Retinoic acid induces the differentiation of B cell hybridomas from patients with common variable immunodeficiency.

Human-human B cell hybridomas constructed from B lymphocytes of common variable immunodeficiency (CVI) patients and the nonsecreting cell line WIL2/729 HF consistently secrete low levels of Ig and appear to retain a defect characteristic of the CVI patient's B cells. We assessed the differentiative capacity of retinoic acid (RA) on these hybridomas, as well as on hybridomas constructed from normal B cells and from patients with selective IgA deficiency. RA at concentrations varying between 10(-5) and 10(-9) M augmented IgM secretion 4-20-fold from four of four CVI hybridomas tested, but did not affect Ig secretion from normal or IgA-deficiency hybridomas. In support of this elevated Ig secretion, RA enhanced the de novo synthesis of biosynthetically labeled light (kappa) and heavy (mu) Ig (up to 4- and 15-fold, respectively) in the CVI hybridoma line JK32.1. The increase in IgM synthesis/secretion could not be accounted for by RA-induced alteration in the cell cycle. In inducing this increase in IgM production, RA was found to affect two aspects of Ig gene expression: (a) the steady-state levels of heavy and light chain mRNAs were enhanced, and (b) the processing of mu heavy chain transcripts to the secreted mRNA form became favored over the membrane mRNA form. We also show that expression of Leu-17 (CD38), a surface marker that is re-expressed in the late pre-plasma stage of B cell development, was increased by RA from less than 20% to greater than 90% of the total cell population, with a concomitant 4-10-fold augmentation in the mean fluorescence intensity. Changes in both Leu-17 expression and de novo Ig synthesis were prominent by 24 h, but could be observed as early as 8 h after induction. Taken together, our study demonstrates that RA affects a marked alteration in the differentiated state of the CVI hybridoma clones. This finding suggests that retinoids can enhance the functional capabilities of B cells with defects in maturation and support further studies to evaluate their clinical potential in CVI

Detectable HIV Viral Load in Kenya: Data from a Population-Based Survey.

IntroductionAt the individual level, there is clear evidence that Human Immunodeficiency Virus (HIV) transmission can be substantially reduced by lowering viral load. However there are few data describing population-level HIV viremia especially in high-burden settings with substantial under-diagnosis of HIV infection. The 2nd Kenya AIDS Indicator Survey (KAIS 2012) provided a unique opportunity to evaluate the impact of antiretroviral therapy (ART) coverage on viremia and to examine the risks for failure to suppress viral replication. We report population-level HIV viral load suppression using data from KAIS 2012.MethodsBetween October 2012 to February 2013, KAIS 2012 surveyed household members, administered questionnaires and drew serum samples to test for HIV and, for those found to be infected with HIV, plasma viral load (PVL) was measured. Our principal outcome was unsuppressed HIV viremia, defined as a PVL ≥ 550 copies/mL. The exposure variables included current treatment with ART, prior history of an HIV diagnosis, and engagement in HIV care. All point estimates were adjusted to account for the KAIS 2012 cluster sampling design and survey non-response.ResultsOverall, 61·2% (95% CI: 56·4-66·1) of HIV-infected Kenyans aged 15-64 years had not achieved virological suppression. The base10 median (interquartile range [IQR]) and mean (95% CI) VL was 4,633 copies/mL (0-51,596) and 81,750 copies/mL (59,366-104,134), respectively. Among 266 persons taking ART, 26.1% (95% CI: 20.0-32.1) had detectable viremia. Non-ART use, younger age, and lack of awareness of HIV status were independently associated with significantly higher odds of detectable viral load. In multivariate analysis for the sub-sample of patients on ART, detectable viremia was independently associated with younger age and sub-optimal adherence to ART.DiscussionThis report adds to the limited data of nationally-representative surveys to report population- level virological suppression. We established heterogeneity across the ten administrative and HIV programmatic regions on levels of detectable viral load. Timely initiation of ART and retention in care are crucial for the elimination of transmission of HIV through sex, needle and syringe use or from mother to child. Further refinement of geospatial mapping of populations with highest risk of transmission is necessary

