Cardiac risk after craniopharyngioma therapy

Although long-term survival after craniopharyngioma treatment is excellent in childhood and early adulthood, sudden deaths in two craniopharyngioma survivors with cardiac findings suggest a need to determine whether treated patients exhibit potential substrates for sudden cardiac death. We present a retrospective review of two index patients with cardiac mortality. This motivated a prospective cardiac screening of 12 survivors that identified nearly a third with significant QTc prolongation. QTc-prolonging medication and stimulants should be used with caution in this population, and routine electrocardiogram screening may identify those at highest risk.     

Identification and characterization of a low-affinity granulocyte- macrophage colony-stimulating factor receptor on primary and cultured human melanoma cells

Hematopoietic growth factor receptors are present on cells of normal nonhematopoietic tissues such as endothelium and placenta. We previously demonstrated functional human granulocyte-macrophage colony- stimulating factor (GM-CSF) receptors on small cell carcinoma of the lung cell lines, and others have reported that certain solid tumor cell lines respond to GM-CSF in clonogenic assays. In the current study, we examine human melanoma cell lines and fresh specimens of melanoma to determine whether they have functional GM-CSF receptors. Scatchard analyses of 125I-GM-CSF equilibrium binding to melanoma cell lines showed a mean of 542 +/- 67 sites per cell with a kd of 0.72 +/- 0.14 nmol/L. Cross-linking studies in the melanoma cell line, M14, showed a major GM-CSF receptor species of 84,000 daltons. Under the conditions tested, the M14 cells did not have a proliferative response to GM-CSF in vitro, nor was any induction of primary response genes detected by Northern analysis in response to GM-CSF. Studies to determine internal translocation of the receptor-ligand complex indicated less than 10% of the 125I-GM-CSF internalized was specifically bound to receptors. Primary melanoma cells from five surgical specimens had GM-CSF receptors; Scatchard analysis was performed on one sample, showing 555 sites/cell with a kd of 0.23 nmol/L. These results indicate that human tumor cells may express a low-affinity GM-CSF receptor protein that localizes to the cell surface and binds ligand, but lacks functional components or accessory factors needed to transduce a signal.     

Naturally occurring amino acid polymorphisms in human immunodeficiency virus type 1 (HIV-1) Gag p7(NC) and the C-cleavage site impact Gag-Pol processing by HIV-1 protease

Human immunodeficiency virus type 1 (HIV-1) protease activity is targeted at nine cleavage sites comprising different amino acid sequences in the viral Gag-Pol polyprotein. Amino acid polymorphisms in protease and in regions of Gag, particularly p7(NC) and the C-cleavage site between p2 and p7(NC), occur in natural variants of HIV-1 within infected patients. Studies were designed to examine the role of natural polymorphisms in protease and to identify determinants in Gag that modulate protease processing activity. Closely related Gag-Pol regions from an HIV-1-infected mother and two children were evaluated for processing in an inducible expression system, for protease activity on cleavage-site analogues, and for impact on replication by recombinant viruses. Gag-Pol regions displayed one of three processing phenotypes based on the appearance of Gag intermediates and accumulation of mature p24(CA). Gag-Pol regions that were processed rapidly to produce p24(CA) resulted in high-level replication by recombinant viruses, while slow-processing Gag-Pol variants resulted in recombinant viruses that replicated with reduced kinetics in both T cell lines and peripheral blood mononuclear cells. Direct impact by Gag sequences on processing by protease was assessed by construction of chimeric Gag-Pol regions and by site-directed mutagenesis. Optimal protease activity occurred when Gag and Pol regions were derived from the same gag-pol allele. Heterologous Gag regions generally diminished rates and extent of protease processing. Natural polymorphisms in novel positions in p7(NC) and the C-cleavage site have a dominant effect on protease processing activity. Accumulation of Gag products after processing at the C site appears to delay subsequent cleavage and production of mature p24(CA).     

