Neurochemical and neurobehavioral effects of repeated gestational exposure to chlorpyrifos in maternal and developing rats

Acute exposure to the organophosphate pesticide chlorpyrifos (CPF) on gestation day 12 (GD12, 200 mg/kg/ml, SC) causes extensive neurochemical changes in maternal brain but lesser changes in fetal brain. In the present study, we examined the relative neurotoxicity of repeated, lower-level CPF exposures during gestation in rats. Pregnant Sprague-Dawley rats were exposed to CPF (6.25, 12.5, or 25 mg/kg per day, SC) from GD12-19 and sampled at either GD16, GD20, or postnatal day 3 (PND3) for measurement of various maternal and developmental neurochemical markers. In contrast to the high acute dose exposure, no maternal toxicity was noted with repeated lower-level dosing. Extensive acetylcholinesterase (AChE) inhibition (83-90%) was noted in maternal brain at all three time points following repeated exposures (25 mg/kg). Higher AChE inhibition (58%) was noted in fetal brain at GD20 compared to 19-25% on PND3 in treated pups cross-fostered to control dams and in control pups cross-fostered to treated dams following repeated exposures (25 mg/kg per day). Whereas similar reductions in brain muscarinic receptor binding were noted at GD20 and PND3 in dams and developing brain between acute and repeated dosing regimens, greater changes in [3H]CD and [3H]cytisine binding were evident following repeated exposures. Righting reflex and cliff avoidance tests were markedly altered following repeated exposures. The results suggest that lower-level repeated exposures to CPF cause extensive neurochemical and neurobehavioral changes in developing rats in the absence of maternal toxicity.     

Clinical presentations and results of therapy of 63 acromegalic patients Chang Gung Memorial Hospital

The role of nitric oxide in inflammatory responses to substance P and other mediators of inflammation was examined in rat skin microvasculature in a blister base raised on the hind footpad. Superfusion of substance P (1 microM) over the blister base caused an increase in plasma extravasation and a vasodilator response which was not maintained. N(G)-Nitro-L-arginine (100 microM), an inhibitor of nitric oxide biosynthesis, attenuated vasodilatation and plasma extravasation due to substance P. The inactive isomer N(G)-nitro-D-arginine was without effect. Neurokinin A (1 microM), 5-hydroxytryptamine (1 microM), ATP (50 microM) and vasoactive intestinal polypeptide (1 microM) elicited vasodilation, which for vasoactive intestinal polypeptide was maintained even after washout. 5-Hydroxytryptamine and neurokinin A, but not ATP or vasoactive intestinal polypeptide, significantly increased plasma extravasation. Vasodilatation to neurokinin A, 5-hydroxytryptamine and ATP, and the increase in plasma extravasation due to neurokinin A and 5-hydroxytryptamine were unaffected by N(G)-nitro-L-arginine (100 microM), whereas vasodilation due to vasoactive intestinal polypeptide was significantly attenuated. These findings suggest that in rat skin microvasculature in vivo, nitric oxide is involved in vasodilator responses due to substance P and vasoactive intestinal polypeptide, and plasma extravasation due to substance P, but does not contribute significantly to vasodilatation induced by neurokinin A, 5-hydroxytryptamine or ATP, or the plasma extravasation induced by neurokinin A or 5-hydroxytryptamine.     

The molecular pathology of urological malignancies

BACKGROUND: Effective esophageal peristalsis is a major determinant of esophageal clearance function. The relation of esophageal body function with a mechanically defective lower esophageal sphincter and the development of esophageal mucosal injury in patients with gastroesophageal reflux disease is unclear. STUDY DESIGN: We analyzed the relations among the manometrically determined esophageal clearance function, lower esophageal sphincter dysfunction, esophageal acid exposure, and the presence and severity of esophageal mucosal injury in patients with gastroesophageal reflux disease. Normal values for the manometric assessment of esophageal clearance function were established in 50 normal volunteers and subsequently applied to 160 symptomatic patients with increased esophageal exposure to gastric juice and various grades of esophageal mucosal injury (no minimal surgery, esophagitis, stricture, and Barrett's esophagus). RESULTS: Defective clearance function was present in 47.5% of the patients; a defective lower esophageal sphincter was documented in 63.1%. Compromised esophageal clearance function was significantly more common in patients with a defective lower esophageal sphincter than in those with normal sphincter function (55% versus 33.8%). Esophageal acid exposure time and the prevalence and severity of esophageal mucosal injury were highest in patients with a defective sphincter and compromised clearance function. CONCLUSIONS: These data show that esophageal motor function deteriorates with increasing severity of mucosal injury. This appears to be due to persistent reflux of gastric juice across a mechanically defective lower esophageal sphincter. This may influence the choice and outcome of antireflux surgery. Surgical correction of a mechanically defective sphincter before the loss of esophageal body function is advocated.     

Intestinal lipid absorption in the nephrotic rat

Phage display technology represents a powerful tool for the identification of peptides reacting with disease-related antibodies present in human sera. The application of this technology to type 1 diabetes could provide a set of novel reagents for diabetes prediction and could also lead to the identification of novel autoantigens or even of environmental factors possibly causing the disease. In the present study, sera of prediabetic and high risk individuals were used to select candidate peptides from phage-displayed random peptide libraries. Diabetes specific phage clones were then identified from these through screening and counter screening, using sera from diabetic and non-diabetic individuals. The results presented in this paper demonstrate the feasibility of this methodology to identify peptides reacting preferentially with antibodies present in the serum of diabetic patients.     

Oral calcium phosphate: a new therapy for Crigler-Najjar disease?

BACKGROUND & AIMS: Calcium phosphate binds unconjugated bilirubin in vitro, and dietary calcium phosphate supplementation reduces the serum bilirubin level in rats with hereditary unconjugated hyperbilirubinemia (Gunn rats). The aim of this study was to evaluate the effect of oral calcium phosphate supplementation on plasma bilirubin levels in patients with Crigler-Najjar disease. METHODS: A placebo-controlled, double-blind, crossover design was used. Eleven patients, 2-42 years of age, participated. The group included 5 patients with type I disease who were all treated with phototherapy and 6 patients with type II disease who were primarily treated with phenobarbital. In addition to plasma bilirubin levels, dietary intake and urinary and fecal excretion of calcium and phosphate were evaluated. RESULTS: A modest but significant decrease in serum bilirubin was observed in patients with type I disease (18% +/- 6%, P = 0.03) but not in patients with type II disease during treatment with calcium phosphate. Urinary output of calcium and phosphate did not change during the treatment period. CONCLUSIONS: Oral calcium phosphate may be a useful adjuvant to photo-therapy in Crigler-Najjar type I disease.     

Denaturant m values and heat capacity changes: relation to changes in accessible surface areas of protein unfolding

Denaturant m values, the dependence of the free energy of unfolding on denaturant concentration, have been collected for a large set of proteins. The m value correlates very strongly with the amount of protein surface exposed to solvent upon unfolding, with linear correlation coefficients of R = 0.84 for urea and R = 0.87 for guanidine hydrochloride. These correlations improve to R = 0.90 when the effect of disulfide bonds on the accessible area of the unfolded protein is included. A similar dependence on accessible surface area has been found previously for the heat capacity change (delta Cp), which is confirmed here for our set of proteins. Denaturant m values and heat capacity changes also correlate well with each other. For proteins that undergo a simple two-state unfolding mechanism, the amount of surface exposed to solvent upon unfolding is a main structural determinant for both m values and delta Cp.