Intracranial capillary hemangiomas: literature review in pediatric and adult population

Neurosurgical Review - Capillary hemangiomas (CHs) of the central nervous system represent a rare diagnosed pathology. CHs are benign vascular tumors whose most common manifestations are dermal and...     

Phase I and pharmacologic evaluation of intraperitoneal 5-fluoro-2′-deoxyuridine

Summary Intraperitoneal (i.p.) 5-fluoro-2-deoxyuridine (Floxuridine, FUdR, FdUrd) was evaluated in a phase I study at a starting level of 500 mg given on 1 day in 2 I 1.5% dialysate. Escalations within patients were allowed every other cycle. A total of 23 patients (age, 32–78 years) received 108 treatment courses. Local tolerance at all dose levels was excellent, with no cases of drug-related peritonitis being observed. Nausea and vomiting increased in severity in relation to dose and was universal at >3,000 mg ×3 days. One patient each developed grade 1 mucositis as well as diarrhea at a dose of 3,000 mg×3 days and leukopenia and thrombocytopenia at 5,000 mg×3 days. Peritoneal fluid (PF) and plasma (PL) FdUrd profiles were monitored by an HPLC method in 13 subjects, with 7 being studied serially at 2–4 increment doses for up to 6 h. Profiles that exhibited apparent linear pharmacokinetics gave PF drug levels 2–4 logs higher than the PL counterparts, with the latter essentially declining in parallel to the former, indicating that the disposition of FdUrd from the peritoneal compartment is rate-determining. The mean terminal half-life for PF FdUrd was found to be 115 min and mean peritoneal clearance was 25 ml/min. The vast differences in drug levels and AUC found between the PF and the PL profiles suggests a high systemic clearance of FdUrd, which was confirmed in two patients receiving 2 g FdUrd by short i.v. infusion. A disproportionate increase in the plasma FdUrd levels and the corresponding AUC values was found with increasing dose, suggesting a disproportionate increase in the systemic partitioning of FdUrd when doses were escalated within a patient. Substantial levels of peritoneal 5-fluorouracil (FUra) were also detected in most of the subjects. Thus, FdUrd was found to have several desirable properties for i.p. administration: (1) a 2- to 4-log pharmacologic advantage, (2) the absence of local toxicities, and (3) a favorable antitumor spectrum and some evidence of antitumor effects in this phase I and pharmacology study. A 3,000-mg dose given in 2 l 1.5% dialysate for 3 consecutive days exhibited antitumor activity and produced no systemic toxicity except nausea and vomiting, which was controlled by antiemetics. This dose schedule is therefore recommended for phase II trials directed against small-volume disease in the peritoneal cavity, such as may be found in some stages of ovarian and gastrointestinal cancers. In addition, it is suitable for further exploration as a part of regimens including systemic therapy or drugs that modulate the action of fluoropyrimidines.Supported in part by Cancer Center Core Grant CA 14089, by ROI CA 50 412, by an ACS Institutional Grant (IN21Z, to C. R.) and by the Italian-American Foundation award (to N. C.)Deceased     

Influence of semen processing technique on human sperm DNA integrity

Objectives. To compare the effects of density-gradient centrifugation and swim-up technique on sperm DNA integrity.Methods. Semen samples (n = 22) were obtained from consecutive nonazoospermic men presenting for infertility evaluation. Individual samples were divided into three aliquots (whole semen, density-gradient centrifugation, and swim-up) for subsequent analysis of sperm motility and DNA integrity. Sperm DNA integrity was evaluated by flow cytometry analysis of acridine orange-treated spermatozoa and expressed as the percentage of spermatozoa demonstrating denatured DNA.Results. Mean sperm motility (±SEM) improved significantly after processing with two-layer density-gradient and swim-up compared with whole semen (65.6% ± 4.0% and 73.0% ± 3.0% versus 52.0% ± 3.6%, respectively, P <0.005), with no significant difference in motility between Percoll-treated and swim-up-treated spermatozoa. In contrast, the percentage of spermatozoa with denatured DNA was reduced significantly in swim-up-treated but not in Percoll-treated spermatozoa compared with whole semen (4.8% ± 1.2% and 13.6% ± 3.6% versus 10.1% ± 2.3%, respectively, P <0.0001).Conclusions. Although density-gradient centrifugation is comparable to swim-up technique in recovering spermatozoa with enhanced motility, spermatozoa recovered after swim-up possess higher DNA integrity. These data urge us to reexamine our current sperm processing techniques in order to minimize sperm DNA damage.     

