Frail institutionalized older persons: A comprehensive review on physical exercise, physical fitness, activities of daily living, and quality-of-life.
The objective of this study was to perform a systematic review on training outcomes influencing physical fitness, activity of daily living performance, and quality-of-life in institutionalized older people. We reviewed 27 studies on older people (age, ≥70 yrs) in long-term care facilities and nursing homes. Our ultimate goal was to propose criteria for an evidence-based exercise protocol aimed at improving physical fitness, activity of daily living performance, and quality-of-life of frail institutionalized older people. The interventions, described in the reviewed studies that showed strong or very strong effect sizes were used to form an exercise prescription. The conclusion is that there is firm evidence for training effects on physical fitness, functional performance, activity of daily living performance, and quality-of-life. The training should contain a combination of progressive resistance training, balance training, and functional training. The proposed intensity is moderate to high, assessed on a 0-10 scale for muscle strengthening activities. The training frequency was three times a week, and the total duration was at least 10 wks.


Rasburicase represents a new tool for hyperuricemia in tumor lysis syndrome and in gout.
Hyperuricemia is a feature of several pathologies and requires an appropriate and often early treatment, owing to the severe consequences that it may cause. A rapid and massive raise of uric acid, during tumor lysis syndrome (TLS), and also a lower and chronic hyperuricemia, as in gout, mainly damage the kidney. To prevent or treat these consequences, a new therapeutic option is represented by rasburicase, a recombinant form of an enzyme, urate oxidase. This enzyme converts hypoxanthine and xanthine into allantoin, a more soluble molecule, easily cleared by kidney. The several types of urate oxidase have followed each other, with progressive reduction of adverse reactions. The most important among them are allergenicity and the development of antibodies which compromise their effectiveness. Nevertheless, a limit of rasburicase's use remains its cost, which obliges to a judicious choice to prevent TLS in high risk patients with cancer and in case of allergy or impossibility to take allopurinol orally both in TLS and in gout. A large body of evidence confirms the efficacy and safety of rasburicase, even in comparison to the standard drugs used in the aforementioned pathologies.


The role of yeast DNA 3'-phosphatase Tpp1 and rad1/Rad10 endonuclease in processing spontaneous and induced base lesions.
Tpp1 is a DNA 3'-phosphatase in Saccharomyces cerevisiae that is believed to act during strand break repair. It is homologous to one domain of mammalian polynucleotide kinase/3'-phosphatase. Unlike in yeast, we found that Tpp1 could confer resistance to methylmethane sulfonate when expressed in bacteria that lack abasic endonuclease/3'-phosphodiesterase function. This species difference was due to the absence of delta-lyase activity in S. cerevisiae, since expression of bacterial Fpg conferred Tpp1-dependent resistance to methylmethane sulfonate in yeast lacking the abasic endonucleases Apn1 and Apn2. In contrast, beta-only lyases increased methylmethane sulfonate sensitivity independently of Tpp1, which was explained by the inability of Tpp1 to cleave 3' alpha,beta-unsaturated aldehydes. In parallel experiments, mutations of TPP1 and RAD1, encoding part of the Rad1/Rad10 3'-flap endonuclease, caused synthetic growth defects in yeast strains lacking Apn1. In contrast, Fpg expression led to a partial rescue of apn1 apn2 rad1 synthetic lethality by converting lesions into Tpp1-cleavable 3'-phosphates. The collected experiments reveal a profound toxicity of strand breaks with irreparable 3' blocking lesions, and extend the function of the Rad1/Rad10 salvage pathway to 3'-phosphates. They further demonstrate a role for Tpp1 in repairing endogenously created 3'-phosphates. The source of these phosphates remains enigmatic, however, because apn1 tpp1 rad1 slow growth could be correlated with neither the presence of a yeast delta-lyase, the activity of the 3'-phosphate-generating enzyme Tdp1, nor levels of endogenous oxidation.


Concurrent and Adjuvant Temozolomide for Newly Diagnosed Grade III Gliomas without 1p/19q Co-deletion: A Randomized, Open-Label, Phase 2 Study (KNOG-1101 Study).
We investigated the efficacy of temozolomide during and after radiotherapy in Korean adults with anaplastic gliomas without 1p/19q co-deletion. This was a randomized, open-label, phase 2 study and notably the first multicenter trial for Korean grade III glioma patients. Eligible patients were aged 18 years or older and had newly diagnosed non-co-deleted anaplastic glioma with an Eastern Cooperative Oncology Group performance status of 0-2. Patients were randomized 1:1 to receive radiotherapy alone (60 Gy in 30 fractions of 2 Gy) (control group, n=44) or to receive radiotherapy with concurrent temozolomide (75 mg/m2/day) followed by adjuvant temozolomide (150-200 mg/m2/day for 5 days during six 28-day cycles) (treatment group, n=40). The primary end-point was 2-year progression-free survival (PFS). Seventy patients (83.3%) were available for the analysis of the isocitrate dehydrogenase 1 gene (IDH1) mutation status. The two-year PFS was 42.2% in the treatment group and 37.2% in the control group. Overall survival (OS) did not reach to significant difference between the groups. In multivariable analysis, age was a significant risk factor for PFS (hazard ratio [HR], 2.08; 95% confidence interval [CI], 1.04 to 4.16). The IDH1 mutation was the only significant prognostic factor for PFS (HR, 0.28; 95% CI, 0.13 to 0.59) and OS (HR, 0.19; 95% CI, 0.07 to 0.50). Adverse events over grade 3 were seen in 16 patients (40.0%) in the treatment group and were reversible. Concurrent and adjuvant temozolomide in Korean adults with newly diagnosed non-co- deleted anaplastic gliomas showed improved 2-year PFS. The survival benefit of this regimen needs further analysis with long-term follow-up at least more than 10 years.


Immobilization and cold stress affect sympatho-adrenomedullary system and pituitary-adrenocortical axis of rats exposed to long-term isolation and crowding.
Changes in plasma levels of noradrenaline (NA), adrenaline (A), adrenocorticotropic hormone (ACTH) and corticosterone (CORT), as well as in cytosol glucocorticoid receptor (GR) and heat shock protein 70 (Hsp 70) in hippocampus of adult rat males exposed to two long-term types of psychosocial stress, both under basal conditions and in response to immobilization and cold as heterotypic additional stressor were studied. Long-term isolation produced a significant elevation of basal plasma ACTH and CORT levels, but did not affect that of NA and A, while long-term crowding conditions did not elevate the basal plasma levels of these hormones. Long-term isolation of rats exposed to 2 h of immobilization or cold led to a significant elevation of plasma NA, A and CORT in comparison with the controls. Long-term crowding conditions and exposure of animals to immobilization or cold also resulted in an increased plasma NA, A and CORT levels, but to a lesser extent in comparison with the long-term isolation. At the same time, plasma ACTH was significantly more elevated in long-term crowded than in long-term isolated rats. Both kinds of long-term psychosocial stresses (isolation and crowding) had similar but less pronounced effects on cytosol GR and Hsp 70 concentrations in hippocampus comparing to acute immobilization and cold stress. It seems that long-term psychosocial stresses attenuate the effects of an additional stress on hippocampal GR and Hsp 70 concentrations. These data suggest that individual housing of rats appear to act as a stronger stressor than crowding conditions. When the animals suffering a long-term isolation were exposed to either acute immobilization or cold, a stronger activation of the sympatho-adrenomedullary system (SAS) was recorded in comparison with that found in the long-term crowded group subjected to short-term immobilization or cold. No significant differences in the activity of hypotalamo-pituitary-adrenal (HPA) axis were observed between long-term isolated and long-term crowded rats.


Prospective cohort study of general and central obesity, weight change trajectory and risk of major cancers among Chinese women.
General obesity, typically measured using body mass index (BMI), has been associated with an increased risk of several cancers. However, few prospective studies have been conducted in Asian populations. Although central obesity, often measured using waist-hip ratio (WHR), is more predictive for type 2 diabetes and cardiovascular diseases (CVD) risk than BMI, knowledge of its association with cancer incidence is limited. In a cohort of 68,253 eligible Chinese women, we prospectively investigated the association of BMI, WHR and weight change during adulthood with risk of overall cancer and major site-specific cancers using multivariate Cox proportional hazard models. Compared to the BMI group of 18.5-22.9 kg/m(2) , obese (BMI ≥ 30 kg/m(2) ) women were at an increased risk of developing overall cancer (hazard ratio = 1.36, 95% confidence interval = 1.21-1.52), postmenopausal breast cancer (HR: 2.43, 95% CI: 1.73-3.40), endometrial cancer (HR: 5.34, 95% CI: 3.48-8.18), liver cancer (HR: 1.93, 95% CI: 1.14-3.27) and epithelial ovarian cancer (HR: 2.44, 95% CI: 1.37-4.35). Weight gain during adulthood (per 5 kg gain) was associated with increased risk of all cancers combined (HR: 1.05, 95% CI: 1.03-1.08), postmenopausal breast cancer (HR: 1.17, 95% CI: 1.10-1.24) and endometrial cancer (HR: 1.37, 95% CI: 1.27-1.48). On the other hand, WHR was not associated with cancer risk after adjustment for baseline BMI. These findings suggest that obesity may be associated with cancer risk through different mechanisms from those for type 2 diabetes and CVD and support measures of maintaining health body weight to reduce cancer risk in Chinese women.


A prospective, randomised study of a novel transforming methacrylate dressing compared with a silver-containing sodium carboxymethylcellulose dressing on partial-thickness skin graft donor sites in burn patients.
This prospective, randomised study compares a new transforming methacrylate dressing (TMD) with a silver-containing carboxymethylcellulose dressing (CMC-Ag) after application to split-thickness skin graft (STSG) donor sites. This was an unblinded, non-inferiority, between-patient, comparison study that involved patients admitted to a single-centre burn unit who required two skin graft donor sites. Each patient's donor sites were covered immediately after surgery: one donor site with TMD and the other with CMC-Ag. The donor sites were evaluated until healing or until 24 days post-application, whichever came first. Study endpoints were time to healing, daily pain scores, number of dressing changes, patient comfort and physicians' and patients' willingness to use the dressings in the future. Nineteen patients had both the dressings applied. No statistically significant difference was noted in time to healing between the two dressings (14·2 days using TMD compared with 13·2 days using CMC-Ag). When pain scores were compared, TMD resulted in statistically significantly less pain at three different time periods (2-5 days, 6-10 days and 11-15 days; P < 0·001 at all time periods). Patients also reported greater comfort with TMD (P < 0·001). Users rated TMD as being less easy to use because of the time and technique required for application. Reductions in pain and increased patient comfort with the use of the TMD dressing, compared with CMC-Ag, were seen as clinical benefits as these are the major issues in donor site management.


