The significance of underlying coronary stenosis for recovery of myocardial function after transient ischemia in the dog

The rate of recovery of myocardial function after transient coronary occlusion (CO) has been considered to depend on the duration and frequency of CO. However, underlying coronary stenosis has not been previously demonstrated to be a determinant of the rate of myocardial functional recovery. Thus, 12 open-chest dogs were studied to examine the influence of critical coronary stenosis (CCS) on functional recovery after transient CO. Regional functional recovery following 2-minute CO was examined under two different conditions in eight dogs: patent coronary artery stenosis and fixed CSS that exhausted coronary reserve but did not cause a deficit in resting coronary flow or regional function. Following reperfusion with the coronary artery patent, regional function in the ischemic zone was fully recovered (100 +/- 18.0% of pre-CO value) at 30 seconds and was significantly increased (postischemic hypercontraction) compared to pre-CO value at 1 and at 2 minutes after reperfusion. Following CO and reperfusion in the setting of CCS, regional functional recovery was delayed and regional function remained depressed until 2 minutes after reperfusion. No cumulative effect on functional recovery following repeated 2-minute CO was demonstrated in a control group of four dogs. We conclude that coronary artery patency is a determinant of the rate of myocardial function recovery after a transient ischemic episode, and postischemic hypercontractility was suppressed by the underlying CCS.     

Comprehensive gene expression profiling of anaplastic thyroid cancers with cDNA microarray of 25 344 genes

Little is known about the genetic mechanisms of anaplastic thyroid cancer (ATC). This is the most virulent of all human malignancies, and it is believed to result from transformation of differentiated thyroid cancers. To identify a set of genes involved in the development of ATC, we investigated expression profiles of 11 cell lines derived from ATC using a cDNA microarray representing 25 344 genes. Semi-quantitative RT-PCR experiments carried out for some genes that had shown altered expression on the microarray verified frequent over-expression of destrin, HSPA8, stathmin, LDH-A, ATP5A1, PSMB6, B23, HDP-1 and LDH-B, and frequent under-expression of thyroglobulin, PBP and c-FES/FPS genes among the cell lines and also among ten primary ATCs. In addition to mRNA expression studies, up-regulation of GDI2, destrin and stathmin were confirmed with immunohistochemical analysis. The extensive list of genes identified provides valuable information towards understanding the development of ATC, and provides a source of possible biomarkers for diagnosis and/or molecular targets for the development of novel drugs to treat ATC.     

Absence of coronary vascular reserve in myocardium distal to a fixed coronary stenosis

In a study to test the hypothesis that vascular reserve is exhausted in the setting of a resting blood flow deficit, the left anterior descending or circumflex artery was cannulated and perfused from the left carotid artery. After reactive hyperaemia had been assessed a stenosis was produced with a screw clamp. In the first experiment a moderate stenosis (diastolic perfusion pressure 40 mmHg) was produced in the left anterior descending artery (three dogs) or left circumflex artery (three dogs). Blood pressure was held constant with aortic constriction during intracoronary adenosine infusion (6 mumol.min-1). The stenosis was then adjusted to the preadenosine perfusion pressure. In the second experiment the anterior interventricular coronary vein was also isolated and segment length crystals were placed in the ischaemic and non-ischaemic zones. Severe stenosis (flow reduction of at least 50% and evidence of decreased segmental shortening) was produced in the cannulated left anterior descending artery (eight dogs). Intracoronary adenosine was given with aortic pressure held constant by transfusion and coronary venous drainage. In the first experiment resting coronary flow (ml.min-1) decreased from 41(3) to 29(6) (p less than 0.05) with stenosis. Coronary flow increased from 29(6) to 34(7) (p less than 0.05) with adenosine and to 50(10) (p less than 0.05) with stenosis adjustment. Subendocardial flow (ml.g-1.min-1) decreased from 0.89(0.26) to 0.78(0.23) (p less than 0.05) with adenosine and then increased from 0.94(0.49) with perfusion pressure adjustment. Subepicardial flow tended to increase with adenosine, and increased further with stenosis adjustment.(ABSTRACT TRUNCATED AT 250 WORDS)     

Autoantibodies against sarcolemmal Na-K-ATPase in patients with dilated cardiomyopathy: autoimmune basis for ventricular arrhythmias in patients with congestive heart failure

