A mechanism for the hypoprothrombinemia of the acquired hypoprothrombinemia-lupus anticoagulant syndrome

Antibodies that bind prothrombin without neutralizing its coagulant activity were demonstrated in the plasma of two patients with the acquired hypoprothrombinemia-lupus anticoagulant syndrome. The first patient's plasma contained less than 1% prothrombin activity and no detectable prothrombin antigen. The second patient's plasma contained about 6% of both prothrombin activity and antigen. Neither patient's plasma neutralized the prothrombin coagulant activity of normal plasma or of purified prothrombin added in vitro. Nevertheless, double immunodiffusion studies and binding experiments utilizing 125I- prothrombin demonstrated the presence of prothrombin antibodies in each patient's plasma. A Scatchard analysis of the binding data obtained with different concentrations of 125I-prothrombin and the first patient's plasma indicated the presence of a high affinity antibody, apparent Kd approximately 10(-10)M, and a lower affinity antibody, apparent Kd approximately 10(-9)M. Studies utilizing purified cleavage products of prothrombin suggested that the antibodies were directed against an epitope or epitopes located on the carboxyl-terminal, latent thrombin segment of the prothrombin molecule. We postulate that the acquired hypoprothrombinemia in these two patients and in other reported patients with the acquired hypoprothrombinemia-lupus anticoagulant syndrome stems from rapid clearance from the circulation of prothrombin antigen-antibody complexes.     

Hospitalization criteria in urinary tract infections

A review of the scientific evidence available on the indications for hospitalization in pediatric patients with urinary tract infection is presented. We found no studies that specifically evaluated the utility of hospitalization in children with urinary tract infection. Only indirect data were found on the identification of high risk infections, but none of the clinical-laboratory parameters evaluated had sufficient sensitivity and specificity to support their use as the basis for decision making. However, in clinical practice, identification of the location of the infection is not important when considering hospitalization. Some studies have shown that ambulatory treatment with oral antibiotics is safe and effective in patients with pyelonephritis with good general status and with no history of uropathy. Consequently, the decision to admit the patient should be mainly based on evaluation of the patient's clinical status and on the estimated risk of general complications.     

Intestinal obstruction: trends in imaging utilization and their influence in its rising hospital bill

The purpose of the study was to evaluate trends in the utilization of different imaging modalities and review how imaging utilization practices affect hospital charges for patients with intestinal obstruction. All patients discharged with a primary diagnosis of intestinal obstruction during 6 fiscal years (1999-2004) were retrospectively studied. We obtained data on patients' demographics, procedures, outcomes, imaging services utilization, and hospital and imaging charges from our institution's transition system (a clinical and financial decision support software system). The institutional review board approved this study. Surgery was performed in 26% of patients in 1999 and in 40% in 2004 (p = 0.01) with the mortality rate significantly (p < 0.01) dropping from 3.8% to 0.4%. A total of 5,292 abdominal imaging studies were obtained; 93% of those were either abdominal radiographs or abdomino-pelvic computed tomography (CT) scans. CT studies per patient increased from 0.5 in 1999 to 1 in 2004 (p < 0.01), while abdominal radiographs (mean = 2.4) did not significantly change over the entire study period (p = 0.6). Average imaging charges doubled during the study period ($1,572 to $3,012, p < 0.01). Average hospital charges increased from $18,138 in 1999 to $32,808 in 2004 (p < 0.01). The fraction of hospital charges attributed to imaging varied between 8.7% and 9.2%. CT utilization for intestinal obstruction increased from 1999 to 2004 without modality substitution. While hospital and imaging charges have significantly increased, the fraction represented by imaging has remained constant, suggesting that imaging is an unlikely cause for the increase in hospital charges.     

手术期间化学疗法与单独手术治疗可切除的胃食管癌疗效比较

背景:表阿霉素(epirubicin)、顺铂、氟尿嘧啶静脉持续滴注(ECF)疗法可以改善不能治愈的患有局部晚期或者转移性胃腺癌患者的生存率。我们对手术期间增加ECF疗法是否可以改善有治愈可能胃癌患者的治疗结果。方法:我们将患有胃部、食管胃交界处或者食管下段癌症的患者随机进行手术期间化学疗法和手术联合治疗(n=250)或者只进行手术治疗(n=253)。化学疗法包括3个手术前和3个手术后疗程:第1天,静脉注射表阿霉素(50mg/m2身体表面积)和顺铂(60mg/m2),并连续21天进行静脉持续滴注氟尿嘧啶(每天200mg/m2)。初期终点为总体生存率。结果:与ECF相关…     

CYP2C8 *3 and *4 define CYP2C8 phenotype: An approach with the substrate cinitapride

