Protective effects of exogenous and endogenous hydrogen sulfide in mast cell-mediated pruritus and cutaneous acute inflammation in mice.

The recently described 'gasomediator' hydrogen sulfide (H2S) has been involved in pain mechanisms, but its effect on pruritus, a sensory modality that similarly to pain acts as a protective mechanism, is poorly known and controversial. The effects of the slow-releasing (GYY4137) and spontaneous H2S donors (Na2S and Lawesson's reagent, LR) were evaluated in histamine and compound 48/80 (C48/80)-dependent dorsal skin pruritus and inflammation in male BALB/c mice. Animals were intradermally (i.d.) injected with C48/80 (3µg/site) or histamine (1µmol/site) alone or co-injected with Na2S, LR or GYY4137 (within the 0.3-100nmol range). The involvement of endogenous H2S and KATP channel-dependent mechanism were also evaluated. Pruritus was assessed by the number of scratching bouts, whilst skin inflammation was evaluated by the extravascular accumulation of intravenously injected 125I-albumin (plasma extravasation) and myeloperoxidase (MPO) activity (neutrophil recruitment). Histamine or C48/80 significantly evoked itching behavior paralleled by plasma extravasation and increased MPO activity. Na2S and LR significantly ameliorated histamine or C48/80-induced pruritus and inflammation, although these effects were less pronounced or absent with GYY4137. Inhibition of endogenous H2S synthesis increased both Tyrode and C48/80-induced responses in the skin, whereas the blockade of KATP channels by glibenclamide did not. H2S-releasing donors significantly attenuate C48/80-induced mast cell degranulation either in vivo or in vitro. We provide first evidences that H2S donors confer protective effect against histamine-mediated acute pruritus and cutaneous inflammation. These effects can be mediated, at least in part, by stabilizing mast cells, known to contain multiple mediators and to be primary initiators of allergic processes, thus making of H2S donors a potential alternative/complementary therapy for treating inflammatory allergic skin diseases and related pruritus.

Hydrogen sulfide donors alleviate itch secondary to the activation of type-2 protease activated receptors (PAR-2) in mice.

Hydrogen sulfide (H2S) has been highlighted as an endogenous signaling molecule and we have previously found that it can inhibit histamine-mediated itching. Pruritus is the most common symptom of cutaneous diseases and anti-histamines are the usual treatment; however, anti-histamine-resistant pruritus is common in some clinical settings. In this way, the involvement of mediators other than histamine in the context of pruritus requires new therapeutic targets. Considering that the activation of proteinase-activated receptor 2 (PAR-2) is involved in pruritus both in rodents and humans, in this study we investigated the effect of H2S donors on the acute scratching behavior mediated by PAR-2 activation in mice, as well as some of the possible pharmacological mechanisms involved. The intradermal injection of the PAR-2 peptide agonist SLIGRL-NH2 (8-80nmol) caused a dose-dependent scratching that was unaffected by intraperitoneal pre-treatment with the histamine H1 antagonist pyrilamine (30mg/kg). Co-injection of SLIGRL-NH2 (40nmol) with either the slow-release H2S donor GYY4137 (1 and 3nmol) or the spontaneous donor NaHS (1 and 0.3nmol) significantly reduced pruritus. Co-treatment with the KATP channel blocker glibenclamide (200nmol) or the nitric oxide (NO) donor sodium nitroprusside (10nmol) abolished the antipruritic effects of NaHS; however, the specific soluble guanylyl cyclase inhibitor ODQ (30µg) had no significant effects. The transient receptor potential ankyrin type 1 (TRPA1) antagonist HC-030031 (20µg) significantly reduced SLIGRL-NH2-induced pruritus; however pruritus induced by the TRPA1 agonist AITC (1000nmol) was unaffected by NaHS. Based on these data, we conclude that pruritus secondary to PAR-2 activation can be reduced by H2S, which acts through KATP channel opening and involves NO in a cyclic guanosine monophosphate (cGMP)-independent manner. Furthermore, TRPA1 receptors mediate the pruritus induced by activation of PAR-2, but H2S does not interfere with this pathway. These results provide additional support for the development of new therapeutical alternatives, mainly intended for treatment of pruritus in patients unresponsive to anti-histamines.

Diagnostic utility of mechanical, pharmacological and orthostatic stimulation of the carotid sinus in patients with unexplained syncope.

