A common mutation of the insulin receptor substrate-1 gene is a risk factor for coronary artery disease

Insulin resistance is associated with increased risk of atherosclerosis. Insulin receptor substrate-1 (IRS-1) plays a key role in tissue insulin sensitivity. A common mutation (G972R) of the IRS-1 gene has been shown to impair IRS-1 function, and it has been associated with reduced insulin sensitivity and lipid abnormalities. This led us to investigate the role of the G972R mutation in predisposing individuals to coronary artery disease (CAD). The DNA of 318 subjects with angiographically documented coronary atherosclerosis (>50% stenosis) and 208 population control subjects was analyzed for the presence of the G972R mutation. This mutation was detected by nested polymerase chain reaction and BstNI restriction enzyme digestion. The frequency of the G972R mutation was significantly higher among patients with CAD than controls (18. 9% versus 6.8%, respectively; P<0.001). After controlling for other coronary risk factors, the relative risk of CAD associated with the G972R mutation was 2.93 (95% CI 1.30 to 6.60; P<0.02) in the entire cohort. This risk was found to be even higher in the subgroups of obese subjects (odds ratio [OR] 6.97, 95% CI 2.24 to 21.4; P<0.001) and subjects with clinical features of insulin resistance syndrome (OR 27.3, 95% CI 7.19 to 104.0; P<0.001). The IRS-1 gene variant was associated with a higher frequency of diabetes mellitus (14.9% among carriers versus 6.5% among noncarriers; P<0.01) and with a 60% increase of plasma total triglycerides (P<0.001). Also, plasma concentrations of total cholesterol and the ratio of total cholesterol to HDL cholesterol were significantly (P<0.001) higher among carriers than noncarriers, although to lesser a extent. These effects were independent of CAD status. The G972R mutation in the IRS-1 gene was found to be a significant independent predictor of CAD. Moreover, this mutation greatly increased the risk of CAD in obese subjects and in patients with the cluster of abnormalities of insulin resistance syndrome. Besides the increased frequency of diabetes, carriers showed a more atherogenic lipid profile, suggesting a potential role of the IRS-1 gene in the pathogenesis of lipid abnormalities associated with CAD.     

Combination of quinine as a potential reversing agent with mitoxantrone and cytarabine for the treatment of acute leukemias: a randomized multicenter study

A phase III prospective randomized multicenter study was performed to determine whether quinine could improve the response rate of poor-risk acute leukemias (ALs) to standard chemotherapy including a multidrug resistance (MDR)-related cytotoxic agent. The rationale of the study was based on the negative prognostic value of MDR phenotype in ALs and the ability of quinine to reverse this phenotype both in vitro and ex vivo. Three hundred fifteen patients (median age, 49 years; range, 16 to 65) with relapsed (n = 108) or refractory (n = 32) acute myeloblastic leukemia (AML), relapsed (n = 27) or refractory (n = 9) acute lymphoblastic leukemia (ALL), secondary AL (n = 22) or blastic transformation of myelodysplastic syndrome ([MDS] n = 74) or myeloproliferative syndrome ([MPS] n = 43) were randomly assigned to receive mitoxantrone ([MXN] 12 mg/m2/d, days 2 to 5) and cytarabine ([Ara-C] 1 g/m2/12 h, days 1 to 5) alone or in combination with quinine (30 mg/kg/d, days 1 to 5; continuous intravenous infusion beginning 24 hours before MXN infusion). Side effects of quinine were observed in 56 of 161 quinine-treated patients and disappeared in all but four cases after one or two 20% dose decreases. Sera from quinine-treated patients showed increased MXN uptake in an MDR-positive cell line compared with matched sera obtained before quinine infusion. Quinine induced a significant increase in the incidence of nausea, vomiting, mucositis, and cardiac toxicity. A complete response (CR) was observed in 85 of 161 patients (52.8%) from the quinine-treated group versus 70 of 154 patients (45.5%) in the control group (P = .19). The most important differences between quinine and control group CR rates were observed in patients with refractory AMLs and blastic transformation of MDS and MPS. The CR rate was higher in P-glycoprotein-positive cases, although the difference was not significant. Failure of the regimen due to blastic persistence or blast number increase was higher in the control group (61 of 154 patients) than in the quinine group (45 of 161, P = .04). Early death was observed in eight cases (four in each arm) and death in aplasia in 27 cases (20 in quinine group v seven in control group, P = .01). The significant increase of toxicity in the quinine arm could have masked the clinical benefit of MDR reversion in poor- risk ALs.     