Cinitapride is a gastrointestinal prokinetic drug, prescribed for the treatment of functional dyspepsia, and as an adjuvant therapy for gastroesophageal reflux disease. In this study, we aimed to explore the impact of relevant variants in CYP3A4 and CYP2C8 and other pharmacogenes, along with demographic characteristics, on cinitapride pharmacokinetics and safety; and to evaluate the impact of CYP2C8 alleles on the enzyme''s function. Twenty‐five healthy volunteers participating in a bioequivalence clinical trial consented to participate in the study. Participants were genotyped for 56 variants in 19 genes, including cytochrome P450 (CYP) enzymes (e.g., CYP2C8 or CYP3A4) or transporters (e.g., SLC or ABC), among others. CYP2C8*3 carriers showed a reduction in AUC of 42% and C_max of 35% compared to *1/*1 subjects (p = 0.003 and p = 0.011, respectively). *4 allele carriers showed a 45% increase in AUC and 63% in C_max compared to *1/*1 subjects, although these differences did not reach statistical significance. CYP2C8*3 and *4 alleles may be used to infer the following pharmacogenetic phenotypes: ultrarapid (UM) (*3/*3), rapid (RM) (*1/*3), normal (NM) (*1/*1), intermediate (IM) (*1/*4), and poor (PM) metabolizers (*4/*4). In this study, we properly characterized RMs, NMs, and IMs; however, additional studies are required to properly characterize UMs and PMs. These findings should be relevant with respect to cinitapride, but also to numerous CYP2C8 substrates such as imatinib, loperamide, montelukast, ibuprofen, paclitaxel, pioglitazone, repaglinide, or rosiglitazone.     

抗癌药物的研究：4－氯苯氧乙酰胺衍生物的合成

抗癌药物的研究：４－氯苯氧乙酰胺衍生物的合成李兰敏，徐世平（中国医学科学院，中国协和医科大学药物研究所北京１０００５０）在抗癌领域里，人们曾利用除莠剂能杀灭杂草而不伤害禾苗，有的甚至在杀灭杂草的同时还能刺激作物的生长这一选择作用，探索该类化合物抗癌的...     

Genetic homogeneity,high-resolution mapping,and mutation analysis of the urofacial (Ochoa) syndrome and exclusion of the glutamate oxaloacetate transaminase gene (GOT1) in the critical region as the disease gene

The urofacial (Ochoa) syndrome (UFS) is a rare autosomal recessive disorder characterized by abnormal facial expression and urinary abnormalities. Previously, we mapped the gene to a genomic interval of approximately 1 cM on chromosome region 10q23-24, using families from Columbia. Here we demonstrate genetic homogeneity of the syndrome through homozygosity mapping in American patients with Irish heritage. We established a physical map and identified novel polymorphic markers in the UFS critical region. Haplotype analysis using the new markers mapped the UFS gene within one YAC clone of 1,410 kb. We also determined the precise location of the gene encoding for glutamate oxaloacetate transaminase (GOT1) within the new UFS critical region and determined its genomic structure. However, mutation analysis excluded GOT1 as a candidate for the UFS gene. Am. J. Med. Genet. 84:454–459, 1999. © 1999 Wiley-Liss, Inc.     

Using PDX animal models to identify and stratify adenoid cystic carcinoma patients presenting an enhanced response to HDAC inhibitors

Adenoid cystic carcinoma (ACC) patients face a highly infiltrative and metastatic disease characterized by poor survival rates and suboptimal response to available therapies. We have previously shown that sensitization of ACC tumors to chemotherapy using histone deacetylase inhibitors (HDACi) constitutes a promising therapeutic strategy to manage tumor growth. Here, we used patient-derived xenografts (PDX) from ACC tumors to evaluate the effects of in vivo administration of the HDAC inhibitor Entinostat combined with Cisplatin over tumor growth. RNA from PDX tumor samples receiving the proposed therapy were analyzed using NanoString technology to identify molecular signatures capable of predicting ACC response to the therapy. We also used an RNAseq dataset from 68 ACC patients to validate the molecular signature identified by the NanoString platform. We found that the administration of Entinostat combined with Cisplatin resulted in a potent tumor growth inhibition (TGI) ranging from 38% to 106% of the original tumor mass. Enhanced response to therapy is consistent with the reactivation of tumor suppressor genes, including SFRP1, and the downregulation of oncogenes like FGF8 and CCR7. Nanostring data from PDX tumors identified a genetic signature capable of predicting tumor response to therapy. We further stratified 68 ACC patients containing RNAseq data accordingly to the activity levels of the identified genetic signature. We found that 23% of all patients exhibit a genetic signature consistent with a high ACC tumor response rate to Entinostat and Cisplatin. Our study provides compelling preclinical data supporting the deployment of a powerful systemic anticancer therapy crafted and explicitly tested for ACC tumors.