Live attenuated oral cholera vaccines

Live, orally administered, attenuated vaccine strains of Vibrio cholerae have many theoretical advantages over killed vaccines. A single oral inoculation could result in intestinal colonization and rapid immune responses, obviating the need for repetitive dosing. Live V. cholerae organisms can also respond to the intestinal environment and immunological exposure to in vivo expressed bacterial products, which could result in improved immunological protection against wild-type V. cholerae infection. The concern remains that live oral cholera vaccines may be less effective among partially immune individuals in cholera endemic areas as pre-existing antibodies can inhibit live organisms and decrease colonization of the gut. A number of live oral cholera vaccines have been developed to protect against cholera caused by the classical and El Tor serotypes of V. cholerae O1, including CVD 103-HgR, Peru-15 and V. cholerae 638. A number of live oral cholera vaccines have also been similarly developed to protect against cholera caused by V. cholerae O139, including CVD 112 and Bengal-15. Live, orally administered, attenuated cholera vaccines are in various stages of development and evaluation.     

Differential effects of cannabis extracts and pure plant cannabinoids on hippocampal neurones and glia

We have shown previously that the plant cannabinoid cannabidiol (CBD) elevates intracellular calcium levels in both cultured hippocampal neurones and glia. Here, we investigated whether the main psychotropic constituent of cannabis, Δ⁹-tetrahydrocannabinol (THC) alone or in combination with other cannabis constituents can cause similar responses, and whether THC affects the responses induced by CBD. Our experiments were performed with 1 μM pure THC (pTHC), with 1 μM pure CBD (pCBD), with a high-THC, low CBD cannabis extract (eTHC), with a high-CBD, low THC cannabis extract (eCBD), with a mixture of eTHC and eCBD (THC:CBD = 1:1) or with corresponding ‘mock extracts’ that contained only pTHC and pCBD mixed in the same proportion as in eTHC, eCBD or the 1:1 mixture of eTHC and eCBD.     

Enumeration of Gut-Homing β7-Positive,Pathogen-Specific Antibody-Secreting Cells in Whole Blood from Enterotoxigenic Escherichia coli- and Vibrio cholerae-Infected Patients,Determined Using an Enzyme-Linked Immunosorbent Spot Assay Technique

Vibrio cholerae and enterotoxigenic Escherichia coli (ETEC) are noninvasive mucosal pathogens that cause acute watery diarrhea in people in developing countries. Direct assessment of the mucosal immune responses to these pathogens is problematic. Surrogate markers of local mucosal responses in blood are increasingly being studied to determine the mucosal immune responses after infection. However, the volume of blood available in children and infants has limited this approach. We assessed whether an approach that first isolates β7-positive cells from a small volume of blood would allow measurement of the antigen-specific immune responses in patients with cholera and ETEC infection. β7 is a cell surface marker associated with mucosal homing. We isolated β7-expressing cells from blood on days 2, 7, and 30 and used an enzyme-linked immunosorbent spot (ELISPOT) assay to assess the gut-homing antibody-secreting cells (ASCs) specific to pathogen antigens. Patients with ETEC diarrhea showed a significant increase in toxin-specific gut-homing ASCs at day 7 compared to the levels at days 2 and 30 after onset of illness and to the levels in healthy controls. Similar elevations of responses to the ETEC colonization factors (CFs) CS6 and CFA/I were observed in patients infected with CS6- and CFA/I-positive ETEC strains. Antigen-specific gut-homing ASCs to the B subunit of cholera toxin and cholera-specific lipopolysaccharides (LPS) were also observed on day 7 after the onset of cholera using this approach. This study demonstrates that a simple ELISPOT assay can be used to study the mucosal immunity to specific antigens using a cell-sorting protocol to isolate mucosal homing cells, facilitating measurement of mucosal responses in children following infection or vaccination.     

Targeted loss of SHP1 in murine thymocytes dampens TCR signaling late in selection

SHP1 is a tyrosine phosphatase critical to proximal regulation of TCR signaling. Here, analysis of CD4‐Cre SHP1^fl/fl conditional knockout thymocytes using CD53, TCRβ, CD69, CD4, and CD8α expression demonstrates the importance of SHP1 in the survival of post selection (CD53⁺), single‐positive thymocytes. Using Ca²⁺ flux to assess the intensity of TCR signaling demonstrated that SHP1 dampens the signal strength of these same mature, postselection thymocytes. Consistent with its dampening effect, TCR signal strength was also probed functionally using peptides that can mediate selection of the OT‐I TCR, to reveal increased negative selection mediated by lower‐affinity ligand in the absence of SHP1. Our data show that SHP1 is required for the survival of mature thymocytes and the generation of the functional T‐cell repertoire, as its absence leads to a reduction in the numbers of CD4⁺ and CD8⁺ naïve T cells in the peripheral lymphoid compartments.     

Effects of once-daily darunavir/ritonavir versus atazanavir/ritonavir on insulin sensitivity in HIV-infected persons over 48 weeks: results of an exploratory substudy of METABOLIK,a phase 4, randomized trial

Background: The phase 4, METABOLIK trial demonstrated that changes in metabolic parameters with darunavir with low-dose ritonavir (DRV/r) were comparable to those observed with atazanavir with low-dose ritonavir (ATV/r). A comprehensive assessment of the effects of these agents on insulin sensitivity will provide additional, relevant clinical information.

