Assistants, Guides, Collaborators, Friends: The Concealed Figures of Conflict Research

Recent scholarship has demonstrated an increasing awareness of the need for more grounded, empirical research into the micro-level dynamics of violent contexts. Research in these difficult, dangerous, and potentially violent conflict or post-conflict settings necessitates the formation of new relationships of dependency, and assistants, friends, collaborators, and guides become central figures in the field. However, all too often, these figures are written out of academic accounts and silenced in our analyses. This not only does them a significant disservice, but it also obscures potential biases, complexities, and ethical dilemmas that emerge in the way in which such research is carried out. Drawing upon fieldwork exploring the 2007–2008 Kenyan postelection violence, this paper argues that reliance upon insider-assistants is essential in conflict settings and explores the challenges inherent in these relationships. As researchers become increasingly engaged in micro-level studies of violent contexts, we must interrogate the realities of how our knowledge has been produced and engage in more open and honest discussions of the methodological and ethical challenges of conflict research

Stop Atherosclerosis in Native Diabetics Study (SANDS): Baseline Characteristics of the Randomized Cohort

Objectives: To present baseline characteristics of American Indians in the Stop Atherosclerosis in Native Diabetics Study (SANDS) and compare them with population-based data from American Indians and other ethnic groups. Design: 499 people with type 2 diabetes ≥ age 40, without known CVD, were recruited for a randomized 3-year trial to evaluate treatment targets for LDL-C (70 vs. 100 mg/dL) and systolic blood pressure (BP) (115 vs. 130 mmHg). Baseline evaluations included physical exam, collection of blood and urine samples, and carotid ultrasound and echocardiographic measures. Results: Mean age was 56 years; 66% were female. Average BMI was 33 kg/m2. Average duration of both hypertension and diabetes was 10 years, average A1c was 8.0 %, and mean LDL-C was 104 mg/dL. Participants in the conventional treatment group had slightly higher systolic BPs than participants in the aggressive treatment group (133 mm Hg vs. 128 mm Hg, p \u3c 0.002). Compared with the population-based cohorts of the Strong Heart Study (SHS), NHANES, and the TRIAD registry, SANDS participants had similar values for lipids, BP, and CRP, as well as degree of obesity, smoking rates, and renal function as indicated by estimated glomerular filtration rate. Conclusions: The baseline characteristics of the SANDS cohort are similar to those of a population-based sample of American Indian diabetic men and women and closely resemble diabetic men and women of other ethnic groups. Results from this study can be used to identify appropriate targets for LDL-C and BP lowering in diabetic American Indians and diabetic patients in other ethnic groups

JAK2 Exon 14 Deletion in Patients with Chronic Myeloproliferative Neoplasms

BACKGROUND: The JAK2 V617F mutation in exon 14 is the most common mutation in chronic myeloproliferative neoplasms (MPNs); deletion of the entire exon 14 is rarely detected. In our previous study of >10,000 samples from patients with suspected MPNs tested for JAK2 mutations by reverse transcription-PCR (RT-PCR) with direct sequencing, complete deletion of exon 14 (Deltaexon14) constituted <1% of JAK2 mutations. This appears to be an alternative splicing mutation, not detectable with DNA-based testing. METHODOLOGY/PRINCIPAL FINDINGS: We investigated the possibility that MPN patients may express the JAK2 Deltaexon14 at low levels (<15% of total transcript) not routinely detectable by RT-PCR with direct sequencing. Using a sensitive RT-PCR-based fluorescent fragment analysis method to quantify JAK2 Deltaexon14 mRNA expression relative to wild-type, we tested 61 patients with confirmed MPNs, 183 with suspected MPNs (93 V617F-positive, 90 V617F-negative), and 46 healthy control subjects. The Deltaexon14 variant was detected in 9 of the 61 (15%) confirmed MPN patients, accounting for 3.96% to 33.85% (mean = 12.04%) of total JAK2 transcript. This variant was also detected in 51 of the 183 patients with suspected MPNs (27%), including 20 of the 93 (22%) with V617F (mean [range] expression = 5.41% [2.13%-26.22%]) and 31 of the 90 (34%) without V617F (mean [range] expression = 3.88% [2.08%-12.22%]). Immunoprecipitation studies demonstrated that patients expressing Deltaexon14 mRNA expressed a corresponding truncated JAK2 protein. The Deltaexon14 variant was not detected in the 46 control subjects. CONCLUSIONS/SIGNIFICANCE: These data suggest that expression of the JAK2 Deltaexon14 splice variant, leading to a truncated JAK2 protein, is common in patients with MPNs. This alternatively spliced transcript appears to be more frequent in MPN patients without V617F mutation, in whom it might contribute to leukemogenesis. This mutation is missed if DNA rather than RNA is used for testing