The effects of increased dose of exercise-based therapies to enhance motor recovery after stroke: a systematic review and meta-analysis

Background  

Exercise-based therapy is known to enhance motor recovery after stroke but the most appropriate amount, i.e. the dose, of therapy is unknown. To determine the strength of current evidence for provision of a higher dose of the same types of exercise-based therapy to enhance motor recovery after stroke.     

Myometrial invasion by endometrial carcinoma: sonographic assessment

The depth of myometrial invasion by endometrial carcinoma was evaluated using real-time sonography (US) in 20 patients with histologically proved adenocarcinoma of the endometrium. In 14 of 20 (70%) cases, US-based estimation of the depth of myometrial invasion was within 10% of the actual measurement in the gross specimen. The US-based estimation of tumor invasion was low in seven patients, high in four patients, and agreed with pathologic findings (+/- 5%) in nine patients. In four patients with polypoid intraluminal extension of tumor, a deeply invasive tumor was suspected on US but was not found on pathologic examination. In 12 superficially invasive tumors, the continuity of the demarcating subendometrial halo was intact in nine and incomplete in three. In six patients with deeply invasive tumors, this zone was partially disrupted in four, totally disrupted in one, and intact in one. Errors of estimation of the depth of myometrial invasion on US most frequently occurred when a tumor had a significant intraluminal polypoid extension. Demonstration of a subendometrial halo usually indicated superficial invasion, whereas the absence of a halo was frequently associated with deep invasion.     

Combining gene expression profiles and clinical parameters for risk stratification in medulloblastomas.

PURPOSE: Stratification of risk in patients with medulloblastoma remains a challenge. As clinical parameters have been proven insufficient for accurately defining disease risk, molecular markers have become the focus of interest. Outcome predictions on the basis of microarray gene expression profiles have been the most accurate to date. We ask in a multivariate model whether clinical parameters enhance survival predictions of gene expression profiles. PATIENTS AND METHODS: In a cohort of 55 young patients (whose medulloblastoma samples have been analyzed previously for gene expression profile), associations between clinical and gene expression variables and survival were assessed using Cox proportional hazards models. Available clinical variables included age, stage (ie, the presence of disseminated disease at diagnosis), sex, histologic subtype, treatment, and status. RESULTS: Univariate analysis demonstrated expression profiles to be the only significant clinical prognostic factor (P=.03). In multivariate analysis, gene expression profiles predicted outcome independent of other criteria. Clinical criteria did not significantly contribute additional information for outcome predictions, although an exploratory analysis noted a trend for decreased survival of patients with metastases at diagnosis but favorable gene expression profile. CONCLUSION: Gene expression profiling predicts medulloblastoma outcome independent of clinical variables. These results need to be validated in a larger prospective study.     

Health impacts of family planning

Among the many effects of family planning is the influence ithas on mortality and morbidity in women and children throughthe mechanism of changing the number and spacing of children.There is a complex set of relationships between mother's age,parity, birth spacing and infant and child mortality and morbidity.Much effort has been put into untangling this web in the hopeof identifying clear causal connections, but for the most parton the basis of inadequate data. Rather than attempt to establishthe relative importance of child spacing as a cause of decreasesin mortality, this paper takes as its starting point that thereis a connection, and presents some possible causal mechanismswhich explain how short birth intervals and child mortalitycould be related. In addition the most frequently cited hypotheses-maternaldepletion and sibling competition-a third is examined-birthcrowding which, it is suggested, influences the pattern of thetransmission of infectious diseases and, in turn, mortality. In the field of maternal mortality, the data which could beused to quantify the benefits of family planning are in evenshorter supply; however, the causal connections are rather moreeasily identified. The final section combines parity-specificdata on maternal mortality with evidence of changes in fertilitypatterns brought about by family planning to assess how successfulwe can hope to be in reducing through birth control the numberof women who die in childbirth.