Investigation of mesoscale cloud features viewed by LANDSAT

The author has identified the following significant results. Some 50 LANDSAT images displaying mesoscale cloud features were analyzed. This analysis was based on the Rayleigh-Kuettner model describing the formation of that type of mesoscale cloud feature. This model lends itself to computation of the average wind speed in northerly flow from the dimensions of the cloud band configurations measured from a LANDSAT image. In nearly every case, necessary conditions of a curved wind profile and orientation of the cloud streets within 20 degrees of the direction of the mean wind in the convective layer were met. Verification of the results by direct observation was hampered, however, by the incompatibility of the resolution of conventional rawinsonde observations with the scale of the banded cloud patterns measured from LANDSAT data. Comparison seems to be somewhat better in northerly flows than in southerly flows, with the largest discrepancies in wind speed being within 8m/sec, or a factor of two

In the Interests of clients or commerce? Legal aid, supply, demand, and 'ethical indeterminacy' in criminal defence work

As a professional, a lawyer's first duty is to serve the client's best interests, before simple monetary gain. In criminal defence work, this duty has been questioned in the debate about the causes of growth in legal aid spending: is it driven by lawyers (suppliers) inducing unnecessary demand for their services or are they merely responding to increased demand? Research reported here found clear evidence of a change in the handling of cases in response to new payment structures, though in ways unexpected by the policy's proponents. The paper develops the concept of 'ethical indeterminacy' as a way of understanding how defence lawyers seek to reconcile the interests of commerce and clients. Ethical indeterminacy suggests that where different courses of action could each be said to benefit the client, the lawyer will tend to advise the client to decide in the lawyer's own interests. Ethical indeterminacy is mediated by a range of competing conceptions of 'quality' and 'need'. The paper goes on to question the very distinction between 'supply' and 'demand' in the provision of legal services

Hematoma Enlargement Among Patients with Traumatic Brain Injury: Analysis of a Prospective Multicenter Clinical Trial

Observational studies suggest that hematomas continue to enlarge during hospitalization in patients with traumatic brain injury (TBI). There is limited data regarding factors associated with hematoma enlargement and on whether hematoma enlargement contributes directly to death and disability in patients with TBI. We analyzed data collected as part of the Resuscitation Outcomes Consortium Hypertonic Saline and TBI Study. Hematoma enlargement was ascertained and collected as a predefined safety endpoint. We evaluated the effect of hematoma enlargement on the risk of death and disability at 6 months based on the Extended Glasgow Outcome Scale (GOSE) (dichotomized as \u3e4 or ≤4) using stepwise logistic regression analysis. We adjusted for age (continuous variable), admission GCS score (dichotomized at \u3e5 and ≤5), and computed tomography (CT) scan classification (Marshall grades entered as a categorical variable). Of the 1200 patients with severe TBI analyzed, 238 (19.8%) patients were reported to have hematoma enlargement as an adverse event. The proportion of patients who reached favorable outcome at 6 months was significantly lower (defined by GOSE of \u3e4) among patients with hematoma enlargement (29.0% vs. 40.1%, p\u3c.0001). The proportion of patients who died within 6 months was significantly higher among patients with hematoma enlargement (31.9% vs. 20.7%, p\u3c.0001). After adjusting for age, admission GCS score, and initial injury score, the odds of favorable outcome was lower in patients with hematoma enlargement (odds ratio 0.7, 95% confidence interval [CI]; 0.5–0.97). Our results suggest that hematoma enlargement may be a direct contributor to death and disability in patients with TBI at 6 months. Future clinical trials must continue to evaluate new therapeutic interventions aimed at reducing hematoma enlargement with a favorable risk benefit ratio in patients with TBI

Overexpression of Mouse D-Type Cyclins Accelerates G(1) Phase in Rodent Fibroblasts

Mammalian D-type cyclins are growth factor-regulated, delayed early response genes that are presumed to control progression through the G1 phase of the cell cycle by governing the activity of cyclin-dependent kinases (cdks). Overexpression of mouse cyclin D1 in serum-stimulated mouse NIH-3T3 and rat-2 fibroblasts increased their rates of G0 to S- and G1- to S-phase transit by several hours, leading to an equivalent contraction of their mean cell generation times. Although such cells remained contact inhibited and anchorage dependent, they manifested a reduced serum requirement for growth and were smaller in size than their normal counterparts. Ectopic expression of cyclin D2 in rodent fibroblasts, either alone or together with exogenous cdk4, shortened their G0- to S-phase interval and reduced their serum dependency, but cyclin D2 alone did not alter cell size significantly. When cells were microinjected during the G2 interval with a monoclonal antibody specifically reactive to cyclin D1, parental rodent fibroblasts and derivatives overexpressing this cyclin were inhibited from entering S phase, but cells injected near the G1/S phase transition were refractory to antibody-induced growth suppression. Thus, cyclin D1, and most likely D2, are rate limiting for G1progression

