Modulatory action of noradrenergic system on spinal motoneurons in humans.

Previous findings in animals demonstrated that the noradrenergic coeruleospinal system exerts a tonic facilitation on spinal reflexes and that activation of alpha2-autoinhibitory receptors can be responsible for a disfacilitation of the spinal activity. To investigate this issue further, we examined whether this system is also involved in descending facilitatory control of spinal motoneurons in healthy humans. The H-reflex technique was utilized to assay the motoneuronal excitability. The ratio between the maximal reflex response (H) and maximal direct response (M) was determined in each subject and was calculated at 10 min intervals before and after i.v. administration of the alpha2-agonist clonidine (0.5 microg/kg). In all subjects a marked decrease of the H/M ratio, due to depression of the H response, occurred 10 min following the clonidine injection and reached its maximum within 30 min. No significant changes of blood pressure values were provoked by drug injections. These results suggest that an autoinhibitory action may be induced by alpha2-receptor activation of locus coeruleus neurons in humans, and that this device may serve as a mechanism for a myotonolytic action on spinal motoneurons.     

Immunohistochemical modifications of vasoactiveneuropeptides and excitatory amino acids in the nervoustissue of the mongolian gerbil after transient cerebralischemia

Modifications in the tissue concentration of vasoactive peptides (Endothelin,Calcitonin Gene Related Peptide, Atrial Natriuretic Peptide) and excitatory amino acids(glutamate, aspartate) were found in the nervous tissue of Mongolian gerbils after transientcerebral ischemia which was induced by unilateral occlusion of the common carotid artery for 30min–4 h. In fact, immunostaining for these peptides was more intense in the ischemic tissue : thegreatest increases of tissue immunoreactivity were observed for Endothelin ; smaller differenceswere found for Calcitonin Gene Related Peptide and Atrial Natriuretic Peptide. Immunostainingfor Neuropeptide Y, another vasoactive neuropeptide, was virtually unchanged. Infarct areas,when present, contained numerous Endothelin-immunoreactive cell bodies. On the contrary, thesame areas were completely void of glutamate- or aspartate-immunostained neurons, normallypresent in the correspondent regions of the control tissue. The present results suggest that severecerebral ischemia is paralleled by an unbalance of local vasoactive factors. The predominance ofvasoconstrictor action of Endothelin might play a major role in the irreversible damage, togetherwith the excitotoxic effect of the extracellular accumulation of excitatory amino acids, probablydue to a leakage from neuronal cell somata, as suggested by the disappearance of glutamate- oraspartate-immunostained neurons.     

Bench-to-bedside review: Chloride in critical illness

Chloride is the principal anion in the extracellular fluid and is the second main contributor to plasma tonicity. Its concentration is frequently abnormal in intensive care unit patients, often as a consequence of fluid therapy. Yet chloride has received less attention than any other ion in the critical care literature. New insights into its physiological roles have emerged together with progress in understanding the structures and functions of chloride channels. In clinical practice, interest in a physicochemical approach to acid-base physiology has directed renewed attention to chloride as a major determinant of acid-base status. It has also indirectly helped to generate interest in other possible effects of disorders of chloraemia. The present review summarizes key aspects of chloride physiology, including its channels, as well as the clinical relevance of disorders of chloraemia. The paper also highlights current knowledge on the impact of different types of intravenous fluids on chloride concentration and the potential effects of such changes on organ physiology. Finally, the review examines the potential intensive care unit practice implications of a better understanding of chloride.     

Enhanced shedding of cytomegalovirus in semen of human immunodeficiency virus-seropositive homosexual men.

Site-specific shedding of cytomegalovirus (CMV) was assessed in a longitudinal study of homosexual and bisexual men. At initial testing, CMV was cultured from the semen of 33% (19 of 58) of asymptomatic and mildly symptomatic men who were seropositive for human immunodeficiency virus (HIV) at the time of entry into the study, whereas it was cultured from the semen of 17% (10 of 58) of the men who were HIV seronegative. CMV was isolated much more frequently from semen than from urine or throat washing specimens, and it was rarely recovered from stool or blood, regardless of the subject's HIV serostatus. CMV was cultured from the semen of 31% (16 of 52) of the men relatively early after seroconversion to HIV (mean, 12.8 months). CMV was persistently isolated from the semen of a greater proportion of the HIV-seropositive men than from the semen of the HIV-seronegative men during a 4.5-year follow-up period (52 of 110 - [47%] and 15 of 58 [26%] men, respectively). There was an increased relative risk for shedding of CMV in semen in association with decreased CD4+ cell numbers and increased levels of serum immunoglobulin A. However, there was no association of CMV shedding with an increased risk for the development of AIDS.     

