Involvement of central dopamine and D1 receptors in stress-induced colonic motor alterations in rats.

The role of central versus peripheral influence of dopamine (DA) in the genesis of emotional stress (ES) induced by fear to receive electric footshocks on colonic motility was evaluated in rats equipped with implanted electrodes on the proximal colon. In control rats, the frequency of colonic spike bursts increased from 7.5 +/- 1.9 to 16.0 +/- 2.1 per 10 min when the rats were placed in a test box where they had previously received electric footshocks. This increase induced by ES was significantly p less than 0.05, reduced by previous ICV or IP administration of (+)SCH 23390 (a D1 receptor antagonist) at doses of 10 and 100 micrograms/Kg, respectively. Although sulpiride (a D2 antagonist) injected ICV or IP at similar doses had no effect on the ES-induced increase in the frequency of colonic spike bursts. DA (100 micrograms/kg), and the selective D1 (SKF 38383) or D2 (quinpirole) receptor agonist injected ICV at a dose of 5 micrograms/kg also increased significantly by 48.7, 54.8, and 68.7%, respectively, the colonic spike burst frequency whereas they are inactive when injected IP at similar and higher doses. These results suggest that, in rats, (a) emotional stress stimulates colonic motility through the stimulation of dopaminergic neurons involving D1 receptors and (b) exogenous activation of central D1 and D2 receptors similarly stimulate colonic motility by increasing the occurrence of colonic spike bursts.     

Indomethacin increases the effect of isosorbide dinitrate on cerebral hemodynamic in migraine patients: pathogenetic and therapeutic implications

Intracerebral vascular reactivity induced by the nitric oxide (NO) donor isosorbide dinitrate (IDN, 5 mg sublingually) is more major and longer-lasting in migraine patients who develop delayed headache in response to the drug. The headache is purportedly due to neuronally-mediated vascular mechanisms. Indomethacin inhibits prostaglandin synthesis, which is involved in NO generation. Indomethacin also decreases cerebral blood flow by constricting precapillary resistance vessels. In the present study, the hemodynamic effects of indomethacin were evaluated in migraine patients and healthy controls by means of transcranial Doppler monitoring. Indomethacin caused a significant decrease in mean flow velocity in the middle cerebral artery. This was an additional effect to the mean velocity decrease induced by IDN. The interactions between the two drugs suggest that their effects on cerebral hemodynamics (and pain) may be of relevance both in understanding the role of NO in migraine pathogenesis and in evaluating symptomatic treatments for migraine attacks.     

Combination of ABO blood group incompatibility and glucose-6-phosphate dehydrogenase deficiency: effect on hemolysis and neonatal hyperbilirubinemia

The incidence (%) of hyperbilirubinemia (serum bilirubin ≥257 μmol/l) was similar in neonates with a combination of ABO incompatibility and glucose-6-phosphate dehydrogenase (G-6-PD) deficiency (45%), with ABO incompatibility (54%) or G-6-PD deficiency (37%), alone (ns). Carboxyhemoglobin values, corrected for inspired CO, were similarly elevated in all three groups (0.87 ± 0.32%, 0.82 ± 0.29%, 0.76 ± 0.18%, respectively, ns), but correlated with bilirubin only in those with ABO incompatibility alone. ABO-incompatible/G-6-PD-deficient neonates, compared with those with either condition alone, are not at increased risk for hemolysis or hyperbilirubinemia.     

-2-Hydroxyglutaric acid inhibits mitochondrial creatine kinase activity from cerebellum of developing rats

L-2-Hydroxyglutaric acid (LGA) is the biochemical hallmark of patients affected by the neurometabolic disorder known as L-2-hydroxyglutaric aciduria (LHGA). Although this disorder is predominantly characterized by severe neurological findings and pronounced cerebellum atrophy, the neurotoxic mechanisms of brain injury are virtually unknown. In the present study, we investigated the effect of LGA, at 0.25-5mM concentrations, on total creatine kinase (tCK) activity from cerebellum, cerebral cortex, cardiac muscle and skeletal muscle homogenates of 30-day-old Wistar rats. CK activity was measured also in the cytosolic (Cy-CK) and mitochondrial (Mi-CK) fractions from cerebellum. We verified that tCK activity was significantly inhibited by LGA in the cerebellum, but not in cerebral cortex, cardiac muscle and skeletal muscle. Furthermore, CK activity from the mitochondrial fraction was inhibited by LGA, whereas that from the cytosolic fraction of cerebellum was not affected by the acid. Kinetic studies revealed that the inhibitory effect of LGA on Mi-CK was non-competitive in relation to phosphocreatine. Finally, we verified that the inhibitory effect of LGA on tCK was fully prevented by pre-incubation of the homogenates with reduced glutathione (GSH), suggesting that this inhibition is possibly mediated by oxidation of essential thiol groups of the enzyme. Considering the importance of creatine kinase activity for energy homeostasis, our results suggest that the selective inhibition of this enzyme activity by increased levels of LGA could be possibly related to the cerebellar degeneration characteristically found in patients affected by L-2-hydroxyglutaric aciduria.     

