Acute cardiovascular effects of magnesium and their relationship to systemic and myocardial magnesium concentrations after short infusion in awake sheep

The temporal relationship between the systemic and myocardial concentrations of magnesium and some of its acute cardiovascular effects were examined after short i.v. infusion administration of magnesium (30 mmol over 2 min) in five awake chronically instrumented sheep. Magnesium decreased mean arterial blood pressure and systemic vascular resistance (SVR) by 23 and 41% from baseline, respectively. These hemodynamic changes were consistent with magnesium producing primary reductions in SVR with partial heart rate (HR)-mediated compensation of blood pressure. Cardiac output and HR increased by 38 and 38% from baseline, respectively. Magnesium had little effect on myocardial contractility, but substantially increased myocardial blood flow (MBF, 77% above baseline) primarily due to direct myocardial vasodilation. The peak arterial and coronary sinus serum magnesium concentrations were 6.94 +/- 0.26 (mean +/- S.E.M.) and 6.51 +/- 0.20 mM, respectively, at 2 min. Both arterial and coronary sinus magnesium concentrations at the end of the study were still more than 3 mM, whereas all the cardiovascular effects were back to baseline. The myocardial kinetics of magnesium was consistent with rapid equilibration of magnesium (half-life 0.4 min) with a small distribution volume (71 ml) consistent with the extracellular space of the heart. In conclusion, magnesium was shown to have a rapid equilibration between the plasma/serum concentrations of magnesium and its extracellular concentration in the myocardium. However, the primary cardiovascular effect of magnesium (reductions in SVR) preceded its extracellular concentrations, and was a direct function of its arterial concentration. A "threshold" model for changes in SVR was preferred when linked to the arterial magnesium concentration.     

Seguimiento a largo plazo del cabestrillo AdVance®/AdVanceXP®. ¿Qué piensa el cirujano?, ¿qué piensa el paciente?

Objectives

To analyse the safety, efficacy and quality of life of patients with male stress urinary incontinence after radical prostatectomy treated with the AdVance^® and AdvanceXP^® slings.

Role of p75 neurotrophin receptor in the neurotoxicity by beta-amyloid peptides and synergistic effect of inflammatory cytokines

The neurodegenerative changes in Alzheimer's disease (AD) are elicited by the accumulation of beta-amyloid peptides (Abeta), which damage neurons either directly by interacting with components of the cell surface to trigger cell death signaling or indirectly by activating astrocytes and microglia to produce inflammatory mediators. It has been recently proposed that the p75 neurotrophin receptor (p75(NTR)) is responsible for neuronal damage by interacting with Abeta. By using neuroblastoma cell clones lacking the expression of all neurotrophin receptors or engineered to express full-length or various truncated forms of p75(NTR), we could show that p75(NTR) is involved in the direct signaling of cell death by Abeta via the function of its death domain. This signaling leads to the activation of caspases-8 and -3, the production of reactive oxygen intermediates and the induction of an oxidative stress. We also found that the direct and indirect (inflammatory) mechanisms of neuronal damage by Abeta could act synergistically. In fact, TNF-alpha and IL-1beta, cytokines produced by Abeta-activated microglia, could potentiate the neurotoxic action of Abeta mediated by p75(NTR) signaling. Together, our results indicate that neurons expressing p75(NTR), mostly if expressing also proinflammatory cytokine receptors, might be preferential targets of the cytotoxic action of Abeta in AD.     

Synthesis and antileishmanial activities of novel 3-substituted quinolines

The antileishmanial efficacy of four novel quinoline derivatives was determined in vitro against Leishmania chagasi, using extracellular and intracellular parasite models. When tested against L. chagasi-infected macrophages, compound 3b demonstrated 8.3-fold greater activity than did the standard pentavalent antimony. No significant activity was found for compounds 3a, 4a, and 4b. The antilesihmanial effect of compound 3b was independent of host cell activation, as demonstrated by nitric oxide production. Ultrastructural studies of promastigotes treated with compound 3b showed mainly enlarged mitochondria, with matrix swelling and reduction in the number of cristae. Synthetic analogues based on the quinoline ring structure, already an established template for antiparasitic drugs, could provide further useful compounds.     

Injury control: a primer for physicians

Injuries are a disease process that costs billions of dollars every year in direct and indirect costs. Despite recent emphasis on prehospital systems and trauma care, prevention of injuries remains an area underutilized by physicians. As a disease process, injuries are amenable to evaluation with epidemiologic tools and subject to prevention by modifying the transmission of energy to human beings. This may occur by either active or passive means of intervention. Physician leadership in the prevention of injuries is important, yet few physicians have training in injury control. The concepts of injury control are presented by defining the components that create injury and by examining the factors that affect each component. Strategies for identifying countermeasures are described and the merits of each of the applications of countermeasures are discussed. The physician must understand these basic concepts of injury control to an effective leader in developing strategies that mitigate injury in the community.     

