Electrophysiological effects of flecainide acetate on stretched guinea pig left atrial muscle fibers

Summary The electrophysiological effects of flecainide acetate (3×10^–6 M) on stretched atrial tissue were investigated using guinea-pig left atrial muscle fibers. Before stretching, the resting membrane potential was not affected by flecainide at 1 Hz, although the overshoot potential (Eov) and the action potential duration at 50% repolarization (APD₅₀) were slightly but significantly decreased by 2±1 mV and 2±1 msec, respectively. The effective refractory period (ERP) was increased by 3±1 msec. The reduction of max was 20.6±1.2%. The half-maximum potential (Vh) of the relationship between max and the resting potential was shifted to become more negative by flecainide (from –60.6±2.1 mV to –63.2±1.7 mV). After 90–120 min of washout with drug-free Tyrode's solution, the tissue was mechanically stretched to 150% of its slack length. Stretching significantly decreased the max by 16.9±3.1%, along with a slight but significant increase in ERP (3±1 msec) and shifted Vh to become more negative (from –60.6±2.1 to –63.1±1.8 mV). In the presence of flecainide, max further decreased by 20.2±2.6%, and Vh shifted from –63.1±1.8 to –65.0±1.5 mV. Comparison with the control unstretched fibers showed that flecainide significantly decreased max by 34.0±2.7%, reduced the resting membrane potential by 3±1 mV, decreased Eov by 4±1 mV, and shifted Vh from –60.6±2.1 to –65.0±1.5 mV, while the APD₅₀ and ERP did not change. In conclusion, the reduction of max in the presence of flecainide was much greater in the stretched atrial muscle fibers than in the unstretched fibers, because the max-resting potential relationship was shifted towards more negative potentials by both flecainide and stretching. These results suggest that flecainide exerts a stronger antiarrhythmic action on stretched atrial muscle fibers than on normal fibers.     

New tumor necrosis factor-α-inducing protein released from<Emphasis Type="Italic"> Helicobacter pylori</Emphasis> for gastric cancer progression

Purpose To investigate the association between Helicobacter pylori infection and its inflammatory reaction in gastritis, gastric ulcer, and gastric cancer, a new tumor necrosis factor- (TNF-)-inducing protein of H. pylori was studied.Methods The HP0596 gene of H. pylori was identified as the TNF--inducing protein (Tip) gene from genome sequence of H. pylori strain 26695. Using recombinant Tip (rTip) and deleted Tip (rdel-Tip) proteins, the latter of which lacks six amino acids containing two cysteines in the N-terminal domain, we examined their activities in TNF- gene expression and NF-B activation in both Bhas 42 (v-H-ras transfected BALB/3T3) cells and mouse gastric epithelial cell line MGT-40, and in vitro transformation of Bhas 42 cells.Results Tip protein as a homodimer form (38 kDa) was found in both extracts and culture medium of various H. pylori strains. rTip significantly induced TNF- gene expression and NF-B activation in both Bhas 42 cells and MGT-40, and induced in vitro transformation of Bhas 42 cells. However, rdel-Tip did not. Treatment with MG-132, a proteasome inhibitor, inhibited translocation of NF-B p65, and abrogated TNF- induction induced by Tip protein.Conclusion Tip is a new carcinogenic factor released from H. pylori mediated through NF-B activation.     

Carotid intima-media thickness is increased in subjects with ischemic heart disease having a familial incidence

OBJECTIVES: A family history of ischemic heart disease (IHD) is an independent risk factor for cardiovascular events. However, the mechanisms underlying this susceptibility have not been fully elucidated. The authors hypothesized that an important mediator of the familial incidence of IHD is subclinical atherosclerosis, which is detectable by noninvasive imaging. METHODS: One hundred forty-seven consecutive subjects (mean age 61.9 years, 57% men) were studied for one year using carotid ultra-sonogrophy for general medical screening, and familial IHD events were validated. Using a 7.5 MHz linear array transducer, carotid intima-media thickness (IMT) and carotid plaque were assessed. Subjects were subsequently divided into four groups based on the severity of IMT. RESULTS: The familial incidence of IHD and incidence of plaque were associated with the severity of IMT. No significant differences in risk factors were found between subjects with and without a family history of IHD. CONCLUSIONS: These findings suggest that subclinical atherosclerosis, as assessed in the carotid arteries, is more prevalent in individuals with a family history of IHD.     

