A systematic review and meta-analysis of the relative efficacy and safety of treatment regimens for HIV-associated cerebral toxoplasmosis: is trimethoprim-sulfamethoxazole a real option?

OBJECTIVES: The objective of this study was to perform a systematic review and meta-analysis of the literature to evaluate the efficacy and safety of therapies for cerebral toxoplasmosis in HIV-infected adults. The pyrimethamine plus sulfadiazine (P-S) combination is considered the mainstay therapy for cerebral toxoplasmosis and pyrimethamine plus clindamycin (P-C) is the most common alternative treatment. Although trimethoprim-sulfamethoxazole (TMP-SMX) has potential advantages, its use is infrequent. METHODS: We searched PubMed and four other databases to identify randomized controlled trials (RCTs) and cohort studies. Two independent reviewers searched the databases, identified studies and extracted data. Risk ratios (RRs) were pooled across studies using random-effects models. RESULTS: Nine studies were included (five RCTs, three retrospective cohort studies and one prospective cohort study). In comparison to P-S, treatment with P-C or TMP-SMX was associated with similar rates of partial or complete clinical response [P-C: RR 0.87; 95% confidence interval (CI) 0.70-1.08; TMP-SMX: RR 0.97; 95% CI 0.78-1.21], radiological response (P-C: RR 0.92; 95% CI 0.82-1.03), skin rash (P-C: RR 0.81; 95% CI 0.56-1.17; TMP-SMX: RR 0.17; 95% CI 0.02-1.29), gastrointestinal impairment (P-C: RR 5.16; 95% CI 0.66-40.11), and drug discontinuation because of adverse events (P-C: RR 0.32; 95% CI 0.07-1.47). Liver impairment was more frequent with P-S than P-C (P-C vs. P-S: RR 0.48; 95% CI 0.24-0.97). CONCLUSIONS: The current evidence fails to identify a superior regimen in terms of relative efficacy or safety for the treatment of HIV-associated cerebral toxoplasmosis. Use of TMP-SMX as preferred treatment may be consistent with the available evidence and other real-world considerations. Larger comparative studies are needed.

Obesity-related insulin resistance in adolescents: a systematic review and meta-analysis of observational studies.

Insulin resistance is common among obese adolescents; however, the extent of this problem is not clear. We conducted a systematic review of PubMed-Medline, CINAHL, The Web of Science, EMBASE and Scopus for observational studies evaluating components defining insulin resistance (insulin, C-peptide and homeostatic model assessment-insulin resistance [HOMA-IR]) in obese adolescents (12-18 years) versus non-obese adolescents. Our systematic review and meta-analysis followed the PRISMA guidelines. Data were combined using a random-effects model and summary statistics were calculated using the mean differences (MDs). 31 studies were included (n = 8655). In 26 studies, fasting insulin levels were higher in obese adolescents when compared to non-obese adolescents (MD = 64.11 pmol/L, 95%CI 49.48-78.75, p < 0.00001). In three studies, fasting C-peptide levels were higher in obese adolescents when compared to non-obese adolescents (MD = 0.29 nmol/L, 95%CI 0.22-0.36, p < 0.00001). In 24 studies, HOMA-IR values were higher in obese adolescents when compared to non-obese adolescents (MD = 2.22, 95%CI 1.78-2.67, p < 0.00001). Heterogeneity of effects among studies was moderate to high. Subgroup analyses showed similar results to the main analyses. Circulating insulin and C-peptide levels and HOMA-IR values were significantly higher in obese adolescents compared to those non-obese.

Meta-analysis of the association between obstructive sleep apnoea and postoperative outcome.