IBD5 polymorphisms in inflammatory bowel disease： Association with response to infliximab

AIM: Inflammatory bowel diseases (IBD) are multifactorial pathologies of unknown etiology. One susceptibility locus, IBD5, has been mapped to chromosome 5q31. We analyzed our Spanish cohorts of Crohn's disease (CD) and ulcerative colitis (DC) patients to determine whether this locus is associated with IBD, and to ascertain the main clinical phenotype influenced by this risk factor. The kind of interaction, either genetic heterogeneity or epistasis, between this IBD5 susceptibility region and the NOD2/CARD15 gene mutations was studied as well. Finally, we assessed whether this locus can predict response to infliximab therapy. METHODS: A case control study was performed with 274 CD and 211 UC patients recruited from a single center and 511 healthy ethnically matched controls. Two polymorphisms were genotyped in the IBD5 locus and three in the CARD15/NOD2 gene. RESULTS: Our results evidence association only with CD especially with the fistulizing phenotype and in the absence of NOD2/CARD15 variants (mutant allele frequency in patients vs controls: OR = 2.03, 95% CI = 1.35-3.06, P<0.01). The frequency of the IBD5 homozygous mutant genotype significantly increased in CD patients lacking response to infliximab (RR = 3.88, 95% CI = 1.18-12.0, P<0.05). UC patients overall do not show association with 5q31 polymorphisms, although a similar trend to the one observed in CD is found within the worse prognosis group. CONCLUSION: The IBD5 variants may enhance an individual carrier's risk for CD, mainly in the absence of the NOD2/CARD15 mutations and in fistulizing patients. The data presented suggest the potential role of the 5q31 polymorphisms as markers of response to infliximab.     

Immunocytochemical localization of heat-shock protein 60-related protein in Beta-cell secretory granules and its altered distribution in non-obese diabetic mice

Summary Immuno-electron microscopy technique was employed to investigate the cellular distribution of 60 kDa heat-shock protein (HSP60) in pancreatic Beta cells of control and non-obese diabetic mice. In thin sections prepared from control mice, antibody to mammalian HSP60 cross-reacted with protein(s) located to mitochondria and secretory granules. In particular, prominent binding of the antibody was seen to the insulin core of the mature insulin-secreting granules. In comparison, very little immunoreactivity was observed with immature secretory granules or with the Golgi apparatus. No binding to secretory granules or mitochondria was observed with normal mouse serum or with unrelated sera. On Western blots, HSP60 antibody specifically interacted with a single 62 kDa islet cell protein. These results suggest the existence of an HSP60-related protein with a novel location in mature secretory granules of Beta cells. The preferential association of the HSP60-related protein with the insulin core was gradually lost in Beta cells of pre-diabetic non-obese diabetic mice, and correlated with the progression of insulitis. The decrease in the granular binding of the HSP60 antibody was accompanied by an increase in cytoplasm staining, and was concomitant with a significant expansion of the insulin core diameter. The altered distribution of the HSP60-related protein in prediabetic mice, together with our observation that immature secretory granules accumulate in these animals indicate that the presence of HSP60-related protein in secretory granules might be associated with the secretory function of Beta cells.     

Intrathoracic lymphadenopathy. A rare manifestation of rheumatoid pulmonary disease

This is the first antemortem report of a patient with long-standing RA and interstitial lung disease who developed reactive mediastinal adenopathy coincident with increases in the activity of his interstitial process. Mediastinal adenopathy was discovered by means of CT of the chest as part of an evaluation of interstitial lung disease. The increasing use of better imaging techniques for this purpose will undoubtedly reveal more patients with this finding. Mediastinal lymphadenopathy complicating rheumatoid lung is clinically relevant; speculation is provided regarding the mechanism of the lymph node enlargement in this setting.     

Physiopathological Heterogeneity of the Duodenal Mechanisms that Inhibit Gastric Acid Secretion in Duodenal Ulcer Patients

The effect of duodenal acidification on pentagastrin-stimulated gastric acid secretion was studied in 43 duodenal ulcer patients and in 17 normal controls. Three types of responses were observed: group A, no inhibition of gastric acid secretion occurred in 17 (40%) ulcer patients and in three (18%) controls (p less than 0.05); group B, inhibition of gastric acidity occurred in seven (16%) ulcer patients and in 12 (71%) controls (p less than 0.05), and group C, retarded gastric acid inhibition occurred in 19 (44%) duodenal ulcer patients and in 2 (12%) controls (p less than 0.05). Secretin levels did not increase after duodenal acidification, the higher percentages of failure being observed in groups A and C (p less than 0.05). The pH of the duodenal aspirate was 4.9 +/- 2 and 7.7 +/- 1.4 in ulcer patients and controls, respectively (p less than 0.05), with the low levels being detected in groups A and C (4.7 +/- 2 and 5.3 +/- 2.1) compared to group B (7.3 +/- 1.7; p less than 0.05). The results show that responses of duodenal ulcer patients to duodenal acidification are heterogeneous, and that failure of gastric secretion inhibition and defective intraduodenal acid neutralization are related.