Differential regulation of superoxide dismutases in plants exposed to environmental stress.
Superoxide dismutases (SODs) are metalloproteins that catalyze the dismutation of superoxide radicals to hydrogen peroxide and oxygen. The enzyme is ubiquitous in aerobic organisms where it plays a major role in defense against oxygen radical-mediated toxicity. In plants, environmental adversity often leads to the increased generation of reduced oxygen species and, consequently, SOD has been proposed to be important in plant stress tolerance. Here we describe the isolation of a cDNA clone encoding a cytosolic copper/zinc SOD from Nicotiana plumbaginifolia. Using this, together with previously isolated cDNAs encoding the mitochondrial manganese SOD and the chloroplastic iron SOD as probes in RNA gel blot analyses, we have studied SOD transcript abundance during different stress conditions: in response to light, during photoinhibitory conditions (light combined with high or low temperatures), and in response to a xenobiotic stress imposed by the herbicide paraquat. Evidence is presented that iron SOD mRNA abundance increases whenever there is a chloroplast-localized oxidative stress, similar to the previous finding that manganese SOD responds to mitochondria-localized events. The diverse effects of the different stress conditions on SOD mRNA abundance thus might provide an insight into the way that each treatment affects the different subcellular compartments.


The Role of Malassezia spp. in Atopic Dermatitis.
Malassezia spp. is a genus of lipophilic yeasts and comprises the most common fungi on healthy human skin. Despite its role as a commensal on healthy human skin, Malassezia spp. is attributed a pathogenic role in atopic dermatitis. The mechanisms by which Malassezia spp. may contribute to the pathogenesis of atopic dermatitis are not fully understood. Here, we review the latest findings on the pathogenetic role of Malassezia spp. in atopic dermatitis (AD). For example, Malassezia spp. produces a variety of immunogenic proteins that elicit the production of specific IgE antibodies and may induce the release of pro-inflammatory cytokines. In addition, Malassezia spp. induces auto-reactive T cells that cross-react between fungal proteins and their human counterparts. These mechanisms contribute to skin inflammation in atopic dermatitis and therefore influence the course of this disorder. Finally, we discuss the possible benefit of an anti-Malassezia spp. treatment in patients with atopic dermatitis.


Microfluidic Cell Culture Platforms to Capture Hepatic Physiology and Complex Cellular Interactions.
Animal models such as rats and primates provide body-wide information for drug and metabolite responses, including organ-specific toxicity and any unforeseen side effects on other organs. Although effective in the drug-screening process, their translatability to humans is limited because of the lack of high concordance and correlation among enzymatic mechanisms, cellular mechanisms, and resulting toxicities. A significant mode of failure for safety prediction in drug screening is hepatotoxicity, resulting in ∼30% of all safety-related drug failures and withdrawals from the market. The liver is a multifunctional organ with diverse metabolic, secretory, and inflammatory response roles and is essential for maintaining key body functions. Conventional cell culture platforms (such as multiwell plate cultures) and metabolic enzyme systems (microsomes, cytochrome P450 enzymes) have been routinely used to assess drug pharmacokinetics and metabolism. However, current in vitro models often fail to recapitulate the complexity and dynamic nature of human tissues, imposing a heavy reliance on in vivo testing using preclinical species that have metabolic processes, disease mechanisms, and modes of toxicity distinct from humans. Recently, microphysiological systems (MPS) have gained attention as powerful tools with the potential to generate human-relevant information that can supplant and fill the gap of knowledge between preclinical animal models and simpler, conventional in vitro cell culture systems. Developments in microfabrication technologies for generating complex microfluidic systems, along with the ability to establish and maintain multicellular models to capture dynamic, human-relevant behavior, have provided new avenues to generate such physiologically relevant systems. These MPS platforms, when designed and developed with in vivo-derived design parameters, have the potential to capture key aspects and better mimic organ functionality. In this review, we discuss developments in microtechnologies for fabricating, establishing, and maintaining hepatic cell culture systems, with a specific focus on models that aim to capture in vivo physiology in vitro. By designing microscale systems to impart specific in vivo physiologic parameters, it is possible to create a dynamic system that can capture multiple aspects of the hepatic microenvironment, bringing us closer to a comprehensive in vitro testing platform for hepatic responses and toxicities.


Synergistic effects of arsenic trioxide and radiation in osteosarcoma cells through the induction of both autophagy and apoptosis.
Osteosarcoma is the most common primary malignant bone tumor, occurring mainly in children and adolescents, and survival largely depends on their response to chemotherapy. However, the risk of relapse and adverse outcomes is still high. We investigated the synergistic anti-cancer effects of ionizing radiation combined with arsenic trioxide (ATO) and the mechanisms underlying apoptosis or autophagy induced by combined radiation and ATO treatment in human osteosarcoma cells. We found that exposure to radiation increased the population of HOS cells in the G(2)/M phase within 12 h in a time-dependent manner. Radiation combined with ATO induced a significantly prolonged G(2)/M arrest, consequently enhancing cell death. Furthermore, combined treatment resulted in enhanced ROS generation compared to treatment with ATO or radiation alone. The enhanced cytotoxic effect of combined treatment occurred from the increased induction of autophagy and apoptosis through inhibition of the PI3K/Akt signaling pathway in HOS cells. The combined treatment of HOS cells pretreated with Z-VAD, 3-MA or PEG-catalase resulted in a significant reduction of cytotoxicity. In addition, G(2)/M arrest and ROS generation could be involved in the underlying mechanisms. The data suggest that a combination of radiation and ATO could be a new potential therapeutic strategy for the treatment of osteosarcoma.


Clinical outcome after antipsychotic treatment discontinuation in functionally recovered first-episode nonaffective psychosis individuals: a 3-year naturalistic follow-up study.
The timing of antipsychotic discontinuation in patients who have fully recovered from their initial episode of psychosis is still open to discussion. We aimed to evaluate the risk of symptom recurrence during the 3 years after antipsychotic discontinuation in a sample of functionally recovered first-episode nonaffective psychosis (FEP) patients (DSM-IV criteria) with schizophrenia spectrum disorder. Participants in this open-label, nonrandomized, prospective study were drawn from an ongoing longitudinal intervention program of FEP from a university hospital setting in Spain. From July 2004 to February 2011, functionally recovered FEP individuals were eligible if they met the inclusion criteria of (1) a minimum of 18 months on antipsychotic treatment, (2) clinical remission for at least 12 months, (3) functional recovery for at least 6 months, and (4) stabilization at the lowest effective doses for at least 3 months. Forty-six individuals who were willing to discontinue medication were included in the discontinuation group (target group). Twenty-two individuals opted to stay on the prescribed antipsychotic medication and therefore were included in the maintenance group (control group). Primary outcome measures were relapse rate at 18 and 36 months and time to relapse. The rates of relapse over the 3-year period were 67.4% (31 of 46) in the discontinuation group and 31.8% (7 of 22) in the maintenance group. The mean time to relapse was 209 (median = 122) days and 608 (median = 607) days, respectively (log rank = 10.106, P = .001). The resumption of antipsychotic medication after the relapse occurred was associated with clinical stability and lack of further relapses. When the overall group of relapsed individuals from the 2 conditions (N = 38) was compared to those who remained asymptomatic after 3 years (N = 30), there were significant differences (P < .05) in total scores on the Scale for the Assessment of Negative Symptoms, the Clinical Global Impressions scale, and the Disability Assessment Schedule. Antipsychotic treatment discontinuation in individuals who had accomplished a functional recovery after a single psychotic episode was associated with a high risk of symptom recurrence. Relapsed individuals had a greater severity of symptoms and lower functional status after 3 years. ClinicalTrials.gov identifier: NCT02220504.


Large-scale genome-wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ4.
We conducted a combined genome-wide association study (GWAS) of 7,481 individuals with bipolar disorder (cases) and 9,250 controls as part of the Psychiatric GWAS Consortium. Our replication study tested 34 SNPs in 4,496 independent cases with bipolar disorder and 42,422 independent controls and found that 18 of 34 SNPs had P < 0.05, with 31 of 34 SNPs having signals with the same direction of effect (P = 3.8 × 10(-7)). An analysis of all 11,974 bipolar disorder cases and 51,792 controls confirmed genome-wide significant evidence of association for CACNA1C and identified a new intronic variant in ODZ4. We identified a pathway comprised of subunits of calcium channels enriched in bipolar disorder association intervals. Finally, a combined GWAS analysis of schizophrenia and bipolar disorder yielded strong association evidence for SNPs in CACNA1C and in the region of NEK4-ITIH1-ITIH3-ITIH4. Our replication results imply that increasing sample sizes in bipolar disorder will confirm many additional loci.


An antibacterial from Hypericum acmosepalum inhibits ATP-dependent MurE ligase from Mycobacterium tuberculosis.
In a project to characterise new antibacterial chemotypes from plants, hyperenone A and hypercalin B were isolated from the hexane and chloroform extracts of the aerial parts of Hypericum acmosepalum. The structures of both compounds were characterised by extensive one- and two-dimensional nuclear magnetic resonance (NMR) spectroscopy and were confirmed by mass spectrometry. Hyperenone A and hypercalin B exhibited antibacterial activity against multidrug-resistant strains of Staphylococcus aureus, with minimum inhibition concentration ranges of 2-128 mg/L and 0.5-128 mg/L, respectively. Hyperenone A also showed growth-inhibitory activity against Mycobacterium tuberculosis H37Rv and Mycobacterium bovis BCG at 75 mg/L and 100mg/L. Neither hyperenone A nor hypercalin B inhibited the growth of Escherichia coli and both were non-toxic to cultured mammalian macrophage cells. Both compounds were tested for their ability to inhibit the ATP-dependent MurE ligase of M. tuberculosis, a crucial enzyme in the cytoplasmic steps of peptidoglycan biosynthesis. Hyperenone A inhibited MurE selectively, whereas hypercalin B did not have any effect on enzyme activity.


Diversity of haemoprotozoan parasites infecting the wildlife of South Africa.
Tissue samples from wildlife from South Africa were opportunistically collected and screened for haemoprotozoan parasites using nonspecific PCR primers. Samples of 127 individuals were tested, comprising over 50 different species. Haemogregarines were the most commonly identified parasites, but sarcocystids and piroplasmids were also detected. Phylogenetic analyses estimated from the 18S rDNA marker highlighted the occurrence of several novel parasite forms and the detection of parasites in novel hosts. Phylogenetic relationships, which have been recently reviewed, appear to be much more complex than previously considered. Our study highlights the high diversity of parasites circulating in wildlife in this biodiverse region, and the need for further studies to resolve taxonomic issues.


