Cystamine Treatment Fails to Prevent the Development of Pulmonary Hypertension in Chronic Hypoxic Rats.

INTRODUCTION: Pulmonary hypertension is characterized by vasoconstriction and remodeling of pulmonary arteries, leading to right ventricular hypertrophy and failure. We have previously found upregulation of transglutaminase 2 (TG2) in the right ventricle of chronic hypoxic rats. The hypothesis of the present study was that treatment with the transglutaminase inhibitor, cystamine, would inhibit the development of pulmonary arterial remodeling, pulmonary hypertension, and right ventricular hypertrophy. METHODS: Effect of cystamine on transamidase activity was investigated in tissue homogenates. Wistar rats were exposed to chronic hypoxia and treated with vehicle, cystamine (40 mg/kg/day in mini-osmotic pumps), sildenafil (25 mg/kg/day), or the combination for 2 weeks. RESULTS: Cystamine concentration-dependently inhibited TG2 transamidase activity in liver and lung homogenates. In contrast to cystamine, sildenafil reduced right ventricular systolic pressure and hypertrophy and decreased pulmonary vascular resistance and muscularization in chronic hypoxic rats. Fibrosis in the lung tissue decreased in chronic hypoxic rats treated with cystamine. TG2 expression was similar in the right ventricle and lung tissue of drug and vehicle-treated hypoxic rats. DISCUSSION/CONCLUSIONS: Cystamine inhibited TG2 transamidase activity, but cystamine failed to prevent pulmonary hypertension, right ventricular hypertrophy, and pulmonary arterial muscularization in the chronic hypoxic rat.

Comparison of test results from two separate video head impulse test systems in a cohort of patients diagnosed with a unilateral vestibular schwannoma.

PURPOSE: Video head impulse testing (vHIT) is a relatively new technology enabling evaluation of vestibular function. The aim of this study was to compare the test results from two separate vHIT systems in a group of patients diagnosed with a unilateral vestibular schwannoma (VS) with regards to sensitivity, specificity and inter-examiner differences. METHODS: Forty-two patients were examined with two separate vHIT systems: EyeSeeCam® (system A) and ICS Impulse® (system B), by one of two examiners. All six semicircular canals (SCCs) were tested under standardized conditions, and strict criteria were set up for post-test interpretation. RESULTS: With the majority of test parameters, the two test systems were in agreement. Vestibular deficits were found in 40.5% (system A) to 45% (system B) of patients with a VS on the tested side; corresponding to a positive predictive value (PPV) of 86.4% (system B) to 94.4% (system A). The specificity was 97.6% for system A and 92.9% for system B. An overall agreement between the two vHIT systems measured as kappa was computed to be 0.61. There were no significant inter-examiner differences. When testing the vertical SCCs, a tendency of too high mean gain values was seen with system A but not with system B. CONCLUSION: In patients with unilateral VS, vHIT is a test with moderate sensitivity and high specificity in regard to identification of a vestibular deficit. There were no significant differences in test results between the two vHIT systems.

Involvement of Potassium Channels and Calcium-Independent Mechanisms in Hydrogen Sulfide-Induced Relaxation of Rat Mesenteric Small Arteries.

Endogenous hydrogen sulfide (H2S) is involved in the regulation of vascular tone. We hypothesized that the lowering of calcium and opening of potassium (K) channels as well as calcium-independent mechanisms are involved in H2S-induced relaxation in rat mesenteric small arteries. Amperometric recordings revealed that free [H2S] after addition to closed tubes of sodium hydrosulfide (NaHS), Na2S, and GYY4137 [P-(4-methoxyphenyl)-P-4-morpholinyl-phosphinodithioic acid] were, respectively, 14%, 17%, and 1% of added amount. The compounds caused equipotent relaxations in isometric myographs, but based on the measured free [H2S], GYY4137 caused more relaxation in relation to released free H2S than NaHS and Na2S in rat mesenteric small arteries. Simultaneous measurements of [H2S] and tension showed that 15 µM of free H2S caused 61% relaxation in superior mesenteric arteries. Simultaneous measurements of smooth muscle calcium and tension revealed that NaHS lowered calcium and caused relaxation of NE-contracted arteries, while high extracellular potassium reduced NaHS relaxation without corresponding calcium changes. In NE-contracted arteries, NaHS (1 mM) lowered the phosphorylation of myosin light chain, while phosphorylation of myosin phosphatase target subunit 1 remained unchanged. Protein kinase A and G, inhibitors of guanylate cyclase, failed to reduce NaHS relaxation, whereas blockers of voltage-gated KV7 channels inhibited NaHS relaxation, and blockers of mitochondrial complex I and III abolished NaHS relaxation. Our findings suggest that low micromolar concentrations of free H2S open K channels followed by lowering of smooth muscle calcium, and by another mechanism involving mitochondrial complex I and III leads to uncoupling of force, and hence vasodilation.