Methods: In this substudy of METABOLIK, HIV-1–infected, antiretroviral agent–naïve male subjects aged ≥18 years with a viral load of >1,000 copies/mL were randomized to receive DRV/r 800/100 mg once daily (qd) or ATV/r 300/100 mg qd, both with a fixed dose of tenofovir disoproxil fumarate/emtricitabine 300/200 mg qd. The effects of DRV/r versus ATV/r on insulin sensitivity over 48 weeks were compared using the euglycemic hyperinsulinemic clamp, the preferred method to assess insulin sensitivity; primary end point was the effect on insulin sensitivity during the first 12 weeks.

Results: Twenty-seven subjects completed the study. In the DRV/r arm (n = 14), median glucose disposal from baseline through weeks 12 and 48 was 9.3, 11.4, and 9.9 mg/kg*min, respectively; in the ATV/r arm (n = 13), these values were 8.9, 8.6, and 9.1 mg/kg*min, respectively. Median insulin sensitivity in the DRV/r arm at baseline, week 12, and week 48 was 24.0, 25.0, and 21.5 mg/kg*min per μIU/mL?×?100, respectively; these values in the ATV/r arm were 20.7, 22.0, and 22.0 mg/kg*min per μIU/mL?×?100, respectively. Most subjects had ≥1 adverse event, including three serious adverse events (n = 2 [DRV/r], n = 1 [ATV/r]).

Conclusions: DRV/r and ATV/r displayed similar modest effects on insulin sensitivity using a euglycemic hyperinsulinemic clamp.     

Plasma HIV-1 RNA viral load rebound among people who inject drugs receiving antiretroviral therapy (ART) in a Canadian setting: an ethno-epidemiological study

Background

People who inject drugs (PWID) living with HIV often experience sub-optimal antiretroviral therapy (ART) treatment outcomes, including HIV plasma viral load (PVL) rebound. While previous studies have identified risk factors for PVL rebound among PWID, no study has examined the perspectives of PWID who have experienced PVL rebound episodes. We conducted an ethno-epidemiological study to investigate the circumstances surrounding the emergence of rebound episodes among PWID in Vancouver, BC, Canada.

Methods

Comprehensive clinical records linked to a community-based prospective observational cohort of HIV-positive drug users were used to identify PWID who had recently experienced viral rebound. In-depth qualitative interviews with 16 male and 11 female participants explored participant perspectives regarding the emergence of viral rebound. A timeline depicting each participant’s HIV viral load and adherence to ART was used to elicit discussion of circumstances surrounding viral rebound.

Findings

Viral rebound episodes were shaped by interplay between various individual, social, and environmental factors that disrupted routines facilitating adherence. Structural-environmental influences resulting in non-adherence included housing transitions, changes in drug use patterns and intense drug scene involvement, and inadequate care for co-morbid health conditions. Social-environmental influences on ART adherence included poor interactions between care providers and patients producing non-adherence, and understandings of HIV treatment that fostered intentional treatment discontinuation.

Conclusions

This study describes key pathways which led to rebound episodes among PWID receiving ART and illustrates how environmental forces may increase vulnerability for non-adherence leading to treatment failure. Our findings have potential to help inform interventions and supports that address social-structural forces that foster non-adherence among PWID.

     

Is physical activity a part of who I am? A review and meta-analysis of identity,schema and physical activity

Two parallel literatures on the physical activity (PA) identity and schema constructs have the potential to supplement traditional social cognitive approaches used for PA promotion. The purpose of this paper was to review schema/identity research and appraise its relationship with PA via meta-analysis followed by thematic analyses of its correlates, as well as its proposed mechanisms on PA. Eligible studies were from English, peer-reviewed published articles that examined identity and/or schema in the context of PA. Searches were completed in June 2015 in five databases. Sixty-two independent data-sets (32 available for meta-analysis), primarily of modest quality, were identified. Results of the random effects meta-analysis showed that the point-estimate between identity/schema and behaviour was r?=?.44 (CI?=?.39?.48), and invariant to selected study characteristics. Thematic review showed that identity/schema was associated with commitment, ability, affective judgments, identified/integrated regulation and social comparison and predicted intention, self-regulatory efficacy, and self-regulation strategy use. It had reliable evidence as a moderator of the intention–behavior relationship, was associated with increases in the speed of processing of relevant information and created negative affect under hypothetical identity–behavior discrepant situations. While this initial research is promising, more rigorous research designs, including interventions to increase identity/schema, are warranted.     

Ly49i2 is an inhibitory rat natural killer cell receptor for an MHC class Ia molecule (RT1-A1c)

We have exploited strain-specific differences in the NK allorecognition repertoires to generate rat monoclonal antibodies against receptors involved in the control of allogeneic responses by rat NK cells. The monoclonal antibody STOK2 binds to a homodimeric glycoprotein that has been implicated as an inhibitory receptor for an MHC molecule in the PVG strain. In the present study, we haveidentified this glycoprotein as a novel rat Ly49 receptor (Ly49i2) containing an immunoreceptor tyrosine-based inhibitory motif. Ligation of the Ly49i2 receptor induces inhibitory signals, and Ly49i2 coprecipitates with the inhibitory tyrosine phosphatase SHP-1 in stably transfected RNK-16 cells. Moreover, it inhibits natural killing of lymphoblast targets and transfected fibroblast targets expressingthe classical MHC class Ia allele RT1-A1(c). Ly49i2, therefore, is an inhibitory receptor for specific MHC class Ia molecules, similar to inhibitory members of the mouse Ly49 family.