Anti-aversive effects of cannabidiol on innate fear-induced behaviors evoked by an ethological model of panic attacks based on a prey vs the wild snake Epicrates cenchria crassus confrontation paradigm.
Several pharmacological targets have been proposed as modulators of panic-like reactions. However, interest should be given to other potential therapeutic neurochemical agents. Recent attention has been given to the potential anxiolytic properties of cannabidiol, because of its complex actions on the endocannabinoid system together with its effects on other neurotransmitter systems. The aim of this study was to investigate the effects of cannabidiol on innate fear-related behaviors evoked by a prey vs predator paradigm. Male Swiss mice were submitted to habituation in an arena containing a burrow and subsequently pre-treated with intraperitoneal administrations of vehicle or cannabidiol. A constrictor snake was placed inside the arena, and defensive and non-defensive behaviors were recorded. Cannabidiol caused a clear anti-aversive effect, decreasing explosive escape and defensive immobility behaviors outside and inside the burrow. These results show that cannabidiol modulates defensive behaviors evoked by the presence of threatening stimuli, even in a potentially safe environment following a fear response, suggesting a panicolytic effect.


Strategies for integrating primary health services in low- and middle-income countries at the point of delivery.
In some low- and middle-income countries, separate vertical programmes deliver specific life-saving interventions but can fragment services. Strategies to integrate services aim to bring together inputs, organisation, and delivery of particular functions to increase efficiency and people's access. We examined the evidence on the effectiveness of integration strategies at the point of delivery (sometimes termed 'linkages'), including integrated delivery of tuberculosis (TB), HIV/AIDS and reproductive health programmes. To assess the effects of strategies to integrate primary health care services on healthcare delivery and health status in low- and middle-income countries. We searched The Cochrane Central Register of Controlled Trials (CENTRAL) 2010, Issue 3, part of the The Cochrane Library. www.thecochranelibrary.com, including the Cochrane Effective Practice and Organisation of Care Group Specialised Register (searched 15 September 2010); MEDLINE, Ovid (1950 to August Week 5 2010) (searched 10 September 2010); EMBASE, Ovid (1980 to 2010 Week 35) (searched 10 September 2010); CINAHL, EBSCO (1980 to present) (searched 20 September 2010); Sociological Abstracts, CSA Illumina (1952 to current) (searched 10 September 2010); Social Services Abstracts, CSA Illumina (1979 to current) (searched 10 September 2010); POPLINE (1970 to current) (searched 10 September 2010); International Bibliography of the Social Sciences, Webspirs (1951 to current) (searched 01 July 2008); HealthStar (1975 to September 2005), Cab Health (1972 to 1999), and reference lists of articles. We also searched the World Health Organization (WHOLIS) library database, handsearched relevant WHO publications, and contacted experts in the field. Randomised controlled trials, non-randomised controlled trials, controlled before and after studies, and interrupted time series analyses of integration strategies, including strengthening linkages, in primary health care services. Health services in high-income countries, private public partnerships, and hospital inpatient care were excluded as were programmes promoting the integrated management of childhood illnesses. The main outcomes were indicators of healthcare delivery, user views, and health status. Two authors independently extracted data and assessed the risk of bias. The statistical results of individual studies are reported and summarised. Five randomised trials and four controlled before and after studies were included. The interventions were complex.Five studies added an additional component, or linked a new component, to an existing service, for example, adding family planning or HIV counselling and testing to routine services. The evidence from these studies indicated that adding on services probably increases service utilisation but probably does not improve health status outcomes, such as incident pregnancies.Four studies compared integrated services to single, special services. Based on the included studies, fully integrating sexually transmitted infection (STI) and family planning, and maternal and child health services into routine care as opposed to delivering them as special 'vertical' services may decrease utilisation, client knowledge of and satisfaction with the services and may not result in any difference in health outcomes, such as child survival. Integrating HIV prevention and control at facility and community level improved the effectiveness of certain services (STI treatment in males) but resulted in no difference in health seeking behaviour, STI incidence, or HIV incidence in the population. There is some evidence that 'adding on' services (or linkages) may improve the utilisation and outputs of healthcare delivery. However, there is no evidence to date that a fuller form of integration improves healthcare delivery or health status. Available evidence suggests that full integration probably decreases the knowledge and utilisation of specific services and may not result in any improvements in health status. More rigorous studies of different strategies to promote integration over a wider range of services and settings are needed. These studies should include economic evaluation and the views of clients as clients' views will influence the uptake of integration strategies at the point of delivery and the effectiveness on community health of these strategies.


Innovative agents in multiple myeloma.
Multiple myeloma (MM) remains an incurable cancer of the bone marrow plasma cells. However, the overall survival of patients with MM has increased dramatically within the past decade. This is due, in part, to newer agents such as immunomodulatory drugs (lenalidomide, thalidomide, and pomalidomide) and proteasome inhibitors (bortezomib, carfilzomib, MLN9708). These and several other new classes of drugs have arisen from an improved understanding of the complex environment in which genetic changes occur. Improved understanding of genetic events will enable clinicians to better stratify risk before and during therapy, tailor treatment, and test the value of personalized interventions. The ultimate goal in this incurable disease setting is to reduce the impact of cancer- or chemotherapy-related side effects. Nurses and advanced practitioners are integral to the treatment team. Thus, each should be aware of changes to the current drug landscape. Targeted drugs with sophisticated mechanisms of action are currently under investigation. Patients gain access to newer drugs within the context of clinical trials. Awareness of such trials will help accrual and determine if therapeutic benefit exists. In this article, we will describe new agents with unique and targeted mechanisms of action that have activity in patients with relapsed and/or refractory multiple myeloma.


Murine phosphatidylserine-specific phospholipase A1 (Ps-pla1) maps to chromosome 16 but is distinct from the lpd (lipid defect) locus.
We have previously generated a mouse transgenic line with an insertional mutation designated lpd that demonstrates a phenotype of hypertriglyceridemia and fatty liver. Since the recently identified phosphatidylserine-specific phospholipase A1 (PS-PLA1) demonstrates significant homology to triglyceride lipases, we reasoned that the mouse Ps-plaI gene may be the disrupted gene within the lpd locus. Using a rat PS-PLA1 cDNA sequence to search the EST database, we identified a mouse EST homolog AA839424. Sequencing analysis of AA839424 revealed a putative Ps-pla1 protein of 456 amino acids with extensive overall structural conservation with human and rat PS-PLA1 and with triglyceride lipases. Conserved sequences in Ps-pla1 include a lipase consensus sequences GxSxG, a catalytic triad, and eight of the ten conserved cysteine residues that are required for tertiary structure. Mouse Ps-plal carries a phosphatidylserine-binding motif that is absent in all triglyceride lipases. Using a mouse whole-genome radiation hybrid (WG-RH) mapping panel (T31), we mapped mouse Ps-pla1 to Chromosome (Chr) 16 between genetic markers D16Mit194 and D16Mit38, which is 17.1 cM centromeric to the lpd locus. On the basis of chromosome location, we conclude that Ps-pla1 and lpd are distinct genes in lipid metabolism.


Identification of the avian homologues of mammalian CD4 and CD8 antigens.
Two mAb were produced against chicken T cells. The CT4 antibody precipitated a polypeptide of Mr 64,000 under both reducing and non-reducing conditions. The CT8 antibody precipitated a molecule of Mr 63,000 under non-reducing conditions and polypeptide chains of Mr 34,000 under reducing conditions, suggesting that the CT8 molecule is a disulfide-linked homodimer. Tissue distribution studies by immunofluorescence revealed that the CT4 and CT8 Ag were expressed by the majority of thymocytes and by subpopulations of CT3+ cells in peripheral tissues. The CT4 reactive molecule was found on approximately 70% of thymocytes, 10% splenocytes, and 45% of lymphoid cells in blood. The CT8 reactive molecule was expressed on approximately 80% of thymocytes, 50% of spleen cells, and 15% of blood lymphocytes. Two-color immunofluorescence indicated that the CT4 and CT8 Ag were expressed together on most thymocytes and on mutually exclusive subsets of cells in the spleen and blood. Ontogenic studies revealed a sharp increase in the frequencies of CT4+ and CT8+ cells in the thymus between days 13 and 16 embryonic life. Both CT4 and CT8 antibodies inhibited PHA- and Con A-induced proliferative responses of splenocytes, and the degree of inhibition correlated with the frequencies of CT4+ and CT8+ lymphoblasts. Treatment of spleen cells with CT4 antibody and inhibited PWM-induced IL-2 production, and removal of CT8+ cells inhibited the cytolytic activity induced by allogeneic lymphocyte stimulation. Macrophages did not express detectable CT4 reactivity. These results suggest that the CD4 and CD8 molecules and their tissue-restricted patterns of expression are highly conserved in birds and mammals.


Outcome of hospital care of liver disease associated with hepatitis C in the United States.
We describe mortality and resource utilization for inpatient care of hepatitis C (HCV) in comparison to alcohol-induced liver disease (ALD) in the United States and identify factors that affect outcomes. The Healthcare Cost and Utilization Project database, a national inpatient sample was used to identify hospitalization records with diagnoses related to liver disease from HCV and ALD. Outcome of hospitalizations was analyzed in terms of in-hospital deaths and health care resource utilization. For 1995, we estimate that there were 26,700 hospitalizations and 2,600 deaths in acute, nonfederal hospitals in the United States for liver diseases caused by HCV. Total charges for these hospitalizations were $514 million. In comparison, ALD was associated with 101,200 hospitalizations, 13,400 deaths, and $1.8 billion in charges. Simultaneous HCV and alcohol abuse was associated with younger ages at the time of hospitalization and death compared with HCV or ALD alone. In a logistic regression analysis, alcohol abuse (odds ratio [OR], 1.4; 95% confidence interval [CI], 1.2-1.5) and human immunodeficiency virus (HIV) infection (OR, 4.5; 95% CI, 4.0-4.9) were associated with an increased risk of death among those with HCV. Liver transplantation and patient death were associated with the largest increase in hospitalization charges. Major complications of cirrhosis, such as variceal bleeding, encephalopathy, and hepatorenal syndrome, and sociodemographic factors, such as race and health insurance, were also significantly associated with the risk of death and hospitalization charges, which were similar in HCV and ALD. This study provides new estimates regarding the public health impact of HCV, for use in health policy decisions and cost-effectiveness analyses of preventive and therapeutic interventions.


