Molecular diversity and thrombotic risk in protein S deficiency: the PROSIT study

The Protein S Italian Team (PROSIT) enrolled 79 protein S (PS) deficient families and found 38 PROS1 variations (19 novel) in 53 probands. Of these, 23 variants were selected for expression in'vitro, to evaluate their role as possible causative variants. Transient expression showed high secretion levels (>75%) for three variants, which were considered neutral. Seven missense and five nonsense variants showed low (相似文献   

Leptin increase in multiple sclerosis associates with reduced number of CD4(+)CD25+ regulatory T cells

We analyzed the serum and cerebrospinal fluid (CSF) leptin secretion and the interaction between serum leptin and CD4(+)CD25+ regulatory T cells (T(Regs)) in naive-to-therapy relapsing-remitting multiple sclerosis (RRMS) patients. Leptin production was significantly increased in both serum and CSF of RRMS patients and correlated with IFN-gamma secretion in the CSF. T cell lines against human myelin basic protein (hMBP) produced immunoreactive leptin and up-regulated the expression of the leptin receptor (ObR) after activation with hMBP. Treatment with either anti-leptin or anti-leptin-receptor neutralizing antibodies inhibited in vitro proliferation in response to hMBP. Interestingly, in the RRMS patients, an inverse correlation between serum leptin and percentage of circulating T(Regs) was also observed. To better analyze the finding, we enumerated T(Regs) in leptin-deficient (ob/ob) and leptin-receptor-deficient (db/db) mice and observed the significant increase in T(Regs). Moreover, treatment of WT mice with soluble ObR fusion protein (ObR:Fc) increased the percentage of T(Regs) and ameliorated the clinical course and progression of disease in proteolipid protein peptide (PLP(139-151))-induced relapsing-experimental autoimmune encephalomyelitis (R-EAE), an animal model of RRMS. These findings show an inverse relationship between leptin secretion and the frequency of T(Regs) in RRMS and may have implications for the pathogenesis of and therapy for multiple sclerosis.     

Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study

Severe acetaminophen hepatotoxicity frequently leads to acute liver failure (ALF). We determined the incidence, risk factors, and outcomes of acetaminophen-induced ALF at 22 tertiary care centers in the United States. Detailed prospective data were gathered on 662 consecutive patients over a 6-year period fulfilling standard criteria for ALF (coagulopathy and encephalopathy), from which 275 (42%) were determined to result from acetaminophen liver injury. The annual percentage of acetaminophen-related ALF rose during the study from 28% in 1998 to 51% in 2003. Median dose ingested was 24 g (equivalent to 48 extra-strength tablets). Unintentional overdoses accounted for 131 (48%) cases, intentional (suicide attempts) 122 (44%), and 22 (8%) were of unknown intent. In the unintentional group, 38% took two or more acetaminophen preparations simultaneously, and 63% used narcotic-containing compounds. Eighty-one percent of unintentional patients reported taking acetaminophen and/or other analgesics for acute or chronic pain syndromes. Overall, 178 subjects (65%) survived, 74 (27%) died without transplantation, and 23 subjects (8%) underwent liver transplantation; 71% were alive at 3 weeks. Transplant-free survival rate and rate of liver transplantation were similar between intentional and unintentional groups. In conclusion, acetaminophen hepatotoxicity far exceeds other causes of acute liver failure in the United States. Susceptible patients have concomitant depression, chronic pain, alcohol or narcotic use, and/or take several preparations simultaneously. Education of patients, physicians, and pharmacies to limit high-risk use settings is recommended.     

Percutaneous US-guided RF thermal ablation for malignant renal tumors: preliminary results in 13 patients