Transesophageal echocardiography in myocardial ischemia: a review

This article reviews established as well as emerging fields in the application of transesophageal echocardiography (TEE) in the investigation of myocardial ischemia. TEE already has a well defined and established role in stress echocardiography in patients with poor transthoracic acoustic window, and in the detection of intraoperative myocardial ischemia in cardiac and noncardiac surgery. The evaluation of right ventricular ischemia and infarction and the assessment of coronary flow reserve (CFR) are relatively new fields in the application of TEE and the potential of this technique has not yet been fully evaluated. The evidence collected and reviewed in this article is still preliminary but it presupposes a significant role of TEE in the diagnosis and pathophysiological assessment of myocardial ischemia.     

Allogeneic stem cell transplantation with reduced-intensity conditioning is potentially feasible as an outpatient procedure

Allogeneic stem cell transplantation (allo-SCT) after a reduced-intensity conditioning (RIC) protocol is associated with decreased short-term toxicity. This suggests that the procedure could be performed on an outpatient basis. We analysed the incidence and risk factors of grade >or=2 conditioning-related toxicities (CRTs) as a hallmark for hospital admission, in 41 consecutive patients allografted from an HLA identical sibling after RIC. The RIC regimen consisted of fludarabine plus melphalan for lymphoid malignancies, and fludarabine plus busulphan for myeloid malignancies. In all, 11 patients (27%) did not experience any toxicity. The more frequent CRTs observed were neutropenic fever and gastrointestinal toxicity. The median duration of hospitalisation was 27 (range, 17-50) days. If allo-SCT had been planned as an outpatient procedure and admission indicated only in the case of >or=2 CRTs, the inpatient period would have decreased to 9 (range, 0-33) days (P<0.001). No risk factors for CRTs were identified. Allo-SCT after an RIC regimen is a well-tolerated procedure. Our results warrant a prospective pilot trial of nonmyeloablative allo-SCT performed in the outpatient setting.     

Familial occurrence of inflammatory bowel disease in celiac disease

BACKGROUND: The authors have previously reported a possible increased risk of the familial occurrence of Crohn's disease in patients with celiac disease. AIM: The aim of the current study was to evaluate in a case-control study the familial occurrence of inflammatory bowel disease (IBD) in first-degree relatives of patients with celiac disease. METHODS: One hundred eleven consecutive patients with biopsy-proven celiac disease were interviewed to ascertain whether IBD was present in first-degree relatives. The number of relatives, their ages, and possible IBD status were collected in a questionnaire. When a diagnosis of familial IBD was reported, the diagnosis was checked in the hospital records. Two hundred twenty-two controls matched for age and sex (111 from the general population and 111 from orthopedic wards) were also interviewed regarding the possible occurrence of IBD in first-degree relatives. The chi2 test was used to evaluate the difference in proportion of familial occurrence of IBD among individuals with celiac disease and controls. RESULTS: Among 600 first-degree relatives of patients with celiac disease, 10 cases of IBD were identified among first-degree relatives (7 cases of ulcerative colitis and 3 cases of Crohn's disease), whereas only 1 case of IBD was identified among the 1,196 first-degree relatives of control patients (p < 0.01). When ulcerative colitis and Crohn's disease were analyzed separately, only the prevalence of ulcerative colitis was statistically significant (p 相似文献   

Poorly differentiated small cell neuroendocrine carcinoma localized in three different endocrine glands: response to chemotherapy and octreotide LAR