Cosmic ray feedback in galaxies and galaxy clusters: A pedagogical introduction and a topical review of the acceleration, transport, observables, and dynamical impact of cosmic rays.
Understanding the physical mechanisms that control galaxy formation is a fundamental challenge in contemporary astrophysics. Recent advances in the field of astrophysical feedback strongly suggest that cosmic rays (CRs) may be crucially important for our understanding of cosmological galaxy formation and evolution. The appealing features of CRs are their relatively long cooling times and relatively strong dynamical coupling to the gas. In galaxies, CRs can be close to equipartition with the thermal, magnetic, and turbulent energy density in the interstellar medium, and can be dynamically very important in driving large-scale galactic winds. Similarly, CRs may provide a significant contribution to the pressure in the circumgalactic medium. In galaxy clusters, CRs may play a key role in addressing the classic cooling flow problem by facilitating efficient heating of the intracluster medium and preventing excessive star formation. Overall, the underlying physics of CR interactions with plasmas exhibit broad parallels across the entire range of scales characteristic of the interstellar, circumgalactic, and intracluster media. Here we present a review of the state-of-the-art of this field and provide a pedagogical introduction to cosmic ray plasma physics, including the physics of wave-particle interactions, acceleration processes, CR spatial and spectral transport, and important cooling processes. The field is ripe for discovery and will remain the subject of intense theoretical, computational, and observational research over the next decade with profound implications for the interpretation of the observations of stellar and supermassive black hole feedback spanning the entire width of the electromagnetic spectrum and multi-messenger data.


Nanoscale metal-metal contact physics from molecular dynamics: the strongest contact size.
Using molecular dynamics we find that the tensile strength of the contacts between two clean platinum surfaces with nanoscale asperities is strongly size dependent with a maximum strength for contact lengths of approximately 5 nm. This is the first time a strongest size is observed in single crystals. The strengthening with decreasing size down to 5 nm results from a decrease in the initial density of mobile dislocations available for plastic deformation and the subsequent weakening originates from a reduction in the constraint to mechanical deformation inside the contact by the bulk.


The use of technical aids among community-based elderly.
The growing elderly population will increase the need for assistive technology in the form of technical aids and housing adaptations to facilitate independence in activities of daily living. In this study, which was undertaken to facilitate a better understanding of the life-styles of the disabled elderly and the role of technical aids, 57 disabled persons over 74 years of age were studied. All of the subjects were residents of a rural Swedish community. The subjects had a total of 422 aids, an average of 7.4 per person. Seventy-five percent of the aids were being used, and 42 persons had at least one aid that granted autonomy. This finding illustrates the importance of technical aids in home care. It is recommended, therefore, that information about assistive technology be disseminated to personnel at all levels of community-based care.


Vision preference in dynamic posturography analysed according to vestibular impairment and handicap.
The objective of this work was to characterise the implications of vision preference derived from the sensory organisation test of computerised dynamic posturography, in terms of impairment, disability and handicap. This was a prospective assessment of 88 patients suffering from dizziness who denied experiencing any visually induced vertiginous symptoms. The level of impairment of each patient was estimated by performing a complete analysis of vestibular function by means of the caloric and rotatory stimulation tests. Disability and handicap were determined with the Dizziness Handicap Inventory questionnaire (DHI). The results of the caloric test in patients were independent of vision preference although canal paresis was more frequently abnormal in patients without visual preference. No differences were found in the results of rotatory stimulation by means of impulse and sinusoidal tests, both at high velocities of stimuli, in between patients with and without vision preference. Similarly, the responses in the DHI, a common questionnaire for vestibular disability and handicap and, specifically to questions addressing the problem of visual and vestibular disability, were not able to differentiate either group of patients. Nevertheless, we have found that patients with vision preference tend to have poorer balance. We consider that in the patients studied here, vision preference must be considered as a normal finding as this represents a normal strategy in a subject that relies more heavily on visual cues for his or her postural control.


Tumor Mutation Burden and Structural Chromosomal Aberrations Are Not Associated with T-cell Density or Patient Survival in Acral, Mucosal, and Cutaneous Melanomas.
Tumor mutation burden (TMB) has been proposed as a key determinant of immunogenicity in several cancers, including melanoma. The evidence presented thus far, however, is often contradictory and based mostly on RNA-sequencing data for the quantification of immune cell phenotypes. Few studies have investigated TMB across acral, mucosal, and cutaneous melanoma subtypes, which are known to have different TMB. It is also unknown whether chromosomal structural mutations [structural variant (SV) mutations] contribute to the immunogenicity in acral and mucosal melanomas where such aberrations are common. We stained 151 cutaneous and 35 acral and mucosal melanoma patient samples using quantitative IHC and correlated immune infiltrate phenotypes with TMB and other genomic profiles. TMB and SVs did not correlate with the densities of CD8+ lymphocytes, CD103+ tumor-resident T cells (Trm), CD45RO+ cells, and other innate and adaptive immune cell subsets in cutaneous and acral/mucosal melanoma tumors, respectively, including in analyses restricted to the site of disease and in a validation cohort. In 43 patients with stage III treatment-naïve cutaneous melanoma, we found that the density of immune cells, particularly Trm, was significantly associated with patient survival, but not with TMB. Overall, TMB and chromosomal structural aberrations are not associated with protective antitumor immunity in treatment-naïve melanoma.


Activity levels in mothers and their preschool children.
To investigate the association between objectively measured maternal and preschool-aged children's physical activity, determine how this association differs by demographic and temporal factors, and identify factors associated with maternal activity levels. In the UK Southampton Women's Survey, physical activity levels of 554 4-year-olds and their mothers were measured concurrently by using accelerometry for ≤7 days. Two-level mixed-effects linear regression was used to model the association between maternal and children's minutes spent sedentary, in light (LPA) and moderate-to-vigorous physical activity (MVPA). Linear regression was used to investigate correlates of maternal activity. Mother-child daily activity levels were positively associated at all activity intensities (sedentary, LPA, and MVPA; all P < .001). The association for sedentary time was stronger for normal-weight children (versus those who were overweight/obese), and those attending preschool part-time (versus full-time). The mother-child association for LPA differed by maternal education and was stronger at the weekend (versus weekdays). The opposite was true for MVPA. Sedentary time and MVPA were most strongly associated in mornings, with LPA most strongly associated in the evenings. Maternal BMI, age leaving school, number and age of children at home, and working hours were independently associated with maternal daily sedentary time and LPA. Physical activity levels in mothers and their 4-year-old children are directly associated, with associations at different activity intensities influenced by temporal and demographic factors. Influences on maternal physical activity levels also differ by activity intensity. Providing targeted interventions for mothers of young children may increase both groups' activity.


Association of single nucleotide polymorphisms of IL23R and IL17 with ulcerative colitis risk in a Chinese Han population.
Previous studies implicated that IL23R and IL17 genes play an important role in autoimmune inflammation. Genome-wide association studies have also identified multiple single nucleotide polymorphisms (SNPs) in the IL23R gene region associated with inflammatory bowel diseases. This study examined the association of IL23R and IL17A gene SNPs with ulcerative colitis susceptibility in a population in China. A total of 270 ulcerative colitis and 268 healthy controls were recruited for the analyses of 23 SNPs in the IL23R and IL17A regions. Genomic DNA was extracted and analysis of these 23 SNPs using ligase detection reaction allelic (LDR) technology. Genotype and allele associations were calculated using SPSS 13.0 software package. Compared to the healthy controls, the variant alleles IL23R rs7530511, and rs11805303 showed a statistically significant difference for ulcerative colitis susceptibility (0.7% vs 3.3%, P = 0.002; 60.4% vs 53.2%, P = 0.0017, respectively). The linkage disequilibrium (LD) patterns of these SNPs were measured and three LD blocks from the SNPs of IL23R and one block from those of IL17A were identified. A novel association with ulcerative colitis susceptibility occurred in haplotypes of IL23R (Block1 H3 P = 0.02; Block2 H2 P = 0.019; Block3 H4 P = 0.029) and IL17A (H4 P = 0.034). Pair-wise analyses showed an interaction between the risk haplotypes in IL23R and IL17A (P = 0.014). Our study demonstrated that rs7530511, and rs11805303 of IL23R were significantly associated with ulcerative colitis susceptibility in the Chinese population. The most noticeable finding was the linkage of IL23R and IL17A gene region to ulcerative colitis risk due to the gene-gene interaction.


Selective serotonin reuptake inhibitor exposure constricts the mouse ductus arteriosus in utero.
Use of selective serotonin reuptake inhibitors (SSRIs) is common during pregnancy. Fetal exposure to SSRIs is associated with persistent pulmonary hypertension of the newborn (PPHN); however, a direct link between the two has yet to be established. Conversely, it is well known that PPHN can be caused by premature constriction of the ductus arteriosus (DA), a fetal vessel connecting the pulmonary and systemic circulations. We hypothesized that SSRIs could induce in utero DA constriction. Using isolated vessels and whole-animal models, we sought to determine the effects of two commonly prescribed SSRIs, fluoxetine and sertraline, on the fetal mouse DA. Cannulated vessel myography studies demonstrated that SSRIs caused concentration-dependent DA constriction and made vessels less sensitive to prostaglandin-induced dilation. Moreover, in vivo studies showed that SSRI-exposed mice had inappropriate DA constriction in utero. Taken together, these findings establish that SSRIs promote fetal DA constriction and provide a potential mechanism by which SSRIs could contribute to PPHN.


A cross-cultural test of the validity of occupational therapy assessments with patients with schizophrenia.
The validity and use of psychosocial assessments in occupational therapy are ongoing concerns (Moyer, 1984) and were the focus of this study. Fifty African patients with schizophrenia and 10 nondysfunctional African volunteers took an an assessment battery that included the Schroeder, Block, Campbell Adult Psychiatric Sensory Integration Evaluation (SBC) (Schroeder, Block, Trottier, & Stowell, 1978), a daily activity, work, and leisure activity interview based on the Model of Human Occupation (Kielhofner, 1985), and a culture-specific test of functional performance. Data on subjects' psychiatric histories and demographics were collected. Rationale for the assessments used, methods for devising the functional assessment, methods and procedures for data collection, and analysis are presented. A stronger relationship was found to exist between subjects' performances on the SBC and the functional activity test than between interviews based on the Model of Human Occupation and the functional activity test, both for patients and for the whole sample. All assessments were found to differentiate between patients and nonpatients, although the SBC was the best discriminator. Among psychiatric history variables, the strongest relationships were between measures of seriousness of illness and both the SBC and functional activity assessment. The most effective way to measure performance dysfunction and seriousness of illness in persons with schizophrenia was to measure the underlying sensorimotor impairment or to use a culture-specific test of functional performance.


