Phase II trial of 2-chlorodeoxyadenosine for the treatment of cutaneous T-cell lymphoma [see comments]

We investigated the efficacy of 2-chlorodeoxyadenosine (2-CdA) therapy in patients with mycosis fungoides (MF) and the Sezary syndrome (SS). Between February 1991 and November 1993, 21 patients with relapsed or refractory MF/SS were treated with 2-CdA. 2-CdA was administered by continuous intravenous infusion at a dose of 0.1 mg/kg/d for 7 days initially (13 patients), but was subsequently reduced to 5 days (nine patients) due to hematologic toxicity. All patients had failed to respond to at least one prior treatment for MF/SS (median number of total prior therapies, five; median number of systemic prior therapies, three) and had an Eastern Cooperative Oncology Group performance status of two or better. Cycles were administered at 28-day intervals. Assessable patients received at least 5 days of 2-CdA. Fourteen patients received more than one cycle of 2-CdA. An overall response rate of 28% was achieved. Three patients (14%) had a complete response with a median duration of 4.5 months (range, 2.5 to 16). Three (14%) had a partial response with a median duration of 2 months (range, 2 to 4). Fifteen patients (72%) had no response. The most significant toxicities encountered were bone marrow suppression (62% of patients) and infectious complications (62% of patients). Thirty-eight percent of patients experienced no toxicity from 2-CdA. 2-CdA has activity as a single agent in patients with previously treated relapsed MF/SS. Studies in less heavily pretreated individuals with 2-CdA alone or in combination will be undertaken.     

Platelet storage pool deficiency in pigs

We report a new bleeding disease--storage pool deficiency (SPD) of platelets--in pigs from the Mayo swine colony of homozygous von Willebrand's disease (vWD) and of heterozygous carriers of vWD. Levels of factor VIII, von Willebrand factor antigen (vWF:Ag), and ristocetin cofactor (RCof) were similar in the vWD carriers and SPD pigs. The latter pigs, however, had bleeding times of 15 minutes or more and were severe bleeders, in contrast to clinically normal vWD carriers. Platelet aggregation in response to collagen was reduced in most SPD pigs. Total platelet content of ADP, ATP, and serotonin was less than that of normal pigs. While the initial uptake of 14C-labeled serotonin into platelets was similar in SPD and normal pigs, retention of serotonin was reduced in platelets of SPD pigs. Transmission electron microscopy showed a large decrease of dense bodies in the platelets of SPD pigs. These findings support a diagnosis of SPD. Genetic analyses suggest an autosomal recessive mode of inheritance. A breeding program is under way to produce pigs affected only at the SPD gene, thus allowing further characterization of SPD and SPD-carrier pigs.     

Molecular basis of the heterogeneity of expression of glycosyl phosphatidylinositol anchored proteins in paroxysmal nocturnal hemoglobinuria

The purpose of these studies was to determine the molecular basis of the phenotypic mosaicism that is a defining feature of paroxysmal nocturnal hemoglobinuria (PNH). Analysis of T cell clones from a female patient revealed four distinct phenotypes based on surface expression of glycosyl phosphatidylinositol-anchored proteins (GPI-AP). When PIG-A (the gene that is mutant in PNH) from these clones was analyzed, four discrete somatic mutations were identified. Analysis of X chromosomal inactivation among the abnormal T cell clones was consistent with polyclonality. Together, these studies demonstrate that the phenotypic mosaicism that is characteristic of PNH is a consequence of genotypic mosaicism and that, at least in this case, PNH is a polyclonal rather than a monoclonal disease. That four distinct somatic mutations were present in a single patient suggests that in conditions that predispose to PNH PIG-A may be hypermutable.     

Alpha 4 beta 1-integrin expression on sickle reticulocytes: vascular cell adhesion molecule-1-dependent binding to endothelium

Important complications in sickle cell anemia occur secondary to vascular occlusion, which is postulated to be initiated by interactions of erythrocytes with vascular endothelial cells. In patients with sickle cell anemia, up to 25% of reticulocytes express the alpha 4 beta 1-integrin complex. Furthermore, erythrocytes from patients with sickle cell anemia bind to endothelial cells activated by tumor necrosis factor alpha via (TNF alpha) via interactions between erythrocyte alpha 4 beta 1 and endothelial cell vascular cell adhesion molecule-1 (VCAM- 1). Thus, binding of alpha 4 beta 1-expressing reticulocytes to cytokine-activated endothelial cells may initiate vascular complications in sickle cell anemia and perhaps other hemolytic anemias during episodes of infection and inflammation.     