Minimally invasive treatment for small renal cell carcinoma (RCC) can be necessary in selected patients and, anyway, is desirable. In situ ablation techniques, including RFA, have been developed. The aim of this study is to evaluate the feasibility, safety and short-term local effectiveness of percutaneous US-guided RFA in a small series, as well as mid-term patient outcome. Thirteen patients with a total of 18 tumors (17 small lesions, 35 mm in size or less, and a larger one, 75 mm in size) underwent 19 RFA sessions. Seven patients had a solitary kidney, and three suffered from VHL disease, too. We treated four lesions in a patient with a bilateral tumor. In another patient, three lesions were ablated. Seventeen tumors were RCC; one was a metastasis from lung cancer. Eight lesions were parenchymal, six exophytic, two parenchymal/exophytic, one parenchymal/central and one central. A monopolar RF system with multitined expandable electrode needles was used. The 35-mm lesion underwent two sessions; the 75-mm lesion was treated with transcatheter arterial embolization before RFA. Tumors with complete loss of contrast enhancement at short-term CT (or MR) were considered successfully treated. Percutaneous US-guided RFA was always feasible without major complications. The success rate after a single treatment in tumors less than 35 mm in size was 88.2% (15/17) and rose to 94.1% (16/17) after the second treatment of the largest lesion. After a mean 14-month follow-up, no successfully treated lesions recurred locally. Only the patient with metastasis from lung cancer died from disease progression in a further location, while all other patients are alive, with renal function still sufficient to avoid dialysis. US guidance allows an easy and safe percutaneous approach for RFA of small non-parahilar RCC. The treatment is locally effective and can be proposed as a minimally invasive therapy for patients with contraindications to surgery or to those expressing an informed consent. Based on the results of this study and of the literature, mid-term results on the clinical usefulness are very encouraging.Presented at ECR 2003.     

Simultaneous liver-kidney transplantation for glycogen storage disease type IA (von Gierke's disease)

INTRODUCTION: Glycogen storage disease type Ia (GSDIa) is due to the deficiency of glucose-6-phosphatase activity in the liver, kidney, and intestine. Although significant progress has been achieved in the management of patients with GSDIa, complications still emerge. The potential for development of liver adenomatosis and kidney failure makes these patients candidates for simultaneous liver-kidney transplantation (SLKT). Herein, we describe such a transplantation in a patient affected by this rare storage disease. METHODS: A 25-year-old female patient with GSDIa developed hepatic adenoma and kidney failure despite dietary therapy. The patient underwent an SLKT from a cadaveric donor. RESULTS: The operative time was 8 hours without hemotransfusion. Only a transitory lactic acidosis was observed. Laboratory results normalized on postoperative day 7. The patient was discharged on postoperative day 9. After 4 months, the patient is in good condition with well-functioning kidney and liver allografts. CONCLUSION: Patients with end-stage renal disease secondary to GSDIa should be considered for SLKT, especially when the disease is in an early stage.     

Exogenous nucleosides stimulate proliferation of fetal rat hepatocytes

Exogenous nucleotides (NT) have been reported to exert a reparative role in animal models of intestinal and hepatic damage. Thus, the administration of NT in the diet of rats with thioacetamide-induced liver cirrhosis normalized many of the histological and biochemical alterations produced by this hepatotoxin. We are currently studying the mechanism by which NT exert this effect using cell culture models. The aim of this work was to investigate whether exogenous nucleosides (NS) modulate the proliferation of hepatocytes. We used fetal rat hepatocytes, which, unlike adult hepatocytes, are proliferative cells. Fetal rat primary hepatocytes were incubated with mixtures of NS, and cell proliferation was studied. NS added to the medium of fetal hepatocytes were taken up in a selective fashion by the cells. Cell proliferation was enhanced, as demonstrated by the induction of c-myc and h-ras gene expression as well as by the higher percentage of cells in S phase, and exogenous NS increased the expression of alpha-fetoprotein. These results suggest that exogenous NS may in fact stimulate proliferation of hepatic cells and help preserve the undifferentiated state of fetal rat hepatocytes.     

Acanthovagasteroids A-D, four new 19-hydroxylated steroids from the South China Sea gorgonian Acanthogorgia vagae Aurivillius

Four new steroids, acanthovagasteroids A-D (1-4), along with two known analogues (5, 6), were isolated from the gorgonian Acanthogorgia vagae Aurivillius from the South China Sea. The structures of the new compounds, characterized with 19-hydroxy groups, were identified on the basis of extensive spectral analysis as well as by comparison with literature data. This is the first report of 19-hydroxy steroids from a gorgonian and suggests a possible biosynthetic relationship between 19-nor and 19-hydroxy steroids.