Ischaemic colitis during interferon treatment for chronic hepatitis C: report of two cases and literature review.

Ischaemic colitis is known to be a severe emergency complication of interferon (IFN) therapy. However, as ischaemic colitis is an infrequent complication of IFN therapy, limited information is available regarding the safety of resuming IFN therapy after resolution of ischaemic colitis and subsequent recurrence. Here, we report two cases of ischaemic colitis during IFN therapy for chronic hepatitis C. Ischaemic colitis was fully healed within 1 week after its onset and IFN withdrawal, and IFN therapy was resumed following patients' wishes to do so. Ischaemic colitis did not recur after the resumption of IFN therapy, and sustained virological response was achieved in both patients. In this report, we also summarize the findings of 11 cases of IFN-associated ischaemic colitis (nine previously published cases plus our two cases) and review the clinical characteristics of ischaemic colitis during IFN therapy in patients with chronic hepatitis C.

Altered stoichiometry of FKBP12.6 versus ryanodine receptor as a cause of abnormal Ca(2+) leak through ryanodine receptor in heart failure.

BACKGROUND: In the pathogenesis of cardiac dysfunction in heart failure, a decrease in the activity of the sarcoplasmic reticulum (SR) Ca(2+)-ATPase is believed to be a major determinant. Here, we report a novel mechanism of cardiac dysfunction revealed by assessing the functional interaction of FK506-binding protein (FKBP12.6) with the cardiac ryanodine receptor (RyR) in a canine model of pacing-induced heart failure. METHODS AND RESULTS: SR vesicles were isolated from left ventricular muscles (normal and heart failure). The stoichiometry of FKBP12.6 per RyR was significantly decreased in failing SR, as assessed by the ratio of the B(max) values for [(3)H]dihydro-FK506 to those for [(3)H]ryanodine binding. In normal SR, the molar ratio was 3.6 ( approximately 1 FKBP12.6 for each RyR monomer), whereas it was 1.6 in failing SR. In normal SR, FK506 caused a dose-dependent Ca(2+) leak that showed a close parallelism with the conformational change in RyR. In failing SR, a prominent Ca(2+) leak was observed even in the absence of FK506, and FK506 produced little or no further increase in Ca(2+) leak and only a slight conformational change in RyR. The level of protein expression of FKBP12.6 was indeed found to be significantly decreased in failing SR. CONCLUSIONS: An abnormal Ca(2+) leak through the RyR is present in heart failure, and this leak is presumably caused by a partial loss of RyR-bound FKBP12.6 and the resultant conformational change in RyR. This abnormal Ca(2+) leak might possibly cause Ca(2+) overload and consequent diastolic dysfunction, as well as systolic dysfunction.

Small low-density lipoprotein and small low-density lipoprotein/total low-density lipoprotein are closely associated with intima-media thickness of the carotid artery in Type 2 diabetic patients.

BACKGROUND: The intima-media thickness (IMT) of the carotid artery, as determined by ultrasonography, is useful for reflecting the extent of subclinical atherosclerosis. We investigated the relationship between IMT and the serum concentrations of small low-density lipoprotein (LDL) in diabetic patients. METHODS: The study was conducted with 27 Type 2 diabetic patients (14 males and 13 females; mean age=62.6+/-8.3 years) and 12 age-matched healthy controls. The LDL subfraction was measured using a polyacrylamide gel electrophoresis method. Vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) concentrations were measured by an enzyme immunoassay. The IMT was expressed as the maximum IMT (Max-IMT) and average IMT (Ave-IMT) of the carotid artery, measured by ultrasonography. RESULTS: Both the IMT and the small LDL concentrations were significantly increased in the diabetic patients compared with the healthy participants. The IMTs were significantly correlated with small LDL concentration and small LDL/total LDL more than LDL concentrations by multivariate analysis. The IMTs were not significantly correlated with the serum VEGF or PDGF concentrations. The patients with a larger IMT had a significantly higher prevalence of hypertension or ischemic heart disease than did the patients with a normal IMT. CONCLUSIONS: The increased small LDL concentrations and small LDL/total LDL, in addition to total LDL concentrations, in Type 2 diabetic patients are closely associated with increased IMT of the carotid artery.

Enhancement of Rho/Rho-kinase system in regulation of vascular smooth muscle contraction in tachycardia-induced heart failure.

