Treatment of recurrent cerebellar hemangioblastoma with external radiotherapy in a patient with von Hippel-Lindau disease: a case report and review of the literature

Von Hippel-Lindau Disease, a multisystem familial cancer syndrome, is inherited as an autosomal-dominant trait. Common manifestations of the disease are retinal, cerebellar and medullary hemangioblastomas; renal cysts and carcinomas; pancreatic cysts; pheochromocytoma; and papilllary cystadenoma of the epididym. We report the case of a 40-year-old man with type I von Hippel-Lindau disease treated with external radiotherapy for recurrent cerebellar hemangioblastoma.     

A rare cause of intestinal perforation: ingestion of magnet

Background  

Ingestion of foreign objects is a common problem in children. Ingestion of one more magnets may require surgical intervention because of risk of perforation.     

The role of alcohol use in emergency department episodes

This study investigates the association between alcohol use and emergency-department (ED) utilization in the United States using nationally representative data from the 2001 National Health Interview Survey (N = 33,326). Estimates from our probit models indicate that among men, current drinkers are less likely to have visited the ED in the past year than former drinkers. Among women, lifetime abstainers are less likely than current drinkers to have had an ED episode. Finally, frequency of binge drinking significantly increases the likelihood of ED visits for men. The results suggest that focusing solely on problem drinking provides a limited perspective.     

Mycobacterium tuberculosis Dihydrofolate Reductase Is Not a Target Relevant to the Antitubercular Activity of Isoniazid

