Apoptosis and estrogen deficiency in primary Sjögren syndrome

PURPOSE OF REVIEW: Primary Sj?gren syndrome is an autoimmune disorder characterized by lymphocytic infiltrates and destruction of the salivary and lacrimal glands, and systemic production of autoantibodies to the ribonucleoprotein particles SS-A/Ro and SS-B/La. The purpose of this review is to discuss recent advances in the pathogenesis of primary Sj?gren syndrome. RECENT FINDINGS: Although several candidate autoantigens including alpha-fodrin have been reported in Sj?gren syndrome, the pathogenic roles of the autoantigens in initiation and progression of SS are still unclear. It is possible that individual T cells activated by an appropriate self antigen can proliferate and form a restricted clone. Recent evidence suggests that the apoptotic pathway plays a central role in tolerizing T cells to tissue-specific self antigen, and may drive the autoimmune phenomenon. Cleavage of certain autoantigens during apoptosis may reveal immunocryptic epitopes that could potentially induce autoimmune response. The studies reviewed imply that Fas-mediated cytotoxicity and caspase-mediated alpha-fodrin proteolysis are involved in the progression of tissue destruction in Sj?gren syndrome. Fas ligand (FasL), and its receptor Fas are essential in the homeostasis of the peripheral immune system. It can be considered that a defect in activation-induced cell death of effector T cells may result in the development of autoimmune exocrinopathy in Sj?gren syndrome. SUMMARY: Although the mechanisms by which estrogen deficiency influences autoimmune lesions remain unclear, it is possible that antiestrogenic actions might be a potent factor in the formation of pathogenic autoantigens.     

Delayed restenosis after gamma brachytherapy for in-stent restenosis

Intracoronary brachytherapy is a promising modality for inhibition of in-stent restenosis. However, there is a concern of late progression after brachytherapy. This case report describes delayed restenosis after brachytherapy.     

Metastasis of hepatocellular carcinoma to the supramaxillary gingiva and right ventricle

We describe a rare double metastasis of hepatocellular carcinoma to the supramaxillary gingiva and papillary muscle of the right ventricle. The patient was a 72-year-old woman who underwent three sessions of transcatheter arterial embolization for the primary lesions. Control of bleeding from the supramaxillary gingival metastasis was difficult by conservative treatment such as compression with gauze soaked in epinephrine. Therefore, radiotherapy was performed, but it failed to control the bleeding. The patient subsequently died due to hepatic failure. Autopsy revealed metastases of hepatocellular carcinoma to the papillary muscle of the right ventricle and paraaortic lymph node in the abdomen in addition to the supramaxillary gingival metastasis. Histopathological examination showed moderately differentiated hepatocellular carcinoma of both the primary site and metastatic sites to the gingiva and the heart and poorly differentiated in the paraaortic lymph node.     

c-Src and c-Abl kinases control hierarchic phosphorylation and function of the CagA effector protein in Western and East Asian Helicobacter pylori strains

Many bacterial pathogens inject into host cells effector proteins that are substrates for host tyrosine kinases such as Src and Abl family kinases. Phosphorylated effectors eventually subvert host cell signaling, aiding disease development. In the case of the gastric pathogen Helicobacter pylori, which is a major risk factor for the development of gastric cancer, the only known effector protein injected into host cells is the oncoprotein CagA. Here, we followed the hierarchic tyrosine phosphorylation of H. pylori CagA as a model system to study early effector phosphorylation processes. Translocated CagA is phosphorylated on Glu-Pro-Ile-Tyr-Ala (EPIYA) motifs EPIYA-A, EPIYA-B, and EPIYA-C in Western strains of H. pylori and EPIYA-A, EPIYA-B, and EPIYA-D in East Asian strains. We found that c-Src only phosphorylated EPIYA-C and EPIYA-D, whereas c-Abl phosphorylated EPIYA-A, EPIYA-B, EPIYA-C, and EPIYA-D. Further analysis revealed that CagA molecules were phosphorylated on 1 or 2 EPIYA motifs, but never simultaneously on 3 motifs. Furthermore, none of the phosphorylated EPIYA motifs alone was sufficient for inducing AGS cell scattering and elongation. The preferred combination of phosphorylated EPIYA motifs in Western strains was EPIYA-A and EPIYA-C, either across 2 CagA molecules or simultaneously on 1. Our study thus identifies a tightly regulated hierarchic phosphorylation model for CagA starting at EPIYA-C/D, followed by phosphorylation of EPIYA-A or EPIYA-B. These results provide insight for clinical H. pylori typing and clarify the role of phosphorylated bacterial effector proteins in pathogenesis.     

Incidence and risk factors for mortality in paediatric severe sepsis: results from the national paediatric intensive care registry in Japan

Purpose

To assess the incidence, background, outcome and risk factors for death of severe sepsis in Japanese paediatric intensive care units (PICUs).

Methods

A data analysis of a prospective, multicentre, 3-year case registry from nine medical-surgical Japanese PICUs. Children with severe sepsis, aged 0–15?years, who were consecutively admitted to the participating PICUs from 1 January 2007 to 31 December 2009 were enrolled. The incidence, background, causative pathogens or infective foci, outcome and risk factors for death caused by severe sepsis were analysed.

