Studies on the effect of vanadate on endocytosis and shape changes in human red blood cells and ghosts

When amphipathic cationic drugs are added to intact human RBCs, the RBCs first undergo a stomatocytic shape change and then, if relatively large amounts of drug are added and if the metabolic state of the RBC is appropriate, endocytic vacuoles form. Vanadate has a structural similarity to the transition state of phosphate, which presumably accounts for its ability to inhibit phosphohydrolases, although other actions of vanadate have been described. Vanadate inhibited three forms of drug-induced endocytosis in intact RBCs despite the fact that the three drugs chosen (primaquine, chlorpromazine, and vinblastine) are known to have differing requirements for RBC ATP. Vanadate also inhibited the stomatocytic shape change produced by primaquine, chlorpromazine, and vinblastine, but not the stomatocytosis produced by low pH. Vanadate had no effect on RBC echinocytosis produced by lysophosphatidylcholine. In studying endocytosis in hypotonic, leaky, "white" ghosts, we discovered that vanadate inhibited only the endocytosis produced by Mg-ATP and not the endocytosis produced by manipulations that directly attack the cytoskeletal proteins. These findings suggest that ATP hydrolysis has a role in some forms of amphipathic cation-induced stomatocytosis and endocytosis in intact RBCs. In addition, studies in ghosts support the idea that Mg-ATP does indeed produce "energized" endocytosis dependent on utilization or hydrolysis of ATP.     

Molecular characterization of a high A2 beta thalassemia by direct sequencing of single strand enriched amplified genomic DNA

Two families, one of Anglo-Saxon-Dutch descent, and the other, West Indian black, have an atypical beta thalassemia characterized by an unusually high level of Hb A2 in the heterozygous state. Restriction endonuclease mapping showed a deletion of about 1.35 kilobase (kb) in the 5' region of the beta globin gene. Direct sequencing of a specific region of genomic DNA amplified by a new modification of the polymerase chain reaction defined the deletion to be 1,393 base pairs (bp) and to be the same in both families. The deletion extends from 485 bp 5' to the mRNA CAP site to the middle of the second intervening sequence. This deletion, together with three others previously described that remove the 5' end of the beta gene but leave the delta gene intact, are all associated with unusually high levels of Hb A2 in the heterozygous state.     

Intravenous and oral itraconazole versus intravenous amphotericin B deoxycholate as empirical antifungal therapy for persistent fever in neutropenic patients with cancer who are receiving broad-spectrum antibacterial therapy. A randomized, controlled trial

BACKGROUND: Amphotericin B deoxycholate is currently the standard empirical antifungal therapy in neutropenic patients with cancer who have persistent fever that does not respond to antibiotic therapy. However, this treatment often causes infusion-related and metabolic toxicities, which may be dose limiting. OBJECTIVE: To compare the efficacy and safety of itraconazole with those of amphotericin B as empirical antifungal therapy. DESIGN: An open randomized, controlled, multicenter trial, powered for equivalence. SETTING: 60 oncology centers in 10 countries. PATIENTS: 384 neutropenic patients with cancer who had persistent fever that did not respond to antibiotic therapy. INTERVENTION: Intravenous amphotericin B or intravenous itraconazole followed by oral itraconazole solution. MEASUREMENTS: Defervescence, breakthrough fungal infection, drug-related adverse events, and death. RESULTS: For itraconazole and amphotericin B, the median duration of therapy was 8.5 and 7 days and the median time to defervescence was 7 and 6 days, respectively. The intention-to-treat efficacy analysis of data from 360 patients showed response rates of 47% and 38% for itraconazole and amphotericin B, respectively (difference, 9.0 percentage points [95% CI, -0.8 to 19.5 percentage points]). Fewer drug-related adverse events occurred in the itraconazole group than the amphotericin B group (5% vs. 54% of patients; P = 0.001), and the rate of withdrawal because of toxicity was significantly lower with itraconazole (19% vs. 38%; P = 0.001). Significantly more amphotericin B recipients had nephrotoxicity (P < 0.001). Breakthrough fungal infections (5 patients in each group) and mortality rates (19 deaths in the itraconazole group and 25 deaths in the amphotericin B group) were similar. Sixty-five patients switched to oral itraconazole solution after receiving the intravenous formulation for a median of 9 days. CONCLUSIONS: Itraconazole and amphotericin B have at least equivalent efficacy as empirical antifungal therapy in neutropenic patients with cancer. However, itraconazole is associated with significantly less toxicity.     

Marijuana use in hepatitis C infection does not affect liver biopsy histology or treatment outcomes

BACKGROUND:

Marijuana smoking is prevalent among hepatitis C virus-infected patients. The literature assessing the influence of marijuana on liver disease progression and hepatitis C virus antiviral treatment outcomes is conflicting.

METHODS:

The authors evaluated hepatitis C virus RNA-positive patients followed at The Ottawa Hospital Viral Hepatitis Clinic (Ottawa, Ontario) from 2000 to 2009. Using The Ottawa Hospital Viral Hepatitis Clinic database and charts, information regarding demographics, HIV coinfection, alcohol use, liver biopsy results, treatment outcomes and self-reported marijuana use was extracted. Biopsy characteristics and hepatitis C virus antiviral treatment outcomes were assessed for association with categorized marijuana use by adjusted logistic regression; covariates were specified according to clinical relevance a priori.

RESULTS:

Information regarding marijuana use was available for 550 patients, 159 (28.9%) of whom were using marijuana at the time of first assessment. Biopsy fibrosis stage and marijuana use data were available for 377 of these 550 (F0-2=72.3%). Overall, marijuana use did not predict fibrosis stage, inflammation grade or steatosis. Sustained virological response and marijuana use data were available for 359 of the 550 cohort participants; a total of 211 (58.8%) achieved a sustained virological response. Marijuana use was not associated with premature interruption of therapy for side effects, the likelihood of completing a full course of therapy or sustained virological response.

CONCLUSION:

Marijuana use did not influence biopsy histology or alter key hard outcomes of hepatitis C virus antiviral therapy.     

Incidence of major depression diagnoses in the Canadian Armed Forces: longitudinal analysis of clinical and health administrative data

Social Psychiatry and Psychiatric Epidemiology - Major depression is a leading cause of morbidity in military populations. However, due to a lack of longitudinal data, little is known about the...