Human sperm endothelial nitric oxide synthase expression: correlation with sperm motility

Objective: To characterize the pattern of endothelial nitric oxide synthase (eNOS) expression on human spermatozoa and to determine whether sperm eNOS expression correlates with sperm function.

Design: Prospective, observational study.

Setting: University infertility clinic.

Patient(s): Twelve nonazoospermic infertile men.

Intervention(s): Semen samples (n = 12) obtained from nonazoospermic infertile men were fractionated on discontinuous Percoll gradients. Endothelial nitric oxide synthase staining on spermatozoa was correlated with sperm motility in Percoll gradient–fractionated spermatozoa. Endothelial nitric oxide synthase protein was detected with the use of a previously characterized monoclonal antibody. Control slides were incubated with preabsorbed antibody or mouse immunoglobulin G.

Main Outcome Measure(s): Localization of eNOS on human spermatozoa and correlation between the pattern of sperm eNOS expression and sperm motility.

Result(s): Morphologically normal spermatozoa exhibited postacrosomal and equatorial eNOS immunostaining. However, abnormally shaped spermatozoa often exhibited aberrant staining (in the midpiece and/or head region). A significant negative correlation was observed between the percentage of sperm with aberrant eNOS immunostaining and the percentage of motile sperm (r = −.46).

Conclusion(s): The specific localization of eNOS to human spermatozoa suggests that nitric oxide may be involved in normal sperm physiology. However, aberrant patterns of sperm eNOS expression are associated with decreased sperm motility, possibly through the generation of excessive cytotoxic oxidants.     

ABL mutations in late chronic phase chronic myeloid leukemia patients with up-front cytogenetic resistance to imatinib are associated with a greater likelihood of progression to blast crisis and shorter survival: a study by the GIMEMA Working Party on Chronic Myeloid Leukemia.

PURPOSE: Point mutations within the ABL kinase domain of the BCR-ABL gene have been associated with clinical resistance to imatinib mesylate in chronic myeloid leukemia (CML) patients. To shed further light on the frequency, distribution, and prognostic significance of ABL mutations, we retrospectively analyzed a homogeneous cohort of late chronic phase CML patients who showed primary cytogenetic resistance to imatinib. PATIENTS AND METHODS: Using denaturing high-performance liquid chromatography (D-HPLC) and sequencing, we screened for ABL mutations in a total of 178 bone marrow and/or peripheral blood samples from 40 late chronic phase CML patients homogeneously treated with imatinib 400 mg/d, who did not reach a major cytogenetic response at 12 months. RESULTS: Mutations were found in 19 of 40 patients (48%). Mutations were already detectable by D-HPLC at a median of 3 months from the onset of therapy. The presence of a missense mutation was significantly associated with a greater likelihood of subsequent progression to accelerated phase/blast crisis (P = .0002) and shorter survival (P = .001). Patients carrying mutations falling within the P-loop seemed to have a particularly poor outcome in terms of time to progression (P = .032) and survival (P = .045). CONCLUSION: Our results show that, irrespective of the hematologic response, monitoring for emerging mutations in the first months of therapy may play a role in detecting patients with worse prognosis, for whom a revision of the therapeutic strategy should be considered.     

