Activation of CD8 T cells predicts progression of HIV infection in women coinfected with hepatitis C virus.

BACKGROUND: Because activation of T cells is associated with human immunodeficiency virus (HIV) pathogenesis, CD4 and CD8 activation levels in patients coinfected with HIV and hepatitis C virus (HCV) may explain conflicting reports regarding effects of HCV on HIV disease progression. METHODS: Kaplan-Meier and multivariate Cox regression models were used to study the risk of incident clinical AIDS and AIDS-related deaths among 813 HCV-negative women with HIV infection, 87 HCV-positive nonviremic women with HIV coinfection, and 407 HCV-positive viremic women with HIV coinfection (median follow-up time, 5.2 years). For 592 women, the percentages of activated CD4 and CD8 T cells expressing HLA-DR (DR) and/or CD38 were evaluated. RESULTS: HCV-positive viremic women had a statistically significantly higher percentage of activated CD8 T cells (P < .001) and a statistically significantly higher incidence of AIDS compared with HCV-negative women (P < .001 [log-rank test]). The AIDS risk was greater among HCV-positive viremic women in the highest tertile compared with the lowest tertile (>43% vs <26%) of CD8(+)CD38(+)DR(+) T cells (hazard ratio, 2.94 [95% confidence interval, 1.50-5.77]; P = .001). This difference was not observed in the HCV-negative women (hazard ratio, 1.87 [95% confidence interval, 0.80-4.35]; P = .16). In contrast, CD4 activation predicted AIDS in both groups similarly. Increased percentages of CD8(+)CD38(-)DR(+), CD4(+)CD38(-)DR(-), and CD8(+)CD38(-)DR(-) T cells were associated with a >60% decreased risk of AIDS for HCV-positive viremic women and HCV-negative women. CONCLUSION: HCV-positive viremic women with HIV coinfection who have high levels of T cell activation may have increased risk of AIDS. Earlier treatment of HIV and HCV infection may be beneficial.

Functional alterations in protein kinase C beta II expression in melanoma.

Protein kinase C (PKC) is a heterogeneous family of serine/threonine protein kinases that have different biological effects in normal and neoplastic melanocytes (MCs). To explore the mechanism behind their differential response to PKC activation, we analyzed the expression profile of all nine PKC isoforms in normal human MCs, HPV16 E6/E7 immortalized MCs, and a panel of melanoma cell lines. We found reduced PKCbeta and increased PKCzeta and PKCiota expression at both the protein and mRNA levels in immortalized MCs and melanoma lines. We focused on PKCbeta as it has been functionally linked to melanin production and oxidative stress response. Re-expression of PKCbeta in melanoma cells inhibited colony formation in soft agar, indicating that PKCbeta loss in melanoma is important for melanoma growth. PKCbetaII, but not PKCbetaI, was localized to the mitochondria, and inhibition of PKCbeta significantly reduced UV-induced reactive oxygen species (ROS) in MCs with high PKCbeta expression. Thus alterations in PKCbeta expression in melanoma contribute to their neoplastic phenotype, possibly by reducing oxidative stress, and may constitute a selective therapeutic target.

Evaluating the impact of hepatitis C virus (HCV) on highly active antiretroviral therapy-mediated immune responses in HCV/HIV-coinfected women: role of HCV on expression of primed/memory T cells.

OBJECTIVE: To evaluate the impact of hepatitis C virus (HCV) on the immune system before receipt of highly active antiretroviral therapy (HAART) and on immune recovery after receipt of HAART among human immunodeficiency virus (HIV)/HCV-coinfected women enrolled in the Women's Interagency HIV Study. METHODS: The study included 294 HIV-infected women who initiated HAART and attended 2 follow-up visits. The women were grouped on the basis of positive HCV antibody and HCV RNA tests. There were 148 women who were HCV antibody negative, 34 who were HCV antibody positive but RNA negative, and 112 who were HCV antibody and RNA positive. Immune recovery was measured by flow-cytometric assessment for markers of activation and maturation on CD4+ and CD8+ T cells. Data analysis used repeated measures of variance.Results. HIV/HCV coinfection is associated with an increased number of CD4+ and CD8+ primed/memory T cells. HIV/HCV coinfection, however, did not affect any further decreases in CD4+ or CD4+ and CD8+ naive/memory T cell counts or enhanced T cell activation. HIV/HCV coinfection also did not affect HAART responses in the CD4+ and CD8+ T cell compartment. CONCLUSIONS: HCV does not affect immune responses to HAART in HIV/HCV-coinfected individuals but is associated with an expansion of CD4+ and CD8+ memory T cell subsets. Functional impairment in the CD4+ and CD8+ T cell compartments still needs to be assessed in coinfected patients.

Dual atypical neuroleptic use: prescribing patterns at a Veterans Affairs outpatient clinic.

The use of two atypical neuroleptics (ANs) in a single patient is rising. In the study described herein, 57 patients receiving dual ANs were retrospectively evaluated at a Veterans Affairs outpatient medical center in South Carolina. Only 3% of all patients receiving ANs were prescribed two such drugs, and only 58% of patients taking dual ANs met the age-specific criteria for addition of a second drug. In 90% of cases, both prescriptions were written by the same prescriber. No evidence was noted of lack of communication between two prescribers treating the same patient.

Assessment of clinical pharmacist management of lipid-lowering therapy in a primary care setting.

