[Liver failure caused by recurrent biliary bleeding associated with Osler's disease: a case report].

A 34-year-old female patient with epigastric pain was admitted to our hospital. She reported an underlying condition of Rendu-Osler-Weber disease and a history of coil embolization for pulmonary arteriovenous fistula. A blood test revealed high hepatobiliary enzyme levels. An abdominal contrast-enhanced computed tomography revealed numerous arterioportal and arteriovenous shunts in the liver and a high-density area in the bile duct, which was diagnosed as biliary bleeding. She underwent transpapillary biliary drainage by endoscopic retrograde cholangiopancreatography, but recurrent biliary bleeding caused cholangitis, which was complicated by multiple liver abscesses. She was awaiting her turn for liver transplantation from brain-dead donors, but the liver abscesses were difficult to improve. Further, liver failure, septic pulmonary embolism, and disseminated intravascular coagulation were complicated. Thus, recurrent further biliary bleeding resulted in hemorrhagic shock, which required frequent blood transfusions. Furthermore, the continuous abscess to the intrahepatic bile duct in the anterior superior segment penetrated her diaphragm, causing hemothorax and eventually, death. Establishing progressive treatment, including liver transplantation, is considered necessary for this intractable disease.

Preoperative detection and localization of small bowel hemangioma: Two case reports.

Among the various diagnostic modalities for small bowel hemangioma, video capsule endoscopy (VCE) and double-balloon enteroscopy (DBE) can be recommended as part of the work-up in patients with obscure gastrointestinal bleeding (OGIB). DBE is superior to VCE in the accuracy of diagnosis and therapeutic potential, while in most cases total enteroscopy cannot be achieved through only the antegrade or retrograde DBE procedures. As treatment for small bowel bleeding, especially spout bleeding, localization of the lesion for the decision of DBE insertion facilitates early treatment, such as endoscopic hemostatic clipping, allowing patients to avoid useless transfusion and the worsening of their disease into life-threatening status. Applying endoscopic India ink marking prior to laparoscopic surgical resection is a particularly useful technique for more minimally invasive treatment. We report two cases of small bowel hemangioma found in examinations for OGIB that were treated with combination of laparoscopic and endoscopic modalities.

[A case of liver and bone metastases after complete resection of gastric GIST effectively treated with radiotherapy and imatinib mesylate].

A 70's man was admitted to our hospital because of lumbago and paresthesia in the right lower extremity. He underwent surgical resection of gastric gastrointestinal stromal tumor (GIST), which was classified to the high-risk group according to the modified-Fletcher's classification, one and half years ago. CT, MRI, and PET-CT showed metastases to a part of the liver (S3-4), the 12th thoracic vertebra, and the sacral bone. Subsequently, radiotherapy for the bone metastasis and administration of imatinib mesylate were started. Four months after the initial admission, the liver and the bone metastatic lesions achieved PET-complete response (CR). This report shows that multimodality therapy with radiotherapy and imatinib mesylate was effective for liver and bone metastases after complete resection of gastric GIST.

Speech disturbance at stroke onset is correlated with stroke early mortality.

BACKGROUND: Speech disturbance is a common symptom of stroke and is important as a prompt identifier of the event. The frequency of the symptom among each stroke subtype, differences between patients with and without speech disturbance and its correlation to early mortality remain unclear. METHODS: The Kyoto prefecture of Japan has established a registry to enroll new stroke patients in cooperation with the Kyoto Medical Association and its affiliated hospitals. It is named the Kyoto Stroke Registry (KSR). We confirmed the existence or absence of speech disturbance in 1693 stroke patients registered to the KSR and investigated associations between speech disturbance and other characteristics. RESULTS: Speech disturbance was observed in 52.6% of cerebral infarction (CI), 47.5% of cerebral hemorrhage (CH), and 8.0% of subarachnoid hemorrhage (SAH) cases. Characteristics showing statistically significant differences between patients with and without speech disturbance and patients were age, blood pressure, history of hypertension, arrhythmia and diabetes mellitus, habit of tobacco and alcohol, and paresis. Mortality rates of patients with/without speech disturbance were 5.2%/1.2% for CI, 12.5% /4.1% for CH, and 62.5%/ 9.0% for SAH. Adjusted hazard ratios were 2.63 (1.14-6.13, p = 0.024) in CI, 4.15 (1.41-12.23, p = 0.010) in CH, and 20.46 (4.40-95.07, p < 0.001) in SAH). CONCLUSION: Speech disturbance was frequently observed in stroke patients at the onset and therefore could be useful to identify the problem at the earliest stage. Hazard ratio for death was higher in stroke patients with speech disturbance than patients without. Speech disturbance is a prompt predictor of stroke early mortality.Hiromi Nakano, Yoshiyuki Watanabe, Tatsuyuki Sekimoto, Kouichiro Shimizu, Akihiko Nishizawa, Atsushi Okumura and Masahiro Makino contributed equally to this work.