BACKGROUND: Autoimmunity is one of the mechanisms of pathogenesis of idiopathic dilated cardiomyopathy (DCM) as well as virus infection and genetic predisposition. Autoantibodies against sarcolemmal Na-K-ATPase may be involved in the development of ventricular tachycardia and cardiac sudden death in patients with DCM. METHODS AND RESULTS: By using enzyme-linked immunosorbent assay, autoantibodies were detected in 26% patients with DCM and in 2% age-matched control subjects. Na-K-ATPase activity in the presence of patient IgG was lower in patients with autoantibodies than without autoantibodies, but there was no difference in the control subjects. Western blots showed that autoantibodies recognized the alpha-subunit of Na-K-ATPase, and 3H-ouabain bindings in the presence of patient IgG showed that the dissociation constant was higher in patients with autoantibodies than without autoantibodies, although maximal binding sites were similar between the two groups. No difference existed between subjects with regard to age, sex, New York Heart Association functional class, cardiac function, or neurohormone levels, except for plasma norepinephrine which was higher in patients with autoantibodies than without autoantibodies, Ventricular arrhythmias were more common in patients with autoantibodies than without autoantibodies, and multiple logistic regression analysis demonstrated that the presence of autoantibodies, but not plasma norepinephrine, was an independent predictor for the occurrence of ventricular tachycardia. Cardiac sudden death was independently predicted by the presence of autoantibodies, as well as poor systolic function. CONCLUSIONS: Patients with DCM express autoantibodies against sarcolemmal Na-K-ATPase, and these autoantibodies could be responsible for the electrical instability in some patients.     

Hypertension: a systemic key to understanding local keloid severity

This study assessed whether hypertension, a circulating factor, influences local keloid severity. This retrospective cross‐sectional study involved 304 consecutive patients (13–78 years old) with keloids who were surgically treated in our hospital between January 2011 and August 2013. Their blood pressure (BP), age and gender, and the size and number of their keloids before surgery were recorded. Ordinal logistic regression analyses showed that BP associated significantly with both keloid size and number (all p < 0.0001). Age also associated with keloid size (p < 0.0001). However, a Goodness‐of‐fit chi‐square test showed that the prevalence of hypertension was not higher among keloid patients than in the general Japanese population. This study provides epidemiological evidence for the possibility that primary hypertension may aggravate keloids. We propose that the skin, along with the heart and liver, is a target organ of hypertension. The observations of this study, which require validation with large‐scale prospective interventional trials, suggest that keloid patients should be screened for hypertension and that antihypertensive treatments may be of prophylactic and therapeutic value for skin fibrosis.     

Immunological responses, histopathological finding and disease resistance of blue mussel (Mytilus edulis) exposed to treated and untreated municipal wastewater

This study provides new information on the response of the immune system of Mytilus edulis exposed to untreated and treated sewage, linking immune response to ecologically relevant endpoints, such as disease resistance. Our goal was to assess the potential effects of sewage on the immune system (phagocytic activity and production of cytotoxic metabolites, disease resistance) and gills (light microscope) of mussels through a bioassay and field study in an estuarine receiving environment (RE). A semi-static experiment was developed in a wastewater treatment plant in New Glasgow, NS Canada. Mussels were exposed for 21 days to 12.5%, 25%, 50% and 100% of untreated sewage influent and artificial seawater control. Sampling occurred after 7, 14 and 21 days of exposure. In the field study, eight sites were selected in East River and Pictou Harbour, NS, positioned upstream and downstream of sewage effluents outfalls. Caged mussels were exposed to the RE for 90 days (May-July 2005). Mussels were challenged to test their efficiency at eliminating the bacteria, Listonella anguillarium in the bioassay and field studies. The bioassay results showed that higher concentrations of untreated sewage could modulate the immune system of mussels through increased of phagocytic activity (PA), nitric oxide (NO) and hydrogen peroxide (H(2)O(2)) production during 14 days of exposure, and decreased activity and production at 21 days, with the exception of H(2)O(2) production which was high even at 21 days. Mussels exposed to untreated sewage RE also presented a high PA, NO and H(2)O(2) production and lower number of haemocytes compared to mussels from reference sites. In the bacterial challenge, mussels pre-exposed to 100% sewage died 24h after being infected with L. anguillarium, while mussels pre-exposed to 50% eliminated bacteria had a mortality rate of 30%. Mussels from the control, 12.5% and 25% groups eliminated bacteria and no mortality was observed. No significant difference was observed in bacterial clearance in mussels exposed to effluents in the RE. The lesions observed in gills in both studies were: infiltration of haemocytes in the tissue, epithelium proliferation, lamellar fusion and dilated haemolymphatic sinus. In summary, untreated municipal wastewater affected the immune system of blue mussels during 21 days of exposure and the effects were reflected in their capability to resist pathogens. And an immune modulation was observed in mussels exposed to untreated sewage in a RE, but this modulation was not reflected in the mussel's capability in eliminating pathogens.     