BACKGROUND: Pharmacists have been shown to positively impact the outcomes of care for treatment of many different kinds of disease states. In particular, pharmacist-run lipid clinics have enjoyed varying degrees of success, depending on the outcome assessed. At our hospital, when a patient is transferred to the pharmacist-coordinated lipid clinic, the primary care pharmacist is responsible for ordering and interpreting labs and prescribing and monitoring lipid-altering therapy. OBJECTIVE: This study was designed to assess if there is a statistically significant difference between the magnitude of serum cholesterol reduction for patients receiving lipid-altering pharmacotherapy when clinically trained pharmacists are actively prescribing and adjusting the drug therapy compared to other health care practitioners (usual care). METHODS: Patient records from the hospital computer databases were retrospectively and randomly selected for analysis. Following evaluation for inclusions and exclusions, 41 patient records remained for statistical analysis for the cohort group, and 47 records remained from the group of patients managed by a clinical pharmacist. RESULTS: Management of dyslipidemia by a clinical pharmacist was associated with a significant reduction in overall mean low-density lipoprotein (LDL, 18.5%) compared to the cohort that did not have a clinical pharmacist as the primary manager of dyslipidemia (6.5%, P=0.049). This suggests improved clinical outcomes, defined as greater LDL reduction, when clinical pharmacists participate in lipid management, including drug prescribing. The magnitude reduction in LDL was found to be related to the number of clinical pharmacy visits (11.4% for 1 visit, 23.2% for 2 visits, and 23.7% for >3 visits), compared to the usual care group (-11.0%, 18.0%, and 7.4%; statistically significant, P=0.038, for >3 visits only). These results occurred even though the group of dyslipidemic patients managed primarily by a clinical pharmacist contained a statistically greater number of patients with 2 or more risk factors and high-density lipoprotein (HDL) levels less than 40 mg/dL. CONCLUSION: Interdisciplinary medical teams that include clinical pharmacists who are actively prescribing and adjusting lipid drug therapy may achieve greater reductions in LDL for patients who have been assessed with multiple risk factors compared to patients managed without clinical pharmacists. Active participation by clinical pharmacists in lipid management for patients with elevated LDL resulted in improved treatment success as measured by the magnitude reduction in LDL. The reduction in LDL was between 5% and 22% per visit greater for patients being treated by clinical pharmacists versus usual care, even in a patient population with more risk factors. These intermediate outcomes may translate into long-term outcomes in fewer cardiovascular events, improved quality of life for patients with dyslipidemia, and lower costs associated with sequelae of dyslipidemias.

Gabapentin for the treatment of ethanol withdrawal.

Benzodiazepines (BZDs) are the drug of choice for the suppression of alcohol withdrawal symptoms. Gabapentin, a drug approved for use as adjunctive therapy in the treatment of partial seizures, has none of the BZD-type difficulties (drug interactions, abuse potential). We retrospectively report on the use of gabapentin for ethanol withdrawal in 49 patients. Thirty-one patients were treated in the outpatient program and 18 in the general inpatient psychiatric unit. Positive outcomes as evidenced by completion of gabapentin therapy were achieved in 25 out of 31 outpatients and 17 out of 18 inpatients. Statistical significance was reached regarding the positive relationship between prior ethanol use and inpatient "as needed" benzodiazepine use. Both sets of data suggest that gabapentin works well for the mild to moderate alcohol withdrawal patient.

Nonsteroidal antiinflammatory drug starter packs for chronic musculoskeletal pain.

STUDY OBJECTIVE: To determine whether prescribing a nonsteroidal antiinflammatory drug (NSAID) starter pack for chronic musculoskeletal pain expedites the process of finding an appropriate drug for a given patient. DESIGN: Prospective patient interviews. SETTING: Veterans Affairs Medical Center. PATIENTS: Sixty-four patients with chronic musculoskeletal pain were prescribed NSAID starter packs. Of those, 42% were interviewed and their data evaluated. INTERVENTION: Between March and June 2001, patients received starter packs containing 1-week supplies of the following NSAIDs: ibuprofen, salsalate, etodolac, naproxen, sulindac, and piroxicam. The patients took one drug each week, then returned to their providers to receive a prescription for the agent that was considered most effective and tolerable. MEASUREMENTS AND MAIN RESULTS: Patients assessed pain each day based on a numeric pain-rating scale. During telephone interviews, seven patients reported better pain control when they were able to select a drug from the starter pack than when they were prescribed a specific drug by their providers. Providers rated the starter pack as easy to use by patients and generally effective for finding the best NSAID for a particular patient. Drugs prescribed after completing the starter pack were salsalate 25.9%, piroxicam 22.2%, etodolac 14.8%, ibuprofen 14.8%, naproxen 11.1%, celecoxib 7.4%, and an opiate 3.7%. CONCLUSION: The NSAID starter pack appears to be a successful method for quickly and easily finding an NSAID that is effective and tolerated.

Nefazodone in the treatment of patients with post-traumatic stress disorder.

Post-traumatic stress disorder occurs in patients who have undergone a traumatic experience and manifests itself through a cluster of symptoms, including re-experiencing, avoidance and hyperarousal. Post-traumatic stress disorder is commonly found among veterans of war and victims of sexual trauma, natural disasters and accidents. Nefazodone is a medication that has an FDA-approved indication for treating depression. Nefazodone has also been reported to be efficacious in treating post-traumatic stress disorder. Despite recent reports of hepatotoxicity, when used appropriately, nefazodone is generally as well-tolerated as the medications currently FDA-indicated for post-traumatic stress disorder, the selective serotonin reuptake inhibitors. Through its mechanism inhibiting neuronal uptake of serotonin and norepinephrine and as a potent postsynaptic serotonergic antagonist, nefazodone has proven to be effective in treating post-traumatic stress disorder in several open-label trials. The results of such trials warrant its study in larger, double-blind, placebo-controlled clinical trials.