Mycobacterium tuberculosis enoyl-acyl-ACP reductase (InhA) has been demonstrated to be the primary target of isoniazid (INH). Recently, it was postulated that M. tuberculosis dihydrofolate reductase (DHFR) is also a target of INH, based on the findings that a 4R-INH-NADP adduct synthesized from INH by a nonenzymatic approach showed strong inhibition of DHFR in vitro, and overexpression of M. tuberculosis dfrA in M. smegmatis conferred a 2-fold increase of resistance to INH. In the present study, a plasmid expressing M. tuberculosis dfrA was transformed into M. smegmatis and M. tuberculosis strains, respectively. The transformant strains were tested for their resistance to INH. Compared to the wild-type strains, overexpression of dfrA in M. smegmatis and M. tuberculosis did not confer any resistance to INH based on the MIC values. Similar negative results were obtained with 14 other overexpressed proteins that have been proposed to bind some form of INH-NAD(P) adduct. An Escherichia coli cell-based system was designed that allowed coexpression of both M. tuberculosis katG and dfrA genes in the presence of INH. The DHFR protein isolated from the experimental sample was not found bound with any INH-NADP adduct by enzyme inhibition assay and mass spectroscopic analysis. We also used whole-genome sequencing to determine whether polymorphisms in dfrA could be detected in six INH-resistant clinical isolates known to lack mutations in inhA and katG, but no such mutations were found. The dfrA overexpression experiments, together with the biochemical and sequencing studies, conclusively demonstrate that DHFR is not a target relevant to the antitubercular activity of INH.In 1952, isoniazid (INH) was discovered to have bactericidal activity against Mycobacterium tuberculosis (4). Since then, it has been used as a potent front-line drug against tuberculosis (5). The mechanism of action of INH has been studied for more than 50 years. Through lipid profiling, INH was found to inhibit mycolic acid biosynthesis in M. tuberculosis (28). In addition, the INH-induced inhibition of mycolic acid biosynthesis was demonstrated to correlate with the bactericidal activity of INH (21). Further analysis of the lipids of INH-treated M. tuberculosis indicated that the elongation of fatty acids beyond C26 was inhibited, which suggested that the target of INH is an enzyme in fatty acid elongation (20).INH is a prodrug that must first be activated by KatG, an endogenous catalase/peroxidase (29). The mode of INH action remained unclear until an INH-NAD adduct was identified as the bound inhibitor in the active site of InhA, the enoyl-acyl ACP reductase involved in long-chain fatty acid biosynthesis, by protein crystallography (18). It was hypothesized that KatG cleaves the hydrazide on INH to an isonicotinoyl radical, which then reacts with NAD to form an adduct that binds to and inhibits InhA (23). The crystal structure of InhA bound with the adduct indicates that an isonicotinoyl moiety was covalently attached to the 4-position of the nicotinamide ring of NAD cofactor in an S configuration. The chemical structure of the INH-NAD adduct was found to be consistent with the molecular weight obtained by the mass analysis (18). Later studies demonstrated that INH-NAD adduct could be generated by a KatG-catalyzed oxidation in the presence of NAD⁺ (13, 27), which strongly inhibits InhA (K_i = 5 nM) to block mycolic acid biosynthesis (18, 25, 17).Mutations within the protein-coding and promoter regions of inhA are frequently observed in clinical isolates resistant to INH (7, 22). An S94A mutation in InhA, which was originally identified in an INH-resistant M. smegmatis strain, was later found in three M. tuberculosis clinical isolates that conferred resistance to both INH and ethionamide (ETH) (16, 3). The S94A allele of inhA has been transferred into M. tuberculosis by a specialized linkage transduction, which was sufficient to confer 5-fold resistance to INH (25). Moreover, overexpression of inhA in M. tuberculosis was found to confer >10-fold resistance to INH (12). These genetic observations support that InhA is the primary target of INH.Although genetic and biochemical studies have provided convincing evidence that InhA is the primary target of INH, other putative targets of INH have also been proposed (15, 24). Recently, 17 proteins other than InhA were identified from M. tuberculosis lysate that could tightly bind to an affinity matrix derived from INH-NADP or INH-NAD adducts by proteomic analysis (1). Among these proteins, M. tuberculosis dihydrofolate reductase (DHFR) was shown to be strongly inhibited by an INH-NADP adduct in vitro (K_iapp = 1 nM) in a separate study (2). This INH-NADP adduct was synthesized by incubating INH and NADP⁺ in the presence of Mn(III) as a catalyst. The crystal structure of the complex indicated that an acyclic 4R INH-NADP adduct was selectively bound in the active site of DHFR. In addition, overexpression of dfrA in M. smegmatis caused a 2-fold increase of resistance to INH compared to the wild-type (2). These observations were taken to suggest that M. tuberculosis DHFR is also a target of INH (1, 2).There are several observations which conflict with the proposal that DHFR might be a target of INH. First, the MIC difference (2-fold) between the dfrA overexpressed M. smegmatis strain and the wild-type strain is not significant compared to the error of this type of experiment. Second, dfrA has not been clearly shown to be essential to M. tuberculosis. Although it is an essential gene for nucleotide biosynthesis in many other organisms (10, 6), disruption of dfrA by transposon mutagenesis was found not to attenuate M. tuberculosis infection in mice (19). Third, the endogenous formation of the 4R INH-NADP adduct by KatG catalysis has not been demonstrated. To determine whether M. tuberculosis DHFR is a molecular target of INH, we investigated (i) whether overexpression of dfrA under relevant conditions confers resistance to INH in M. smegmatis and M. tuberculosis, (ii) whether the INH-NADP adduct is an activated INH product generated by KatG catalysis inside the cell, and (iii) whether mutations in dfrA could be observed in INH-resistant clinical isolates.     

Medulloblastoma/primitive neuroectodermal tumor in adults: prognostic factors and treatment results: a single-center experience from Turkey

We performed retrospective review of 29 adult patients with cerebellar medulloblastoma/primitive neuroectodermal tumor (PNET) who received craniospinal radiotherapy in Ankara Oncology Hospital between years 2000 and 2005. All patients were operated followed by craniospinal irradiation; 11 of 29 patients also received chemotherapy. All patients had no distant or spinal metastases at the time of diagnosis. Median follow up time was 26 months. Progression-free survival was 86% at 2 years, 55% at 5 years. Mean progression-free survival was 25 months in patients with PNET; 61.4 months in patients with medulloblastoma (P = 0.0016). Mean survival was 61.33% months in patients <25 age, 38 months in patients >25 age. (P = 0.04). Overall mean survival was 59.80 months in patients who received chemotherapy and 41.4 months in patients who did not have chemotherapy (P = 0.15). Cranial relapses were observed in 3 of 29 patients, and 3 of 29 patients had distant metastases. The mean time to cranial recurrence was 19 months; to distant metastases was 18 months. In conclusion, adult patients with PNET have worse survival rates than patients with medulloblastoma, like in childhood patients. Patients younger than 25 years of age also had statistically significant better survival.