4 weeks to replenish pills; patients attended 61% of revisits. The main reasons for nonenrollment and defaulting were lack of transport, being away from home, and sickness. Drug-related adverse events, mainly itching and rash, were seen in 4% of participants. Although bacterial resistance rate to cotrimoxazole was high, the adjusted mortality incidence rate ratio was significantly reduced after the introduction of cotrimoxazole (0.76; 95% confidence interval, 0.60-0.96; P = 0.020). Overall febrile events and morbidity rates were unchanged after the introduction of cotrimoxazole, but the incidence of malaria was reduced (incidence rate ratio, 0.31; 95% confidence interval, 0.13-0.72). Cotrimoxazole prophylaxis can be introduced into routine HIV clinic activities and is associated with a reduction in overall mortality and malaria morbidity, even in an area with high bacterial resistance. These results reinforce the need for large-scale provision of cotrimoxazole prophylaxis for all HIV-positive patients in developing countries.


Modes and models of forebrain cholinergic neuromodulation of cognition.
As indicated by the profound cognitive impairments caused by cholinergic receptor antagonists, cholinergic neurotransmission has a vital role in cognitive function, specifically attention and memory encoding. Abnormally regulated cholinergic neurotransmission has been hypothesized to contribute to the cognitive symptoms of neuropsychiatric disorders. Loss of cholinergic neurons enhances the severity of the symptoms of dementia. Cholinergic receptor agonists and acetylcholinesterase inhibitors have been investigated for the treatment of cognitive dysfunction. Evidence from experiments using new techniques for measuring rapid changes in cholinergic neurotransmission provides a novel perspective on the cholinergic regulation of cognitive processes. This evidence indicates that changes in cholinergic modulation on a timescale of seconds is triggered by sensory input cues and serves to facilitate cue detection and attentional performance. Furthermore, the evidence indicates cholinergic induction of evoked intrinsic, persistent spiking mechanisms for active maintenance of sensory input, and planned responses. Models have been developed to describe the neuronal mechanisms underlying the transient modulation of cortical target circuits by cholinergic activity. These models postulate specific locations and roles of nicotinic and muscarinic acetylcholine receptors and that cholinergic neurotransmission is controlled in part by (cortical) target circuits. The available evidence and these models point to new principles governing the development of the next generation of cholinergic treatments for cognitive disorders.


Changes in Corneal Detection Thresholds After Repeated Tear Film Instability.
To use a human-based model to study the effects of repeated tear film instability on corneal detection thresholds to cold, mechanical, and chemical stimuli. Twenty-five subjects participated in three study visits. A computer-controlled Belmonte esthesiometer was used to estimate corneal detection thresholds to cold, mechanical, and chemical stimuli before, after, and 30 minutes following 10 consecutive sustained tear exposure (STARE) trials. Subjects turned a pain knob (0-10) to indicate discomfort during STARE trials. The area of tear breakup and thinning in each trial was analyzed. Symptoms were evaluated by the Current Symptom Questionnaire (CSQ). There was a significant time effect on CSQ symptoms during both visits (Friedman test, P < 0.001), with immediately after repeated STARE and 30 minutes later significantly differing from before STARE (Wilcoxon, P < 0.017). Tear breakup occurred in every trial, ranging from 25% to 88% of the exposed corneal area and all subjects indicated discomfort during trials. There was a significant time effect on mechanical thresholds between before STARE mechanical thresholds and 30 minutes later (repeated measures analysis of variance [ANOVA] P < 0.001), but not cold (P = 0.057) or chemical (P = 0. 565) thresholds. In this study, tear breakup during STARE trials was associated with discomfort, which when repeated, resulted in increased symptoms of ocular discomfort and alterations of mechanical sensory thresholds after 30 minutes. These results suggest that tear film instability, which is thought to occur repeatedly during normal blinking among dry eye patients over the day, can produce neurosensory alterations.