A case of acute promyelocytic leukemia with morphologic multilineage dysplastic changes.

Although reports of typical acute promyelocytic leukemia (APL) cases rarely mention dysplastic changes, this report concerns a rare case of APL with tri-lineage dysplastic changes resembling the characteristic features of myelodysplastic syndrome (MDS). The patient, a 77-year-old Japanese male, was diagnosed as having pancytopenia with hematologic morphological abnormalities comprising micro - megakaryocytes, neutrophils with hypo-granulation and negative peroxidase activity, and erythroblasts containing nuclei with abnormalities such as karyorrhexis. Although there is one report of a case of transformation of de novo MDS into APL and several reports of cases of therapy-related MDS transformed into APL, our patient had no history of cytopenia or of either chemo or radiation therapy. Our case can thus be considered to constitute a rare case of APL with dysplastic morphology.

Characteristics, risk factors and mortality of stroke patients in Kyoto, Japan.

OBJECTIVES: The aim of the study was to evaluate the characteristics, risk factors and outcome of recent stroke patients in Kyoto, Japan. DESIGN: We analysed stroke patients in the registry with regard to their characteristics, risk factors and mortality. Cox proportional hazards regressions were used to calculate adjusted HRs for death. SETTINGS: The Kyoto prefecture of Japan has established a registry to enrol new stroke patients in cooperation with the Kyoto Medical Association and its affiliated hospitals PARTICIPANTS: The registry now has data on 14 268 patients enrolled from 1 January 1999 to 31 December 2009. Of these, 12 774(89.5%) underwent CT, 9232 (64.7%) MRI, 2504 (17.5%) angiography and 342 (2.4%) scintigraphy. Excluding 480 (3.3%) unclassified patients, 13 788 (96.6%) patients formed the basis of further analyses which were divided into three subtypes: cerebral infarction (CI), cerebral haemorrhage (CH) and subarachnoid haemorrhage (SAH). RESULTS: A total of 13 788 confirmed stroke patients in the study cohort comprised 9011 (86.3%) CI, 3549 (25.7%) CH and 1197 (8.7%) SAH cases. The mean age ±SD was 73.3±11.8, 69.1±13.6 and 62.7±13.5 in the CI, CH and SAH cases, respectively. Men were predominant in the CI and CH cases, whereas women were predominant in the SAH cases. The frequencies of risk factors were different among the subtypes. Mortality was worst in SAH, followed by CH, and least in CI. HRs for death adjusted for age, sex, histories of hypertension, arrhythmia, diabetes mellitus and hyperlipaemia and use of tobacco and/or alcohol showed a significant (p<0.001) difference among CI (as reference), CH (3.71; 3.11 to 4.43) and SAH (8.94; 7.21 to 11.11). CONCLUSIONS: The characteristics, risk factors and mortality were evaluated in a quantitative manner in a large Japanese study cohort to shed light on the present status of stroke medicine.

Vomiting should be a prompt predictor of stroke outcome.

