Toxicity of Amphotericin B Deoxycholate-Based Induction Therapy in Patients with HIV-Associated Cryptococcal Meningitis

Amphotericin B deoxycholate (AmBd) is the recommended induction treatment for HIV-associated cryptococcal meningitis (CM). Its use is hampered by toxicities that include electrolyte abnormalities, nephrotoxicity, and anemia. Protocols to minimize toxicity are applied inconsistently. In a clinical trial cohort of AmBd-based CM induction treatment, a standardized protocol of preemptive hydration and electrolyte supplementation was applied. Changes in blood counts, electrolyte levels, and creatinine levels over 14 days were analyzed in relation to the AmBd dose, treatment duration (short course of 5 to 7 days or standard course of 14 days), addition of flucytosine (5FC), and outcome. In the 368 patients studied, the hemoglobin levels dropped by a mean of 1.5 g/dl (95% confidence interval [CI], 1.0 to 1.9 g/dl) following 7 days of AmBd and by a mean of 2.3 g/dl (95% CI, 1.1 to 3.6 g/dl) after 14 days. Serum creatinine levels increased by 37 μmol/liter (95% CI, 30 to 45 μmol/liter) by day 7 and by 49 μmol/liter (95% CI, 35 to 64μmol/liter) by day 14 of AmBd treatment. Overall, 33% of patients developed grade III/IV anemia, 5.6% developed grade III hypokalemia, 9.5% had creatinine levels that exceeded 220 μmol, and 6% discontinued AmBd prematurely. The addition of 5FC was associated with a slight increase in anemia but not neutropenia. Laboratory abnormalities stabilized or reversed during the second week in patients on short-course induction. Grade III/IV anemia (adjusted odds ratio [aOR], 2.2; 95% CI, 1.1 to 4.3; P = 0.028) and nephrotoxicity (aOR, 4.5; 95% CI, 1.8 to 11; P = 0.001) were risk factors for 10-week mortality. In summary, routine intravenous saline hydration and preemptive electrolyte replacement during AmBd-based induction regimens for HIV-associated CM minimized the incidence of hypokalemia and nephrotoxicity. Anemia remained a concerning adverse effect. The addition of flucytosine was not associated with increased neutropenia. Shorter AmBd courses were less toxic, with rapid reversibility.     

The valine allele of the V89L polymorphism in the 5-alpha-reductase gene confers a reduced risk for hypospadias

CONTEXT: Hypospadias is one of the most common malformations in man, with an incidence of 1:300 in newborn boys. No gene has been identified that causes isolated hypospadias, but the androgenic influence is important during male genital development. OBJECTIVE: A key enzyme for the androgenic function is steroid 5-alpha-reductase (SRD5A2). The V89L polymorphism in the SRD5A2 gene has been studied and found to be of functional importance. The leucine version of the enzyme is 30% less efficient than the valine variant. DESIGN, SETTING, PATIENTS, AND RESULTS: We have genotyped 158 hypospadias cases and 96 unaffected controls for this polymorphism and found a significant negative association for the V89 allele in hypospadias (odds ratio, 0.24; 95% confidence interval, 0.14-0.41 for homozygous individuals). This indicates that a fully functional 5-alpha-reductase enzyme (homozygous for V89) protects the male urethral development. This association is shown regardless of heredity, ethnicity, and severity of phenotype. We have also sequenced a selected material of 37 sporadic cases of more severe hypospadias for mutations in the androgen receptor AR, SRD5A2, and 17beta-hydroxysteroid dehydrogenase HSD17B3 genes and found only two previously described mutations, one in the AR and one in the SRD5A2 gene. CONCLUSION: This finding is in accordance with the assumption that functional polymorphisms may play an important role in complex disorders such as hypospadias when several genes as well as environmental factors contribute to the etiology.     

A fatal case of primary cutaneous gamma–delta T‐cell lymphoma complicated by HLH and cardiac amyloidosis

Gamma–delta T‐cell lymphomas (GD‐TCL) are rare and rapidly fatal neoplasms that are often associated with Hemophagocytic Lymphohistiocytosis (HLH), a syndrome of fevers, cytopenias, and multiorgan failure that often leads to a rapid death. We report the first case demonstrating an association between GD‐TCL, HLH, and cardiac amyloidosis, presenting a novel mechanism for rapid deterioration in these patients.     

Estimating the prevalence of coinfection with influenza virus and the atypical bacteria Bordetella pertussis,Chlamydophila pneumoniae,and Mycoplasma pneumoniae

Coinfections with common bacterial respiratory pathogens and influenza viruses are well-known causes of disease, often via synergistic interactions between the influenza virus, the bacteria, and the human host. However, relatively little is known about interactions between atypical bacteria and influenza viruses. A recent report by Reinton et al. explored this issue by analyzing data from 3,661 patients seeking medical assistance for the presence of Mycoplasma pneumoniae, Chlamydophila pneumoniae, and Bordetella pertussis, as well as influenza A or B virus in nasal swab specimens. The report, however, did not accurately assess the epidemiologic interactions of these pathogens. We aimed to describe the interactions between these bacterial species and influenza infections. Strong and highly statistically significant antagonistic interspecies interactions were detected between C. pneumoniae and influenza virus [odds ratio (OR): 0.09; p?M. pneumoniae and influenza virus infections (OR: 0.29; p?=?0.003). No association was detected between B. pertussis and influenza infection (p?=?0.34), contrary to the initial report, and coinfection was not detected at a higher-than-by-chance frequency within the population. Further support of these results is supplied by the analysis of two earlier investigations reporting data on influenza virus and these atypical bacteria. Our results supplement the large body of literature regarding interactions between influenza virus and typical respiratory pathogens, providing a fuller picture of the spectrum of interactions between influenza viruses and respiratory bacteria. Further, we demonstrate the importance of choosing the most appropriate reference populations for the analysis being performed and describe the pitfalls that may occur when care is not taken in this regard.     

The association between polypharmacy and late life deficits in cognitive,physical and emotional capability: a cohort study

International Journal of Clinical Pharmacy - Background Polypharmacy is a growing health concern for older adults and is associated with poorer clinical outcome. Objective This study aim is to...