Novel Alleles of gon-2, a C. elegans Ortholog of Mammalian TRPM6 and TRPM7, Obtained by Genetic Reversion Screens.

TRP (Transient Receptor Potential) cation channels of the TRPM subfamily have been found to be critically important for the regulation of Mg2+ homeostasis in both protostomes (e.g., the nematode, C. elegans, and the insect, D. melanogaster) and deuterostomes (e.g., humans). Although significant progress has been made toward understanding how the activities of these channels are regulated, there are still major gaps in our understanding of the potential regulatory roles of extensive, evolutionarily conserved, regions of these proteins. The C. elegans genes, gon-2, gtl-1 and gtl-2, encode paralogous TRP cation channel proteins that are similar in sequence and function to human TRPM6 and TRPM7. We isolated fourteen revertants of the missense mutant, gon-2(q338), and these mutations affect nine different residues within GON-2. Since eight of the nine affected residues are situated within regions that have high similarity to human TRPM1,3,6 and 7, these mutations identify sections of these channels that are potentially critical for channel regulation. We also isolated a single mutant allele of gon-2 during a screen for revertants of the Mg2+-hypersensitive phenotype of gtl-2(-) mutants. This allele of gon-2 converts a serine to phenylalanine within the highly conserved TRP domain, and is antimorphic against both gon-2(+) and gtl-1(+). Interestingly, others have reported that mutation of the corresponding residue in TRPM7 to glutamate results in deregulated channel activity.

Testing an optimized community-based human immunodeficiency virus (HIV) risk reduction and antiretroviral adherence intervention for HIV-infected injection drug users.

The authors conducted a preliminary study of the 4-session Holistic Health for HIV (3H+), which was adapted from a 12-session evidence-based risk reduction and antiretroviral adherence intervention. Improvements were found in the behavioral skills required to properly adhere to HIV medication regimens. Enhancements were found in all measured aspects of sex-risk reduction outcomes, including HIV knowledge, motivation to reduce sex-risk behavior, behavioral skills related to engaging in reduced sexual risk, and reduced risk behavior. Improvements in drug use outcomes included enhancements in risk reduction skills as well as reduced heroin and cocaine use. Intervention effects also showed durability from post-intervention to the follow-up assessment point. Females responded particularly well in terms of improvements in risk reduction skills and risk behavior. This study suggests that an evidence-based behavioral intervention may be successfully adapted for use in community-based clinical settings where HIV-infected drug users can be more efficiently reached.

A pilot survey of attitudes and knowledge about opioid substitution therapy for HIV-infected prisoners.

A majority of inmates in the state of Connecticut Department of Corrections use opioids or are opioid dependent before incarceration. None of the state's prisons offer opioid substitution therapy other than for detoxification or maintenance therapy for women during pregnancy. On release to the community, most prisoners relapse to drug use and this has been associated with higher recidivism rates, and less adherence to antiretroviral medications for HIV-infected persons. Nationally and internationally, methadone (METH) and buprenorphine (BUP) have been found to decrease relapse to drug use, decrease recidivism rates, improve adherence to antiretroviral medications, decrease HIV-risk taking behaviors, and improve mortality. However, the general knowledge about opioid substitution therapy among correctionalfacility staff has been reported as substandard. This pilot study compiled results of answers to anonymous surveys from 27 individuals who work directly with inmates in a patient-care capacity for the Connecticut Department of Corrections (CT DOC) and CT DOC case-management referral program (Project TLC) in the year 2006. The surveys included questions regarding current attitudes and knowledge about opioid substitution therapy for prisoners. A minority of respondents refer released prisoners with a history of opioid dependency to METH or BUP treatment. The majority of correctional workers and case-management referral workers did not have knowledge about BUP or METH's ability to improve health and decrease HIV risk taking behaviors. This study found that more education of individuals treating and caring for HIV-infected opioid dependent prisoners is needed.

Estimating GFR using serum cystatin C alone and in combination with serum creatinine: a pooled analysis of 3,418 individuals with CKD.

BACKGROUND: Serum cystatin C was proposed as a potential replacement for serum creatinine in glomerular filtration rate (GFR) estimation. We report the development and evaluation of GFR-estimating equations using serum cystatin C alone and serum cystatin C, serum creatinine, or both with demographic variables. STUDY DESIGN: Test of diagnostic accuracy. SETTING & PARTICIPANTS: Participants screened for 3 chronic kidney disease (CKD) studies in the United States (n = 2,980) and a clinical population in Paris, France (n = 438). REFERENCE TEST: Measured GFR (mGFR). INDEX TEST: Estimated GFR using the 4 new equations based on serum cystatin C alone, serum cystatin C, serum creatinine, or both with age, sex, and race. New equations were developed by using linear regression with log GFR as the outcome in two thirds of data from US studies. Internal validation was performed in the remaining one third of data from US CKD studies; external validation was performed in the Paris study. MEASUREMENTS: GFR was measured by using urinary clearance of iodine-125-iothalamate in the US studies and chromium-51-EDTA in the Paris study. Serum cystatin C was measured by using Dade-Behring assay, standardized serum creatinine values were used. RESULTS: Mean mGFR, serum creatinine, and serum cystatin C values were 48 mL/min/1.73 m(2) (5th to 95th percentile, 15 to 95), 2.1 mg/dL, and 1.8 mg/L, respectively. For the new equations, coefficients for age, sex, and race were significant in the equation with serum cystatin C, but 2- to 4-fold smaller than in the equation with serum creatinine. Measures of performance in new equations were consistent across the development and internal and external validation data sets. Percentages of estimated GFR within 30% of mGFR for equations based on serum cystatin C alone, serum cystatin C, serum creatinine, or both levels with age, sex, and race were 81%, 83%, 85%, and 89%, respectively. The equation using serum cystatin C level alone yields estimates with small biases in age, sex, and race subgroups, which are improved in equations including these variables. LIMITATIONS: Study population composed mainly of patients with CKD. CONCLUSIONS: Serum cystatin C level alone provides GFR estimates that are nearly as accurate as serum creatinine level adjusted for age, sex, and race, thus providing an alternative GFR estimate that is not linked to muscle mass. An equation including serum cystatin C level in combination with serum creatinine level, age, sex, and race provides the most accurate estimates.

