Effect of scopolamine on the efflux of dopamine and its metabolites after clozapine, haloperidol or thioridazine

The extracellular concentrations of dopamine (DA) and its metabolites, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), in the striatum and the nucleus accumbens were measured in awake, freely-moving rats. Clozapine (20 mg/kg, i.p.) increased extracellular DA and HVA in both regions but increased DOPAC only in the striatum. Scopolamine (1 mg/kg), although it had no effect by itself in the striatum or nucleus accumbens, inhibited the ability of clozapine to increase extracellular DA, DOPAC and HVA concentrations in the striatum. The clozapine-induced increase in DA in the frontal cortex was not blocked by scopolamine. Haloperidol (1 mg/kg, i.p.) and thioridazine (10 mg/kg, i.p.) also increased extracellular DA, DOPAC and HVA in the striatum, but scopolamine pretreatment did not inhibit these increases. The results suggest that clozapine differs from haloperidol and thioridazine in that the effect of clozapine, but not that of the two neuroleptic drugs, to increase DA release in the striatum acutely depends on muscarinic receptor stimulation. These results suggest that clozapine, despite its strong muscarinic antagonist properties, does not produce full blockade of muscarinic receptors in vivo in the striatum. The interaction of clozapine with the cholinergic system in the striatum could be relevant to its lack of ability to produce extrapyramidal symptoms or tardive dyskinesia.     

Beta-thalassemia in Iran: a high incidence of the nonsense codon 39 mutation on the island of Queshm

Optic disc blood flow velocity was measured in healthy patients, those with primary open angle glaucoma (POAG), and patients with normal pressure glaucoma (NPG). The velocity of the red blood cells (RBCs) in the capillaries of the optic nerve head (ONH) has been measured with a laser Doppler velocimeter (LDV), and blood viscosity has been evaluated notably by determining the aggregability of the RBCs with an erythroaggregameter. Our results in POAG patients and NPG patients showed that their optic nerve blood flow velocity was reduced and that the aggregability of the RBCs was increased. The hyperaggregability of the erythrocytes is responsible for the increase of the local viscosity in the papillary capillary network. These haemodynamic modifications observed in patients with glaucoma support the hypothesis of a vasogenic mechanism that could impair the optic nerve in glaucoma patients.     

Sequence alterations of insulin-like growth factor binding protein 3 in neoplastic and normal gastrointestinal tissues

Insulin-like growth factor binding protein 3 (IGFBP-3) is an important regulator of normal and malignant cell growth. It modulates the mitogenic effects of insulin-like growth factors (IGFs) by inhibiting growth through mechanisms both dependent on and independent of IGF binding. IGF-I and IGF-II levels are regulated by binding to the IGF-II receptor, which is inactivated by mutation in human gastrointestinal (GI) tumors. We have previously demonstrated elevated IGF-II ligand expression in IGF-II receptor-mutant GI tumors, implicating the IGF signaling system in GI tumorigenesis. Therefore, to investigate the potential involvement of IGFBP-3 in human GI carcinogenesis, direct DNA sequencing of exons 1-4 and intron-exon boundaries of the IGFBP-3 gene was performed in 10 colorectal cancers, 10 gastric cancers, and 10 esophageal cancers. Four distinct sequence alterations were identified: (a) in one gastric and one esophageal tumor, an A to C transversion occurred at nucleotide 5795 (CAC-->CCC), leading to a His-->Pro substitution at codon 179; (b) a second esophageal tumor had a C to T transition at nucleotide 8291 (ACC-->ATC), leading to a Thr-->Ile substitution at codon 277 of IGFBP-3; (c) one alteration comprised a G to C transversion in exon 1 at nucleotide 2132 (GGG-->GCG), leading to a Gly-->Ala substitution at codon 32 in two gastric cancers, seven esophageal cancers, and nine colon cancers; and (d) a C to G transversion located 17 nucleotides from the 3' splice site in intron 1 was observed in three colon cancers and four esophageal cancers. All of these DNA sequence alterations were present in matched normal DNA from the same subjects, which suggests that some or all of them may represent polymorphisms. However, we cannot exclude the possibility that the germ-line nonconservative amino acid substitutions predicted to occur as a result of these alterations result in subtle changes to IGFBP-3 protein function and a predisposition to developing GI malignancy.     