BACKGROUND: Obstructive sleep apnoea (OSA) is often undiagnosed before elective surgery and may predispose patients to perioperative complications. METHODS: A literature search of PubMed-Medline, Web of Science, Scopus, EMBASE, Cochrane Database of Systematic Reviews, and Cochrane Central Register of Controlled Trials up to November 2010 was conducted. Our search was restricted to cohort or case-control studies in adults diagnosed with OSA by screening questionnaire, oximetry, or polysomnography. Studies without controls, involving upper airway surgery, and with OSA diagnosed by ICD-9 codes alone were excluded. The primary postoperative outcomes were desaturation, acute respiratory failure (ARF), reintubation, myocardial infarction/ischaemia, arrhythmias, cardiac arrest, intensive care unit (ICU) transfer, and length of stay. RESULTS: Thirteen studies were included in the final analysis (n=3942). OSA was associated with significantly higher odds of any postoperative cardiac events [45/1195 (3.76%) vs 24/1420 (1.69%); odds ratio (OR) 2.07; 95% confidence interval (CI) 1.23-3.50, P=0.007] and ARF [33/1680 (1.96%) vs 24/3421 (0.70%); OR 2.43, 95% CI 1.34-4.39, P=0.003]. Effects were not heterogeneous for these outcomes (I(2)=0-15%, P>0.3). OSA was also significantly associated with higher odds of desaturation [189/1764 (10.71%) vs 105/1881 (5.58%); OR 2.27, 95% CI 1.20-4.26, P=0.01] and ICU transfer [105/2062 (5.09%) vs 58/3681 (1.57%), respectively; OR 2.81, 95% CI 1.46-5.43, P=0.002]. Both outcomes showed a significant degree of heterogeneity of the effect among studies (I(2)=57-68%, P<0.02). Subgroup analyses had similar conclusions as main analyses. CONCLUSIONS: The incidence of postoperative desaturation, respiratory failure, postoperative cardiac events, and ICU transfers was higher in patients with OSA.

Metabolism of 5 alpha reduced androgens by various tissues of the male rat.

Since an animal model for the study of peripheral androgen metabolism is needed, we studied the metabolism of 5 alpha-reduced androgens in various tissues of the rat. Labeled DHT and 3 alpha androstanediol (3 alpha diol) were added to tissue minces of male rat scrotal skin, muscle, prostate, or liver. Conversion ratios of the interconverting pair DHT in equilibrium with 3 alpha diol or the formation of the respective glucuronides (G) were determined over a 3 h period. Major differences in the activity and the oxidation/reduction relationship were observed between tissues. Scrotal skin was very active and balanced in the DHT in equilibrium with 3 alpha diol interconversion (31 and 33%/100 mg/3 h, respectively, whereas liver was minimally active (3.1/2.7%). 3 alpha reduction was prominent in muscle (37.0/2.7%), although 3 alpha oxidation was more active in prostate (6.0/31.5%). Steroid glucuronidation also differed in the various tissues. Sexual skin formed about 2% 3 alpha diol G, but much smaller amounts of DHTG. Liver, muscle, and prostate formed minimal (less than 0.2%) 3 alpha diol G, although liver synthesized 1.2% of DHTG. Addition of DHT or 3 alpha diol increased formation of the respective glucuronides by liver, whereas DHT blocked the synthesis of 3 alpha diol G, and 3 alpha diol markedly increased formation of 3 alpha diol G in skin. These studies indicate a similarity in DHT metabolism between rat and human sexual skin and a high rate of glucuronidation compared with other tissues. The pathway of 3 alpha diol G formation in skin is DHT----3 alpha diol----3 alpha diol G. Steroid 3 alpha oxidase is more active than 3 alpha reductase in muscle whereas 3 alpha oxidase predominates in prostate. This may be a mechanism whereby DHT levels and action as a nuclear androgen is favored in prostate, whereas testosterone is the major androgen in muscle.(ABSTRACT TRUNCATED AT 250 WORDS)

Tumor necrosis factor and interleukin-1 stimulate testosterone secretion in adult male rat Leydig cells in vitro.

The actions of two cytokines, tumor necrosis factor (TNF) and interleukin-1 (IL-1), on testosterone production by dispersed adult testis cells and purified Leydig cells in culture were studied. In one set of experiments, testis cells from adult (90-day-old) rats were enzymatically dispersed. In another set of experiments, the dispersed testis cells were placed on a Percoll density gradient and were centrifuged to yield purified (greater than 85%) Leydig cells. Both whole testis cells and purified Leydig cells were cultured in the presence of varying doses of TNF or IL-1 with or without maximally stimulating doses of human chorionic gonadotropin (hCG). Both TNF and IL-1 stimulated basal secretion of testosterone in whole testis cells, as well as purified Leydig cells. Additionally, both TNF and IL-1 augmented maximally hCG stimulated testosterone secretion. Both cytokines stimulated testosterone secretion by dispersed testis cells as early as 4 hours, and the effect continued for up to 72 hours. The cytokines slightly, but significantly, stimulated testosterone production in purified Leydig cells after 24 hours, and continued for up to 72 hours. We have concluded from this data that TNF and IL-1 stimulate the testosterone secretion by adult rat Leydig cells. While this effect might be mediated through the action of the cytokines on testicular macrophages, there might also be a direct effect on the Leydig cell since augmentation of secretion occurred in purified Leydig cells, as well as whole testis cells. Therefore, TNF and IL-1 may serve as local regulators of Leydig cell function.

Conversion of dihydrotestosterone to androstanediol glucuronide by female sexual skin.

