Serum androgen levels in women who have recurrent miscarriages and their correlation with markers of endometrial function

The dose proportionality of lubeluzole, a drug in clinical development for the treatment of acute ischemic stroke, was evaluated in a Phase I, single-center, open-label, randomized-dosing-sequence, three-way crossover clinical trial in 12 healthy adults. An equal number of male and female volunteers were enrolled in the trial, with a mean weight (+/- SD) of 73.2 +/- 11.9 kg, mean height (+/- SD) of 66.8 +/- 4.6 inches, and a mean age of 36.1 +/- 5.2 years. Subjects received intravenous infusions of 5 (A), 10 (B), and 15 mg (C) of lubeluzole over 1 hour on three separate occasions, with a minimum washout period of 2 weeks. The treatment sequences were A-B-C; A-C-B; B-A-C; B-C-A; C-A-B; and C-B-A. One male and one female were assigned to each sequence. After the 5-, 10-, and 15-mg doses, maximum concentration (Cmax) was 58.1, 113, and 138 microg/L, respectively, and the area under the curve from 0 to (AUC(0-infinity)) was 771, 1384, and 2025 microg x h/L. There were no statistically significant differences among the groups in mean terminal half-life, steady-state volume of distribution, total plasma clearance, or dose-normalized AUC(0-infinity). Dose-normalized values of Cmax differed significantly between the groups. No serious adverse events were reported, and no changes were observed in cardiac function, as judged by the QT(c) interval. The pharmacokinetics of lubeluzole appear to be linear at intravenous infusion doses of 5, 10, and 15 mg, and these doses are well tolerated by healthy adults.     

Allergenic and antigenic activity of peptide fragments in a whey hydrolysate formula

BACKGROUND: Milk hydrolysates, although frequently used as substitutes in cases of cow's milk allergy, show a reduced but never a complete abolishment of antigenicity and allergenicity. OBJECTIVE: Our purpose was to determine the lower molecular weight limit of peptides to elicit skin reactions and to bind IgE antibodies in vitro. METHODS: Using FPLC, an ultrafiltrated whey hydrolysate, was fractionated in different molecular weight fractions. Skin-prick tests were performed with the hydrolysate and its fractions in five cow's milk allergic children, and RAST inhibition tests were done using the serum of these children. RESULTS: On the basis of the lowest extinction values between two peaks of the chromatogram, seven fractions with molecular weights between 15000 and 125 Da were obtained. Peptides of > 2600 Da elicited a clearly positive skin reaction and inhibited IgE-binding, while peptides of < 1400 Da did not give any positive skin reaction but were still able to inhibit to a small extent IgE-binding to the hydrolysate. CONCLUSION: Our findings suggest that for skin reactivity peptides of > 1400 Da are needed. The minimal molecular mass for IgE binding in vitro appears to be situated between 1400 and 970 Da. Such peptides might be used to develop a safe formula for patients reacting to milk hydrolysates or even for tolerance induction.     

Transformation of primary human endothelial cells by Kaposi's sarcoma-associated herpesvirus

Kaposi's sarcoma-associated herpesvirus (KSHV), or human herpesvirus 8, is invariably present in Kaposi's sarcoma lesions. KSHV contains several viral oncogenes and serological evidence suggests that KSHV infection is necessary for the development of Kaposi's sarcoma, but cellular transformation by this virus has not so far been demonstrated. KSHV is found in the microvascular endothelial cells in Kaposi's sarcoma lesions and in the spindle 'tumour' cells, which are also thought to be of endothelial origin. Here we investigate the biological consequences of infecting human primary endothelial cells with purified KSHV particles. We find that infection causes long-term proliferation and survival of these cells, which are associated with the acquisition of telomerase activity and anchorage-independent growth. KSHV was present in only a subset of cells, and paracrine mechanisms were found to be responsible for the survival of uninfected cells. Their survival may have been mediated by upregulation of a receptor for vascular endothelial growth factor. Our results indicate that transformation of endothelial cells by KSHV, as well as paracrine mechanisms that are induced by this virus, may be critical in the pathogenesis of Kaposi's sarcoma.     