Nanobacteria: an alternative mechanism for pathogenic intra- and extracellular calcification and stone formation

Calcium phosphate is deposited in many diseases, but formation mechanisms remain speculative. Nanobacteria are the smallest cell-walled bacteria, only recently discovered in human and cow blood and commercial cell culture serum. In this study, we identified with energy-dispersive x-ray microanalysis and chemical analysis that all growth phases of nanobacteria produce biogenic apatite on their cell envelope. Fourier transform IR spectroscopy revealed the mineral as carbonate apatite. The biomineralization in cell culture media resulted in biofilms and mineral aggregates closely resembling those found in tissue calcification and kidney stones. In nanobacteria-infected fibroblasts, electron microscopy revealed intra- and extracellular acicular crystal deposits, stainable with von Kossa staining and resembling calcospherules found in pathological calcification. Previous models for stone formation have led to an hypothesis that elevated pH due to urease and/or alkaline phosphatase activity is a lithogenic factor. Our results indicate that carbonate apatite can be formed without these factors at pH 7.4, at physiological phosphate and calcium concentrations. Nanobacteria can produce apatite in media mimicking tissue fluids and glomerular filtrate and provide a unique model for in vitro studies on calcification.     

IgE, IgA, and IgG responses to common yeasts in atopic patients

To assess the incidence of HIV infection and risk factors associated with HIV seroconversion among patients attending clinics for sexually transmitted diseases (STD), medical record reviews were conducted in 12 clinics in 7 U.S. cities. The records of all patients who initially tested negative for HIV from 1991 through 1996 and who received at least one additional HIV test during the study period were reviewed. In each of 7 cities, 5 to 112 patients seroconverted. Of the 286 seroconverters identified in total, 53% (152 of 286) were heterosexual men and 28% (81 of 286) were women. HIV incidence rates among men who have sex with men (MSM) ranged by city from 0.81 to 7.0 new infections/100 person-years. Rates among heterosexual men and women ranged from 0.018 to 1.2 infections/100 person-years. Multivariate analyses showed that drug use was associated with HIV seroconversion only among heterosexuals. Most new HIV infections in these clinics are being transmitted heterosexually and are associated with drug use. Nevertheless, MSM, particularly young MSM, are at greatest risk for HIV in this population: 1 of 47 seroconvert/year. The effective use of targeted prevention efforts depends upon the continued ability to monitor the incidence of HIV infection.     

Molecular and cell biological aspects of neuroendocrine tumors of the gastroenteropancreatic system

Neurons and neuroendocrine cells share a variety of common characteristics. Cell and molecular biological studies in recent years have improved our understanding of physiological and pathophysiological processes such as cellular growth, adhesion, and secretion of neuroendocrine cells. Here we review current findings from the area of basic research and from current clinical research relevant to improving the diagnosis and therapy of neuroendocrine tumors of the gastroenteropancreatic system.     

Stromelysin 3 is overexpressed in human pancreatic carcinoma and regulated by retinoic acid in pancreatic carcinoma cell lines

OBJECTIVE: To develop a simple prognostic index for anticipating more precisely the early clinical course of primary superficial bladder cancer. PATIENTS AND METHODS: The prognostic value of patient and tumour characteristics was examined in 333 patients with primary Ta or T1 bladder cancer who participated in a multicentre prospective study already completed. Primary tumour multiplicity, a diameter of > 3 cm, stage T1, and grade 2 or 3 were independent predictors of earlier recurrence in a multivariate analysis. A simplified prognostic index consisted of the number of adverse tumour characteristics (ATCs) initially present. RESULTS: After a median follow-up of 35.3 months, the 60 patients free of ATCs (19%) had a recurrence-free probability at 12 and 24 months of 86% and 69%, respectively, and none experienced progression. Recurrence outcomes deteriorated consistently as the number of ATCs increased among the other three groups. In patients with 3-4 ATCs, the 12- and 24-month recurrence-free probability was as low as 30% and 19%, and recurrence and tumour rates were about 2.6 times higher than in patients free of ATCs; 7% of these patients experienced progression within 35 months of follow-up. CONCLUSION: A prognostic index based on the number of ATCs (primary tumour multiplicity, diameter > 3 cm, stage T1, and grade 2 or 3) is a strong indicator of the clinical course of superficial bladder cancer within 3 years of the first endoscopic resection. This proposal is suggested for discussion and for validation in future studies but if confirmed, this simple prognostic index may greatly help to identify indicators for adjuvant intravesical therapy and to determine the optimal periodicity of control cystoscopy regimens.     

Retinoic acid receptor gamma1 expression determines retinoid sensitivity in pancreatic carcinoma cells

A highly enriched spindle pole preparation was prepared from budding yeast and fractionated by SDS gel electrophoresis. Forty-five of the gel bands that appeared enriched in this fraction were analyzed by high-mass accuracy matrix-assisted laser desorption/ ionization (MALDI) peptide mass mapping combined with sequence database searching. This identified twelve of the known spindle pole components and an additional eleven gene products that had not previously been localized to the spindle pole. Immunoelectron microscopy localized eight of these components to different parts of the spindle. One of the gene products, Ndc80p, shows homology to human HEC protein (Chen, Y., D.J. Riley, P-L. Chen, and W-H. Lee. 1997. Mol. Cell Biol. 17:6049-6056) and temperature-sensitive mutants show defects in chromosome segregation. This is the first report of the identification of the components of a large cellular organelle by MALDI peptide mapping alone.