Diabetic status and the relation of the three domains of glycemic control to mortality in critically ill patients: an international multicenter cohort study

Introduction

Hyperglycemia, hypoglycemia, and increased glycemic variability have each been independently associated with increased risk of mortality in critically ill patients. The role of diabetic status on modulating the relation of these three domains of glycemic control with mortality remains uncertain. The purpose of this investigation was to determine how diabetic status affects the relation of hyperglycemia, hypoglycemia, and increased glycemic variability with the risk of mortality in critically ill patients.

Methods

This is a retrospective analysis of prospectively collected data involving 44,964 patients admitted to 23 intensive care units (ICUs) from nine countries, between February 2001 and May 2012. We analyzed mean blood glucose concentration (BG), coefficient of variation (CV), and minimal BG and created multivariable models to analyze their independent association with mortality. Patients were stratified according to the diagnosis of diabetes.

Results

Among patients without diabetes, mean BG bands between 80 and 140 mg/dl were independently associated with decreased risk of mortality, and mean BG bands >140 mg/dl, with increased risk of mortality. Among patients with diabetes, mean BG from 80 to 110 mg/dl was associated with increased risk of mortality and mean BG from 110 to 180 mg/dl with decreased risk of mortality. An effect of center was noted on the relation between mean BG and mortality. Hypoglycemia, defined as minimum BG <70 mg/dl, was independently associated with increased risk of mortality among patients with and without diabetes and increased glycemic variability, defined as CV >20%, was independently associated with increased risk of mortality only among patients without diabetes. Derangements of more than one domain of glycemic control had a cumulative association with mortality, especially for patients without diabetes.

Conclusions

Although hyperglycemia, hypoglycemia, and increased glycemic variability is each independently associated with mortality in critically ill patients, diabetic status modulates these relations in clinically important ways. Our findings suggest that patients with diabetes may benefit from higher glucose target ranges than will those without diabetes. Additionally, hypoglycemia is independently associated with increased risk of mortality regardless of the patient''s diabetic status, and increased glycemic variability is independently associated with increased risk of mortality among patients without diabetes.See related commentary by Krinsley, http://ccforum.com/content/17/2/131See related commentary by Finfer and Billot, http://ccforum.com/content/17/2/134     

镉相关翻译启动因子TIF3致Ras癌基因蛋白的异常表达

目的 研究镉相关翻译启动因子TIF3对多种细胞肿瘤相关基因表达的影响,探索镉的分子致癌机制。方法应用TIF3基因真核细胞稳定表达系统和Western blot检测技术,用各种单克隆抗体检测细胞肿瘤相关基因蛋白的表达情况。结果 相对于载体转染中国仓鼠卵巢(CHO)对照细胞,在4株具有高效稳定表达TIF3编码蛋白质的CHO细胞系中均有pan—ras癌基因蛋白异常表达,其编码蛋白(21kDa)含量均明显高于对照组;其余肿瘤相关基因蛋白如c—myc．c-jun,MDM2,ODC,P16,p53,Cyclin D1的表达蛋白在TIF3转基因细胞与对照细胞之间未见明显差别。结论 镉相关翻译启动因子TIF3是一种镉应答原癌基因,TIF3的超额表达可导致Ras癌基因蛋白异常表达,这可能是镉应答原癌基因TIF3的分子致癌机制。     

Facteurs associés aux perdus de vue des patients sous traitement antirétroviral dans un centre de traitement ambulatoire du VIH à Conakry,Guinée

Background

Late or inadequate therapeutic management increases the risk of mortality associated with HIV/AIDS. The aim of this study was to analyze the proportion and factors associated with loss of follow-up in HIV patients who receiving antiretroviral therapy at Conakry.

Successful Treatment of Bone Marrow Failure in Gaucher's Disease with Low-dose Modified Glucocerebrosidase

We report the beneficial effects of enzyme replacement therapywith mannose-terminated human glucocerebrosidase (‘Ceredase’)in a patient suffering from transfusion-dependent bone marrowfailure due to Gaucher's disease. Treatment with low-dose enzymeinfusions, given twice weekly, rapidly reversed the haematopoieticfailure and incapacitating skeletal disease. It appears likelythat prior splenectomy favourably influenced the response tothis therapy.