ABO antibody titres: a multisite comparative study of equivalency and reproducibility for automated solid-phase and haemagglutination titration,and manual dilution with gel column agglutination technology

BackgroundABO antibody titres are important in many clinical decisions; however, much variability is observed in titre results. For reliable and reproducible titre results, automated ABO titration methods have been developed. In this 10-site study, we evaluated the equivalency of the automated ABO titration assays on the Galileo NEO, a fully automated blood bank analyzer (Immucor, Inc.) to manual titration with gel Column Agglutination Technology (CAT), as well as the reproducibility of both methods.Materials and methodsTen different locations participated in this study. The equivalency study included 70 random samples at each site. The reproducibility study tested the same blinded 30-sample panel at each study site. Anti-A and anti-B IgM and IgG antibody titres were tested with both the automated and manual methods; additionally, dithiothreitol (DTT) treatment was used to inactivate IgM antibodies in the manual CAT method.ResultsThe equivalency between CAT manual method and Galileo NEO automated titres at each site ranged from 38 to 88%; equivalency for each isotype was 66.2% for IgM, 60.6% for IgG, and 88.5% for DTT-treated IgG. The reproducibility study evaluated the titre variation of each sample obtained from the 10 sites. The average titre ranges (in doubling dilutions) for the automated and manual methods, respectively, were 2.15±1.0 and 4.03±1.8 for IgM, and 1.53±0.7 and 4.10±1.9 for IgG; for the manual DTT-treated IgG, the average titre range was 3.45±1.8 doubling dilutions.DiscussionThe results demonstrated that the Galileo NEO automated and manual CAT ABO titres are not equivalent. However, the study also demonstrated that titre reproducibility is enhanced with the Galileo NEO automated ABO titration assays relative to the manual CAT ABO titration method. Therefore, to improve management of patients receiving care across multiple institutions, our study supports the use of automated ABO titration.     

HTR1B as a risk profile maker in psychiatric disorders: a review through motivation and memory

Purpose  

Serotonin receptor 1B (HTR1B) is involved in the regulation of the serotonin system, playing different roles in specific areas of the brain. We review the characteristics of the gene coding for HTR1B, its product and the functional role of HTR1B in the neural networks involved in motivation and memory; the central role played by HTR1B in these functions is thoroughly depicted and show HTR1B to be a candidate modulator of the mnemonic and motivationally related symptoms in psychiatric illnesses.     

Metformin Decreases Circulating Androgen and Estrogen Levels in Nondiabetic Women With Breast Cancer

IntroductionDiabetic patients treated with metformin have a lower risk of developing BC or a better BC prognosis. Metformin might reduce cancer growth through direct antiproliferative effects or through indirect mechanisms, particularly the reduction of insulin. In a randomized study on nondiabetic BC patients in natural menopause with high testosterone levels, we observed a significant decrease in insulin and in testosterone levels with metformin 1500 mg/d compared with 1000 mg/d. We present the results of a new analysis of our study on the effect of metformin on the bioavailability of sex hormones.Patients and MethodsOne hundred twenty-four eligible women were initially invited to take metformin 500 mg/d for 3 months. The 108 women who completed the first 3 months continued the study using 1000 mg/d for 1 month. The women were then randomized into 2 groups, and, for the subsequent 5 months, 1 group increased the dose to 1500 mg/d, and the other group continued with 1000 mg/d.ResultsNinety-six women completed the study, 43 receiving metformin 1500 mg/day, and 53 receiving 1000 mg/day. The women receiving 1500 mg/d showed a greater and significant reduction of free testosterone (?29%) and estradiol (?38%), a borderline significant reduction of estrone and insulin-like growth factor-1, and a nonsignificant reduction of androstenedione. They also showed a nonsignificant increase of dehydroepiandrosterone sulfate.ConclusionMetformin does not interfere with the production of dehydroepiandrosterone sulfate. Besides, it decreases estradiol levels, basically through the reduction of testosterone. These hormonal changes might have clinical relevance.