Pathways to child and adolescent psychiatric clinics: a multilevel study of the significance of ethnicity and neighbourhood social characteristics on source of referral

<p>Abstract</p> <p>Background</p> <p>In the Swedish society, as in many other societies, many children and adolescents with mental health problems do not receive the help they need. As the Swedish society becomes increasingly multicultural, and as ethnic and economic residential segregation become more pronounced, this study utilises ethnicity and neighbourhood context to examine referral pathways to child and adolescent psychiatric (CAP) clinics.</p> <p>Methods</p> <p>The analysis examines four different sources of referrals: family referrals, social/legal agency referrals, school referrals and health/mental health referrals. The referrals of 2054 children aged 11-19 from the Stockholm Child-Psychiatric Database were studied using multilevel logistic regression analyses.</p> <p>Results</p> <p>Results indicate that ethnicity played an important role in how children and adolescents were referred to CAP-clinics. Family referrals were more common among children and adolescents with a Swedish background than among those with an immigrant background. Referrals by social/legal agencies were more common among children and adolescents with African and Asian backgrounds. Children with Asian or South American backgrounds were more likely to have been referred by schools or by the health/mental health care sector. A significant neighbourhood effect was found in relation to family referrals. Children and adolescents from neighbourhoods with low levels of socioeconomic deprivation were more likely to be referred to CAP-clinics by their families in comparison to children from other neighbourhoods. Such differences were not found in relation in relation to the other sources of referral.</p> <p>Conclusions</p> <p>This article reports findings that can be an important first step toward increasing knowledge on reasons behind differential referral rates and uptake of psychiatric care in an ethnically diverse Swedish sample. These findings have implications for the design and evaluation of community mental health outreach programs and should be considered when developing measures and strategies intended to reach and help children with mental health problems. This might involve providing information about the availability and accessibility of health care for children and adolescents with mental health problems to families in certain neighbourhoods and with different ethnic backgrounds.</p

In Vivo RNAi Screening Identifies a Leukemia-Specific Dependence on Integrin Beta 3 Signaling

We used an in vivo small hairpin RNA (shRNA) screening approach to identify genes that are essential for MLL-AF9 acute myeloid leukemia (AML). We found that Integrin Beta 3 (Itgb3) is essential for murine leukemia cells in vivo and for human leukemia cells in xenotransplantation studies. In leukemia cells, Itgb3 knockdown impaired homing, downregulated LSC transcriptional programs, and induced differentiation via the intracellular kinase Syk. In contrast, loss of Itgb3 in normal hematopoietic stem and progenitor cells did not affect engraftment, reconstitution, or differentiation. Finally, using an Itgb3 knockout mouse model, we confirmed that Itgb3 is dispensable for normal hematopoiesis but is required for leukemogenesis. Our results establish the significance of the Itgb3 signaling pathway as a potential therapeutic target in AML.National Institutes of Health (U.S.) (Harvard Stem Cell Institute. GlaxoSmithKline. Grant P01 CA108631)National Institutes of Health (U.S.) (Harvard Stem Cell Institute. GlaxoSmithKline. Grant RC1 CA145229)National Institutes of Health (U.S.) (Harvard Stem Cell Institute. GlaxoSmithKline. Grant R01 CA140292)National Institutes of Health (U.S.) (Harvard Stem Cell Institute. GlaxoSmithKline. Grant CA148180

