The genetics of glioma: molecular classification

Gliomas result from specific genetic alterations--such as activation of specific oncogenes and/or inactivation of specific tumor suppressor genes. These alterations affect specific pathways involved in either signal transduction or cell cycle control, leading to phenotypic changes such as uncontrolled proliferation, inhibition of apoptosis, genetic instability, invasive properties. Tumoral progression includes multiple molecular pathways of clinical relevance: early alterations (p53 mutations for astrocytomas, 1p and 19q loss for oligodendrogliomas) and late alterations (EGF-R amplification, PTEN and P16/CDKN2A inactivation). Genetic profile is not only of diagnostic--but also prognostic relevance, as shown by 1p associated to 19q loss in oligodendrogliomas which is predictive of better prognosis and higher response rate.     

Efavirenz-associated gynecomastia: report of five cases and review of the literature

The prognosis of HIV infection has improved dramatically since the introduction of highly active antiretroviral therapy (HAART). However, numerous adverse effects and limitations regarding tolerability remain a concern. Lipomastia (pseudogynecomastia), a breast enlargement due to central adiposity, may occur as part of a fat redistribution syndrome which has been associated with HAART regimens and several pathogenic mechanisms have been advocated in its development. Here we report an observational longitudinal study of five patients diagnosed of gynecomastia associated with efavirenz-based HAART regimens. All cases reached successful immunologic and virologic responses to HAART. The delay of appearance of gynecomastia from the beginning of HAART ranged between 4 to 15 months. In all five cases, gynecomastia regressed after efavirenz withdrawal (mean period of 5 months). In summary, we think that HAART induced gynecomastia should be suspected in HIV patients receiving efavirenz-containing regimens. Although pathogenesis is unclear, this study and a review of the English literature implicates two possible mechanisms: (a) immune restoration processes and (b) efavirenz mediated estradiol-like effects.     

Chronic treatment with progesterone but not medroxyprogesterone acetate restores the endothelial control of vascular tone in the mesenteric artery of ovariectomized rats

OBJECTIVE: To examine whether chronic administration of the natural hormone progesterone or a synthetic progestogen, medroxyprogesterone acetate, to ovariectomized rats affects the endothelial control of arterial tone in the isolated mesenteric artery. DESIGN: Sham-operated rats received a daily subcutaneous injection of solvent (sesame oil), whereas ovariectomized rats received either sesame oil, progesterone (22 mg kg/day), or medroxyprogesterone acetate (22 mg kg/day) for 4 weeks, according to their respective group. RESULTS: Phenylephrine-induced contractions were significantly increased (about 200% at 10 microM) by N-nitro-L-arginine, a nitric oxide synthase inhibitor, in intact mesenteric arterial rings from the sham-operated but not from the ovariectomized group. The progesterone but not the medroxyprogesterone treatment restored the potentiating effect of N-nitro-L-arginine on phenylephrine-induced contraction (about 180% at 10 microM). Contractions to phenylephrine were not affected by the combination of charybdotoxin plus apamin, two inhibitors of endothelium-derived hyperpolarizing factor-mediated responses, in all groups. Acetylcholine induced endothelium-dependent relaxations, which were partially inhibited by N-nitro-L-arginine and abolished by the combination of N-nitro-L-arginine plus charybdotoxin and apamin, in all groups. Acetylcholine induced similar charybdotoxin and apamin-sensitive hyperpolarizations in intact mesenteric artery segments from all groups. CONCLUSIONS: Chronic administration of progesterone, but not medroxyprogesterone, to ovarictomized rats restores the endothelium-dependent attenuation of contractile responses to phenylephrine in mesenteric arterial rings through the endothelial formation of nitric oxide. Thus, an enhancement of the protective effect of endothelial cells on the arterial wall might contribute to the beneficial effect of certain progestogen-containing preparations during hormonal treatment.     

