T helper 17 polarization in familial Mediterranean fever.

Autoinflammatory attacks in familial Mediterranean fever (FMF) are accompanied by elevated levels of interleukin-6 (IL-6), and are controllable by IL-1-targeting drugs. In combination, IL-6 and IL-1 are known to be potent inducers of T helper (Th) 17 cells development. Therefore, we studied the Th17 population size, and activation potential, of FMF patients. Based on the relative mRNA expression of the Th1, Th2, Treg and Th17 transcription factors T-bet, GATA3, FOXP3 and retinoic acid-related orphan receptor γT (RORγT), respectively, the Th17 population in peripheral blood mononuclear cells (PBMCs) of healthy subjects was estimated at 2.5% of the entire Th population and 4.4% in FMF patients in remission (n=6 for each group, P=0.03). IL-17 secretion after universal stimulation of the T-cell receptor in PBMCs culture was twice higher in cultures of patients with frequent attacks (n=18) than in those of patients with infrequent attacks (n=10, 1124±266 vs 615±196 pg ml(-1), P=0.009). IL-17 secretion correlated well with IL17A mRNA level. Part of the increased secretion was related to the deleterious, MEFV p.M694V homozygous genotype (n=19, 1.5-fold, P=0.03). Almost all IL-17 producer cells were CD4-positive (CD4(+)IL-17(+)). In conclusion, frequent attacks and the deleterious FMF genotype appear to drive FMF patients to a heightened Th17 response.

Lymph isolated from a regional scald injury produces a negative inotropic effect in dogs.

Large surface-area burns in patients have been associated with a severe impairment in cardiac performance, as evidenced by a decline in cardiac output. The mechanisms responsible for this profound myocardial dysfunction are largely unknown. We investigated the effects of lymph isolated from the scalded hind limb of dogs on regional myocardial blood flow, coronary vascular reactivity, and contractile performance. Dogs were instrumented with ultrasonic dimension crystals in the myocardium supplied by the left anterior descending (LAD) and by the left circumflex (LCx) coronary arteries. After cannulating a hind limb lymphatic, lymph was infused directly into the LAD before and after a 10-second 100 degrees C hind limb scald. Scalding alone did not alter myocardial contractile performance in the LAD or LCx regions, coronary artery blood flow, or systemic hemodynamics. Interestingly, postburn lymph infused into the LAD resulted in a 38% decline in LAD zone segment shortening (p < 0.01 vs baseline) that lasted throughout the 5-hour observation period. In contrast, segment shortening in the (control) LCx region was unaffected by postburn lymph injections into the LAD. Regional myocardial blood flow (radiolabeled microspheres) in the LAD and LCx regions was unchanged after scald injury or intracoronary injection of postburn lymph. In addition, LAD coronary artery vascular reactivity to acetylcholine and nitroglycerin was also unaffected by the regional thermal injury or by injection of lymph into the LAD. These data suggest that a regional scald injury results in the production and release of a potent myocardial depressant factor(s) that produces a direct negative inotropic effect on the canine myocardium.

Alpha-trinositol reduces edema formation at the site of scald injury.

BACKGROUND: The effects of alpha-trinositol (1D-myo-inositol-1,2,6-triphosphate, IP3) on burn-induced edema formation were investigated. METHODS: Lymph flow (QL; microliter/min) and lymph-to-plasma protein ratio (CL/CP) were monitored in groups of five to six dogs before and 4 hours after (1) a 5-second 100 degrees C or 90 degrees C foot paw scald; (2) IP3 (45 mg/kg intravenous bolus, then a 20 mg/kg/hr infusion) 30 minutes before or after 100 degrees C scald, or 30 minutes after 90 degrees C scald. Hind paw venous pressure was elevated and maintained by outflow restriction until reaching steady state QL and (CL/CP)min. Macromolecular reflection coefficient (1-CL/CP) was measured. Fluid filtration coefficient (Kf; ml/min/mm Hg/100 gm) was calculated. Relative paw weight gain (%) was measured. RESULTS: Compared with preburn values, scald uniformly produced significant increases in QL, CL/CP, and Kf, IP3 significantly (p < 0.02, ANOVA) reduced paw weight gain when given before, but not after, 100 degrees C burn (41% +/- 5% versus 18% +/- 7% preburn IP3 and 31% +/- 3% postburn IP3). Compared with 90 degrees C burn animals, postburn treatment significantly (p < 0.017) attenuated 4-hour increases in QL (550 +/- 87 versus 252 +/- 29 microliters/min), Kf (0.016 +/- 00 versus 0.007 +/- 00 microliter/min/mm/Hg/100 gm), and relative paw weight gain (28% +/- 3% versus 12% +/- 5%). CONCLUSIONS: alpha-Trinositol given after a 90 degrees C scald blunted edema formation at the site of scald, likely through reduced transmembrane fluid flux.

Burn edema reduction by methysergide is not due to control of regional vasodilation.

To determine the extent to which edema modulation by methysergide is due to a blunting of the regional vasodilator response to scald and/or local reduction of transvascular fluid flux, a canine hind limb lymphatic was cannulated. Femoral blood flow (Qa; ml/min), lymph flow (QL; microliter/min/100 g), and lymph-to-plasma protein ratios (CL/CP) were monitored in groups of five dogs before and 4 hr after 5-sec, 100 degrees C foot paw scald; high (1.0 mg/kg) or low (.5 mg/kg) dose of methysergide 30 min before scald. The compression on a clamp placed around the femoral artery in other dogs was adjusted after scald to simulate the blunting effect on Qa observed in methysergide treated dogs. Hind leg venous pressure was elevated to approximately = 40 mm Hg before experimentation until steady state QL and (CL/CP)min were reached. Protein reflection coefficient (sigma d; 1-C1/ CP) and fluid filtration coefficient (Kf) were calculated. Compared to preburn values, all groups showed significant (P < 0.002, analysis of variance) increases in CL/CP and Kf. Contrasted with the burn only group, methysergide blunted increases in Qa, Kf and paw weight gain in a dose-dependent fashion, with no effect on the reflection coefficient. Compression clamp control of femoral Qa caused no effects on permeability. Methysergide limits burn edema in a dose-related fashion, though not due to a blunting of the regional vasodilator response. Local, not regional, mechanism(s) likely mediate this response.

The detrimental effects of electric current on normal human sperm.

This in vitro study was conducted to determine the direct effects of electric current and associated increase in temperature on human sperm. Washed sperm samples from normal volunteers were subjected to an electric current (0 to 100 mA) in a small, customized Plexiglas chamber for up to 10 minutes. Resistive heating was monitored by a miniature temperature probe. An aliquot (7 microliters) obtained from the exposed sample (at 0, 3, 7, and 10 minute intervals) was evaluated for sperm motion parameters, viability, gross morphology, and electron microscopic analyses. As the current increased, there was a time-dependent decrease in the percentages of motility, viability, and curvilinear velocity. Light and electron microscopic evaluations of the sperm showed no demonstrable damage to the head, mid piece, or tail regions on electric stimulation. A gradual time-dependent increase in the temperature of the medium was observed with electric current. Separate evaluations in the absence of an electric current showed a significant increase in percent motility and curvilinear velocity until 40 degrees C. These results suggest that an electric current, independent of temperature (up to 40 degrees C), is detrimental to sperm motion and viability. Further studies are indicated to evaluate whether electric current during electroejaculation may be in part responsible for poor sperm recovery in men with spinal cord injury.