Efficacy of naltrexone treatment with combined crack and opiate users: A descriptive study of a new treatment service in Bristol,UK

Naltrexone has been shown to be clinically effective in treating opioid dependence, although there are reports that it may be unsafe in treatment of unselected cases. Although there are no generally accepted pharmacological treatments for crack cocaine addiction alone, there is evidence that naltrexone can be useful in cases of concurrent cocaine and heroin use. In 2005 Bristol Specialist Drug Service initiated a naltrexone treatment programme targeted at pre-release offenders using both crack cocaine and heroin. Of 172 referrals, only 51 (30%) were inducted into treatment, and only 16% of these were retained at 3 months, and 4% at 9 months. There was evidence to support induction in prison, as 90% of those who were inducted there continued treatment on release. An integrated approach between criminal justice and community services is of primary importance in getting users into treatment. Interviews highlighted that the environment outside of prison can trigger relapse, and that community clinics need to separate clients on an abstinence programme from those who continue to use. Of clients interviewed, 52% reported that they use heroin to mitigate severe come down from crack, and it is suggested that naltrexone may be of use for these specialized combined users.     

Impact of Glycemic Control Strategies on the Progression of Diabetic Peripheral Neuropathy in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) Cohort

OBJECTIVE

The Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial demonstrated similar long-term clinical effectiveness of insulin-sensitizing (IS) versus insulin-providing (IP) treatments for type 2 diabetes on cardiovascular outcomes in a cohort with documented coronary artery disease. We evaluated the effects of randomized glycemic control strategy (IS vs. IP) on the prevalence and incidence of diabetic peripheral neuropathy (DPN).

RESEARCH DESIGN AND METHODS

DPN (defined as Michigan Neuropathy Screening Instrument [MNSI] clinical examination score >2) was assessed at baseline and yearly for 4 years. DPN prevalence and incidence were compared by intention-to-treat modeling by logistic generalized estimating equation models for prevalence and Kaplan-Meier estimates and Cox regression models for incidence rates.

RESULTS

Results are reported for 2,159 BARI 2D participants (70% males) with valid baseline and at least one follow-up MNSI score (mean age 62 ± 9 years, mean HbA_1c 7.7 ± 1.6%, diabetes duration 10 ± 9 years). There were no differences in the prevalence of DPN between the IS and the IP groups throughout the 4 years of follow-up. In 1,075 BARI 2D participants with no DPN at baseline, the 4-year cumulative incidence rate of DPN was significantly lower in the IS (66%) than in the IP (72%) strategy group (P = 0.02), which remained significant after adjusting for the in-trial HbA_1c (P = 0.04). In subgroup analyses, IS strategy had a greater benefit in men (hazard ratio 0.75 [99% CI 0.58–0.99], P < 0.01).

CONCLUSIONS

Among patients with type 2 diabetes followed for up to 4 years during BARI 2D, a glycemic control therapy with IS significantly reduced the incidence of DPN compared with IP therapy and may add further benefit for men.Diabetic peripheral neuropathies (DPNs) are consequences of diabetes-induced large and small, myelinated and unmyelinated, nerve fiber injury and are among the most common and perplexing complications of diabetes. Although the clinical manifestations, pattern of neurological deficits, symptoms, and clinical course are quite heterogeneous, DPN ultimately affects >50% of patients with diabetes (1). DPN is a major cause of disability and is associated with high mortality and poor quality of life (1). Patients with DPN have a 25% cumulative risk of a lower-extremity amputation (2). The 3-year survival rate in patients with DPN is 20% less than in age- and sex-matched diabetic patients without this complication (1,2).Intensive glucose control has proven efficacy in delaying or preventing DPN in type 1 diabetes (T1DM) (3–5) but with less evidence for benefit in patients with type 2 diabetes (T2DM). In any case, most people with diabetes do not reach and maintain the glycemic levels needed to achieve these benefits (5–7). Despite promising preclinical data, large-scale pharmacologic interventions for established DPN have been disappointing. To date, no disease-modifying treatment other than glycemic control is available for DPN.The Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial enrolled 2,368 participants with both T2DM and angiographically documented coronary artery disease (CAD). Participants were randomly assigned in a factorial design to either prompt revascularization or initial intensive medical therapy for CAD and to either insulin-sensitizing (IS) or insulin-providing (IP) drugs for glycemic control (8). The primary outcomes of BARI 2D have been reported (8). BARI 2D offered a unique opportunity to compare the effects of IS versus IP strategies on DPN outcomes among participants with T2DM and stable CAD.In a previous cross-sectional analysis of the baseline DPN evaluations, we found that ∼50% of BARI 2D participants had DPN at baseline. Multivariate analysis showed that insulin use was associated with a higher prevalence of DPN, whereas IS use was associated with a trend for lower prevalence of DPN (9). The aim of the present longitudinal analysis was to determine whether after a 4-year follow-up, an IP-based strategy differed from an IS-based strategy with regard to the incidence of DPN onset and remission in the BARI 2D participants according to the absence or presence of DPN at baseline, respectively.     

