Hepatitis B surface antigen particles of subtypes adw and adr, and compound subtype (adwr) in symptom-free carriers in Japan.

Of sera from 1,878 Japanese blood donors who carried hepatitis B surface antigen (HBsAg), 420 were subtyped as adw (22.4%) and 1,443 as adr (76.8%); only 15 (0.8%) contained HBsAg of subtype ayw or ayr. Sera with HBsAg/adr had higher HBsAg titres than those with HBsAg/adw (geometric mean of haemagglutination titre: 10.1 +/- 2.4 vs. 9.7 +/- 2.4, p less than 0.01), and a higher prevalence of hepatitis B e antigen (24% vs. 13%, p less than 0.001). Carriers of HBsAg/adr progressively predominated over those of HBsAg/adw with increasing age. Of sera from 1,863 carriers of HBsAg/adw or HBsAg/adr, 182 (9.8%) contained HBsAg particles with both subtypic determinants in the w/r allele. The presence of w and r determinants on the same particles was ascertained by sandwiching them between monoclonal antibody with the specificity for w and that with the specificity for r. HBsAg particles of compound subtype (adwr) were found more often in sera with hepatitis B e antigen than those without it (145/403 [36.0%] vs. 37/1,460 [2.5%], p less than 0.001). Sera with HBsAg/adwr particles had HBsAg titres higher than those without them (12.4 +/- 1.9 vs. 9.7 +/- 2.3, p less than 0.001). HBsAg/adwr particles arise from phenotypic mixing of the S-gene product of wild-type virus and that of mutants with point mutations for subtypic changes. The results obtained indicated that HBV strains of subtype adr have a higher replicative activity than those of adw, and suggested that mutations in the S gene for subtypic changes would be associated with an active replication of hepatitis B virus.     

Strain combination-dependent genesis of necrotizing arteritis in anti-ICAM-1 antibody-perfused renal allografts in the rat

Rat kidneys were perfused with anti-intercellular adhesion molecule-1 (anti-ICAM-1) monoclonal antibody prior to allo-transplantation. In the two strain combinations examined, LEJ-to-WKAH transplants resulted in accelerated graft loss, and no prolongation of graft survival. The accelerated graft logs was the resut of frequent occurrence of necrotizing arterttis wlthln the grafts. In contrast, TO-to-WKAH transplants resulted in no change In graft survival and no arteritis. Necratidng vasculitis in the LEJ-to-WKAH grafts was characterlzed by flbrinoid necrosis, collection of cellular infiltrates and serum macromolecular protein entrapment. The F(ab')² form of anti-ICAM-1 antlbody partially preserved the antibody's capacity to accelerate graft loss. Therefore, although endothelial injury by Fc-mediated cytotoxicity may be involved in vascular damage, other mechanisms also come into play. The amount and distribution pattern of ICAM-1 antigen were identical in both TO and LEJ strains. Intravenous anti-CAM-1 antibody administration combined with lipopolysaccharide, Poly(1)-Poly(C), warm ischemia to the kidney, or subcutaneous immunization with allogeneic spleen cells, but without renal transplantation, did not generate necrotizing vasculitis or proteinuria. These observations plus our previous data on the rat liver transplantation model clearly show that graft perfusion with anti-ICAM-1 monoclonal antibody invokes extensive vascular damage within allografts by Fc-mediated and Fc-independent mechanisms, depending on the donor-to-host combination.     