Network-based survival analysis reveals subnetwork signatures for predicting outcomes of ovarian cancer treatment.
Cox regression is commonly used to predict the outcome by the time to an event of interest and in addition, identify relevant features for survival analysis in cancer genomics. Due to the high-dimensionality of high-throughput genomic data, existing Cox models trained on any particular dataset usually generalize poorly to other independent datasets. In this paper, we propose a network-based Cox regression model called Net-Cox and applied Net-Cox for a large-scale survival analysis across multiple ovarian cancer datasets. Net-Cox integrates gene network information into the Cox's proportional hazard model to explore the co-expression or functional relation among high-dimensional gene expression features in the gene network. Net-Cox was applied to analyze three independent gene expression datasets including the TCGA ovarian cancer dataset and two other public ovarian cancer datasets. Net-Cox with the network information from gene co-expression or functional relations identified highly consistent signature genes across the three datasets, and because of the better generalization across the datasets, Net-Cox also consistently improved the accuracy of survival prediction over the Cox models regularized by L(2) or L(1). This study focused on analyzing the death and recurrence outcomes in the treatment of ovarian carcinoma to identify signature genes that can more reliably predict the events. The signature genes comprise dense protein-protein interaction subnetworks, enriched by extracellular matrix receptors and modulators or by nuclear signaling components downstream of extracellular signal-regulated kinases. In the laboratory validation of the signature genes, a tumor array experiment by protein staining on an independent patient cohort from Mayo Clinic showed that the protein expression of the signature gene FBN1 is a biomarker significantly associated with the early recurrence after 12 months of the treatment in the ovarian cancer patients who are initially sensitive to chemotherapy. Net-Cox toolbox is available at http://compbio.cs.umn.edu/Net-Cox/.


A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1.
A strong candidate for the 17q-linked BRCA1 gene, which influences susceptibility to breast and ovarian cancer, has been identified by positional cloning methods. Probable predisposing mutations have been detected in five of eight kindreds presumed to segregate BRCA1 susceptibility alleles. The mutations include an 11-base pair deletion, a 1-base pair insertion, a stop codon, a missense substitution, and an inferred regulatory mutation. The BRCA1 gene is expressed in numerous tissues, including breast and ovary, and encodes a predicted protein of 1863 amino acids. This protein contains a zinc finger domain in its amino-terminal region, but is otherwise unrelated to previously described proteins. Identification of BRCA1 should facilitate early diagnosis of breast and ovarian cancer susceptibility in some individuals as well as a better understanding of breast cancer biology.


Rates of evolutionary change in viruses: patterns and determinants.
Understanding the factors that determine the rate at which genomes generate and fix mutations provides important insights into key evolutionary mechanisms. We review our current knowledge of the rates of mutation and substitution, as well as their determinants, in RNA viruses, DNA viruses and retroviruses. We show that the high rate of nucleotide substitution in RNA viruses is matched by some DNA viruses, suggesting that evolutionary rates in viruses are explained by diverse aspects of viral biology, such as genomic architecture and replication speed, and not simply by polymerase fidelity.


Deformylation reaction-based probe for in vivo imaging of HOCl.
The detection of hypochlorous acid (HOCl) in vivo is vitally important because the local concentration of HOCl is highly correlated with some diseases such as atherosclerosis and rheumatoid arthritis. However, in vivo detection of HOCl remains a challenge due to the lack of a suitable probe. We report here a near-infrared (NIR) emissive "turn-on" probe (FDOCl-1) based on a methylene blue derivative, which can quickly detect HOCl via a newly found deformylation mechanism. FDOCl-1 displays remarkable selectivity and sensitivity towards HOCl. The dramatic changes in colour and NIR emission were used to detect HOCl in vitro and in vivo in a mouse arthritis model.


The epigenetic role of vitamin C in health and disease.
Recent advances have uncovered a previously unknown function of vitamin C in epigenetic regulation. Vitamin C exists predominantly as an ascorbate anion under physiological pH conditions. Ascorbate was discovered as a cofactor for methylcytosine dioxygenases that are responsible for DNA demethylation, and also as a likely cofactor for some JmjC domain-containing histone demethylases that catalyze histone demethylation. Variation in ascorbate bioavailability thus can influence the demethylation of both DNA and histone, further leading to different phenotypic presentations. Ascorbate deficiency can be presented systematically, spatially and temporally in different tissues at the different stages of development and aging. Here, we review how ascorbate deficiency could potentially be involved in embryonic and postnatal development, and plays a role in various diseases such as neurodegeneration and cancer through epigenetic dysregulation.