Illicit Drug Use From Adolescence to Young Adulthood Among Child Welfare-Involved Youths

This study examined illicit substance use among 1,004 adolescents, ages 11–21, involved with the Child Welfare System (CWS) and followed from 1999 to 2007. By the time they reached transition age, more than 60% of the sample had used an illicit substance in their lifetime. Predictors of regular use during adolescence were having a prior CWS report, externalizing behavior problems, delinquency, and any sexual experience. Exposure to physical abuse was predictive of escalating substance use trajectories. Protective factors included having a child at any point during the study, parental monitoring, and being placed in kinship care.     

Perceived racial, socioeconomic and gender discrimination and its impact on contraceptive choice

Background

The study was conducted to determine whether perceived racial, economic and gender discrimination has an impact on contraception use and choice of method.

Methods

We analyzed the first 2,500 women aged 14–45 years enrolled in the Contraceptive CHOICE Project, a prospective cohort study aimed to reduce barriers to obtaining long-acting reversible contraception. Items from the “Experiences of Discrimination” (EOD) scale measured experienced race-, gender- and economic-based discrimination.

Results

Overall, 57% of women reported a history of discrimination. Thirty-three percent reported gender- or race-based discrimination, and 24% reported discrimination attributed to socioeconomic status (SES). Prior to study enrollment, women reporting discrimination were more likely to report any contraception use (61% vs. 52%, p<.001) but were more likely to use less effective methods (e.g., barrier methods, natural family planning or withdrawal; 41% vs. 32%, p<.001). In adjusted analyses, gender-, race- or SES-based discrimination were associated with increased current use of less effective methods [adjusted risk ratio (aRR) 1.22, 95% confidence interval (CI) 1.06–1.41; aRR 1.25, CI 1.08–1.45; aRR 1.23, CI 1.06–1.43, respectively]. After enrollment, 66% of women with a history of experience of discrimination chose a long-acting reversible contraceptive method (intrauterine device or implantable) and 35% chose a depo-medroxyprogesterone acetate or contraceptive pill, patch or ring.

Conclusions

Discrimination negatively impacts a woman's use of contraception. However, after financial and structural barriers to contraceptive use were eliminated, women with EOD overwhelmingly selected effective methods of contraception. Future interventions to improve access and utilization of contraception should focus on eliminating barriers and targeting interventions that encompass race-, gender- and economic-based discrimination.     