BACKGROUND: To predict the outcome of stroke at an acute stage is important but still difficult. Vomiting is one of the commonest symptoms in stroke patients. The aim of this study is threefold: first, to examine the percentage of vomiting in each of the three major categories of strokes; second, to investigate the association between vomiting and other characteristics and third, to determine the correlation between vomiting and mortality. METHODS: We investigated the existence or absence of vomiting in stroke patients in the Kyoto prefecture cohort. We compared the characteristics of patients with and without vomiting. We calculated the HR for death in both types of patients, adjusted for age, sex, blood pressure, arrhythmia, tobacco and alcohol use and paresis. RESULTS: Of the 1968 confirmed stroke patients, 1349 (68.5%) had cerebral infarction (CI), 459 (23.3%) had cerebral haemorrhage (CH) and 152 (7.7%) had subarachnoid haemorrhage (SAH). Vomiting was seen in 14.5% of all stroke patients. When subdivided according to stroke type, vomiting was observed in 8.7% of CI, 23.7% of CH and 36.8% of SAH cases. HR for death and 95% CI were 5.06 and 3.26 to 7.84 (p<0.001) when all stroke patients were considered, 5.27 and 2.56 to 10.83 (p<0.001) in CI, 2.82 and 1.33 to 5.99 (p=0.007) in CH and 5.07 and 1.87 to 13.76 (p=0.001) in SAH. CONCLUSIONS: Compared with patients without vomiting, the risk of death was significantly higher in patients with vomiting at the onset of stroke. Vomiting should be an early predictor of the outcome.

Usefulness of immature platelet fraction for the clinical evaluation of myelodysplastic syndromes.

Ratios of young platelets or reticulated platelets can be routinely obtained as an immature platelet fraction (IPF) with the XE-2100 automated hematology analyzer (Sysmex, Kobe, Japan). We combined IPF analysis of 31 patients with myelodysplastic syndrome (MDS) with a complete blood count, a bone marrow examination, and a chromosome analysis. The patients with >40 x 10(9)/L platelets were classified as group A, and those with > or =40 x 10(9)/L were placed in group B. The 2 groups were subclassified as A1 or B1 for patients with an IPF of <10% and as A2 or B2 for those with an IPF > or =10%. Categories A1, A2, B1, and B2 comprised 12 patients, 6 patients, 7 patients, and 6 patients, respectively. Patients with a relatively high IPF (>10%) (category A2 or B2) showed distinctive characteristics. Group B2 showed a higher frequency of chromosomal abnormalities than B1 (P = .029), and group A2 tended to show a higher incidence of clinical improvement than A1 (P = .08). IPF determination may be clinically useful for the assessment of prognosis for MDS patients.

PDK1 regulates cell proliferation and cell cycle progression through control of cyclin D1 and p27Kip1 expression.

PDK1 (3-phosphoinositide-dependent protein kinase 1) is a key mediator of signaling by phosphoinositide 3-kinase. To gain insight into the physiological importance of PDK1 in cell proliferation and cell cycle control, we established immortalized mouse embryonic fibroblasts (MEFs) from mice homozygous for a "floxed" allele of Pdk1 and from wild-type mice. Introduction of Cre recombinase by retrovirus-mediated gene transfer resulted in the depletion of PDK1 in Pdk1(lox/lox) MEFs but not in Pdk1(+/+) MEFs. The insulin-like growth factor-1-induced phosphorylation of various downstream effectors of PDK1, including Akt, glycogen synthase kinase 3, ribosomal protein S6, and p70 S6 kinase, was markedly inhibited in the PDK1-depleted (Pdk1-KO) MEFs. The rate of serum-induced cell proliferation was reduced; progression of the cell cycle from the G(0)-G(1) phase to the S phase was delayed, and cell cycle progression at G(2)-M phase was impaired in Pdk1-KO MEFs. These cells also manifested an increased level of p27(Kip1) expression and a reduced level of cyclin D1 expression during cell cycle progression. The defect in cell cycle progression from the G(0)-G(1) to the S phase in Pdk1-KO MEFs was rescued by forced expression of cyclin D1, whereas rescue of the defect in G(2)-M progression in these cells required both overexpression of cyclin D1 and depletion of p27(Kip1) by RNA interference. These data indicate that PDK1 plays an important role in cell proliferation and cell cycle progression by controlling the expression of both cyclin D1 and p27(Kip1).

Restoration of glucokinase expression in the liver normalizes postprandial glucose disposal in mice with hepatic deficiency of PDK1.

Phosphoinositide-dependent kinase-1 (PDK1) is implicated in the metabolic effects of insulin as a key mediator of phosphoinositide 3-kinase-dependent signaling. Here we show that mice with liver-specific PDK1 deficiency manifest various defects in the metabolic actions of insulin in the liver as well as a type 2 diabetes-like phenotype characterized by marked hyperinsulinemia and postprandial hyperglycemia. The hepatic abundance of glucokinase, an important determinant of glucose flux and glucose-evoked signaling in hepatocytes, was substantially reduced in these mice. Restoration of hepatic glucokinase expression, with the use of an adenoviral vector, induced insulin-like effects in the liver and almost completely normalized the fasting hyperinsulinemia and postprandial hyperglycemia in these animals. These results indicate that, if the hepatic abundance of glucokinase is maintained, ingested glucose is normally disposed of even in the absence of acute activation of proximal insulin signaling, such as the activation of Akt, in the liver.