Five-year follow-up of a prospective randomised multi-centre trial of weekly chemotherapy (CAPOMEt) versus cyclical chemotherapy (CHOP-Mtx) in the treatment of aggressive non-Hodgkin''s lymphoma. Central Lymphoma Group

Benign tumors of the pancreatic head are normally treated by a partial duodenopancreatectomy. This operation has been developed for the treatment of malignant alterations in the pancreatic head and includes resection of the gastric bowel, duodenum and common bile duct. The aim of this study was to evaluate whether the less radical duodenum-preserving pancreatic head resection is a suitable surgical procedure in the treatment of benign pancreatic head tumors. From May 1982 to December 1996, seven patients underwent surgical treatment for benign pancreatic head tumors. Two patients suffered from gastrinoma of the pancreatic head, four exhibited a serous or mucinous cystadenoma, and one patient suffered from an intraductal papillary-mucinous tumor in this region. All patients were treated by duodenum-preserving pancreatic head resection. The operation was easily performed with little blood loss and a low rate of complications. None of the patients had to be reoperated upon due to postoperative surgical complications. After a follow-up period of a median 3 years, six of seven patients were had no recurrence of the disease and were symptom-free. One patient who had initially been operated on for gastrinoma still exhibited high gastrin values postoperatively. The endocrine and exocrine pancreatic function was not impaired in the early and late postoperative phase as compared to the preoperative assessment. From our results, it is concluded that duodenum-preserving pancreatic head resection is an adequately radical, yet organ-preserving procedure for the treatment of benign tumors of the pancreatic head without compromising endocrine and exocrine function.     

Cardiovascular mortality among pituitary insufficient patients

The anthelmintic efficacy of milbemycin oxime against dog whipworm, Trichuris vulpis, was evaluated. A total of 21 T. vulpis positive dogs were divided into 3 groups, one (5 dogs) for control and the other two (8 dogs each) for anthelmintic treatment with oral administration of milbemycin oxime.     

Automatic accurate non-invasive quantitation of blood flow, cross-sectional vessel area, and wall shear stress by modelling of magnetic resonance velocity data

OBJECTIVES: To apply a new, automatic and non-invasive method for quantification of blood flow, dynamic cross-sectional vessel area, and wall shear stress (WSS) by in vivo magnetic resonance velocity mapping of normal subjects. DESIGN: Prospective, open study. MATERIALS: Six young volunteers. METHODS: A three-dimensional paraboloid model enabling automatic determination of blood flow, vessel distensibility and WSS was applied to blood velocity determinations in the common carotid artery. Blood flow was also determined by a manual edge detection method. RESULTS: Using the new method, the common carotid mean blood flow was 7.28 (5.61-9.63) (mean (range)) ml/s. By the manual-method blood flow was 7.21 (5.55-9.60) ml/s. Mean luminal vessel area was 26% larger in peak systole than in diastole. Mean/peak WSS was 0.82/2.28 N/m2. Manually and automatically determined flows correlated (r2 = 0.998, p < 0.0001). WSS and peak centre velocity were associated (r2 = 0.805, p < 0.0001). CONCLUSIONS: Blood flow, luminal vessel area dilatation, and WSS can be determined by the automatic three-dimensional paraboloid method. The hypothesis of association between peak centre velocity and WSS was not contradicted by the results of the present study.     

Molecular cloning and functional characterization of a rat somatostatin sst2(b) receptor splice variant

1. The mouse somatostatin (SRIF) sst2 receptor exists in two splice variants, sst2(a) and sst2(b), which differ in their intracellular carboxy-termini only. The murine sst2(b) receptor was reported to be less prone to agonist-induced desensitization as compared with the sst2(a) receptor. To determine whether a sst2(b) splice variant with similar functional characteristics exists in the rat, we have isolated a cDNA fragment from rat gastric mucosa encoding a sst2(b) receptor and expressed the full-length protein in CHO-K1 cells for functional characterization. 2. This study provides the first evidence for the occurrence in the rat of the sst2(b) receptor, which has a 15 amino acid carboxy-terminus differing in composition to the 38 amino acid C-terminus of the rat sst2(a) receptor. 3. In CHO-K1 cells expressing rat recombinant sst2(a) or sst2(b) receptors, SRIF caused concentration-dependent increases in extracellular acidification rates (EAR) with pEC50 values of 9.0 and 9.9, respectively. Pre-treatment with pertussis toxin (Ptx) caused a rightward displacement of the SRIF concentration-effect curves with pEC50 values of 8.3 (sst2(a) and 8.4 (sst2(b)). 4. SRIF (3 pM-3 nM) also caused concentration-dependent inhibition of forskolin-stimulated cyclic AMP formation in CHO-sst2(a) cells (pIC50 10.5) and CHO-sst2(b) cells (pIC50 10.4). The degree of inhibition was less with higher concentrations of SRIF resulting in bell-shaped concentration-effect curves. Following pre-treatment with Ptx, the inhibitory effect of SRIF was abolished and SRIF caused only increases in cyclic AMP formation. 5. Both the SRIF-induced increases in EAR and inhibition of cyclic AMP formation were susceptible to agonist-induced desensitization, but this was less apparent following pre-treatment with Ptx. 6. This demonstrates that the operational characteristics of the recombinant rat sst2(a) and sst2(b) receptors are broadly similar. Both isoforms couple to Ptx-sensitive as well as -insensitive G proteins and are equally prone to agonist-induced desensitization.     