Case series on the safe use of buprenorphine/naloxone in individuals with acute hepatitis C infection and abnormal hepatic liver transaminases.

BACKGROUND: Hepatitis C virus (HCV) is the most prevalent chronic viral illness in the United States. Many individuals with virus HCV are opioid dependent requiring treatment with opiate substitution treatment such as buprenorphine. Previous reports in the literature have suggested hepatotoxicity with buprenorphine tempering initial enthusiasm of the safety of buprenorphine in HCV-infected patients. METHODS: As part of an ongoing SAMHSA-funded grant to expand opiate substitution therapy with buprenorphine, all opioid-dependent patients seeking treatment with buprenorphine undergo a laboratory evaluation including transaminases (AST/ALT) as well as laboratory evaluation for acute and chronic hepatitis. RESULTS: Of the 121 patients screened for entry into buprenorphine treatment, 4 patients had evidence of acute HCV infection. CONCLUSIONS: Despite markedly elevated transaminases in the setting of acute hepatitis C infection, these patients tolerated buprenorphine treatment with improvement in their transaminases during the course of buprenorphine treatment.

Initial strategies for integrating buprenorphine into HIV care settings in the United States.

The Centers for Disease Control and Prevention's HIV Prevention Strategic Plan Through 2005 advocated for increasing the proportion of persons with human immunodeficiency virus (HIV) infection and in need of substance abuse treatment who are successfully linked to services for these 2 conditions. There is evidence that integrating care for HIV infection and substance abuse optimizes outcomes for patients with both disorders. Buprenorphine, a recently approved medication for the treatment of opioid dependence in physicians' offices, provides the opportunity to integrate the treatment of HIV infection and substance abuse in one clinical setting, yet little information exists on the models of care that will most successfully facilitate this integration. To promote the uptake of this type of integrated care, the current review provides a description of 4 recently implemented models for combining buprenorphine treatment with HIV primary care: (1) an on-site addiction/HIV specialist treatment model; (2) a HIV primary care physician model; (3) a nonphysician health professional model; and (4) a community outreach model.

Adherence to hepatitis B virus vaccination at syringe exchange sites.

Injection drug users (IDUs) are at high risk for hepatitis B virus (HBV); however, they often do not receive preventive vaccination. IDUs who use mobile health care services linked to a syringe exchange program in New Haven were routinely screened for HBV, hepatitis C virus, and syphilis. Individuals without prior exposure to HBV were offered three-part vaccination series. Of the 212 IDUs screened for HBV infection, 134 (63%) were eligible (negative for HBV surface and core anti-bodies) for vaccination and 10 (4.7%) had evidence of chronic HBV infection. Compared to those with previous exposure to HBV, vaccine-eligible patients were significantly more likely to be younger and use heroin and less likely to be black, home-less, daily injectors, and cocaine users. Of the 134 vaccine-eligible subjects, 103 (77%) and 89 (66%) completed two and three vaccinations, respectively. Correlates of completing all three vaccinations included older age (OR = 1.06, 95% CI = 1.04-1.07), injecting daily (OR = 2.12, 95% CI = 1.36-6.73), and being homeless (OR = 1.98, 95% CI = 1.14-12.27). These results suggest that IDUs remain at high risk for acquiring HBV infection. Programs that link health care to a syringe exchange program are effective ways to provide preventive health care services to IDUs, particularly HBV vaccination. Trust engendered by and mutual respect afforded by such programs result in repeated encounters by active IDUs over time.

Developing a directly administered antiretroviral therapy intervention for HIV-infected drug users: implications for program replication.

Directly administered antiretroviral therapy (DAART) is one approach to improving adherence to among human immunodeficiency virus (HIV)-infected drug users. We evaluated the essential features of a community-based DAART intervention in a randomized, controlled trial of DAART versus self-administered therapy. Of the initial 72 subjects, 78% were racial minorities, and 32% were women. Social and medical comorbidities among subjects included homelessness (35% of subjects), lack of interpersonal support (86%), major depression (57%), and alcoholism (36%). At baseline, the median CD4+ cell count was 403 cells/mL and the median HIV-1 RNA load was 146,333 copies/mL (log10 5.31 copies/mL). During the prior 6 months, 33% of subjects had missed a medical appointment, and 47% had visited an emergency department. Although most subjects (67%) preferred to take their own medications, 76% would accept DAART if it were made compulsory. A methadone clinic was the DAART venue acceptable to the fewest subjects (36%), and a mobile syringe-exchange program was acceptable to the most subjects (83%). Adherence was higher for supervised than for unsupervised medication administration (P<.0001), a finding that supports use of daily supervision of once-daily regimens. Moreover, DAART should incorporate enhanced elements such as convenience, flexibility, confidentiality, cues and reminders, responsive pharmacy and medical services, and specialized training for staff.