Endotoxin induces the expression of macrophage inflammatory protein 1 alpha mRNA by rat alveolar and bone marrow-derived macrophages.

Macrophage inflammatory protein 1 alpha (MIP-1 alpha) is a newly described cytokine that is present in large amounts in the culture supernatant of an endotoxin-stimulated murine macrophage-like cell line (RAW 264.7). There is increasing information that suggests that this cytokine mediates acute neutrophilic inflammation, although the mechanism of mediation is unknown. Data examining the production and regulation of MIP-1 alpha by primary rat macrophages are lacking, and MIP-1 alpha has not been studied previously in an animal model of endotoxin-induced neutrophilic alveolitis. In this study, we performed Northern analysis of steady-state rat MIP-1 alpha mRNA using an oligonucleotide probe complementary to amino acids 4-13 of murine MIP-1 alpha. Our data demonstrate that rat alveolar and bone marrow-derived macrophages can be induced by in vitro endotoxin treatment to express a 1.1-kb MIP-1 alpha mRNA. Expression of the mRNA could be elicited by treatment with 0.1 to 10.0 micrograms/ml of endotoxin in vitro with peak steady-state levels detectable up to 9 h after adding endotoxin to the media. Alveolar macrophages recovered by whole lung lavage from endotoxin-treated rats expressed increased amounts of the mRNA homologous to MIP-1 alpha mRNA when treated in vitro with endotoxin. We also found that rat neutrophils could be induced by endotoxin in vitro to express the MIP-1 alpha mRNA. We were able to identify MIP-1 alpha in culture supernatant from endotoxin-stimulated rat alveolar and bone marrow-derived macrophages by immunoprecipitation with a specific goat anti-murine MIP-1 alpha.(ABSTRACT TRUNCATED AT 250 WORDS)     

Identification of four new mutations in the short-chain acyl-CoA dehydrogenase (SCAD) gene in two patients: one of the variant alleles, 511C-->T, is present at an unexpectedly high frequency in the general population, as was the case for 625G-->A, together conferring susceptibility to ethylmalonic aciduria

We have shown previously that a variant allele of the short-chain acyl- CoA dehydrogenase ( SCAD ) gene, 625G-->A, is present in homozygous form in 7% of control individuals and in 60% of 135 patients with elevated urinary excretion of ethylmalonic acid (EMA). We have now characterized three disease-causing mutations (confirmed by lack of enzyme activity after expression in COS-7 cells) and a new susceptibility variant in the SCAD gene of two patients with SCAD deficiency, and investigated their frequency in patients with elevated EMA excretion. The first SCAD-deficient patient was a compound heterozygote for two mutations, 274G-->T and 529T-->C. These mutations were not present in 98 normal control alleles, but the 529T-->C mutation was found in one allele among 133 patients with elevated EMA excretion. The second patient carried a 1147C-->T mutation and the 625G- ->A polymorphism in one allele, and a single point mutation, 511C-->T, in the other. The 1147C-->T mutation was not present in 98 normal alleles, but was detected in three alleles of 133 patients with elevated EMA excretion, consistently as a 625A-1147T allele. On the other hand, the 511C-->T mutation was present in 13 of 130 and 15 of 67 625G alleles, respectively, of normal controls and patients with elevated EMA excretion, and was never associated with the 625A variant allele. This over-representation of the haplotype 511T-625G among the common 625G alleles in patients compared with controls was significant ( P < 0.02), suggesting that the allele 511T-625G-like 511C-625A- confers susceptibility to ethylmalonic aciduria. Expression of the variant R147W SCAD protein, encoded by the 511T-625G allele, in COS-7 cells showed 45% activity at 37 degrees C in comparison with the wild- type protein, comparable levels of activity at 26 degrees C, and 13% activity when incubated at 41 degrees C. This temperature profile is different from that observed for the variant G185S SCAD protein, encoded by the 511C-625A allele, where higher than normal activity was found at 26 and 37 degrees C, and 58% activity was present at 41 degrees C. These results corroborate the notion that the 511C-625A variant allele is one of the possible underlying causes of ethylmalonic aciduria, and suggest that the 511C-->T mutation represents a second susceptibility variation in the SCAD gene. We conclude that ethylmalonic aciduria, a commonly detected biochemical phenotype, is a complex multifactorial/polygenic condition where, in addition to the emerging role of SCAD susceptibility alleles, other genetic and environmental factors are involved.