The validity of the California Q-set Alexithymia Prototype

Classic antihistamines, namely diphenhydramine, chlorpheniramine, clemastine, perphenazine, hydroxyzine, and tripelennamine, share structural features with substrates and inhibitors of the polymorphic cytochrome P450 (CYP) isozyme CYP2D6. Therefore, the current study was undertaken to characterize the in vitro inhibition of CYP2D6 by these commonly used, histamine H1 receptor antagonists. Microsomal incubations were performed using bufuralol as a specific CYP2D6 substrate and microsomes derived from human cells transfected with CYP2D6 cDNA. Reaction velocities were assessed in the absence and presence of antihistamines (20 microM) at 11 substrate concentrations (1, 2.5, 5, 7.5, 10, 15, 20, 25, 50, 75, and 100 microM), as well as at three nonsaturating substrate concentrations (2.5, 5, and 20 microM) and three inhibitor concentrations (5, 20, and 50 microM). In the presence of all antihistamines, the Vmax and KM of bufuralol 1'-hydroxylation were significantly altered, compared with the uninhibited reaction (p < 0.05). Lineweaver-Burke plots suggested competitive inhibition of the reaction by diphenhydramine and mixed inhibition by all other antihistamines tested. Diphenhydramine and chlorpheniramine, with estimated Ki values of approximately 11 microM, were the weakest inhibitors of CYP2D6 in vitro. Whereas tripelennamine, promethazine, and hydroxyzine were similar in their inhibitory capacities (Ki approximately 4-6 microM), clemastine appeared to be significantly more potent, with a Ki of approximately 2 microM. These data demonstrate that classic histamine H1 receptor antagonists, available in over-the-counter preparations, inhibit CYP2D6 in vitro. Furthermore, the CYP2D6-inhibitory concentrations of these antihistamines are in the range of their expected hepatic blood concentrations, suggesting that, under specific circumstances, clinically relevant interactions between classic antihistamines and CYP2D6 substrates might occur.     

Parathyroid hormone--related protein (PTHrP) is an epidermal growth factor-regulated secretory product of human prostatic epithelial cells

Integral membrane proteins have one or more transmembrane alpha-helical domains and carry out a variety of functions such as enzyme catalysis, transport across membranes, transducing signals as receptors of hormones and growth factors, and energy transfer in ATP synthesis. These transmembrane domains are not mere structural units anchoring the protein to the lipid bilayer but seem to-contribute in the overall activity. Recent findings in support of this are described using some typical examples-LDL receptor, growth factor receptor tyrosine kinase, HMG-CoA reductase, F0-ATPase and adrenergic receptors. The trends in research indicate that these transmembrane domains participate in a variety of ways such as a linker, a transducer or an exchanger in the overall functions of these proteins in transfer of materials, energy and signals.     

2-Iminopyrrolidines as potent and selective inhibitors of human inducible nitric oxide synthase

A series of substituted 2-iminopyrrolidines has been prepared and shown to be potent and selective inhibitors of the human inducible nitric oxide synthase (hiNOS) isoform versus the human endothelial nitric oxide synthase (heNOS) and the human neuronal nitric oxide synthase (hnNOS). Simple substitutions at the 3-, 4-, or 5-position afforded more potent analogues than the parent 2-iminopyrrolidine 1. The effect of ring substitutions on both potency and selectivity for the different NOS isoforms is described. Substitution at the 4- and 5-positions of the 2-iminopyrrolidine yielded both potent and selective inhibitors of hiNOS. In particular, (+)-cis-4-methyl-5-pentylpyrrolidin-2-imine, monohydrochloride (20), displayed potent inhibition of hiNOS (IC50 = 0.25 microM) and selectivities of 897 (heNOS IC50/hiNOS IC50) and 13 (hnNOS IC50/hiNOS IC50). Example 20 was shown to be an efficacious inhibitor of NO production in the mouse endotoxin assay. Furthermore, 20 displayed in vivo selectivity, versus heNOS isoform, by not elevating blood pressure at multiples of the effective dose in the mouse.     