Passive harmonic mode-locked soliton fiber laser stabilized by an optically pumped saturable Bragg reflector.
Stabilization of passive harmonic mode locking is achieved for what is believed to be the first time in an Er-Yb soliton fiber laser by optical pumping of the semiconductor saturable absorber above the bandgap. The results show 35-dB mode suppression of undesired harmonics.


Concurrent partnerships among adolescents in a Latino community: the Mission District of San Francisco, California.
Latino adolescents in the United States are disproportionately affected by sexually transmitted infections, yet knowledge of their sexual networks, particularly concurrent sex partners, is limited. The goal of this study was to describe the prevalence, patterns, and correlates of sexual concurrency among adolescents in an urban neighborhood. The authors conducted cross-sectional analyses of 368 sexually active youth recruited from public venues within a predominantly Latino neighborhood in San Francisco, California. During the prior 6 months, 20% of sexually experienced youth had concurrent partnerships, but this was more likely among males (27%) as females (12%) (odds ratio = 2.6; 95% confidence interval = 1.5-4.5). Sexually transmitted infection prevalence was too low to examine its association with concurrency. Factors that increased the likelihood of concurrency among males included: immigrant generation and being below grade level; and among females: older age and use of illegal substances. Ample opportunities to transmit sexually transmitted infections through concurrency were present, yet very few adolescents were infected, perhaps owing to adequate condom use within a neighborhood with low sexually transmitted infection prevalence.


Real-time size discrimination and elemental analysis of gold nanoparticles using ES-DMA coupled to ICP-MS.
We report the development of a hyphenated instrument with the capacity to quantitatively characterize aqueous suspended gold nanoparticles (AuNPs) based on a combination of gas-phase size separation, particle counting, and elemental analysis. A customized electrospray-differential mobility analyzer (ES-DMA) was used to achieve real-time upstream size discrimination. A condensation particle counter and inductively coupled plasma mass spectrometer (ICP-MS) were employed as downstream detectors, providing information on number density and elemental composition, respectively, of aerosolized AuNPs versus the upstream size selected by ES-DMA. A gas-exchange device was designed and optimized to improve the conversion of air flow (from the electrospray) to argon flow required to sustain the ICP-MS plasma, the key compatibility issue for instrumental hyphenation. Our work provides the proof of concept and a working prototype for utilizing this construct to successfully measure (1) number- and mass-based distributions; (2) elemental compositions of nanoparticles classified by size, where the size classification and elemental analysis are performed within a single experiment; (3) particle concentrations in both solution (before size discrimination) and aerosol (after size discrimination) phases; and (4) the number of atoms per nanoparticle or the nanoparticle density.


Inbound medical tourism to Barbados: a qualitative examination of local lawyers' prospective legal and regulatory concerns.
Enabled by globalizing processes such as trade liberalization, medical tourism is a practice that involves patients' intentional travel to privately obtain medical care in another country. Empirical legal research on this issue is limited and seldom based on the perspectives of destination countries receiving medical tourists. We consulted with diverse lawyers from across Barbados to explore their views on the prospective legal and regulatory implications of the developing medical tourism industry in the country. We held a focus group in February 2014 in Barbados with lawyers from across the country. Nine lawyers with diverse legal backgrounds participated. Focus group moderators summarized the study objective and engaged participants in identifying the local implications of medical tourism and the anticipated legal and regulatory concerns. The focus group was transcribed verbatim and analyzed thematically. Five dominant legal and regulatory themes were identified through analysis: (1) liability; (2) immigration law; (3) physician licensing; (4) corporate ownership; and (5) reputational protection. Two predominant legal and ethical concerns associated with medical tourism in Barbados were raised by participants and are reflected in the literature: the ability of medical tourists to recover medical malpractice for adverse events; and the effects of medical tourism on access to health care in the destination country. However, the participants also identified several topics that have received much less attention in the legal and ethical literature. Overall this analysis reveals that lawyers, at least in Barbados, have an important role to play in the medical tourism sector beyond litigation - particularly in transactional and gatekeeper capacities. It remains to be seen whether these findings are specific to the ecology of Barbados or can be extrapolated to the legal climate of other medical tourism destination countries.