Brown spider (Loxosceles intermedia) venom triggers endothelial cells death by anoikis

Brown spider (Loxosceles sp.) venom affects the endothelium of vessels and triggers disruptive activity in the subendothelial matrix. The vascular disorders observed after venom exposure include leukocyte and platelet activation, disseminated intravascular coagulation, an increase in vessel permeability and hemorrhage into the dermis. In this study, we report additional evidence regarding the mechanism of endothelial cell cytotoxicity induced by Loxosceles intermedia venom. Exposure to venom led to endothelial cell detachment in a time-dependent manner. Loss of cell anchorage and cell-cell adhesion following venom exposure was accompanied by changes in the distribution of the α₅β₁ integrin and VE-cadherin. An ultrastructural analysis of cells treated with venom revealed morphological alterations characteristic of apoptosis. Moreover, after venom exposure, the ratio between Bax and Bcl-2 proteins was disturbed in favor of Bax. In addition, late apoptosis was only observed in cells detached by the action of venom. Accordingly, there was no increase in apoptosis when cells were exposed to L. intermedia venom in suspension, suggesting that the loss of cell anchorage provides the signal to initiate apoptosis. Thus, L. intermedia venom likely triggers endothelial cell death indirectly through an apoptotic mechanism known as anoikis.     

IFN-γ is essential for the inhibition of B16BL6 melanoma lung metastasis in chronic alcohol drinking mice

We previously found that chronic alcohol consumption (20% w/v in drinking water) that models the level consumed by human alcoholics, when administered to female C57BL/6 mice inhibits B16BL6 melanoma metastasis to the lung; however, the mechanism is not known. Chronic alcohol consumption increases IFN-γ producing NK, NKT, CD4⁺, and CD8⁺ T cells. To examine the impact of IFN-γ on metastasis, we inoculated B16BL6 melanoma cells i.v. into control and chronic alcohol drinking IFN-γ knockout (KO) mice. Knockout of the ifn-γ gene abrogated the anti-metastatic effects associated with alcohol consumption. We examined metastasis in common gamma-chain (γC) KO mice, which are deficient in NK, NKT and CD8⁺ T cells, and in Vα14Jα281^−/− KO mice, which are deficient in invariant NKT (iNKT) cells, in order to assess the importance of specific IFN-γ producing cell types to this effect. We found that the antimetastatic effect of alcohol was still present in γC KO mice and also in γC KO mice depleted of Gr-1⁺ cells. Knockout of iNKT cells reduced the degree but not the antimetastatic effect associated with alcohol. These results indicate that the antimetastatic effect induced by chronic alcohol consumption is IFN-γ dependent and that multiple IFN-γ producing cell types contribute to this effect.     

A phase II study of adoptive immunotherapy using dendritic cells pulsed with tumor lysate in patients with hepatocellular carcinoma

This is a phase II clinical trial investigating the safety and efficacy of intravenous vaccination with mature autologous dendritic cells (DCs) pulsed ex vivo with a liver tumor cell line lysate (HepG2) in patients with advanced hepatocellular carcinoma (HCC). HCC is an attractive target for immunotherapy as evidenced by an active recruitment of tumor-infiltrating lymphocytes that are capable of lysing autologous tumor cells in ex vivo studies. DCs are the most potent antigen-presenting cells, with the capacity to take up, process, and present tumor antigens to T cells and stimulate an immune response, thus providing a rational platform for vaccine development. Thirty-five patients with advanced HCC and not suitable for radical or loco-regional therapies received a maximum of six DC vaccinations each at 3-week intervals. In total, 134 DC infusions were administered with no significant toxicity and no evidence of autoimmunity. Twenty-five patients who received at least three vaccine infusions were assessed clinically for response. The radiologically determined disease control rate (combined partial response and stable disease >or=3 months) was 28%. In 17 patients the baseline serum alpha-fetoprotein (AFP) was >or= 1,000 ng/mL; in four of these patients, it fell to <30% of baseline following vaccination. In one patient there was a radiological partial response associated with a fall in AFP to <10% of baseline. Immune responses were assessed using an ELIspot assay of interferon-gamma (IFN-gamma) release. In several cases there was induction of T cell responses to the vaccine and/or AFP following vaccination. CONCLUSION: Autologous DC vaccination in patients with HCC is safe and well tolerated with evidence of antitumor efficacy assessed radiologically and serologically, with generation of antigen-specific immune responses in some cases.