Liquid chromatographic determination of tilmicosin in swine feed at 200-400 mg/kg level: interlaboratory study

An analytical method for the determination of tilmicosin at 200-400 mg/kg, the intended use concentration range, was evaluated in an interlaboratory study involving 5 laboratories, including the sponsor. The interlaboratory study evaluated the intra- and interlaboratory precision and accuracy of a tilmicosin feed method. The method procedure involved extracting tilmicosin from feed by adding 200 mL extractant to 20 g feed and shaking for 1 h. The extract is filtered and analyzed by gradient liquid chromatography which separates tilmicosin from feed matrix in 30 min. Each laboratory assayed 5 replicates of fortified feed at concentrations of 0, 100, 200, 400, and 600 mg/kg. The mean recovery among fortified samples ranged from 81.4 to 98.8%, with a percent coefficient of variation (%CV) ranging from 0.3 to 4.0%. For all blank control feed samples no significant interferences were observed. In addition, each laboratory assayed 5 replicates of medicated feed samples prepared at 2 levels (200 and 400 mg/kg) with either a horizontal or vertical mixer. Along with the medicated feed samples were included 5 replicates of a blank control feed. The identities of the medicated and blank control feed samples were blinded to the analysts. The results for the medicated feed samples ranged from 95.8 to 106% of label claim, with a %CV ranging from 2.1 to 6.7%.     

Spatial distribution of collagen type I mRNA in Paracentrotus lividus eggs and embryos

We have identified the presence of type I collagen (COLL1alpha) mRNA in Paracentrotus lividus unfertilized egg, indicating a maternal origin of this mRNA. By in situ whole mount hybridization the spatial distribution of COLL1alpha mRNA in egg and embryo at different developmental stages was established. Moreover, the presence of COLL1alpha gene in Paracentrotus lividus genome was analyzed by Southern blot experiments. The localization pattern indicates that the maternal mRNA is placed in the fertilized egg in a fixed position, relative to the embryonic axes. Furthermore, the embryonic expression is spatially restricted during development, suggesting involvement in sea urchin embryo cell specification events. The presence of two bands in Southern blot hybridization may indicate that two genes specific for COLL1alpha are present in the sea urchin genome.     

Use of ionizing radiation to prevent restenosis in interventional cardiology

It is well known that the expression of carbohydrate chains on cell changes during the development and progression of carcinoma. Some carbohydrate chains have been used in clinical practice as tumor markers. Some, such as sialyl Lewis a (CA 19.9), sialyl Lewis X, and Tn, are known to function as adhesion molecules. However, their role in the development of hematogenous metastasis is still controversial. In this paper, many investigations concerning this issue are reviewed. Clinical trials for treatment of patients with advanced cancer using carbohydrate chains are also mentioned.     

Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia

Stroke is the third leading cause of death, and vascular dementia the second cause of dementia after Alzheimer's disease. CADASIL (for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) causes a type of stroke and dementia whose key features include recurrent subcortical ischaemic events and vascular dementia and which is associated with diffuse white-matter abnormalities on neuroimaging. Pathological examination reveals multiple small, deep cerebral infarcts, a leukoencephalopathy, and a non-atherosclerotic, non-amyloid angiopathy involving mainly the small cerebral arteries. Severe alterations of vascular smooth-muscle cells are evident on ultrastructural analysis. We have previously mapped the mutant gene to chromosome 19. Here we report the characterization of the human Notch3 gene which we mapped to the CADASIL critical region. We have identified mutations in CADASIL patients that cause serious disruption of this gene, indicating that Notch3 could be the defective protein in CADASIL patients.     

Aortic compliance measured by non-invasive Doppler ultrasound: application of a personal computer based MkII system and its repeatability

