Comparison between testosterone oenanthate-induced azoospermia and oligozoospermia in a male contraceptive study. IV. Suppression of endogenous testicular and adrenal androgens

Administration of supraphysiological doses of testosterone to normal men causes inhibition of spermatogenesis, but while most become azoospermic, 30-55% maintain a low rate of spermatogenesis. We have investigated whether there are differences in endogenous androgen production, of testicular and adrenal origin, which may be related to the degree of suppression of spermatogenesis. Thirty-three healthy Caucasian men were given weekly i.m. injections of 200 mg testosterone oenanthate (TE), 18 became azoospermic, while 15 remained oligozoospermic. Urinary excretion of epitestosterone, a specific testicular product, was reduced to <10% of pretreatment values, with no differences between the groups. Similar results were obtained for other markers of testicular steroidogenesis. Urinary and plasma adrenal androgens were also reduced during TE treatment: a statistically significant decrease in both (P < 0.001 and P < 0.05 respectively) was seen in the azoospermic but not oligozoospermic responders. These results suggest that testicular steroidogenesis is decreased to <10% by the administration of supraphysiological doses of exogenous testosterone. Differences in the degree of ongoing steroidogenesis in the testis do not appear to account for incomplete suppression of spermatogenesis, thus differences in androgen metabolism may underlie this heterogeneous response. A small but significant reduction in secretion of adrenal androgens was also detectable, the relevance of which is unclear.      

Mechanical evaluation of a respiratory device

This article aims to characterize the mechanical behaviour of the Flutter VRP1, a respiratory physiotherapy device designed to aid sputum clearance of the airways of patients. The device resembles a smoking pipe with a conical cavity containing a stainless steel sphere which floats up and down while the patient comes with a forced expiration through it. The sphere's oscillatory movement is function of the air flow rate and angular orientation of the device. When the sphere's oscillatory frequency matches the natural frequency of the patient's chestwall+abdomen system, it will produce resonance which, in turn, will enhance sputum clearance. A dynamical model of the Flutter was formulated and an experimental setup was assembled in order to study the oscillatory frequency of the sphere under different conditions of air flow rate, fluid pressure, angular orientation and sphere's material and weight. Interesting results presented by this article point to eventual mechanical optimization of the device and show information that could be beneficial to the professional of the respiratory physiotherapy.     

Microsatellite analysis of synchronous and metachronous tumors: a tool for double primary tumor and metastasis assessment.

Despite well-established histopathological features and the development of immunostaining of human neoplasms, there are a number of cases in which surgical pathologists cannot assure the origin of synchronous and metachronous tumors. In many cases, the classification of these lesions as either two separate primary tumors or as a single primary tumor with a metastasis has significant implications with respect to patient prognosis and recommendations for therapy. To establish the origin of tumors, we assessed tumor cell clonality using PCR-based microsatellite analysis on microdissected archival tissues for loss of heterozygosity (LOH) and microsatellite instability (MSI) in a series of 19 paired synchronous and metachronous tumors from several organs. As a control group, 15 autopsy cases with an unequivocally recognizable primary tumor and associated metastases were also examined. Based on LOH and MSI findings, and using a panel of 4 to 12 (median 7) microsatellite markers, we were able to establish the clonal pattern of microsatellite changes in 17 out of 19 (89%) biopsy cases and thus determine if they were either double primary tumors (41%) or metastases (59%). Of interest, identical or similar pattern of microsatellite abnormalities were detected in 15 primary tumors and corresponding metastasis from autopsies. Our results indicate that microsatellite analysis for LOH and MSI, as an expression of clonality, provides a useful tool to distinguish double primary neoplasms and metastases in synchronous and metachronous tumors.     

Involvement of rat cytochrome 1A1 in the biotransformation of kaempferol to quercetin: relevance to the genotoxicity of kaempferol

Kaempferol is a flavonoid widely distributed in edible plantsand has been shown to be genotoxic to V79 cells in the absenceof external metabolizing systems. The presence of an externalmetabolizing system, such as rat liver homogenates (S9 mix),leads to an increase in its genotoxicity, which is attributedto its biotransformation to the more genotoxic flavonoid quercetin,via the cytochrome P450 (CYP) mono-oxygenase system. In thepresent work we investigated the mechanisms of the genotoxicityof kaempferol further. Special attention has been given to therole of CYP in the genotoxicity of this flavonoid. We studiedthe induction of mutations in Salmonella typhimurium TA98 inthe presence and in the absence of S9 mix and the inductionof chromosomal aberrations (CAs) and micronuclei (MN) by kaempferolin V79 cells in the presence and in the absence of S9 mix. Toevaluate the role of different CYP in the biotransformationof kaempferol we studied the induction of CAs and MN in V79cells genetically engineered for the expression of rat CYP 1A1,1A2 and 2B1. In addition we performed CYP inhibition studiesusing the above-mentioned indicators and high performance liquidchromatography (HPLC) analysis. The results obtained in thiswork suggest that rat CYP 1A1 is, among the cytochromes studied,the one that plays the major role in the transformation of kaempferolinto quercetin. The relevance of these findings to the humansituation is discussed. ⁴To whom correspondence should be addressed     

STXBP1: the second synaptic vesicle release gene involved in epilepsy

De novo mutations in the gene encoding STXBP1 (MUNC18‐1) cause early infantile epileptic encephalopathy
Saitsu et al. (2008)
Nature Genetics 40: 782–788     

Predominance of null mutations in ataxia-telangiectasia

Ataxia-telangiectasia (A-T) is an autosomal recessive disorder involving cerebellar degeneration, immunodeficiency, chromosomal instability, radiosensitivity and cancer predisposition. The responsible gene, ATM, was recently identified by positional cloning and found to encode a putative 350 kDa protein with a Pl 3-kinase-like domain, presumably involved in mediating cell cycle arrest in response to radiation-induced DNA damage. The nature and location of A-T mutations should provide insight into the function of the ATM protein and the molecular basis of this pleiotropic disease. Of 44 A-T mutations identified by us to date, 39 (89%) are expected to inactivate the ATM protein by truncating it, by abolishing correct initiation or termination of translation, or by deleting large segments. Additional mutations are four smaller in-frame deletions and insertions, and one substitution of a highly conserved amino acid at the Pl 3-kinase domain. The emerging profile of mutations causing A-T is thus dominated by those expected to completely inactivate the ATM protein. ATM mutations with milder effects may result in phenotypes related, but not identical, to A-T.