Role of hepatic STAT3 in brain-insulin action on hepatic glucose production.

STAT3 regulates glucose homeostasis by suppressing the expression of gluconeogenic genes in the liver. The mechanism by which hepatic STAT3 is regulated by nutritional or hormonal status has remained unknown, however. Here, we show that an increase in the plasma insulin concentration, achieved either by glucose administration or by intravenous insulin infusion, stimulates tyrosine phosphorylation of STAT3 in the liver. This effect of insulin was mediated by the hormone's effects in the brain, and the increase in hepatic IL-6 induced by the brain-insulin action is essential for the activation of STAT3. The inhibition of hepatic glucose production and of expression of gluconeogenic genes induced by intracerebral ventricular insulin infusion was impaired in mice with liver-specific STAT3 deficiency or in mice with IL-6 deficiency. These results thus indicate that IL-6-STAT3 signaling in the liver contributes to insulin action in the brain, leading to the suppression of hepatic glucose production.

Ablation of PDK1 in pancreatic beta cells induces diabetes as a result of loss of beta cell mass.

The total mass of islets of Langerhans is reduced in individuals with type 2 diabetes, possibly contributing to the pathogenesis of this condition. Although the regulation of islet mass is complex, recent studies have suggested the importance of a signaling pathway that includes the insulin or insulin-like growth factor-1 receptors, insulin receptor substrate and phosphatidylinositol (PI) 3-kinase. 3-Phosphoinositide-dependent protein kinase 1 (PDK1) is a serine-threonine kinase that mediates signaling downstream of PI 3-kinase. Here we show that mice that lack PDK1 specifically in pancreatic beta cells (betaPdk1-/- mice) develop progressive hyperglycemia as a result of a loss of islet mass. The mice show reductions in islet density as well as in the number and size of cells. Haploinsufficiency of the gene for the transcription factor Foxo1 resulted in a marked increase in the number, but not the size, of cells and resulted in the restoration of glucose homeostasis in betaPdk1-/- mice. These results suggest that PDK1 is important in maintenance of pancreatic cell mass and glucose homeostasis.

Requirement for 3-phosphoinositide-kependent dinase-1 (PDK-1) in insulin-induced glucose uptake in immortalized brown adipocytes.

To provide insight into the physiological importance of 3-phosphoinositide-dependent kinase-1 (PDK-1) in the metabolic actions of insulin, we have generated mice that harbor a PDK-1 gene containing LoxP sites (PDK-1(lox/lox) mice) and established immortalized brown preadipocyte cell lines both from these animals and from wild-type mice. Exposure to appropriate hormonal inducers resulted in the differentiation of >80% of the immortalized brown preadipocytes derived from both types of mice into mature adipocytes. Introduction of the Cre recombinase with the use of adenovirus-mediated gene transfer induced a dose-dependent decrease in the abundance of PDK-1 in PDK-1(lox/lox) adipocytes but not in the wild-type cells. In Cre-expressing PDK-1(lox/lox) adipocytes in which the abundance of PDK-1 was reduced by approximately 85%, the insulin-induced phosphorylation both of Akt on threonine 308 and of p70 S6 kinase on threonine-389 was markedly inhibited. The phosphorylation both of Akt on serine 473 and of p42 and p44 isoforms of mitogen-activated protein kinase induced by insulin was not affected by Cre expression, indicating that the latter specifically inhibits PDK-1-dependent signaling. Both glucose uptake and the translocation of glucose transporter 4 to the plasma membrane induced by insulin as well as glucose uptake induced by a constitutively active form of phosphoinositide 3-kinase were also greatly inhibited by Cre expression in PDK-1(lox/lox) adipocytes. Phosphorylation of AMP-activated protein kinase and glucose uptake induced by 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) were not affected by Cre expression in PDK-1(lox/lox) adipocytes. These results indicate that PDK-1 is essential for insulin-induced glucose uptake in adipocytes.