A non-invasive pulse-wave-velocity Doppler ultrasound technique for the assessment of aortic compliance is described. A computational approach for correcting for the effect of non-chronic changes in blood pressure is considered and applied to compliance measurements performed on an age-select cohort of 70 normotensive, normal healthy volunteers. In order to permit the wider availability of the pulse-wave-velocity Doppler ultrasound technique, the authors have developed a MkII system based on a standard 80486/33 MHz IBM compatible WINDOWS based personal computer; real-time spectral analysis being achieved using a relatively inexpensive but fast analogue to digital signal processing card. An overview of the new apparatus is provided and verification work to compare the repeatability of the MkI and MkII systems is described. Medical disorders such as atherosclerosis, diabetes mellitus, familial hypercholesterolaemia, growth hormone deficiency, and Ehlers-Danlos and Marfan's syndromes have all been shown to affect arterial wall compliance. We suggest that the in vivo clinical measurement of blood pressure corrected aortic distensibility using the MkII system may be a useful, reproducible, non-invasive tool for assessing such patients' susceptibility to atheromatous arterial disease as well as for monitoring their response to therapeutic interventions. Measurements in the aorta may be especially pertinent since the natural history of fatty streaks there tends to parallel that in the coronary vasculature thereby potentially affording a convenient surrogate estimate of coronary heart disease.     

Glutathione movements during cold preservation of rat hepatocytes

PURPOSE: Power-Doppler sonography is regarded as a very sensitive method for detecting low-velocity and low-volume blood flows. The purpose of our study was to investigate whether increased vascularity in breast carcinoma can be visualized by power-Doppler sonography and whether new criteria for differentiating benign and malign lesions can be found. METHOD: 315 patients were examined with a 13-MHz high-resolution linear transducer. If a suspicious lesion was found, it was evaluated further by power-Doppler sonography. Compared to normal breast parenchyma (reference structure), a focal increase in blood flow signals was registered using a 3-step grading system with a 4th step for no flow increase. RESULTS: In 97 cases the sonographic findings were correlated with histology (n = 95) or cytology (n = 2). There were 50 benign lesions, 42 cases of invasive and 5 cases of in-situ carcinoma. 73.5% benign lesions showed no or just minimal increases in flow signal. 81% of invasive cancer presented middle- or high-flow increases compared to normal breast parenchyma. The extend of flow increase was linked to tumor size in invasive cancer. In stage T1b to T4, 94.3% of invasive carcinoma presented middle or high flow increases. CONCLUSION: Power-Doppler sonography is able to visualize vascularization in breast tumors. According to first clinical results PD sonography is a promising additional diagnostic tool which seems to offer new criteria for differential diagnosis in breast tumors.     

Oral contraceptives and risk of venous thromboembolism: impact of duration of use

BACKGROUND: At therapeutic dosage, cetirizine and ebastine induce significant inhibition of skin reactivity to histamine. The consistency of their efficacy, that is, efficacy with the least interindividual variability among subjects, has not been carefully assessed, however. OBJECTIVE: To compare the consistency and efficacy of these antihistamines on skin reactivity. METHODS: Twenty-four healthy volunteers participated in a randomized double-blind crossover study. The areas of wheals and flares induced by increasing (0, 5, 10, 50, 100, 200, and 300 mg/mL) histamine concentrations, administered by prick tests, were measured before and four hours after intake of 10 mg of each antihistamine, allowing concentration-response curves to be established. The threshold histamine concentrations inducing wheal areas of 3 mm2 (positivity) were calculated by interpolation. The coefficient of variation (SD/mean %) was used to evaluate the consistency of the response. RESULTS: Pretreatment concentration-response curves were similar, and threshold concentrations identical (0.29 mg/mL and 0.34 mg/mL for cetirizine and ebastine, respectively). For both, curves were lower after treatment than before. After cetirizine, the threshold concentration was significantly higher (217 mg/mL) than after ebastine (0.82 mg/mL) (P < .001), and total inhibition of the wheal reaction was observed in 21 of 24 patients at the lowest histamine concentration and in 17 of 24 at the highest. Ebastine never totally inhibited reaction, even to 5 mg/mL of histamine. Over the entire concentration-response curve, the coefficient of variation for the wheal reaction was 6.3% for cetirizine and 72.6% for ebastine, and, for flares, 11.0% and 83.7%, respectively. Hence, variability was much lower after cetirizine. CONCLUSION: Our study shows clearly that the efficacy of a single therapeutic dosage of cetirizine is consistently good for suppression of cutaneous reactivity to histamine in healthy volunteers. The need for ebastine to metabolize into the active carebastine might explain its lesser consistency.