The effects of interleukin-10 in hemorrhagic shock

BACKGROUND: Interleukin-10 (IL-10) counteracts the effects of the proinflammatory cytokines interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor (TNF). Experimental data suggest that inhibition of these proinflammatory cytokines improves outcome in sepsis, endotoxemia, necrotizing pancreatitis, and other severe inflammatory states. We hypothesized that the administration of IL-10 would attenuate the release of proinflammatory cytokines after severe hemorrhagic shock. METHODS: To test our hypothesis, male Sprague-Dawley rats (N = 20) were divided into control and experimental groups. We induced hemorrhagic shock by removing a sufficient quantity of blood to maintain a mean arterial pressure of 50 mm Hg or less for 120 min. The animals were then resuscitated with shed blood and an equal volume of 0.9% saline. The experimental group received 10,000 units of IL-10 at the initiation of shock. Serum IL-1, IL-6, TNF, and lactate were measured at baseline, after 120 min of shock, and 60 min after resuscitation. The rats were followed for 72 h to calculate survival. RESULTS: Similar levels of hypoperfusion were obtained in both groups as demonstrated by lactate levels and amount of shed blood. The survival rate (70%) was the same in both groups. Serum levels of IL-1 and IL-6 were not significantly different between the two groups, although there was a trend toward IL-6 suppression. TNF, however, was significantly lower in the IL-10-treated group at the end of shock (Wilcoxon test, P < 0. 025). CONCLUSION: Administration of IL-10 suppresses the TNF surge observed after severe hemorrhagic shock.     

Stenting of partial and total coronary occlusions in Trinidad and Tobago

In order to evaluate the efficacy and safety of coronary stenting, we reviewed the first 32 consecutive patients (34 vessels) who underwent elective coronary stenting during the period August 1999 to August 2000 inclusive at the Digital Lab installed at the Eric Williams Medical Sciences Complex, Trinidad and Tobago. Aspirin, heparin and ticlopidine were used routinely. Abciximab was used in selected cases (38%). The mean age of patients was 55 +/- 10 years. Eighty-one per cent were male, 52% were hypertensive and 21% were diabetic. Sixty-five per cent had severe angina. Prior Coronary Artery Bypass Grafting (CABG) was performed in 3% and previous Percutaneous Transluminal Coronary Angioplasty (PTCA) in 3%. Multivessel disease was present in 43%. The mean left ventricular ejection fraction was 53 +/- 12%. The culprit lesion was located in either the native left anterior descending (LAD) coronary artery (53%), right coronary artery (RCA) (31%), circumflex artery 13% and saphenous vein graft (3%). The mean baseline diameter stenosis was 91 +/- 9% and this was reduced to 13 +/- 33% after stenting. Procedural success was 100% for 26 partially occluded vs 50% for 8 totally occluded vessels. For the total occlusions, procedural success was inversely related to the duration of the occlusion. There were no cases of death, acute vessel closure, Q-wave myocardial infarction, repeat PTCA or emergent Coronary Artery Bypass Graft (CABG) during and following the procedure. Distal embolization occurred in one patient. The mean duration of hospital stay was one day (for 30 outpatient cases). One patient had recurrence of symptoms with a negative stress test. No patient underwent repeat angiography during the first year of follow-up. Coronary stents were successfully implanted at a tertiary care facility in the Caribbean with low in-hospital morbidity and mortality. Stents markedly reduced the diameter stenosis of the coronary lesion during PTCA. The incidence of clinical restenosis was low. Coronary revascularisation can be successfully achieved by coronary stenting in the Caribbean.     

Two kinds of nigrostriatal asymmetry: relationship to dopaminergic drug sensitivity and 6-hydroxydopamine lesion effects in Long-Evans rats

Recent work in this laboratory has provided evidence for a two-population model of normal rotational behavior: some rats circle predominantly away from the side containing the striatum with the greater dopamine levels and some rats circle predominantly towards the side containing the striatum with the greater dopamine levels. The two populations also respond differently to 6-hydroxydopamine lesions of the substantia nigra ipsilateral to the preferred direction of circling. The present study replicated these findings in another strain of rats and showed further that the two populations could be distinguished behaviorally by their relative responses to indirectly acting ( -amphetamine, cocaine) and directly acting (apomorphine, pergolide) dopamine agonists. The results suggest that the two populations differ with respect to the balance between pre- and postsynaptic elements within the striatum.     

Effects of intravascular volume expansion on the cardiovascular response to naloxone in a canine model of severe endotoxin shock.