OBJECTIVES: The purpose of the present study was to systematically evaluate the diagnostic utility of mechanical, pharmacological and orthostatic stimulation of the carotid sinus in a consecutive series of patients with recurrent unexplained syncope. BACKGROUND: Carotid sinus hypersensitivity (CSH) is an infrequently recognized cause of recurrent unexplained syncope usually diagnosed by carotid sinus massage (CSM) in the supine position. The diagnostic utility of systematic assessment of mechanical, pharmacological and orthostatic stimulation of the carotid sinus has not been clearly established. METHODS: Eighty consecutive patients (63 +/- 12 years) with a history of recurrent unexplained syncope (mean episodes: 6 +/- 3); 30 age-matched controls (65 +/- 14 years) and 16 patients (59 +/- 12 years) with syncope not related to CSH were studied. Pharmacological stimulation of the carotid sinus was achieved by randomly administering bolus injections of nitroprusside and phenylephrine. Mechanical stimulation of the carotid sinus was performed by CSM applied for 5 s in the supine position and after 2 min at 60 degrees. A 60 degree low-dose isoproterenol head-up tilt test (HUTT) was also performed for a total duration of 30 min. RESULTS: Carotid sinus hypersensitivity was elicited by CSM in the supine position in seven (8.7%) patients, two (6.6%) controls and one (6.3%) patient with syncope unrelated to CSH, compared with 48 (60%) patients, two (6.6%) controls and one (6.3%) syncope unrelated to CSH patient after 60 degree HUTT, increasing the diagnostic yield by 51%. Baroreceptor gain was significantly reduced in the CSH group. Head-up tilt test was positive in 12 (25%) patients with CSH, two (6.6%) controls and two (12%) with documented syncope but not positive in any of the patients in which syncope remained unexplained. Diagnostic accuracy was enhanced by 38% (31% supine vs. 69% upright) when CSM was performed at 60 degrees. CONCLUSIONS: CSH was documented in 68% of patients, 8.7% in the supine position and 60% in the upright position. Sensitivity was increased by 51%, and diagnostic accuracy was enhanced by 38% by performing CSM in the upright position. Decreased baroreceptor gain was documented and may play a role in the pathophysiology of CSH.

Direct myocardial revascularization without extracorporeal circulation. Experience in 700 patients.

Between May 1978 and March 1990, 700 patients were operated on with direct coronary surgery without extracorporeal circulation (ECC): 529 (76 percent) were male and 171 (24 percent) were female. The average age was 64 years (range, 35 to 86 years), 454 (65 percent) had unstable angina, 163 (23 percent) had stable angina, 51 (7 percent) had postmyocardial infarction angina, and 32 (5 percent) had acute myocardial infarction at the moment of the operation. In this series of patients, all branches of the coronary arteries were bypassed; the mammary artery was used in 40 percent of the cases, the average bypass per patient was 2.2 (range, 1 to 5), and 26 percent had associated disease of high risk to undergo ECC. The morbidity was 4 percent and the mortality for this series of patients was 1 percent; the probability of survival at seven years was 90 percent. This experience shows us that this surgery is an alternative in the treatment of coronary disease, especially for aged patients with associated disease, in some cases of acute transmural infarction, and also for patients who need coronary angioplasty. Also, it can improve the relation cost/benefit in coronary surgery.

Correlation of an invasive measure of right ventricular pressure and mean arterial pressure.

Recently, cardiac pacemakers have been introduced which increase heart rate during exercise. Current rate responsive pacemakers achieve this objective by monitoring minute ventilation via a transvenous impedance measurement and provides a proportional heart rate increase with increases in minute ventilation. These devices are independent of hemodynamic parameters. Therefore, the potential exists for a sufficiently high rate which results in decreased cardiac output by virtue of Starling's Principle. An invasive measure of right ventricular (RV) pressure is compatible with the power and complexity of contemporary implantable pacemakers. In addition, mean arterial pressure is accepted as a diagnostic indicator of left ventricular hemodynamic compromise. Therefore, a correlation of right ventricular pressure and mean arterial pressure was undertaken. Twenty-six patients were studied during normal sinus rhythm and ventricular tachycardia during routine electrophysiology examination. A beat to beat measure of peak to peak RV pressure resulted in a correlation coefficient of 0.68 with mean arterial pressure.

The effect of clinical experience on dental students' ability to design removable partial denture frameworks.

To determine whether clinical experience influenced dental students' ability to correctly design removable partial denture frameworks, four combinations of six casts depicting various partially edentulous situations were used in the study. The authors independently rated the casts as to the degree of difficulty on a three-point scale. Only those casts for which there were 100% agreement were used. All of the casts that were used had a moderate degree of difficulty rating (level 2). The dental student sample consisted of 34 second-year students who had just completed 98 hours of instruction in removable partial dentures. Each student was given six casts on which to design removable partial denture frameworks. The students were evaluated before clinical experience in removable prosthodontics and after 1 year of removable prosthodontic experience. The results indicated that the dental students made significantly fewer errors in framework design after clinical experience. Errors on two of 13 framework design items were increased postclinically. The increase in errors on these two items may have been the result of a lack of attention to detail or a lack of reinforcement in learning certain basic concepts.

Bacteria isolated from plantar ulcers of Ethiopian leprosy patients, with the antibacterial drug sensitivities of the isolates

Bacteriological sampling of grossly infected or chronic plantar ulcers was perfomed in 39 untreated patients with leprosy and in 22 patients who had received antibiotic treatment. Samples were cultured aerobically and anaerobically, and films of pus were stained by Gram´s method. Stained films gave little indication of the type of infecting pathogen, except when Gram-positive cocci alone were seen. From the ulcers of patients untreated with antibiotics anaerobic streptococci were isolated more frequently than any other organism, and and this may be an original observation. Of the 8 Staphylococcus aureus isolates 5 were penicillin sensitive. A renge of Gram-negative bacteria, but no Clostridia, were isolated. From the ulcers of patients who had received antibiotics penicillin-resistant Staph. aureus was most frequently isolated. Some Gram-positive bacteria resistant to tetracycline were sensitive to doxycycline.