Autotaxin-lysophosphatidic acid receptor signalling regulates hepatitis C virus replication.
Chronic hepatitis C is a global health problem with an estimated 170 million hepatitis C virus (HCV) infected individuals at risk of progressive liver disease and hepatocellular carcinoma (HCC). Autotaxin (ATX, gene name: ENPP2) is a phospholipase with diverse roles in the physiological and pathological processes including inflammation and oncogenesis. Clinical studies have reported increased ATX expression in chronic hepatitis C, however, the pathways regulating ATX and its role in the viral life cycle are not well understood. In vitro hepatocyte and ex vivo liver culture systems along with chimeric humanized liver mice and HCC tissue enabled us to assess the interplay between ATX and the HCV life cycle. HCV infection increased hepatocellular ATX RNA and protein expression. HCV infection stabilizes hypoxia inducible factors (HIFs) and we investigated a role for these transcription factors to regulate ATX. In vitro studies show that low oxygen increases hepatocellular ATX expression and transcriptome analysis showed a positive correlation between ATX mRNA levels and hypoxia gene score in HCC tumour tissue associated with HCV and other aetiologies. Importantly, inhibiting ATX-lysophosphatidic acid (LPA) signalling reduced HCV replication, demonstrating a positive role for this phospholipase in the viral life cycle. LPA activates phosphoinositide-3-kinase that stabilizes HIF-1α and inhibiting the HIF signalling pathway abrogates the pro-viral activity of LPA. Our data support a model where HCV infection increases ATX expression which supports viral replication and HCC progression. Chronic hepatitis C is a global health problem with infected individuals at risk of developing liver disease that can progress to hepatocellular carcinoma. Autotaxin generates the biologically active lipid lysophosphatidic acid that has been reported to play a tumorigenic role in a wide number of cancers. In this study we show that hepatitis C virus infection increases autotaxin expression via hypoxia inducible transcription factor and provides an environment in the liver that promotes fibrosis and liver injury. Importantly, we show a new role for lysophosphatidic acid in positively regulating hepatitis C virus replication.


Interventions Within the Scope of Occupational Therapy Practice to Improve Motor Performance for Children Ages 0-5 Years: A Systematic Review.
Occupational therapy practitioners need updated information about which interventions may improve motor skills for young children. To identify the effectiveness of occupational therapy interventions to promote motor development and prevent delay for children ages 0-5 yr. Six databases (CINAHL, MEDLINE, PsycINFO, ERIC, Cochrane, and OTseeker) were searched for articles published from January 2010 to March 2017. The search yielded 4,488 articles that were reviewed for inclusion. Fifty-six studies were entered into both evidence and risk-of-bias tables. Included studies used Level I-III designs, were within occupational therapy's scope of practice, included participants with a mean age younger than 6 yr, and addressed motor skills. Three intervention themes emerged: early intervention for children younger than age 3 yr, interventions for preschool children ages 3-5 yr, and interventions for children with or at risk for cerebral palsy. Occupational therapy practitioners should consider use of interventions with moderate or strong evidence as described in this review. Limitations include high risk of bias and limited evidence for several interventions. This article provides occupational therapy practitioners with updated information on evidence-based practices for children age 5 and younger who have motor delays.


Comparison of clinical and angiographic prognostic risk scores in elderly patients presenting with acute coronary syndrome and referred for percutaneous coronary intervention.
Multiple risk prediction models have been validated in all-age patients presenting with acute coronary syndrome (ACS) and treated with percutaneous coronary intervention (PCI); however, they have not been validated specifically in the elderly. We calculated the GRACE (Global Registry of Acute Coronary Events) score, the logistic EuroSCORE, the AMIS (Acute Myocardial Infarction Swiss registry) score, and the SYNTAX (Synergy between Percutaneous Coronary Intervention with TAXUS and Cardiac Surgery) score in a consecutive series of 114 patients ≥75 years presenting with ACS and treated with PCI within 24 hours of hospital admission. Patients were stratified according to score tertiles and analysed retrospectively by comparing the lower/mid tertiles as an aggregate group with the higher tertile group. The primary endpoint was 30-day mortality. Secondary endpoints were the composite of death and major adverse cardiovascular events (MACE) at 30 days, and 1-year MACE-free survival. Model discrimination ability was assessed using the area under receiver operating characteristic curve (AUC). Thirty-day mortality was higher in the upper tertile compared with the aggregate lower/mid tertiles according to the logistic EuroSCORE (42% vs 5%; odds ratio [OR] = 14, 95% confidence interval [CI] = 4-48; p <0.001; AUC = 0.79), the GRACE score (40% vs 4%; OR = 17, 95% CI = 4-64; p <0.001; AUC = 0.80), the AMIS score (40% vs 4%; OR = 16, 95% CI = 4-63; p <0.001; AUC = 0.80), and the SYNTAX score (37% vs 5%; OR = 11, 95% CI = 3-37; p <0.001; AUC = 0.77). In elderly patients presenting with ACS and referred to PCI within 24 hours of admission, the GRACE score, the EuroSCORE, the AMIS score, and the SYNTAX score predicted 30 day mortality. The predictive value of clinical scores was improved by using them in combination.


Extremely low-frequency magnetic field decreased calcium, zinc and magnesium levels in costa of rat.
Electromagnetic field (EMF) can affect cells due to biochemical change followed by a change in level of ions trafficking through membrane. We aimed to investigate possible changes in some elements in costa of rats exposed to long-term extremely low-frequency magnetic field (ELF-MF). Rats were exposed to 100 and 500 μT ELF-MF, which are the safety standards of public and occupational exposure for 2 h/day during 10 months. At the end of the exposure period, the samples of costa were taken from the rats exposed to ELF-MF and sham. The levels of elements were measured by using atomic absorption spectrophotometry (AAS) and ultraviolet (UV) spectrophotometry. Ca levels decreased in the ELF-500 exposure group in comparison to sham group (p < 0.05). Statistically significant decrease was found in Mg levels in the ELF-500 exposure group in comparison to sham and ELF-100 exposure groups (p < 0.05). Zn levels were found to be lower in the ELF-500 exposure group than those in the sham and ELF-100 exposure groups (p < 0.05). No significant differences were determined between groups in terms of the levels of P, Cu and Fe. In conclusion, it can be maintained that long-term ELF-MF exposure can affect the chemical structure and metabolism of bone by changing the levels of some important elements such as Ca, Zn and Mg in rats.


Imprinting of a genomic domain of 11p15 and loss of imprinting in cancer: an introduction.
Our laboratory has found genomic imprinting of a large genomic domain of human 11p15.5, identifying six imprinted genes within this domain: (a) insulin-like growth factor II (IGF-II), an important autocrine growth factor in a wide variety of malignancies; (b) H19, an untranslated RNA that is a putative growth suppressor gene regulating IGF-II; (c) p57KIP2, a cyclin-dependent kinase inhibitor that causes G1-S arrest; (d) KvLQT1, a voltage-gated potassium channel; (e) TSSC3, a gene that is homologous to mouse TDAG51, which is implicated in Fas-mediated apoptosis; and (f) TSSC5, a putative transmembrane protein-encoding gene. We hypothesize that 11p15 harbors a large domain of imprinted growth-regulatory genes that are important in cancer. Several lines of evidence support this hypothesis: (a) we have discovered a novel genetic alteration in cancer, loss of imprinting, which affects several of these genes, and is one of the most common genetic changes in human cancer; (b) we have found that the hereditary disorder Beckwith-Wiedemann syndrome, which predisposes to cancer and causes prenatal overgrowth, involves alterations in p57KIP2, IGF-II, H19, and KvLQT1; (c) we have found both genetic (somatic mutation in Wilms' tumor) and epigenetic alterations (DNA methylation) in cancer; and (d) we can partially reverse abnormal imprinting using an inhibitor of DNA methylation. We propose a model of genomic imprinting as a dynamic developmental process involving a chromosomal domain. According to this model, cancer involves both genetic and epigenetic mechanisms affecting this imprinted domain and the genes within it.


Mass treatment with azithromycin for trachoma: when is one round enough? Results from the PRET Trial in the Gambia.
The World Health Organization has recommended three rounds of mass drug administration (MDA) with antibiotics in districts where the prevalence of follicular trachoma (TF) is ≥10% in children aged 1-9 years, with treatment coverage of at least 80%. For districts at 5-10% TF prevalence it was recommended that TF be assessed in 1-9 year olds in each community within the district, with three rounds of MDA provided to any community where TF≥10%. Worldwide, over 40 million people live in districts whose TF prevalence is estimated to be between 5 and 10%. The best way to treat these districts, and the optimum role of testing for infection in deciding whether to initiate or discontinue MDA, are unknown. In a community randomized trial with a factorial design, we randomly assigned 48 communities in four Gambian districts, in which the prevalence of trachoma was known or suspected to be above 10%, to receive annual mass treatment with expected coverage of 80-89% ("Standard"), or to receive an additional visit in an attempt to achieve coverage of 90% or more ("Enhanced"). The same 48 communities were randomised to receive mass treatment annually for three years ("3×"), or to have treatment discontinued if Chlamydia trachomatis (Ct) infection was not detected in a sample of children in the community after mass treatment (stopping rule("SR")). Primary outcomes were the prevalence of TF and of Ct infection in 0-5 year olds at 36 months. The baseline prevalence of TF and of Ct infection in the target communities was 6.5% and 0.8% respectively. At 36 months the prevalence of TF was 2.8%, and that of Ct infection was 0.5%. No differences were found between the arms in TF or Ct infection prevalence either at baseline (Standard-3×: TF 5.6%, Ct 0.7%; Standard-SR: TF 6.1%, Ct 0.2%; Enhanced-3×: TF 7.4%, Ct 0.9%; and Enhanced-SR: TF 6.2%, Ct 1.2%); or at 36 months (Standard-3×: TF 2.3%, Ct 1.0%; Standard-SR TF 2.5%, Ct 0.2%; Enhanced-3× TF 3.0%, Ct 0.2%; and Enhanced-SR TF 3.2%, Ct 0.7% ). The implementation of the stopping rule led to treatment stopping after one round of MDA in all communities in both SR arms. Mean treatment coverage of children aged 0-9 in communities randomised to standard treatment was 87.7% at baseline and 84.8% and 88.8% at one and two years, respectively. Mean coverage of children in communities randomized to enhanced treatment was 90.0% at baseline and 94.2% and 93.8% at one and two years, respectively. There was no evidence of any difference in TF or Ct prevalence at 36 months resulting from enhanced coverage or from one round of MDA compared to three. The Gambia is close to the elimination target for active trachoma. In districts prioritised for three MDA rounds, one round of MDA reduced active trachoma to low levels and Ct infection was not detectable in any community. There was no additional benefit to giving two further rounds of MDA. Programmes could save scarce resources by determining when to initiate or to discontinue MDA based on testing for Ct infection, and one round of MDA may be all that is necessary in some settings to reduce TF below the elimination threshold.