Results

One hundred forty-one cases were registered. After the exclusion of 14 patients because of incomplete data or inappropriate entry, 127 patients were eligible for the analysis. There were 60 boys and 67 girls, aged 23 [5–68] (median [IQR]) months and weighed 10 [5.5–16.5]?kg. The incidence was 1.4?% of total PICU admissions. Sepsis was community-acquired in 35?%, PICU-acquired in 37?% and acquired in hospital general wards in 28?%. Methicillin-resistant Staphylococcus aureus was the most frequent pathogen. The crude 28-day mortality was 18.9?%, comparable to the mean PIM-2 predicted mortality (17.7?%). The mortality rate in patients with shock was significantly increased to 28?% compared to those without shock (5?%). The presences of existing haematological disorders (OR 8.97, 95?% CI, 1.56–51.60) and shock (OR 5.35, 1.04–27.44) were significant factors associated with mortality by multivariate analysis.

Conclusions

The mortality from severe sepsis/septic shock in Japanese PICUs was?~19?%. Haematological disorders and presence of shock were associated with death.     

Geographic differences in gastric cancer incidence can be explained by differences between Helicobacter pylori strains

Certain populations with high incidences of Helicobacter pylori infection, such as those in East Asian countries, have high incidences of gastric cancer, while other highly infected populations, such as those in Africa and South Asia, do not. The various rates of gastric cancer associated with different geographic areas can be explained, at least in part, by the differences in the genotypes of H. pylori cagA and vacA. Populations expressing a high incidence of gastric cancer are mostly identical with regions where East Asian type CagA is predominant. In contrast, incidence of gastric cancer is low in Africa, South Asia, and Europe, where strains typically possess Western type CagA. Within East Asia, strains from northern parts, where the incidence of gastric cancer is high, predominantly possess the vacA m1 genotype, whereas the m2 genotype is predominant in southern parts where the gastric cancer incidence is low.     

Tumor-induced hypophosphatemic osteomalacia diagnosed by the combinatory procedures of magnetic resonance imaging and venous sampling for FGF23

This report describes a 37-year-old man with tumor-induced osteomalacia (TIO). The patient had hypophosphatemia and elevated fibroblast growth factor 23 (FGF23) in the peripheral blood. Magnetic resonance imaging detected an abnormal mass in the left greater trochanter. Venous sampling revealed a significantly higher level of FGF23 in the left common iliac vein (proximal to the tumor), verifying that the tumor is responsible for TIO. The serum level of FGF23 decreased and symptoms improved after removal of the tumor. The combined diagnostic procedures of MRI and venous sampling for FGF23 effectively detected the tumor responsible for TIO.     

Growth hormone-releasing hormone and gonadotropin-releasing hormone stimulate nitric oxide production in 17beta-estradiol-primed rat anterior pituitary cells

It was reported that neuronal nitric oxide synthase (nNOS) was expressed only in gonadotrophs and folliculo-stellate cells in the anterior lobe of the pituitary gland. However, recent studies have demonstrated the occurrence of nNOS in the somatotrophs and lactotrophs. In the present study, we investigated effects of growth hormone-releasing hormone (GHRH), gonadotropin-releasing hormone (GnRH), and 17β-estradiol on nitric oxide (NO) release in cultured rat anterior pituitary cells in vitro. The NO ₂ ⁻ level in the incubation medium of the rat anterior pituitary cells was dependent on the cell density. Pretreatment with 10 μM 17β-estradiol resulted in an increase in medium NO ₂ ⁻ level. GHRH and GnRH failed to change medium NO ₂ ⁻ levels, but they elicited increases in medium NO ₂ ⁻ levels in estrogen-treated cells. The GHRH-induced increase in NO ₂ ⁻ level was inhibited by Nχ-nitro-l-arginine methyl ester, a NOS inhibitor. These findings suggest that GnRH and GHRH could activate nNOS in the gonadotrophs and the somatotrophs, respectively.     

Persistent hyperglycemia is associated with left ventricular dysfunction in patients with acute myocardial infarction.

BACKGROUND: The relationship of changes in blood glucose concentrations after admission to left ventricular (LV) dysfunction in patients with recanalized anterior acute myocardial infarction (AMI) remains unclear. METHODS AND RESULTS: Blood glucose concentrations were measured on admission and 24 h after symptom onset in 210 patients with recanalized anterior AMI within 6 h of symptom onset. Of them, 142 had hyperglycemia on admission, defined as a blood glucose >or=8.9 mmol/L, and 68 patients did not. Among the patients with admission hyperglycemia, 49 had persistent hyperglycemia, defined as a blood glucose >or=8.9 mmol/L 24 h after onset, and 93 did not. The incidences of myocardial blush grade of 0/1 after recanalization indicating impaired myocardial perfusion (71%), and peak creatine kinase concentration (5,631+/-2,855 mU/ml) were higher and predischarge LV function (43+/-11%) was lower in patients with persistent hyperglycemia than in those without (p<0.01). Multivariate analysis showed that persistent hyperglycemia was independently associated with LV dysfunction, defined as a predischarge LV ejection fraction 相似文献   

Gallbladder carcinoma presenting as exfoliative dermatitis (erythroderma)

Although exfoliative dermatitis (erythroderma) secondary to malignancy is commonly associated with lymphomas or leukemias, coincident gastrointestinal (GI) malignancy and erythroderma is rare. The authors recently encountered a patient with gallbladder carcinoma presenting as erythroderma. A 77-yr-old Japanese man presented with a 3-mo history of erythematous eruptions with pruritus over almost the entire body. After confirming the diagnosis of erythroderma, asymptomatic gallbladder carcinoma was found. Further investigations detected no malignancies in other organs. An extended cholecystectomy was performed. Histologic examination of resected specimens revealed poorly differentiated adenocarcinoma with negative resection margins. The eruptions with pruritus resolved within 1 wk after the operation. This is the first report, to our knowledge, of coincident biliary malignancy and erythroderma. The experience of the current patient suggests that erythroderma secondary to GI malignancy may resolve spontaneously after curative resection of the tumor.