Differences in composition of sweat induced by thermal exposure and by running exercise

To determine the differences in sweat composition between sweat induced by thermal stress alone and that induced by physical exercise, seven young healthy men first sat in a hot room and then performed running exercise. A 20-minute stay in a climate chamber at 40 degrees C resulted in a 5% reduction in body weight. The same body weight loss was induced by running exercise. Both sodium and chloride concentrations were much lower in the sweat induced by thermal exposure than that induced by the running exercise (p less than 0.01), while urea nitrogen and creatinine concentrations were significantly higher after thermal exposure than after the running exercise (p less than 0.01). Potassium concentrations did not differ significantly with either procedure. These findings suggest that sweat composition varies with the kind of induction and that more salt seems to be lost through exercise-induced sweating than by just sitting in a hot environment.     

A prospective and comparative cohort study on efficacy and drug resistance during long-term lamivudine treatment for various stages of chronic hepatitis B and cirrhosis

Background and Aims: A prospective , non‐randomized cohort study on long‐term lamivudine treatment , comparing efficacy, drug resistance, and prognosis for various stages of chronic hepatitis B virus (HBV)–related liver disease was performed to elucidate the significance and indication of lamivudine for individual patients at each stage of disease. Methods: A total of 158 cases consisting of 87 chronic hepatitis, 28 compensated cirrhosis, and 43 decompensated cirrhosis, with serum HBV‐DNA > 5 log₁₀ copies/mL and with elevated alanine aminotransferase (ALT) over twice the upper normal limit or complications of hepatic insufficiency, were administered 100 mg of lamivudine daily and monitored for HBV markers, biochemistry, and prognosis. Results: Lamivudine reduced HBV‐DNA and ALT equally in all groups. Serum albumin, prothrombin time (%), and platelet count increased in all groups. The increased margin of albumin was the highest in the decompensated cirrhosis and higher in the compensated cirrhosis than the chronic hepatitis groups. Cumulative incidence of virologic breakthrough was 16%, 42%, 49%, and 53% at 12, 24, 36, and 48 months, respectively, and the strongest predictive factor for lamivudine resistance was persistent HBV‐DNA at 3 months. Ascites, encephalopathy, and jaundice improved in the majority of patients with decompensated cirrhosis. On the other hand, hepatic failure developed or deteriorated in 10 patients after virologic breakthrough, and nine of them had decompensated cirrhosis. Conclusions: Lamivudine was effective in reducing HBV‐DNA and improving hepatic reserve at all stages and was most beneficial and significant for decompensated cirrhosis. Meanwhile, close monitoring of viral load and immediate rescue treatment for lamivudine resistance is necessary to prevent hepatic failure in decompensated cirrhosis.     

Early-onset sarcoidosis and CARD15 mutations with constitutive nuclear factor-kappaB activation: common genetic etiology with Blau syndrome

Early-onset sarcoidosis (EOS) and inheritable Blau syndrome (BS) share characteristic clinical features of juvenile-onset systemic granulomatosis syndrome that mainly affects skin, joints, and eyes. However, no direct evidence has been shown for the possible common origin of these 2 diseases. Recent discovery of CARD15 mutations in BS families encouraged us to investigate similar CARD15 mutations in EOS patients. Among 10 EOS cases retrospectively collected in Japan, heterozygous missense mutations were found in 9 cases; 4 showed a 1000C>T (R334W in amino acid change) that has been reported in BS, 4 showed novel 1487A>T (H496L), 1538T>C (M513T), 1813A>C (T605P), and 2010C>A (N670K), and 1 case showed double 1146C>G (D382E)/1834G>A (A612T) mutations on different alleles. All 6 of these variants of CARD15 showed increased basal nuclear factor (NF)-kappaB activity. These findings indicate that the majority of EOS and BS cases share the common genetic etiology of CARD15 mutations that cause constitutive NF-kappaB activation.