The extract from Nandina domestica THUNBERG inhibits histamine- and serotonin-induced contraction in isolated guinea pig trachea

Although the fruit of Nandina domestica THUNBERG (ND) has been used to treat respiratory disorders such as coughing and breathing difficulty in Japan for many years, very little is known about mechanisms underlying its action. In the present study, we investigated effects of the crude extract from ND (NDE) and one of its constituents, nantenine, on contractile responses in isolated guinea pig tracheal ring preparations. In normal experimental condition, guinea pig trachea remained tonically contracted during the resting state, and addition of NDE (1 mg/ml) caused a relaxation of tracheal smooth muscles, but had little effect on the responsiveness of trachea to acetylcholine. The basal, tonic contraction was abolished by the presence of atropine and indomethacin. In this condition, NDE at 0.1-1 mg/ml inhibited histamine-induced contraction in both competitive and non-competitive manners. NDE at 0.01-1 mg/ml inhibited serotonin-induced contraction in a competitive manner. Nantenine (2-20 microM) did not affect histamine-induced contraction, and slightly inhibited serotonin-induced contraction. These results suggest that NDE has inhibitory effects on tracheal smooth muscle contraction, and nantenine cannot account solely for this effect of NDE.     

A case of echocardiographic evaluation of ruptured pseudoaneurysm of the mitral-aortic intervalvular fibrosa by infective endocarditis

This report describes an unusual case of ruptured pseudoaneurysm (PSA) of mitral-aortic intervalvular fibrosa (MAIVF) caused by infective endocarditis. The PSA ruptured into the left sinus of Valsalva in addition to the left atrium, resulting in complicated shunting among the aorta, left ventricle and left atrium, leading to refractory heart failure. The transesophageal echocardiography provided the precise information concerning the anatomical detail of the PSA, which is crucial for the surgical repair. This is the first report describing a patient with PSA of MAIVF with two rupture sites.     

Down-regulation of an inhibitor of cell growth,transmembrane protein 34 (<Emphasis Type="Italic">TMEM34</Emphasis>), in anaplastic thyroid cancer

Purpose Ansaplastic thyroid cancer (ATC) is one of the most lethal malignancies, but the carcinogenic mechanism of ATC has not been clarified. Recently, we performed a cDNA microarray analysis and identified transmembrane protein 34 (TMEM34) that down-regulated in anaplastic thyroid cancer cell lines (ACL)s as compared to normal thyroid tissues. Methods To investigate the role of TMEM34 in ATC carcinogenesis, we examined expression levels of TMEM34 in ACLs as well as differentiated thyroid cancers (DTC)s and normal human tissues. To explore the effect of TMEM34 in ATC development, cell-growth assays with KTA2 cells were performed. Results Expression of TMEM34 was down-regulated in all 11 ACLs, as compared to either normal thyroid tissues or cell lines derived from papillary or follicular thyroid cancers. TMEM34 was expressed ubiquitously in normal human tissues tested. Transfection of TMEM34 into KTA2 cells led to inhibition of cell growth. Conclusions Our findings suggest that TMEM34 might be a tumor suppressor gene, associated with the development of ATC from DTC.     

Involvement of tyrosine phosphorylation in the positive inotropic effect produced by H(1)-receptors with histamine in guinea-pig left atrium

We investigated the effect of stimulation of H(1)-receptors with histamine on protein tyrosine phosphorylation levels in guinea-pig left atrium and evaluated the influences of tyrosine kinase inhibitors on the positive inotropic effect mediated by H(1)-receptors in this tissue. Histamine induced an increase in tyrosine phosphorylation in four main clusters of proteins with apparent molecular weights of 25, 35, 65 and 150 kDa. Tyrosine phosphorylation of these proteins attained a peak around 2 - 3 min following histamine stimulation and then declined to or below basal levels. Histamine-induced protein tyrosine phosphorylation was antagonized by the H(1)-receptor antagonists mepyramine (1 microM) and chlorpheniramine (1 microM), but not by the H(2)-receptor antagonist cimetidine (10 microM). The positive inotropic effect of histamine was depressed in a concentration-dependent manner by the tyrosine kinase inhibitors tyrphostin A25 (50 to 100 microM) and genistein (10 to 50 microM) but not by the inactive genistein analogue daidzein (50 microM). The positive inotropic effect of isoprenaline was unchanged by tyrphostin A25 and genistein. At a concentration of 1 microM histamine produced a dual-component positive inotropic response composed of an initial increasing phase and a second and late developing, greater positive inotropic phase. Treatment with tyrphostin A25 (100 microM) and genistein (50 microM), but not daidzein (50 microM), significantly attenuated the two components of the inotropic response, although genistein suppressed the initial component more markedly than the late component. We conclude that increased protein tyrosine phosphorylation may play an important role in initiating at least some part of the positive inotropic effect of H(1)-receptor stimulation in guinea-pig left atrium.