OBJECTIVE: The Rho/Rho-kinase system regulates Ca(2+) sensitivity in vascular smooth muscle. A new drug, Y-27632, specifically inhibits Rho-kinase and hence decreases the phosphorylation of myosin light chain, thus reducing contraction. Here, we compare the effects of Y-27632 and nifedipine on the vasoconstrictor response of the femoral artery in heart failure. METHODS: Heart failure (HF) was produced by chronic rapid RV pacing (250 bpm, 28 days, six dogs). Indo1-AM was loaded into endothelium-denuded femoral artery segments for measuring intracellular [Ca(2+)]. Tension and changes in intracellular [Ca(2+)] [the change in the ratio (418 nm/468 nm) of Indo1 fluorescence (F(ratio))] were simultaneously measured in Krebs-Ringer solution. RESULTS: In HF: (i) norepinephrine (10 microM) produced greater tension (784+/-52 g/cm(2)) than in control (502+/-64 g/cm(2)) despite a similar increase in F(ratio), indicating increased Ca(2+) sensitivity in vascular smooth muscle; (ii) nifedipine attenuated this enhanced response by only a maximum of 27% at 1 micromol/l with a 56% reduction in F(ratio); (iii) Y-27632 attenuated it by a maximum of 80% at 100 micromol/l without a significant change in F(ratio); (iv) RhoA protein and mRNA expression levels in the femoral artery were up-regulated by +110% and +56%, respectively, while those of Rho-kinase were unchanged. CONCLUSIONS: The Ca(2+)-sensitizing mechanism involving the Rho/Rho-kinase system may be deeply involved in the enhanced arterial vasoconstriction seen in HF. Since Y-27632 attenuated this response in small arteries, it shows potential as a novel, potent vasodilator for the treatment of HF.

Sialidosis type 2 in Japan. Clinical study in two siblings' cases and review of literature.

Clinical and biochemical findings in two siblings (24-year-old sister and 20-year-old brother), born to consanguineous parents, are described. Both showed progressive generalized myoclonus, macular cherry-red spots, moderate cerebellar ataxia, coarse facies, vertebral deformities, vacuolation of peripheral lymphocytes, bone marrow cells and epithelial cells of conjunctiva, but had normal intelligence. The excretion of sialyloligosaccharides in the urine of both was 3-5 times larger than in the controls. The activities of alpha-neuraminidase and beta-galactosidase in leukocytes and cultured skin fibroblasts were reduced. The clinical and biochemical findings were those of the newly described condition, sialidosis type 2. Review of all Japanese cases considered as sialidosis type 2 showed that the most characteristic clinical features as distinct from type 1, were coarse facies and bone deformities, especially of vertebral bodies.

Adrenoleukodystrophy with olivopontocerebellar atrophy-like lesions.

In a 46-year-old Japanese man with chronic psychiatric and neurologic symptoms, autopsy revealed enlarged adrenal cortical cells with trilamellar cytoplasmic inclusions and demyelinating lesions, marked in the fronto-parietal lobes and in the cerebellar hemispheres and corresponding to the pathology of adrenoleukodystrophy (ALD). Unusual gray matter lesions were found in the thalamus, cerebellar cortex, inferior olive and pontine nucleus, and the latter three lesions resembled those seen in cases of olivopontocerebellar atrophy (OPCA). These lesions are attributed to secondary changes due to disruption of the thalamo-cortical, cerebro-ponto-cerebellar and olivo-cerebellar connections.

Kawasaki disease complicated by acute myocardial infarction due to thrombotic occlusion of coronary aneurysms 19 years after onset.

A 25-year-old man with a history of Kawasaki disease from the age of 7 had acute inferior myocardial infarction. Emergency right coronary arteriogram showed successive coronary aneurysms at the proximal to middle portion of the right coronary artery, and total occlusion at the proximal segment. Intracoronary thrombolysis was performed and the right coronary artery was recanalized. On left coronary arteriography, coronary aneurysms and mild localized stenoses at the inlet and outlet of the aneurysms were found. It was suggested that the myocardial infarction was caused by thrombotic occlusion of coronary aneurysms complicated with Kawasaki disease.

[A 62-year-old survivor with Ebstein's anomaly without right ventricular failure].