The specific opiate receptor antagonist, naloxone, can produce haemodynamic improvement and increased survival in experimental shock. The efficacy of naloxone therapy in a canine model of endotoxin shock has been evaluated both with and without intravascular volume replacement. Animals were anaesthetized with alpha-chloralose and allowed to breathe spontaneously. A large bolus dose of endotoxin was followed by a continuous infusion and treatment was instituted one hour after the endotoxin bolus. In the absence of volume replacement, naloxone caused only limited and transient increases in mean arterial pressure (MAP) and left ventricular (LV) dp/dt max, with little effect on cardiac index (CI). Total peripheral resistance index (TPRI) tended to rise in both control and naloxone-treated dogs. In volume-replaced animals, naloxone produced substantial and sustained increases in the MAP and LV dp/dt max with an associated rise in the CI. TPRI rose initially in this series and then fell progressively. Further analysis of the improvements in the CI showed an increase in stroke index with a tendency for heart rate to fall. These findings suggest a myocardial action of naloxone in endotoxin shock, which is augmented by volume replacement. An initial, transient vasoconstrictor effect cannot, however, be excluded. Further work is required to determine the mechanism of the effects described.     

Synthesis, conformational properties, and antibody recognition of peptides containing beta-turn mimetics based on alpha-alkylproline derivatives

Peptide recognition by monoclonal antibodies may provide a useful model for drug development, in particular to test the effects of conformational restriction on ligand binding. We have tested the influence of novel peptide mimetics upon conformation and binding affinity for the case of monoclonal antibodies raised to a peptide antigen which displays a preference for a beta-turn conformation in aqueous solution. Two monoclonals were isolated that recognized the peptide Ac-Tyr-Pro-Tyr-Asp-Val-Pro-Asp-Tyr-Ala specifically at the beta-turn formed by Tyr-Pro-Tyr-Asp. Peptide analogues were then synthesized containing mimetics designed to stabilize this conformation. One, analogue (3), contained a spirocyclic gamma-lactam bridge between the alpha-position of proline-2 and the N atom of tyrosine-3, while another (2) contained (S)-alpha-methylproline at position 2. NMR spectroscopy and molecular modeling suggest that both analogues adopt reverse-turn conformations stabilized relative to that in the native sequence. For the (S)-alpha-methylproline analogue binding to both monoclonal antibodies was substantially improved, compared with the native antigen, whereas the gamma-lactam analogue (3) was not recognized by either antibody. Quantitative equilibrium ultrafiltration binding assays showed that the affinities of the (S)-alpha-methylproline analogue (2) for the two antibodies were improved over those measured with the native antigen by -2.3 and -0.65 kcal/mol. The origins of these free energy differences cannot be explained wholly on the basis of presumed extra hydrophobic contacts between the new methyl substituent and the antigen binding sites. We propose that the increased conformational stability of the analogue plays a decisive role, implying that the reverse turn detected in the native antigen, possibly a type-I turn, is important for recognition by the two antibodies.     

A waterborne outbreak of hepatitis A in Meade County, Kentucky.

In November 1982, Meade County, Kentucky health officials noted a sudden increase in the incidence of hepatitis A. Using a standardized interview of 73 cases (68 serologically confirmed), and 85 controls (all negative for antibody to hepatitis A virus), the most important risk factor identified was household use of untreated water from a single spring. A dose-response relationship was found for consumption of unboiled spring water. Water samples taken from the spring during the outbreak were contaminated with fecal coliforms.     

Fat embolism syndrome

Although first reported in 1862, the fat embolism syndrome continues to arouse controversy. Current views on its pathophysiology, diagnosis, treatment and prophylaxis are reviewed here.     

Characterization of the Descemet's membrane/posterior collagenous layer isolated from Fuchs' endothelial dystrophy corneas

The combined Descemet's membrane (DM) and posterior collagenous layer (PCL) of Fuchs' endothelial dystrophy corneas were isolated and characterized by biochemical and immunofluorescence methods. The amino acid composition of the Fuchs' DM-PCL was similar to age-matched normal Descemet's membranes (DM). As determined by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and ¹²⁵I two-dimensional peptide mapping, normal DM and Fuchs' DM-PCL contained the same collagen types [type IV and endothelial cell (EC) collagen], but a slight discrepancy was seen in the electrophoretic mobility of some collagen chains. Immunofluorescence staining localized fibrinogen/fibrin to Fuchs' DM-PCL but not to normal DM. These data suggest (1) that the appearance of 110 nm banded material in sheets and fusiform bundles characteristic of Fuchs' PCL is not due to the presence of a new (abnormal) collagen type but may represent altered assembly of collagen molecules, and (2) that the fibrinolytic system may play a role in the degenerative process of Fuchs' endothelial dystrophy.