Head and neck sarcomas: the first report addressing the duration of symptoms and diagnostic work up.

Background: Head and neck sarcomas are rare and difficult to diagnose and manage.Aim: To describe a population of patients with head and neck sarcomas focusing on the effect of symptom duration and time to diagnosis on mortality and recurrence risk.Materials and methods: Fifty-one patients treated in our department between 1998-2013 were retrospectively included. Patient and tumour characteristics as well as dates of interest were obtained from sarcoma registries, charts and pathology records. The effect of symptom duration and time to diagnosis on mortality and risk of recurrence was tested by multivariate analysis.Results: There was a wide range in symptom duration (1-144 months, median 5) and time for diagnosis (0-234 days, median 14) without significant effect on overall mortality, disease-specific mortality or risk of recurrence. Chondrosarcomas in the larynx dominated among the patients with the longest diagnostic duration.Conclusion and significance: The diagnostic process is challenging and in some cases of extremely long duration without effect on mortality. The symptom duration and time to diagnosis in relation to mortality and risk of recurrence has not previously been described. Early biopsy, better imaging and advanced pathological techniques can hopefully speed up the diagnostic process and reduce morbidity and mortality.

Streptococcal toxic shock syndrome complicating a peritonsillar abscess.

A 68-year-old man was admitted to hospital in an acute confusional state with a 2-week history of fever, influenza-like illness and sore throat. He quickly developed coagulation disturbances, hypotension and renal function impairment. Despite broad-spectrum antibiotic therapy, he deteriorated. Group A streptococcus (GAS) was recovered from blood cultures, which gave the diagnosis streptococcal toxic shock syndrome (STSS). A computed tomography scan showed a right-sided peritonsillar abscess (PTA). Acute tonsillectomy was carried out and the patient recovered. STSS complicating PTA has not previously been described in the literature, but GAS is a common pathogen in PTA. Clinicians should be aware that STSS can develop secondary to tonsillar infections and that abscess development should be suspected in STSS patients who do not respond to antibiotic treatment.

The role of endogenous H2S in cardiovascular physiology.

Recent research has shown that the endogenous gas hydrogen sulphide (H2S) is a signalling molecule of considerable biological potential and has been suggested to be involved in a vast number of physiological processes. In the vascular system, H2S is synthesized from cysteine by cystathionine-γ-lyase (CSE) in smooth muscle cells (SMC) and 3- mercaptopyruvate sulfuresterase (3MST) and CSE in the endothelial cells. In pulmonary and systemic arteries, H2S induces relaxation and/or contraction dependent on the concentration of H2S, type of vessel and species. H2S relaxes SMC through a direct effect on KATP-channels or Kv-channels causing hyperpolarization and closure of voltage-dependent Ca2+-channels followed by a reduction in intracellular calcium. H2S also relaxes SMC through the release of endothelium- derived hyperpolarizing factor (EDHF) and nitric oxide (NO) from the endothelium. H2S contracts SMC through a reduction in nitric oxide (NO) availability by reacting with NO forming a nitrosothiol compound and through an inhibitory effect on endothelial nitric oxide synthase (eNOS) as well as a reduction in SMC cyclic AMP concentration. Evidence supports a role for H2S in oxygen sensing. Furthermore, reduced endogenous H2S production may also play a role in ischemic heart diseases and hypertension, and treatment with H2S donors and cysteine analogues may be beneficial in treatment of cardiovascular disease.