Digitalis poisoning from medicinal herbs. Two different mechanisms of production]

Two cases of digitalis toxicity due to uncontrolled ingestion of medicinal herbs are presented. The first of them was caused by oleander (Nerium oleander); digoxinemia levels were very high in this patient (4.44 ng/l), who presented many brady- and tachyarrhythmias. These arrhythmias disappeared when digoxinemia returned to normal values. The second patient had atrial fibrillation with slow ventricular rate, severe hypokalemia (2.1 mEq/l) and normal digoxinemia levels. He was taking medicinal herbs for a cold, with sorbitol between its components. Sorbitol may be similar to mannitol and glycerol (osmotic diuretic drugs) when taken at high doses. Uncontrolled ingestion of medicinal herbs is not safe, and severe poisoning can occur.     

Molecular interactions between dendritic cells and Salmonella: escape from adaptive immunity and implications on pathogenesis

Dendritic cells (DCs) constitute the link between innate and adaptive immunity by directly recognizing pathogen-associated molecular patterns (PAMPs) on bacteria and by processing and presenting bacterial antigens to T cells. Recognition of PAMPs renders DCs as professional antigen-presenting cells with the ability to prime naive T cells and to initiate the adaptive immune response against pathogen-derived antigens. For this reason, any interference with DC function might be advantageous for bacterial survival and dissemination. Identification of the molecular interactions occurring between DCs and bacterial pathogens is necessary to understand the mechanisms that virulent bacteria have evolved to prevent recognition by the adaptive immune system. This could be helpful in the identification of possible new targets that might lead to the design of effective therapies aimed at preventing or treating serious infections by these pathogens. In this article, we focus on Salmonella enterica serovar Typhimurium, the causative agent of typhoid-like disease in the mouse, and how it is able to escape from DC-mediated antigen presentation by avoiding lysosomal degradation. This feature of virulent Salmonella requires the functional expression of the Type Three Secretion System (TTSS) and effector proteins encoded within the Salmonella pathogenicity island 2 (SPI-2). Recent studies have demonstrated that impairment of DC function by the activity of SPI-2 gene products is crucial for Salmonella pathogenesis.     

Comparison of the fertilizing capability of spermatozoa from ejaculates, epididymal aspirates and testicular biopsies using intracytoplasmic sperm injection

A prospective study was carried out to compare the fertilizing capability and pregnancy outcome following intracytoplasmic sperm injection (ICSI) using spermatozoa obtained from ejaculates, or surgically from epididymis or seminiferous tubules. A total of 77 ICSI cycles (one per patient) was included. In all, 28 patients had severe oligoasthenoteratozoospermia, 19 patients had obstructive azoospermia and 30 patients had non-obstructive azoospermia. The main outcome measures were fertilization rate per injected metaphase II oocyte and the clinical pregnancy rate per embryo transferred back to the female recipients. In patients with severe oligoasthenoteratozoospermia, the fertilization and pregnancy rates were 79 and 25 %. In patients with obstructive azoospermia, for whom epididymal spermatozoa were used, these were 75 and 28%, and in the non-obstructive group for which testicular spermatozoa were used for injection, they were 69 and 21% respectively. These rates were not significantly different in the three groups (P = 0.85 and P = 0.14 respectively), suggesting that spermatozoa from the ejaculates and epididymal or testicular biopsies are able to fertilize equally by using ICSI. Live birth per embryo transfer was significantly reduced in patients with non-obstructive azoospermia compared to the other two groups. The high abortion rate (50%) in the group in which testicular spermatozoa were used raises doubts about the developmental competence of such embryos.