Pharmacologic properties of candesartan cilexetil--possible mechanisms of long-acting antihypertensive action

Candesartan cilexetil has shown potent and long-lasting antihypertensive effects in clinical trials and in several animal models of hypertension. In spontaneously hypertensive rats, the duration of the antihypertensive effect of candesartan cilexetil was compared to those of losartan, valsartan, eprosartan, and irbesartan at the same degree of maximal blood pressure reduction. A single oral dose of candesartan cilexetil at 0.3 mg/kg reduced maximal blood pressure by about 25 mm Hg, and the antihypertensive effect of candesartan cilexetil lasted the longest, continuing for more than 1 week, without an effect on circadian rhythm. In a rabbit aortic preparation, candesartan, active form of candesartan cilexetil, decreased the maximal contractile response of angiotensin II. This inhibitory mode was different from that of other angiotensin II-receptor antagonists, and showed a shift to the right in the angiotensin II-induced contraction curve and/or a small depression of the maximal response. In kinetic studies using bovine adrenal cortical membrane and tritiated candesartan, both receptor association and dissociation were found to be slow. The dissociation rate of tritiated candesartan binding (t1/2 = 66 min) was five times slower than that of radiolabelled angiotensin II binding (t1/2 = 12 min). The insurmountable inhibition of candesartan in vascular contraction is the result of its tight binding and slow dissociation from angiotensin II AT1 receptors. These characteristics are related to the potency and long duration of action in candesartan cilexetil.     

Effects of aging on plasma islet amyloid polypeptide basal level and response to oral glucose load.

To delineate the effects of aging on basal and glucose-stimulated secretion of islet amyloid polypeptide (IAPP), we compared the basal level of plasma IAPP and its response to an oral glucose load in elderly subjects with those of young subjects. Plasma IAPP level was determined by radioimmunoassay. Basal level of plasma IAPP in 20 elderly subjects (mean age 63 yr) was 5.3 +/- 0.4 pmol/l, which was not significantly different from 5.0 +/- 0.3 pmol/l in 22 young subjects (mean age 26 yr). Plasma glucose levels after an oral glucose load in elderly subjects (n = 8, mean age 67 yr) and young subjects (n = 8, mean age 29 yr) were within normal limits. However, the plasma glucose response in the aged group was significantly higher than that in the young group. The plasma insulin response to a glucose load in elderly subjects was not different from that in young subjects. The plasma IAPP level in the aged group significantly increased from 5.3 +/- 0.5 to 16.4 +/- 2.3 pmol/l 120 min after the oral glucose load. This result was quite similar to that in the young group whose plasma IAPP level increased from 4.9 +/- 0.5 to 14.1 +/- 1.5 pmol/l 120 min after the glucose load. We concluded that the basal level of plasma IAPP and its response to glucose were not affected by aging.     

Autochthonous Dengue Fever,Tokyo, Japan, 2014

After 70 years with no confirmed autochthonous cases of dengue fever in Japan, 19 cases were reported during August–September 2014. Dengue virus serotype 1 was detected in 18 patients. Phylogenetic analysis of the envelope protein genome sequence from 3 patients revealed 100% identity with the strain from the first patient (2014) in Japan.     

Is Memorial Sloan-Kettering Cancer Center risk classification appropriate for Japanese patients with metastatic renal cell carcinoma in the cytokine era?

ObjectivesWe investigated the prognosis of Japanese patients with metastatic renal cell carcinoma (RCC), and analyzed the validity of Memorial Sloan-Kettering Cancer Center (MSKCC) risk classification.Materials and methodsThe endpoint of the present study was overall survival. Relationships between overall survival and potential prognostic factors were assessed using the Cox proportional hazard model with a step-wise procedure. Prognostic assessment was also performed according to the MSKCC risk classification. The predictive accuracy of the MSKCC risk classification was measured employing the concordance index.ResultsThe median survival for all patients was 22 months (95% CI, 19–28 months). The eight factors were identified as independent prognostic factor; time from initial diagnosis to metastasis, low hemoglobin (Hb), lactate dehydrogenase (LDH), corrected serum calcium (cCa), C-reactive protein (CRP), and the presence or absence of liver metastasis, bone metastasis, and lymph node metastasis. When the MSKCC risk classification was applied to patients, the median overall survival was not reached and 26 and 10 months in the patients classified as favorable, intermediate, and poor risk, respectively. The c-index was 0.73.ConclusionsThe prognosis of Japanese metastatic renal cell carcinoma patients may be better than that of previous studies from North America or Europe. Although there are some differences in the rate of patients in the risk groups and survival time by risk group between these patients, the MSKCC risk classification may be applicable for Japanese patients with metastatic renal cell carcinoma.     