Priming-mediated systemic resistance in cucumber induced by Pseudomonas azotoformans GC-B19 and Paenibacillus elgii MM-B22 against Colletotrichum orbiculare.
Induced systemic resistance (ISR) can be activated by biotic agents, including root-associated beneficial bacteria to inhibit pathogen infection. We investigated priming-mediated ISR in cucumber induced by Pseudomonas azotoformans GC-B19 and Paenibacillus elgii MM-B22 against Colletotrichum orbiculare (causal fungus of anthracnose). In addition, we examined whether this ISR expression was bacterial density-dependent by assessing peroxidase activity in the presence and absence of the pathogen. As a result, root treatment with the ISR-eliciting strains GC-B19 and MM-B22 or the chemical inducer DL-β-amino-n-butyric acid (positive control) significantly inhibited fungal infection process (conidial germination and appressorium formation) and disease severity compared with the non-ISR-eliciting strain, Pseudomonas aeruginosa PK-B09 (negative control), and MgSO4 solution (untreated control). These treatments effectively induced rapid elicitation of hypersensitive reaction-like cell death with H2O2 generations, and accumulation of defense-related enzymes (β-1,3-glucanase, chitinase, and peroxidase) in cucumber leaves in the "primed" state against C. orbiculare. In addition, ISR expression was dependent on the bacterial cell density in the rhizosphere. This ISR expression was derived from the presence of sustained bacterial populations ranging from 10(4) to 10(6) cells/g of potting mix over a period of time after introduction of bacteria (10(6) to 10(10) cells/g of potting mix) into the rhizosphere. Taken together, these results suggest that priming-mediated ISR against C. orbiculare in cucumber can be induced in a bacterial density-dependent manner by Pseudomonas azotoformans GC-B19 and Paenibacillus elgii MM-B22.


Myeloid-specific tristetraprolin deficiency in mice results in extreme lipopolysaccharide sensitivity in an otherwise minimal phenotype.
Tristetraprolin (TTP) is a mRNA-destabilizing protein that binds to AU-rich elements in labile transcripts, such as the mRNA encoding TNF, and promotes their deadenylation and degradation. TTP-deficient (knockout [KO]) mice exhibit an early-onset, severe inflammatory phenotype, with cachexia, erosive arthritis, left-sided cardiac valvulitis, myeloid hyperplasia, and autoimmunity, which can be prevented by injections of anti-TNF Abs, or interbreeding with TNF receptor-deficient mice. To determine whether the excess TNF that causes the TTP KO phenotype is produced by myeloid cells, we performed myeloid-specific disruption of Zfp36, the gene encoding TTP. We documented the lack of TTP expression in LPS-stimulated bone marrow-derived macrophages from the mice, whereas fibroblasts expressed TTP mRNA and protein normally in response to serum. The mice exhibited a minimal phenotype, characterized by slight slowing of weight gain late in the first year of life, compared with the early-onset, severe weight loss and inflammation seen in the TTP KO mice. Instead, the myeloid-specific TTP KO mice were highly and abnormally susceptible to a low-dose LPS challenge, with rapid development of typical endotoxemia signs and extensive organ damage, and elevations of serum TNF levels to 110-fold greater than control. We conclude that myeloid-specific TTP deficiency does not phenocopy complete TTP deficiency in C57BL/6 mice under normal laboratory conditions, implying contributions from other cell types to the complete phenotype. However, myeloid cell TTP plays a critical role in protecting mice against LPS-induced septic shock, primarily through its posttranscriptional regulation of TNF mRNA stability.


Natural genetic variants influencing type 1 diabetes in humans and in the NOD mouse.
The understanding of the genetic basis of type 1 diabetes and other autoimmune diseases and the application of that knowledge to their treatment, cure and eventual prevention has been a difficult goal to reach. Cumulative progress in both mouse and human are finally giving way to some successes and significant insights have been made in the last few years. Investigators have identified key immune tolerance-associated phenotypes in convincingly reliable ways that are regulated by specific diabetes-associated chromosomal intervals. The combination of positional genetics and functional studies is a powerful approach to the identification of downstream molecular events that are causal in disease aetiology. In the case of type 1 diabetes, the availability of several animal models, especially the NOD mouse, has complemented the efforts to localize human genes causing diabetes and has shown that some of the same genes and pathways are associated with autoimmunity in both species. There is also growing evidence that the initiation or progression of many autoimmune diseases is likely to be influenced by some of the same genes.


Prevalence of plasmid-mediated AmpC beta-lactamases in Escherichia coli and Klebsiella pneumoniae in Korea.
Cefoxitin-resistant Escherichia coli and Klebsiella pneumoniae are relatively prevalent in Korea, suggesting dissemination of plasmid-mediated AmpC beta-lactamases. In this study, 238 isolates of cefoxitin-resistant E. coli and K. pneumoniae (not including subspecies ozaenae and rhinoscleromatis) were collected in 2003 from 16 Korean hospitals. The prevalence of plasmid-mediated AmpC beta-lactamases was determined by PCR. The AmpC gene alleles detected in E. coli and K. pneumoniae were bla(DHA-1), 10 (8.6%) and 93 (76.2%); bla(CMY-1)-like, 14 (12.1%) and 2 (1.6%); and bla(CMY-2)-like, 38 (32.7%) and 1 (0.8%) isolates, respectively. The genes identified were bla(DHA-1), bla(CMY10)-like, and bla(CMY-2)-like, and a new variant, bla(CMY-18). Plasmidmediated AmpC gene allele-positive isolates were present both in large city and in small province hospitals, as well as in isolates from outpatients. The proportions of plasmid-mediated AmpC gene-positive isolates were similar in both expanded spectrum beta-lactamase (ESBL)-producing and -nonproducing isolates. In conclusion, DHA-1, CMY-2-like, and CMY-10-like plasmid-mediated AmpC beta-lactamase-producing K. pneumoniae and E. coli isolates are widely disseminated in both large city and small province hospitals. Absence of bla(CMY-1) and detection of a novel variant of bla(CMY-2), bla(CMY-18), indicate continued evolution of the prototype genes. Similar proportions of plasmid-mediated AmpC gene-positive isolates in both ESBL-producing and -nonproducing isolates suggest unhindered future spread of these resistances.


Corneal allografts induce cytotoxic T cell but not delayed hypersensitivity responses in mice.
In order to study the cellular immune responses induced by corneal allografts transplanted to a nonimmunologically privileged site, we have used a previously described murine heterotopic corneal allograft model. BALB/c (H-2d) corneal allografts transplanted to a vascular graft bed on the thorax of C57BL/6 (H-2b) recipients were rapidly rejected within 14 days, while corneal syngrafts survived indefinitely (greater than 28 days). Analysis of both primary and secondary cytotoxic T lymphocyte (CTL) responses 7, 10, 14, and 21 days after heterotopic transplantation revealed antigen-specific CTL reactivity at all time points tested (P less than 0.01). By contrast, delayed-type hypersensitivity (DTH) responses to corneal alloantigens (footpad swelling assay) were negative (P greater than 0.05) in 83% of the animals tested. The absence of DTH responsiveness to corneal allografts was not a result of the small graft size or antigenic load. Either two or six circular skin allografts (3-mm diam) of BALB/c origin induced both strong CTL and DTH responses (P less than 0.001) in C57BL/6 recipients, while two or six corneal allografts (2-mm diam) induced strong CTL responses, but DTH responses again failed to develop (P less than 0.05) in over 75% of the animals tested. The ability of corneal alloantigens to elicit CTL responses but not DTH reactivity when grafted to a heterotopic site provides a basis for understanding the immune privilege enjoyed by this tissue.


Relationships between EEA1 binding partners and their role in endosome fusion.
Homotypic fusion between early endosomes requires the phosphatidylinositol 3-phosphate (PI3P)-binding protein, Early Endosomal Autoantigen 1 (EEA1). We have investigated the role of other proteins that interact with EEA1 in the fusion of early endosomes derived from Baby Hamster Kidney (BHK) cells. We confirm a requirement for syntaxin 13, but additionally show that the assay is equally sensitive to reagents specifically targeted against syntaxin 6. Binding of EEA1 to immobilised GST-syntaxin 6 and 13 was directly compared; only syntaxin 6 formed a stable complex with EEA1. Early endosome fusion requires the release of intravesicular calcium, and calmodulin plays a vital role in the fusion pathway, as judged by sensitivity to antagonists. We demonstrate that both EEA1 and syntaxin 13 interact with calmodulin. In the case of EEA1, binding to calmodulin requires an IQ domain, which is adjacent to a C-terminal FYVE domain that specifically binds to PI3P. We have assessed the influence of protein binding partners on EEA1 interaction with PI3P and find that both calmodulin and rab5-GTP are antagonistic to PI3P binding, whilst syntaxins 6 and 13 have no effect. These studies reveal a complex network of interactions between the proteins required for endosome fusion.


Arabidopsis NAC1 transduces auxin signal downstream of TIR1 to promote lateral root development.
Auxin plays a key role in lateral root formation, but the signaling pathway for this process is poorly understood. We show here that NAC1, a new member of the NAC family, is induced by auxin and mediates auxin signaling to promote lateral root development. NAC1 is a transcription activator consisting of an N-terminal conserved NAC-domain that binds to DNA and a C-terminal activation domain. This factor activates the expression of two downstream auxin-responsive genes, DBP and AIR3. Transgenic plants expressing sense or antisense NAC1 cDNA show an increase or reduction of lateral roots, respectively. Finally, TIR1-induced lateral root development is blocked by expression of antisense NAC1 cDNA, and NAC1 overexpression can restore lateral root formation in the auxin-response mutant tir1, indicating that NAC1 acts downstream of TIR1.