[Novel migraine treatment with CGRP-related monoclonal antibodies].
Migraine is a common and debilitating neurological disorder characterized by recurrent attacks of moderate to severe throbbing headache accompanied by nausea, vomiting and photophobia/phonophobia. Because of its high prevalence, migraine causes a considerable financial burden on the society as well as impaired quality of life in individual patients. Scientific evidence shows that migraine is a quite complex neurological disorder that involves not only the trigeminovascular and autonomic systems but also the hypothalamus and cerebral cortex. Calcitonin gene-related peptide (CGRP) was originally discovered as a 37-amino acid neuropeptide derived from a calcitonin gene splicing variant. CGRP is found to be expressed in trigeminal ganglion neurons. Much attention has been attracted to this molecule since CGRP was found to be released from trigeminal terminals in animal migraine models. Subsequent studies demonstrated that CGRP administration induced migraine-like headache attacks specifically in migraineurs, thus highlighting a pivotal role of CGRP in the development of migraine attacks. Several CGRP receptor antagonists were shown to be efficacious for the treatment of acute migraine. Among them, telcagepant, was shown to exert a significant migraine prophylactic action as well. Nevertheless, the development of most of these agents were discontinued due to hepatotoxicity. Currently, newer CGRP receptor antagonists are being developed. On the other hand, monoclonal antibodies targeting CGRP and its receptor showed consistent efficacy for migraine prophylaxis with excellent safety profiles in Phase III clinical trials. Furthermore, emerging data support the long-term safety and efficacy of these antibodies. In this review article, the development and perspective of anti-migraine therapeutic strategies using CGRP-related antibodies are discussed.


Efficacy of Deep Cervical Flexor Muscle Training on Neck Pain, Functional Disability, and Muscle Endurance in School Teachers: A Clinical Trial.
Neck pain (NP) is a common work-related disorder, with high prevalence in the profession of teaching. The daily duties of a school teacher involve head-down postures while reading and writing, which expose them to the risk of developing NP. Deep cervical flexor (DCF) muscles have been reported to have lower endurance in patients with cervical impairment, which has additionally been associated with disability. There is limited evidence regarding the efficacy of training of DCF muscles in occupational NP. The objective of this study was to investigate the effects of DCF muscle training on pain, muscle endurance, and functional disability using pressure biofeedback in school teachers with NP. Sixty-five teachers (age, 25-45 years) with more than 5 years of teaching experience participated in this study. They were randomly divided into two groups: the experimental (E) and control (C) groups. In the E group, the subjects underwent DCF muscle training using pressure biofeedback in addition to conventional exercises for neck pain, while those in the C group underwent conventional exercises only. Pain, muscle endurance, and disability were measured at day 0 (before the treatment) and days 14 and 42 after the treatment. Endurance of DCF muscles was measured by the craniocervical flexion test using pressure biofeedback, pain intensity was measured using the numeric pain rating scale, and functional disability was assessed using the neck disability index questionnaire. This study was performed in accordance with CONSORT guidelines. On day 0, there were no significant differences in the age, pain, muscle endurance, and disability levels between the groups. After initiating the intervention, although there were improvements in both groups, there was a statistically significant improvement in muscle endurance, pain, and disability in subjects who received additional training with pressure biofeedback. Besides increasing muscle endurance, specific training of DCF muscles in addition to conventional exercises can improve neck pain and functional disability. These results should be further correlated clinically. A dedicated time for exercises at school could help prevent the development of NP in teachers. This trial is registered with ClinicalTrials.gov NCT03537300 May 24, 2018 (retrospectively registered).