PpiA, a Surface PPIase of the Cyclophilin Family in Lactococcus lactis

Background: Protein folding in the envelope is a crucial limiting step of protein export and secretion. In order to better understand this process in Lactococcus lactis, a lactic acid bacterium, genes encoding putative exported folding factors like Peptidyl Prolyl Isomerases (PPIases) were searched for in lactococcal genomes. Results: In L. lactis, a new putative membrane PPIase of the cyclophilin subfamily, PpiA, was identified and characterized. ppiA gene was found to be constitutively expressed under normal and stress (heat shock, H2O2) conditions. Under normal conditions, PpiA protein was synthesized and released from intact cells by an exogenously added protease, showing that it was exposed at the cell surface. No obvious phenotype could be associated to a ppiA mutant strain under several laboratory conditions including stress conditions, except a very low sensitivity to H2O2. Induction of a ppiA copy provided in trans had no effect i) on the thermosensitivity of an mutant strain deficient for the lactococcal surface protease HtrA and ii) on the secretion and stability on four exported proteins (a highly degraded hybrid protein and three heterologous secreted proteins) in an otherwise wild-type strain background. However, a recombinant soluble form of PpiA that had been produced and secreted in L. lactis and purified from a culture supernatant displayed both PPIase and chaperone activities. Conclusions: Although L. lactis PpiA, a protein produced and exposed at the cell surface under normal conditions, displaye

Professional Service Utilisation among Patients with Severe Mental Disorders

<p>Abstract</p> <p>Background</p> <p>Generally, patients with serious mental disorders (SMD) are frequent users of services who generate high care-related costs. Current reforms aim to increase service integration and primary care for improved patient care and health-care efficiency. This article identifies and compares variables associated with the use by patients with SMD of services offered by psychiatrists, case managers, and general practitioners (GPs). It also compares frequent and infrequent service use.</p> <p>Method</p> <p>One hundred forty patients with SMD from five regions in Quebec, Canada, were interviewed on their use of services in the previous year. Patients were also required to complete a questionnaire on needs-assessment. In addition, data were collected from clinical records. Descriptive, bivariate, and multivariate analyses were conducted.</p> <p>Results</p> <p>Most patients used services from psychiatrists and case managers, but no more than half consulted GPs. Most patients were followed at least by two professionals, chiefly psychiatrists and case managers. Care access, continuity of care, and total help received were the most important variables associated with the different types of professional consultation. These variables were also associated with frequent use of professional service, as compared with infrequent service use. In all, enabling factors rather than need factors were the core predictors of frequency of service utilisation by patients with SMD.</p> <p>Conclusion</p> <p>This study reveals that health care system organisation and professional practice - rather than patient need profiles - are the core predictors of professional consultation by patients with SMD. The homogeneity of our study population, i.e. mainly users with schizophrenia, recently discharged from hospital, may partly account for these results. Our findings also underscored the limited involvement of GPs in this patient population's care. As comorbidity is often associated with serious mental disorders, closer follow-up by GPs is needed. Globally, more effort should be directed at increasing shared-care initiatives, which would enhance coordination among psychiatrists, GPs, and psychosocial teams (including case managers). Finally, there is a need to increase awareness among health care providers, especially GPs, of the level of care required by patients with disabling and serious mental disorders.</p

Targeting Protein-Protein Interactions for Parasite Control

Finding new drug targets for pathogenic infections would be of great utility for humanity, as there is a large need to develop new drugs to fight infections due to the developing resistance and side effects of current treatments. Current drug targets for pathogen infections involve only a single protein. However, proteins rarely act in isolation, and the majority of biological processes occur via interactions with other proteins, so protein-protein interactions (PPIs) offer a realm of unexplored potential drug targets and are thought to be the next-generation of drug targets. Parasitic worms were chosen for this study because they have deleterious effects on human health, livestock, and plants, costing society billions of dollars annually and many sequenced genomes are available. In this study, we present a computational approach that utilizes whole genomes of 6 parasitic and 1 free-living worm species and 2 hosts. The species were placed in orthologous groups, then binned in species-specific ortholgous groups. Proteins that are essential and conserved among species that span a phyla are of greatest value, as they provide foundations for developing broad-control strategies. Two PPI databases were used to find PPIs within the species specific bins. PPIs with unique helminth proteins and helminth proteins with unique features relative to the host, such as indels, were prioritized as drug targets. The PPIs were scored based on RNAi phenotype and homology to the PDB (Protein DataBank). EST data for the various life stages, GO annotation, and druggability were also taken into consideration. Several PPIs emerged from this study as potential drug targets. A few interactions were supported by co-localization of expression in M. incognita (plant parasite) and B. malayi (H. sapiens parasite), which have extremely different modes of parasitism. As more genomes of pathogens are sequenced and PPI databases expanded, this methodology will become increasingly applicable