Photochemistry of 9-acridinecarboxaldehyde in aqueous media.
Dark and photolysis reactions in solution were investigated for 9-acridinecarboxaldehyde (ACL). ACL reacts in the dark at T = 20 °C and pH = 7.0 in an air saturated solution to the main product 9-acridinecarboxylic acid (ACA) and to the minor product 9-acridinemethanol (ACM) with a lifetime of τ = 4.3 days. The dissociation constant of the base ACLH+ was determined to be pKa ± σ = 4.38 ± 0.04. The photolysis of ACL was investigated using a polychromatic Xe-light source. The quantum yield in aqueous solution at T = 20 °C in a concentration range of c0(ACL) = 0.18-16.6 μM for pH > pKa and for nitrogen, air and oxygen aerated solutions was found to be Φ ± σ = (0.015 ± 0.003) mol/mol, independent from concentration. The quantum yield of ACLH+, i.e. for pH ≪ pKa, is by a factor of 2 higher (Φ = 0.029 mol/mol). Quantum yields in methanol and isopropanol are slightly lower compared to water and in acetone lower by about a factor of 20. In acetonitrile ACL was found to be practically photostable. Minimum lifetimes in sunlight for a measurement on September 5, 2017 were in the range of τ = 5-10 minutes. The diurnal photolysis of ACL in sunlight was satisfactory explained using the mean quantum yield, the absorption spectrum and photon fluxes with suitable corrections for cloudiness and the dimensions of the setup. For low concentrations ACR is formed with a yield of practically 100% in the photolysis reaction. However, with increasing concentration of ACL yields of ACR decrease and yields of ACA increase. 9(10H)-Acridinone and ACM were always detected as minor products with yields below 2%. 9-Methylacridine was never detected in any reaction of ACL. Strong indications are presented of a photolysis reaction of ACL in a river located in Lower Saxony (Germany) with a corresponding equimolar formation of ACR. ACL is therefore a direct precursor of ACR in natural surface water.


Severe peripheral edema during an outpatient continuous epidural morphine infusion trial in a patient with failed back surgery syndrome.
Intraspinal drug delivery therapy has been increasingly used in patients with intractable, nonmalignant pain who fail to respond to conventional treatment or cannot tolerate systemic opioid therapy due to side effects. By infusing small amount of analgesics directly into the cerebrospinal fluid in close proximity to the receptor sites in the spinal cord, one is able to achieve the spinally mediated analgesia, sparing side effects due to systemic opioids. Prior to permanent intraspinal pump implantation, an intraspinal opioid screening trial is required to document the efficacy of intraspinal opioid for analgesia. Although there are a few approaches in conducting such screening trials, a patient controlled continuous epidural morphine infusion trial, performed in an outpatient setting, is widely accepted by many interventional pain specialists. The major advantage of conducting an outpatient trial is that it mimics what patients do in their daily living, therefore minimizing the false positive rate. To report a case of severe peripheral edema observed during an outpatient continuous epidural morphine infusion trial. A 64-year-old female, with a 7-year history of severe low back pain and bilateral leg pain due to failed back surgery syndrome, was referred to our clinic for intraspinal drug delivery therapy after failing to respond to conservative treatment, including a previous history of 3 lumbosacral surgeries. Following a pre-implantation psychological evaluation confirming her candidacy, she underwent an outpatient patient-controlled continuous epidural morphine trial. A tunneled lumbar epidural catheter was placed at L2-L3 with catheter tip advanced to T12 under fluoroscopic guidance. Satisfactory catheter placement was confirmed by epidurogram. The proximal tip of the catheter was then tunneled, subcutaneously and connected to a Microject PCEA pump (Codman, Raynham, MA, USA) and reservoir bag containing preservative-free morphine 0.5 mg/mL. The pump was programmed to deliver a basal rate of 0.5 mL/hr. The bolus dose was 0.2 mL with 60 minute lock-out interval. The patient was instructed how to operate the infusion pump before discharging home. During the following 2 weeks, she reported more than 90% reduction of her low back and leg pain. She only had to use the on-demand bolus doses averaging 2 - 3 times a day. She was able to wean off her oral opioids completely. However, she developed bilateral leg edema and gained over 12 pounds during the 2-week infusion trial, despite wearing elastic stockings and keeping her legs elevated whenever possible. She did not experience any other significant side effects. Her edema finally resolved 2 days after termination of the epidural infusion. Peripheral edema may occur and persist during epidural morphine infusion. This report represents the first case report, to the best of our knowledge, describing severe peripheral edema in an otherwise healthy patient while on epidural morphine administration during an outpatient epidural morphine infusion trial. This case report shows that continuous epidural morphine infusion, even in small dose, may cause peripheral edema in some patients.


Role of oxidative stress in infectious diseases. A review.
Oxidative stress plays a dual role in infections. Free radicals protect against invading microorganisms, and they can also cause tissue damage during the resulting inflammation. In the process of infection, there is generation of reactive species by myeloperoxidase, NADPH oxidase, and nitric oxide synthase. On the other hand, reactive species can be generated among others, by cytochrome P450, some metals, and xanthine oxidase. Some pathologies arising during infection can be attributed to oxidative stress and generation of reactive species in infection can even have fatal consequences. This article reviews the basic pathways in which reactive species can accumulate during infectious diseases and discusses the related health consequences.


Exploring lived experience in gender and sexual minority suicide attempt survivors.
Gender and sexual minorities (GSM) are at a higher risk for victimization, discrimination, and emotional distress. GSM also face unique stressors that contribute to negative mental health outcomes, such as family and interpersonal rejection, ostracism and isolation, and internalized gender and sexual stigma. Suicide attempt survivors often experience similar stigma and isolation after an attempt. However, little is known about the specific experiences of GSM individuals who attempt suicide. Transcripts of interviews with 25 GSM attempt survivors conducted as part of the Live Through This project were analyzed using an interpretive phenomenological approach. Five themes that capture the lived experience of suicidality of the participants were identified in the interviews: (a) intersecting identities, (b) identity concealment, (c) internalized stigma and self-hate, (d) the social environment, and (e) the importance of peer support. Findings highlight the compounding stigma that occurs when individuals identify as both a GSM and a suicide attempt survivor. Implications for clinical work include the need for additional peer support for individuals who maintain the dual identity of GSM and suicide attempt survivor. Moreover, there is a need for mental health, crisis, and support resources and services tailored for GSM individuals that emphasize the importance of peer support in healing and recovery after a suicide attempt and in preventing future suicidal behavior. This important information can help us develop strategies to prevent suicide among the GSM population and to provide support for GSM suicide attempt survivors. (PsycINFO Database Record (c) 2018 APA, all rights reserved).


Early molecular events induced by T cell receptor (TCR) signaling in immature CD4+ CD8+ thymocytes: increased synthesis of TCR-alpha protein is an early response to TCR signaling that compensates for TCR-alpha instability, improves TCR assembly, and parallels other indicators of positive selection.
Differentiation of immature CD4+ CD8+ thymocytes into mature CD4+ or CD8+ T cells occurs within the thymus and is dependent upon expression of antigen receptor complexes (T cell receptor [TCR]) containing clonotypic alpha/beta proteins. We have recently found that CD4+ CD8+ thymocytes express low levels of surface TCR because of limitations placed on TCR assembly by the instability of nascent TCR-alpha proteins within the endoplasmic reticulum (ER) of immature thymocytes. Because TCR-alpha/beta expression increases during development, a molecular mechanism must exist for increasing the number of assembled TCR complexes present in immature CD4+ CD8+ thymocytes that have been signaled to differentiate into mature T cells, although no such mechanism has yet been described. In the current report we have examined the molecular consequences of intracellular signals generated by engagement of surface TCR complexes on immature CD4+ CD8+ thymocytes. Isolated TCR engagement generated signals that increased TCR-alpha RNA levels and increased synthesis of TCR-alpha proteins, which, in turn, significantly increased assembly of complete TCR-alpha/beta complexes in CD4+ CD8+ thymocytes. Increased TCR-alpha protein levels in TCR-signaled CD4+ CD8+ thymocytes was the result of increased synthesis and not increased stability of TCR-alpha proteins, indicating that TCR engagement compensates for, but does not correct, the inherent instability of TCR-alpha proteins in the ER of immature thymocytes. Consistent with the delivery by TCR engagement of a positive selection signal, TCR engagement also increased CD5 expression, decreased RAG-1 expression, and decreased CD4/CD8 coreceptor expression in immature CD4+ CD8+ thymocytes. These data identify amplified TCR-alpha expression as an initial response of immature CD4+ CD8+ thymocytes to TCR-mediated positive selection signals and provide a molecular basis for increased surface TCR density on developing thymocytes undergoing selection events within the thymus.


A hierarchical approach to feature extraction and grouping.
In this paper, the problem of extracting and grouping image features from complex scenes is solved by a hierarchical approach based on two main processes: voting and clustering. Voting is performed for assigning a score to both global and local features. The score represents the evidential support provided by input data for the presence of a feature. Clustering aims at individuating a minimal set of significant local features by grouping together simpler correlated observations. It is based on a spatial relation between simple observations on a fixed level, i.e., the definition of a distance in an appropriate space. As the multilevel structure of the system implies that input data for an intermediate level are outputs of the lower level, voting can be seen as a functional representation of the "part-of" relation between features at different abstraction levels. The proposed approach has been tested on both synthetic and real images and compared with other existing feature grouping methods.


Light-induced relaxation dynamics of the ferricyanide ion revisited by ultrafast XUV photoelectron spectroscopy.
Photoinduced charge transfer in transition-metal coordination complexes plays a prominent role in photosynthesis and is fundamental for light-harvesting processes in catalytic materials. However, revealing the relaxation pathways of charge separation remains a very challenging task because of the complexity of relaxation channels and ultrashort time scales. Here, we employ ultrafast XUV photoemission spectroscopy to monitor fine mechanistic details of the electron dynamics following optical ligand-to-metal charge-transfer excitation of ferricyanide in aqueous solution. XUV probe light with a time resolution of 100 fs, in combination with density functional theory employing the Dyson orbital formalism, enabled us to decipher the primary and subsequently populated electronic states involved in the relaxation, as well as their energetics on sub-picosecond timescales. We find strong evidence for the spin crossover followed by geometrical distortions due to vibronic interactions (Jahn-Teller effect) in the excited electronic states, rather than localization/delocalization dynamics, as suggested previously.


Parkinsonian symptoms as an initial manifestation in a Japanese patient with acquired immunodeficiency syndrome and Toxoplasma infection.
We studied a Japanese patient who developed parkinsonian symptoms over 3 months before the diagnosis of acquired immunodeficiency syndrome. Brain MRI showed multiple lesions with mass effect and ring enhancement in the basal ganglia and subcortical white matter suggesting Toxoplasma infection. Anti-Toxoplasma therapy and highly active antiretroviral therapy for 6 months allowed improvement of parkinsonism, brain MRI findings, and immune system.