Neuroendocrine tumors represent a heterogeneous category of neoplasm, with conflicting diagnostic and therapeutic demands. We here describe the case of a 72-yr-old woman with evidence of a poorly differentiated small-cell neuroendocrine carcinoma (NEC) localized in different endocrine glands and other non-endocrine organs. In particular, a large ovarian mass, multinodular thyroid goiter, right adrenal mass, cystic liver metastases and anterior mediastinum lymph node metastasis were present. The largest thyroid nodule caused tracheal restriction and dyspnea. Diagnosis of poorly differentiated metastasized NEC of unknown origin was made on the basis of histological and immunohistochemical findings, and treatment with etoposide (100 mg/m2 in days 1, 2 and 3) and cisplatinum (45 mg/m2 in days 2 and 3) was initiated. Simultaneously, im administration of octreotide LAR 20 mg every 28 days was started, according to the presence of SS receptors at 111In-octreotide scan. Rapid improvement of dyspnea and a reduction of the largest thyroid nodule, liver metastases and adrenal mass by 50% were observed after 3 months of treatment; the dimensions remained stable thereafter, while the pericardial lymph node disappeared. In conclusion, poorly differentiated NEC of unknown primary site is a well-recognized category, usually with an aggressive behavior, rapid growth rate and wide dissemination. Median survival of these patients is 6 months if left untreated. Our patient is alive 18 months after beginning the treatment, reporting good general condition and quality of life over the whole follow-up period.     

Effects of contrast media on renal function in patients with cirrhosis: a prospective study

Patients with cirrhosis are frequently submitted to radiological procedures that require the administration of contrast media. Contrast media is a well-known cause of renal failure, particularly in the presence of some predisposing conditions. However, it is not known whether cirrhosis constitutes a risk factor for contrast media-induced renal failure. The aim of this study was to assess the possible nephrotoxicity of contrast media in patients with cirrhosis. In a first protocol, renal function was evaluated with sensitive methods (glomerular filtration rate using iothalamate I 125 clearance and renal plasma flow using iodohippurate I 131 clearance) before and 48 hours after the administration of contrast media in 31 patients with cirrhosis (20 with ascites, 5 with renal failure). Solute-free water clearance, urine sodium, prostaglandins, and markers of tubular damage were also measured. The administration of contrast media was not associated with significant changes in renal function tests, neither in the whole group of patients nor in patients with ascites or renal failure. Urinary prostaglandin E2 and N-acetyl-beta-D-glucosaminidase increased significantly, but sodium and solute-free water excretion remained unchanged. In a second protocol, a different series of 60 patients with cirrhosis and renal failure were examined prospectively. No patient had renal failure due to contrast media. Only in 1 patient with septic shock was contrast media a possible contributing factor. In conclusion, the administration of contrast media is not associated with adverse effects on renal function in patients with cirrhosis. Cirrhosis does not appear to be a risk factor for the development of contrast media-induced nephrotoxicity.     

Liver-derived fetal hematopoietic stem cells selectively and preferentially home to the fetal bone marrow

In the course of ontogeny, the homing site for the hematopoietic stem cells (HSC) moves with certain predictability from the yolk sac to the liver/spleen and then to the marrow. The pattern of this migration has thus far been established mostly on a morphologic basis. To delineate further the course of this migration and to gain insight into its possible mechanism, we used in utero transplantation of allogeneic or xenogeneic HSC in preimmune sheep fetuses. Sex chromosome, type of hemoglobin, and species-specific surface markers were used to follow the path of transplanted cells in the fetus. Before the development of the bone marrow, transplanted HSC (liver- or marrow-derived) homed exclusively to the liver/spleen. With the development of marrow, around day 60 of gestation (term, 145 days), homing occurred also in the nascent marrow and by day 80 transplanted cells homed exclusively to the marrow. This suggests that there may be a hierarchy in homing sites, with those of the marrow having higher affinity than those of liver/spleen. Interestingly, despite a change in homing that was followed by the expansion of the marrow compartment of HSC (ie, HSC proliferation), these cells did not participate actively in blood cell formation during most of the prenatal period. Liver remained the major hematopoietic organ throughout the gestation. It was only during the perinatal period that this organ assumed the function of hematopoiesis from the liver. This lack of expression of HSC in fetal marrow can possibly be attributable to the immaturity of marrow stroma required for differentiation and maturation of progenitors and the orderly egress of mature cells into the blood stream. The availability of this model allows us to begin studies in the molecular mechanism of stem cell homing in vivo during ontogeny.