Sexual skin biopsies from 13 normal women were obtained and minces/3-h studied after adding either [3H]dihydrotestosterone (DHT) or [3H]androstanediol (3 alpha diol) to RPMI-1640 medium in a Dubnoff apparatus. Unconjugated or conjugated androgens (after hydrolysis) were purified by three chromatography steps. Formation of 3 alpha diol and 3 alpha diol glucuronide (3 alpha diolG) was linear with time. The conversion of DHT to DHT17 beta G was only 4.4 +/- 0.5%/200 mg/3 h, while conversion to 3 alpha diol was 32 +/- 1.7%. The back conversion of 3 alpha diol to DHT was 30 +/- 3% and conversion to 3 alpha diolG was 4.5 +/- 1.25%. The product of the conversion separately measured of DHT to 3 alpha diol and 3 alpha diol to 3 alpha diolG was 1.5%, which is not very different than the overall conversion rate of DHT to 3 alpha diolG of 1.4%. This study indicates that the predominant path in this tissue is DHT in equilibrium 3 alpha diol----3 alpha diolG, rather than formation of DHT17 beta G and then 3 alpha reduction to 3 alpha diolG.

Reverse transcriptase PCR quantitation of hepatitis C virus.

OBJECTIVE: To present a brief review of the diagnostic benefits of quantitating viral load for hepatitis C and how the reverse transcriptase polymerase chain reaction is being used as an aid to better diagnose and manage the disease. DATA SOURCE: Research articles about hepatitis C and the reverse transcriptase polymerase chain reaction, as well as data gathered by the authors. STUDY SELECTION: Performed by the authors. DATA EXTRACTION: Performed by the authors. DATA SYNTHESIS: Hepatitis C viral infection is a worldwide health problem, affecting about 100 million people worldwide. Numerous serological tests exist to detect antibodies to hepatitis C antigens, but some affected people fail to generate an immune response. Reactivity in the reverse transcriptase polymerase chain reaction is definitive proof of hepatitis C infection. The titer of RNA indicates patient response to antiviral therapy. Measuring the presence and quantity of RNA by the reverse transcriptase polymerase chain reaction has become an important aid for diagnosis and monitoring of hepatitis C infection. CONCLUSION: The reverse transcriptase polymerase chain reaction method is a highly sensitive and accurate aid in diagnosing or confirming diagnosis of hepatitis C viral infection. This method is widely used to assess likelihood of patient response to therapy, and to monitor efficacy during therapy.

A systematic review and meta-analysis of the relative efficacy and safety of treatment regimens for HIV-associated cerebral toxoplasmosis: is trimethoprim-sulfamethoxazole a real option?

OBJECTIVES: The objective of this study was to perform a systematic review and meta-analysis of the literature to evaluate the efficacy and safety of therapies for cerebral toxoplasmosis in HIV-infected adults. The pyrimethamine plus sulfadiazine (P-S) combination is considered the mainstay therapy for cerebral toxoplasmosis and pyrimethamine plus clindamycin (P-C) is the most common alternative treatment. Although trimethoprim-sulfamethoxazole (TMP-SMX) has potential advantages, its use is infrequent. METHODS: We searched PubMed and four other databases to identify randomized controlled trials (RCTs) and cohort studies. Two independent reviewers searched the databases, identified studies and extracted data. Risk ratios (RRs) were pooled across studies using random-effects models. RESULTS: Nine studies were included (five RCTs, three retrospective cohort studies and one prospective cohort study). In comparison to P-S, treatment with P-C or TMP-SMX was associated with similar rates of partial or complete clinical response [P-C: RR 0.87; 95% confidence interval (CI) 0.70-1.08; TMP-SMX: RR 0.97; 95% CI 0.78-1.21], radiological response (P-C: RR 0.92; 95% CI 0.82-1.03), skin rash (P-C: RR 0.81; 95% CI 0.56-1.17; TMP-SMX: RR 0.17; 95% CI 0.02-1.29), gastrointestinal impairment (P-C: RR 5.16; 95% CI 0.66-40.11), and drug discontinuation because of adverse events (P-C: RR 0.32; 95% CI 0.07-1.47). Liver impairment was more frequent with P-S than P-C (P-C vs. P-S: RR 0.48; 95% CI 0.24-0.97) CONCLUSIONS: The current evidence fails to identify a superior regimen in terms of relative efficacy or safety for the treatment of HIV-associated cerebral toxoplasmosis. Use of TMP-SMX as preferred treatment may be consistent with the available evidence and other real-world considerations. Larger comparative studies are needed