A 62-year-old woman was admitted our hospital because of concussion of the brain. The level of consciousness improved within several days. Cardiac examination was performed because the patient had experienced feelings of fainting since one year previously, and heart murmur also was heard. The electrocardiogram showed WPW configuration. At the same time that she complained of feelings of fainting, the electrocardiogram showed supraventricular tachycardia. The echocardiogram showed displacement of the septal tricuspid leaflet and mild tricuspid valve, regurgitation. Cardiac catheterization was performed and, using the intracardiac electrocardiogram, we confirmed atrialized right ventricle. We diagnosed this patient as having Ebstein's anomaly with WPW syndrome. The clinical manifestations of this anomaly are quite variable, depending upon the spectrum of pathology and the presence of associated malformations. It is well documented that a considerable proportion of these patients are able to survive into adult life. However, the patient who survives into the sixth decade without a sign of heart failure is extremely rare. We speculate that this patient had not developed right ventricular failure until her 60's because she had a milder form of Ebstein's anomaly and did not have any other congenital heart disease.

Association between diabetic microangiopathy and vascular endothelial function evaluated by flow-mediated vasodilatation in patients with type 2 diabetes.

The main purpose of the study was to investigate the association between vascular endothelial function and diabetic microangiopathy (nephropathy, retinopathy and neuropathy) in patients with type 2 diabetes. In addition, the association between endothelial function and macroangiopathy evaluated by intimal-medial complex thickness (IMT) was also investigated. Endothelial function was evaluated non-invasively by the measurement of flow-mediated vasodilatation (FMD) of the brachial artery. Diabetic nephropathy and neuropathy were assessed by urinary albumin excretion (UAE) and motor or sensory nerve conduction velocity (MCV, SCV), respectively, and retinopathy was evaluated by an ophthalmologist using the Davis classification. FMD was measured in 102 patients with type 2 diabetes and in 20 control subjects, and showed a tendency to be lower in the diabetic patients. There was a significant decrease in FMD in patients with proliferative diabetic retinopathy, compared with those in patients with no diabetic retinopathy. FMD showed significant positive correlations with MCV and SCV, and significant negative correlations with log UAE, systolic blood pressure and diabetic duration, but no correlation was obtained between FMD and IMT. In stepwise regression analysis, MCV alone showed a significant association with FMD. In conclusion, our results show that in patients with type 2 diabetes FMD is closely associated with all types of microangiopathy, with neuropathy being most strongly associated with FMD; however, FMD is not associated with macroangiopathy evaluated by IMT.

Comparison of the effects of pioglitazone and voglibose on circulating total and high-molecular-weight adiponectin, and on two fibrinolysis inhibitors, in patients with Type 2 diabetes.

BACKGROUND: To investigate short-term effects of pioglitazone and voglibose on serum concentrations of both total and high-molecular-weight (HMW) adiponectin measured with a novel sandwich enzyme-linked immunosorbent assay (ELISA) ,and on plasma fibrinolysis indicators, in Type 2 diabetic patients with inadequate glycaemic control on sulphonylureas. METHODS: Thirty-four diabetic patients were randomized to receive pioglitazone or voglibose treatment for 12 weeks, after which serum HMW adiponectin was measured. Plasma plasminogen activator inhibitor (PAI) 1 and thrombin-activatable fibrinolysis inhibitor (TAFI), a recently identified inhibitor of fibrinolysis, were measured as fibrinolysis inhibitors. RESULTS: At baseline, serum HMW adiponectin correlated negatively with plasma TAFI in all patients with Type 2 diabetes (r = -0.367, P = 0.0423). Both groups showed similar improvements in glycaemic control. Serum total and HMW adiponectin increased in patients treated with pioglitazone, but did not change in patients treated with voglibose. The HMW : total adiponectin ratio increased significantly after treatment with pioglitazone (P = 0.0004). The change in HbA(1c) correlated negatively with changes in serum HMW adiponectin in patients treated with pioglitazone (r = -0.694, P = 0.0034). Plasma PAI-1 and TAFI did not change with pioglitazone treatment. CONCLUSION: Increased serum HMW adiponectin may contribute to the improvement in glycaemic control after pioglitazone treatment. Plasma PAI-1 and TAFI were unchanged by either drug.

Spine distribution along the apical dendrites of the pyramidal neurons in Down's syndrome. A quantitative Golgi study.

The number of spines along the apical dendrites of the pyramidal neurons in the hippocampal and cingulate gyri were counted on Golgi preparations of the brains of seven cases of Down's syndrome; they did not show neuropathological senile changes. The number of spines in the middle and distal segments of the apical dendrites of Down's syndrome group were significantly fewer than in those of the control group. The number of spines in aged noncharacteristic mentally retarded cases were not decreaed compared with the controls. The diminution of spines in Down's syndrome is considered to be rather specific in this condition and is not a common finding in other types of mental retardation. It might also be one of the early changes of dendritic degeneration related to senile plaque formation.