Fatal overwhelming postsplenectomy infection due to Streptococcus pneumoniae serotype 10A with atypical polysaccharide capsule in a patient with chromosome 22q11.2 deletion syndrome: A case report

We report the first case of a teenage patient with chromosome 22q11.2 deletion syndrome who died of overwhelming postsplenectomy infection (OPSI) by Streptococcus pneumoniae despite appropriate prevention by pneumococcal vaccine. He had congenital heart disease and underwent several surgeries. Immunodeficiency had not been noticed clinically. Two years prior to death, splenectomy was performed for a drug-resistant idiopathic thrombocytopenic purpura and he was immunized with 23-valent pneumococcal polysaccharide vaccine (PPV23) 4 months after splenectomy. He died suddenly after a mild flu-like symptom. Autopsy was performed and OPSI was diagnosed. Blood culture was positive for S. pneumoniae. This isolated S. pneumoniae strain was serotypically un-typable by polyvalent serum agglutination test. On the contrary, multilocus sequence typing followed by DNA sequencing indicated the molecular serotype as 10A. Additional testing using monovalent and factor-specific sera confirmed the strain as serotype 10A. Ultrastructural observation of this S. pneumoniae strain showed that the polysaccharide capsule was thin and sparse. We speculate that the abnormal morphology of the capsule may have accounted for the polyvalent serum agglutination failure and may possibly be associated with severity of OPSI observed in this case. Chromosome 22q11.2 deletion syndrome is associated with certain immunodeficiency, especially susceptible to S. pneumoniae infections; however, fatal OPSI has not been reported. In addition to vaccination, prophylactic antibiotics may be necessary for these patients who are at risk of immunodeficiency.     

Increased gastric acid secretion in cholecystokinin-1 receptor-deficient Otsuka Long-Evans Tokushima fatty rats

BACKGROUND: It is hypothesized that cholecystokinin stimulates acid secretion directly and indirectly by binding to CCK-2 (CCK-B/gastrin) receptors on both parietal and enterochromaffin-like cells. At the same time, however, it inhibits acid responses by stimulating the paracrine secretion of somatostatin from D cells and thereby exerts a tonic inhibition on the parietal cells. To test the validity of this hypothesis, we determined gastric acid secretion in the CCK-1 (CCK-A) receptor-deficient Otsuka Long-Evans Tokushima fatty (OLETF) rats. METHODS: Gastric acid secretion was determined in the acute fistula OLETF and the control Long-Evans Tokushima Otsuka (LETO) rats. Plasma concentrations of gastrin, CCK, somatostatin and histamine were determined by radioimmunoassay. The levels of CCK-2 receptor mRNA in the mucosa of the glandular stomach were determined by Northern blot analysis. RESULTS: Pentagastrin- and CCK-8-stimulated as well as basal acid outputs in OLETF rats were significantly higher than those in LETO rats. CCK-2 receptor antagonist reduced basal acid outputs and completely suppressed CCK-8-stimulated acid secretion in both strains. CCK-8 enhanced the pentagastrin-stimulated gastric acid output in OLETF rats, but not in LETO rats. In LETO rats, CCK-1 receptor antagonist increased CCK-8-stimulated gastric acid secretions to those in OLETF rats. The level of CCK-2 receptor mRNA in the stomach in OLETF rats was 2-fold higher than that in LETO rats. In OLETF rats, plasma concentrations of CCK and histamine were higher, whereas somatostatin concentrations were lower than those in LETO rats, with no change in basal plasma gastrin concentrations. CONCLUSIONS: These results in the CCK-1 receptor-deficient OLETF rats confirmed that CCK stimulates acid secretion by binding to CCK-2 receptors, but at the same time inhibits acid responses by stimulating the paracrine secretion of somatostatin from D cells in the gastric mucosa.