The relation of virologic and immunologic markers to clinical outcomes after nucleoside therapy in HIV-infected adults with 200 to 500 CD4 cells per cubic millimeter. AIDS Clinical Trials Group Study 175 Virology Study Team.
We studied measures of human immunodeficiency virus (HIV) replication, the viral phenotype, and immune function (CD4 cell counts) and the relation of changes in these indicators to clinical outcomes in a subgroup of patients in a controlled trial of early antiretroviral treatment for HIV, the AIDS Clinical Trials Group Study 175. The 391 subjects, each of whom entered the study with a single screening CD4 cell count of 200 to 500 per cubic millimeter, were randomly assigned to receive zidovudine alone, didanosine alone, zidovudine plus didanosine, or zidovudine plus zalcitabine. Plasma concentrations of HIV RNA were assessed in 366 subjects, and viral isolates from 332 subjects were assayed for the presence of the syncytium-inducing phenotype. After eight weeks, the mean (+/-SE) decrease from base line in the concentration of HIV RNA, expressed as the change in the base 10 log of the number of copies per milliliter, was 0.26+/-0.06 for patients treated with zidovudine alone, 0.65+/-0.07 for didanosine alone, 0.93+/-0.10 for zidovudine plus didanosine, and 0.89+/-0.06 for zidovudine plus zalcitabine (P<0.001 for each of the pairwise comparisons with zidovudine alone). Multivariate proportional-hazards models showed that higher base-line concentrations of plasma HIV RNA, less suppression of plasma HIV RNA by treatment, and the presence of the syncytium-inducing phenotype were significantly associated with an increased risk of progression to the acquired immunodeficiency syndrome and death. After adjustment for these measures of viral replication and for the viral phenotype, CD4 cell counts were not significant predictors of clinical outcome. Both the risk of the progression of HIV disease and the efficacy of antiretroviral therapy are strongly associated with the plasma level of HIV RNA and with the viral phenotype. The changes in the plasma concentration of HIV RNA predict the changes in CD4 cell counts and survival after treatment with reverse-transcriptase inhibitors.


Synovial inflammation, immune cells and their cytokines in osteoarthritis: a review.
Although osteoarthritis (OA) is considered a non-inflammatory condition, it is widely accepted that synovial inflammation is a feature of OA. However, the role of immune cells and their cytokines in OA is largely unknown. This narrative systematic review summarizes the knowledge of inflammatory properties, immune cells and their cytokines in synovial tissues (STs) of OA patients. Broad literature search in different databases was performed which resulted in 100 articles. Of 100 articles 33 solely investigated inflammation in OA ST with or without comparison with normal samples; the remaining primarily focussed on rheumatoid arthritis (RA) ST. Studies investigating different severity stages or cellular source of cytokines were sparse. OA ST displayed mild/moderate grade inflammation when investigated by means of haematoxylin and eosin (H&E) staining. Most frequently found cells types were macrophages, T cells and mast cells (MCs). Overall the number of cells was lower than in RA, although the number of MCs was as high as or sometimes even higher than in RA ST. Cytokines related to T cell or macrophage function were found in OA ST. Their expression was overall higher than in normal ST, but lower than in RA ST. Their cellular source remains largely unknown in OA ST. Inflammation is common in OA ST and characterized by immune cell infiltration and cytokine secretion. This inflammation seems quantitatively and qualitatively different from inflammation in RA. Further research is needed to clarify the role of inflammation, immune cells and their cytokines in the pathogenesis of OA.


Diagnostic utility of droplet digital PCR for HIV reservoir quantification.
Quantitative real-time PCR (qPCR) is implemented in many molecular laboratories worldwide for the quantification of viral nucleic acids. However, over the last two decades, there has been renewed interest in the concept of digital PCR (dPCR) as this platform offers direct quantification without the need for standard curves, a simplified workflow and the possibility to extend the current detection limit. These benefits are of great interest in terms of the quantification of low viral levels in HIV reservoir research because changes in the dynamics of residual HIV reservoirs will be important to monitor HIV cure efforts. Here, we have implemented a systematic literature screening and text mining approach to map the use of droplet dPCR (ddPCR) in the context of HIV quantification. In addition, several technical aspects of ddPCR were compared with qPCR: accuracy, sensitivity, precision and reproducibility, to determine its diagnostic utility. We have observed that ddPCR was used in different body compartments in multiple HIV-1 and HIV-2 assays, with the majority of reported assays focusing on HIV-1 DNA-based applications (i.e. total HIV DNA). Furthermore, ddPCR showed a higher accuracy, precision and reproducibility, but similar sensitivity when compared to qPCR due to reported false positive droplets in the negative template controls with a need for standardised data analysis (i.e. threshold determination). In the context of a low level of detection and HIV reservoir diagnostics, ddPCR can offer a valid alternative to qPCR-based assays but before this platform can be clinically accredited, some remaining issues need to be resolved.


Strengthening clinical cancer research in the United Kingdom.
In 1999, 270,000 cases of cancer were registered in the United Kingdom, placing a large burden on the NHS. Cancer outcome data in 1999 suggested that UK survival rates were poorer than most other European countries. In the same year, a Department of Health review noted that clinical trials accrual was poor (<3.5% of incident cases) and hypothesised that increasing research activity might improve outcomes and reduce the variability of outcomes across England. Thus, the National Cancer Research Network (NCRN) was established to increase participation in cancer clinical research. The NCRN was established in 2001 to provide a robust infrastructure for cancer clinical research and improvements in patient care. Remit of NCRN is to coordinate, support and deliver cancer clinical research through the provision of research support staff across England. The NCRN works closely with similar networks in Scotland, Wales and the Northern Ireland. A key aim of NCRN is to improve the speed of research and this was also assessed by comparing the speed of study delivery of a subset of cancer studies opening before and after NCRN was established. Patient recruitment increased through NCRN, with almost 32,000 (12% of annual incident cases) cancer patients being recruited each year. Study delivery has improved, with more studies meeting the recruitment target - 74% compared with 39% before NCRN was established. The coordinated approach to cancer clinical research has demonstrated increased accrual, wide participation and successful trial delivery, which should lead to improved outcomes and care.


KinImmerse: Macromolecular VR for NMR ensembles.
In molecular applications, virtual reality (VR) and immersive virtual environments have generally been used and valued for the visual and interactive experience - to enhance intuition and communicate excitement - rather than as part of the actual research process. In contrast, this work develops a software infrastructure for research use and illustrates such use on a specific case. The Syzygy open-source toolkit for VR software was used to write the KinImmerse program, which translates the molecular capabilities of the kinemage graphics format into software for display and manipulation in the DiVE (Duke immersive Virtual Environment) or other VR system. KinImmerse is supported by the flexible display construction and editing features in the KiNG kinemage viewer and it implements new forms of user interaction in the DiVE. In addition to molecular visualizations and navigation, KinImmerse provides a set of research tools for manipulation, identification, co-centering of multiple models, free-form 3D annotation, and output of results. The molecular research test case analyzes the local neighborhood around an individual atom within an ensemble of nuclear magnetic resonance (NMR) models, enabling immersive visual comparison of the local conformation with the local NMR experimental data, including target curves for residual dipolar couplings (RDCs). The promise of KinImmerse for production-level molecular research in the DiVE is shown by the locally co-centered RDC visualization developed there, which gave new insights now being pursued in wider data analysis.


Laminar and neurochemical organization of the dorsal cochlear nucleus of the human, monkey, cat, and rodents.
The dorsal cochlear nucleus (DCN) is a brainstem structure that receives input from the auditory nerve. Many studies in a diversity of species have shown that the DCN has a laminar organization and identifiable neuron types with predictable synaptic relations to each other. In contrast, studies on the human DCN have found a less distinct laminar organization and fewer cell types, although there has been disagreement among studies in how to characterize laminar organization and which of the cell types identified in other animals are also present in humans. We have reexamined DCN organization in the human using immunohistochemistry to analyze the expression of several proteins that have been useful in delineating the neurochemical organization of other brainstem structures in humans: nonphosphorylated neurofilament protein (NPNFP), nitric oxide synthase (nNOS), and three calcium-binding proteins. The results for humans suggest a laminar organization with only two layers, and the presence of large projection neurons that are enriched in NPNFP. We did not observe evidence in humans of the inhibitory interneurons that have been described in the cat and rodent DCN. To compare humans and other animals directly we used immunohistochemistry to examine the DCN in the macaque monkey, the cat, and three rodents. We found similarities between macaque monkey and human in the expression of NPNFP and nNOS, and unexpected differences among species in the patterns of expression of the calcium-binding proteins.


The effect of commercial coaching on selection test performance.
To investigate whether commercial coaching affects performance in the Undergraduate Medical and Health Sciences Admission Test (UMAT). The effect of coaching on the UMAT scores of 402 final high school students applying for medicine was examined using t-tests and multiple regression analyses that controlled for academic performance, high school type and gender. Over half (56.2%) of the participants had enrolled in commercial coaching. Coaching had no influence on UMAT Section 1 or 2, even after controlling for academic performance, gender and type of high school. UMAT Section 3 was significantly higher for coached students, but this was only the case for high ability students. Coaching had a slight negative effect for lower ability students. Those attending academically selective high school also had higher UMAT scores. The results have implications for the fairness and validity of the UMAT. The differential effect of coaching possibly occurred because high academic ability students are able to learn solution rules for non-verbal tests. We propose that the effect of school type relates to a competitive culture that drives extended test practice in academically selective schools.


The normative power of food promotions: Australian children's attachments to unhealthy food brands.
The formation of food brand associations and attachment is fundamental to brand preferences, which influence purchases and consumption. Food promotions operate through a cascade of links, from brand recognition, to affect, and on to consumption. Frequent exposures to product promotions may establish social norms for products, reinforcing brand affect. These pathways signify potential mechanisms for how children's exposure to unhealthy food promotions can contribute to poor diets. The present study explored children's brand associations and attachments for major food brands. A cross-sectional online survey was conducted. Fourteen study brands were used, with each child viewing a set of seven logos. The questionnaire assessed perceptions of food brands and perceptions of users of brands, using semantic differential scales, and perceived brand 'personalities', using Likert scales. New South Wales, Australia, October-November 2014. Children aged 10-16 years (n 417). Children demonstrated strong positive affect to certain brands, perceiving some unhealthy food brands to have positive attributes, desirable user traits and alignment to their own personality. Brand personality traits of 'smart' and 'sporty' were viewed as indicators of healthiness. Brands with these traits were ranked lower for popularity. Children's brand associations and attachments indicate the potential normative social influences of promotions. While children are aware of brand healthiness as an attribute, this competes with other brand associations, highlighting the challenge of health/nutrition messaging to counter unhealthy food marketing. Restricting children's exposure to unhealthy food marketing and the persuasive nature of marketing is an important part of efforts to improve children's diet-related health.