Impairment of endothelium-dependent vasorelaxation in experimental atherosclerosis is dependent on gender

OBJECTIVE: Nitric oxide (NO) has been suggested to have antiatherosclerotic effects. It has also been demonstrated that there is a greater basal release of endothelium derived relaxing factor (EDRF) in female as compared to male rabbit aorta, which also might have beneficial effects in atherosclerosis. We thus sought to determine if gender influences the severity of atherosclerosis. METHODS: We studied 18 female and 18 male New Zealand White rabbits that were randomly divided in two groups of 9 animals each and fed either a standard or a cholesterol diet (0.75%) for 15 weeks. RESULTS: In cholesterol-fed rabbits the percentage of atherosclerotic lesions in the aorta was identical in females and males and was inversely correlated with the maximal aortic relaxation to acetylcholine as assessed in organ chamber experiments (females: P < 0.0008, males: P < 0.0002). Importantly, the cholesterol diet induced a significantly (P < 0.025) more severe impairment of maximal vasorelaxation to acetylcholine in males from 78.4 +/- 1.2% to 29.4 +/- 10.2%) compared to females (from 84.4 +/- 1.2% to 60.7 +/- 8.5%). Both male gender (P < 0.0001) and the extent of impairment of endothelium-dependent relaxation (P < 0.0002) were associated with a reduced aortic sensitivity to S-nitroso-N-acetyl-D,L-penicillamine, which releases NO into the organ bath. In contrast, the aortic sensitivity to the organic nitrates pentaerythritol tetranitrate and isosorbide 5-nitrate, which release NO after enzymatic metabolization within the smooth muscle, was not reduced. CONCLUSIONS: These results suggest that the impairment of endothelium-dependent vasorelaxation induced by atherosclerosis is dependent on gender. This may be due to a greater degradation of extracellular NO in the vessel wall of males.     

Ilizarov treatment of congenital pseudarthroses of the tibia

Sundry mevalonate-derived constituents (isoprenoids) of fruits, vegetables and cereal grains suppress the growth of tumors. This study estimated the concentrations of structurally diverse isoprenoids required to inhibit the increase in a population of murine B16(F10) melanoma cells during a 48-h incubation by 50% (IC50 value). The IC50 values for d-limonene and perillyl alcohol, the monoterpenes in Phase I trials, were 450 and 250 micromol/L, respectively; related cyclic monoterpenes (perillaldehyde, carvacrol and thymol), an acyclic monoterpene (geraniol) and the end ring analog of beta-carotene (beta-ionone) had IC50 values in the range of 120-150 micromol/L. The IC50 value estimated for farnesol, the side-chain analog of the tocotrienols (50 micromol/L) fell midway between that of alpha-tocotrienol (110 micromol/L) and those estimated for gamma- (20 micromol/L) and delta- (10 micromol/L) tocotrienol. A novel tocotrienol lacking methyl groups on the tocol ring proved to be extremely potent (IC50, 0.9 micromol/L). In the first of two diet studies, experimental diets were fed to weanling C57BL female mice for 10 d prior to and 28 d following the implantation of the aggressively growing and highly metastatic B16(F10) melanoma. The isomolar (116 micromol/kg diet) and the Vitamin E-equivalent (928 micromol/kg diet) substitution of d-gamma-tocotrienol for dl-alpha-tocopherol in the AIN-76A diet produced 36 and 50% retardations, respectively, in tumor growth (P < 0.05). In the second study, melanomas were established before mice were fed experimental diets formulated with 2 mmol/kg d-gamma-tocotrienol, beta-ionone individually and in combination. Each treatment increased (P < 0.03) the duration of host survival. Our finding that the effects of individual isoprenoids were additive suggests the possibility that one component of the anticarcinogenic action of plant-based diets is the tumor growth-suppressive action of the diverse isoprenoid constituents of fruits, vegetables and cereal grains.