Glycogenosis type II: identification and expression of three novel mutations in the acid alpha-glucosidase gene causing the infantile form of the disease

Glycogenosis type II (GSDII) is an autosomal recessive disorder due to the deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA). We identified three novel point mutations, C399A, T1064C, and C2104T, in three unrelated Italian patients with the infantile form of the disease. The C399A mutation was present in homozygosity in proband 1. The C >A transition introduces a premature stop signal in exon 2 resulting in no enzyme production that is correlated with the severe clinical phenotype in this patient. The other two nucleotide changes were missense mutations. The T1064C mutation, which changes Leu in position 355 into Pro, was carried in homozygosity by proband 2. The C2104T nucleotide change, which substitutes Arg 702 into Cys, was present in proband 3 in combination with a known severe mutation DeltaI17-18. The in vitro expression in COS-1 cells of T1064C and C2104T constructs demonstrated no enzymatic activity with respect to the negative control cells. Western blot analysis revealed that both T1064C and C2104T mutant proteins produced in COS-1 cells migrated in SDS-PAGE as the GAA inactive precursor of 110kDa. Immunofluorescence detection of mutant alpha-glucosidases showed enzyme localization primarily in the ER-Golgi compartment, suggesting that T1064C and C2104T mutations could affect the normal processing and stability of the enzyme. In vitro studies demonstrated that the same degree of deficiency in T1064C and C2104T mutations, which is in contrast with patient phenotype. A better correlation was observed with the in vivo studies since proband 2, with a less severe phenotype, presented with low residual enzyme activity while in proband 3, with a classic severe infantile onset GSDII, fibroblast enzyme activity was completely absent.     

Functional assessment of posterior cordotomy in patients with bilateral vocal fold paralysis

Surgical treatment of bilateral vocal fold paralysis must be undertaken if such a condition lasts 6-12 months or longer and causes dyspnoea. The purpose of the procedures is to assure proper airflow through the glottis and to preserve good voice and unimpaired swallowing. Modern endoscopic surgery of the glottis is performed with CO2 laser. The following paper presents results of laser posterior cordotomy performed in 17 patients aged 19-73 years suffering from bilateral vocal fold paralysis. Results and conclusions: In 7 patients the range of vocal fold resection had to be expanded. 3 individuals developed post-operative granulation in subglottal region. Spirometry and electroglottography were performed before and after the operation to assess the patients' laryngeal functions: respiration and voice quality. The results indicate that laser cordectomy was effective in the discussed group of patients.     

New composite implant for tracheal reconstruction--preliminary study

Stenosis of trachea's diameter occurs the most often as complications after intubation and tracheotomy. Among the other reasons of narrowing of this organ the following are being named: mechanical injuries, chemical damages, primary and metastasis tumors. The therapy of trachea's stenosis includes both alternative and radical treatments. The radical treatment consists of surgical excision of the narrowed segment followed by reconstruction of trachea (anastomosing of free ends or filling of lost segment with use of auto- or allogenic material). There is no appropriate alloplastic material developed to date, the use of which in reconstructive surgery of large segment trachea defects would bring about positive long-term experimental results. The success of alloplastic material implantation in the reconstruction of large tracheal defects is limited by the fact that the biomechanical characteristics of replaced tissue are distinctly different from synthetic material. The work is devoted to evaluation of complex mechanical characteristic of natural sheep trachea before designing the proper synthetic material for large tracheal defects reconstruction. Various mechanical tests were conducted to study the mechanical behavior of total trachea. Samples of tissue cut out from trachea were also examined. The results revealed strong directional--dependent mechanical properties of trachea. Composite constituents, namely carbon fibers and biocompatible and biostable polysulfone were used to manufacture the implant.     

Recent advances in bladder cancer diagnostics

Transitional cell carcinoma of the bladder is a significant cause of morbidity and mortality worldwide. The diagnosis of bladder cancer is based on the information provided by cystoscopy, the gold standard, in combination with urinary cytology findings. Many tumor markers have been evaluated for detecting and monitoring of the disease in serum, bladder washes, and urinary specimens. However, none of these biomarkers reported to date has shown sufficient sensitivity and specificity for the detection of the whole spectrum of bladder cancer diseases in routine clinical practice. The advent of high-throughput microarrays is accelerating the identification process of the molecular events characteristic of bladder tumors' phenotype and subsequent clinical behavior. The information provided by these analyses is resulting not only in the identification of novel therapeutic targets for bladder cancer, but also in the development of diagnostic tools. This review summarizes the reports utilizing high-throughput microarrays in bladder cancer and the implications of these analyses in the diagnosis and clinical management of patients with bladder cancer.