The Role of Corpus Callosum Development in Functional Connectivity and Cognitive Processing

The corpus callosum is hypothesized to play a fundamental role in integrating information and mediating complex behaviors. Here, we demonstrate that lack of normal callosal development can lead to deficits in functional connectivity that are related to impairments in specific cognitive domains. We examined resting-state functional connectivity in individuals with agenesis of the corpus callosum (AgCC) and matched controls using magnetoencephalographic imaging (MEG-I) of coherence in the alpha (8–12 Hz), beta (12–30 Hz) and gamma (30–55 Hz) bands. Global connectivity (GC) was defined as synchronization between a region and the rest of the brain. In AgCC individuals, alpha band GC was significantly reduced in the dorsolateral pre-frontal (DLPFC), posterior parietal (PPC) and parieto-occipital cortices (PO). No significant differences in GC were seen in either the beta or gamma bands. We also explored the hypothesis that, in AgCC, this regional reduction in functional connectivity is explained primarily by a specific reduction in interhemispheric connectivity. However, our data suggest that reduced connectivity in these regions is driven by faulty coupling in both inter- and intrahemispheric connectivity. We also assessed whether the degree of connectivity correlated with behavioral performance, focusing on cognitive measures known to be impaired in AgCC individuals. Neuropsychological measures of verbal processing speed were significantly correlated with resting-state functional connectivity of the left medial and superior temporal lobe in AgCC participants. Connectivity of DLPFC correlated strongly with performance on the Tower of London in the AgCC cohort. These findings indicate that the abnormal callosal development produces salient but selective (alpha band only) resting-state functional connectivity disruptions that correlate with cognitive impairment. Understanding the relationship between impoverished functional connectivity and cognition is a key step in identifying the neural mechanisms of language and executive dysfunction in common neurodevelopmental and psychiatric disorders where disruptions of callosal development are consistently identified

A Novel Mutation in the Upstream Open Reading Frame of the CDKN1B Gene Causes a MEN4 Phenotype

PubMed ID: 23555276This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Intimate partner violence, depression, and sexual behaviour among gay, bisexual and other men who have sex with men in the PROUD trial.

BACKGROUND: Little is known about the prevalence and correlates of intimate partner violence (IPV) among gay, bisexual and other men who have sex with men (GBMSM) in the UK. The aim of this study was to investigate the prevalence of IPV, associations of socio-economic and psychosocial factors with IPV, and the association of IPV with depression and sexual behaviour, among GBMSM in the PROUD trial of pre-exposure prophylaxis (PrEP). METHODS: PROUD enrolled 544 HIV-negative participants in England from 2012 to 2014; participants were randomised to immediate or deferred PrEP. This analysis included 436 GBMSM who had IPV data at month-12 and/or 24. Prevalence of IPV victimization and perpetration (lifetime, and in the past year) was assessed at these time-points. Generalized estimating equations were used to investigate associations with IPV, using pooled data from both time-points. RESULTS: At month-12 (N = 410), 44.9% of men reported ever being a victim of IPV, 15.6% in the last year, and 19.5% reported ever perpetrating IPV, 7.8% in the last year. At month-24 (N = 333), the corresponding prevalence was 40.2 and 14.7% for lifetime and past year IPV victimization and 18.0 and 6.9% for lifetime and past year IPV perpetration. IPV prevalence did not differ by randomised arm. Men reporting internalized homophobia and sexualized drug use were more likely to report IPV. Lifetime and last year experience of IPV victimization and perpetration were strongly associated with depressive symptoms (PHQ-9 ≥ 10) (adjusted for socio-demographics: lifetime IPV victimization PR 2.57 [95% CI: 1.71, 3.86]; past year IPV victimization PR 2.93 [95% CI: 1.96, 4.40]; lifetime IPV perpetration PR 2.87 [95% CI: 1.91, 4.32]; past year IPV perpetration PR 3.47 [95% CI: 2.13, 5.64], p < 0.001 for all); IPV was not consistently associated with measures of condomless anal sex or high partner numbers. CONCLUSIONS: GBMSM at high-risk of HIV who are seeking/taking PrEP may experience a high burden of IPV, which may be linked to depression. Training on awareness of and enquiry for IPV among GBMSM in sexual health clinics is recommended. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02065986 . Registered 19 February 2014 (retrospectively registered)