Serology and ultrasound for diagnosis of choledocholithiasis

Introduction

Magnetic resonance cholangiopancreatography (MRCP) is not a routine investigation to exclude choledocholithiasis unless there is clinical or biochemical suspicion of common bile duct (CBD) stones. This study attempted to determine which radiological or serological parameters best predicted CBD stones.

Methods

All patients undergoing MRCP from 2005 to 2011 were selected. Patients with pancreatitis were excluded. Liver function tests (LFTs) at admission and prior to MRCP were recorded, as was abdominal ultrasonography and MRCP results. Parameters measured routinely on LFTs included alkaline phosphatase (ALP), alanine transaminase (ALT) and bilirubin. Receiver operating characteristic curve area analysis (area under the curve [AUC]) and chi-squared analysis were undertaken.

Results

Overall, 195 patients were identified, 71 of whom had CBD stones on MRCP. Raised ALP levels on admission demonstrated a correlation with CBD stones (AUC: 0.619, odds ratio [OR]: 3.16, p=0.06). At ultrasonography, a dilated CBD (OR: 3.76, p<0.001) and intrahepatic duct dilation (OR: 5.56, p<0.001) were highly significant predictors. However, only 37% of patients had a dilated CBD on ultrasonography. Ongoing elevation of LFT parameters, particularly ALP (AUC: 0.707, OR: 4.64, p<0.001) and ALT (AUC: 0.646, OR: 5.40, p<0.001), displayed a significant correlation with CBD stones.

Conclusions

Ongoing (even if minor) elevations of liver function test parameters should prompt the need to exclude CBD stones even in the presence of a normal CBD diameter on ultrasonography.     

Thrombin causes subsecond changes in protein phosphorylation of platelets

We have developed a general quenched-flow approach to study platelet function as early as 0.3 seconds after stimulation. Phosphorylation of 20- and 40-kd proteins has been analyzed during the first five seconds of platelet response to thrombin from 0.1 to 5.0 U/mL and compared with the progress of aggregation and serotonin secretion. The onset time for aggregation and phosphorylation of both proteins was less than one second, although with lowest (less than 0.5 U/mL) thrombin levels, a lag of up to 0.6 seconds occurred before 40K phosphorylation increased. The thrombin sensitivity of aggregation and 20K phosphorylation was approximately twice that of 40K phosphorylation, with Ka values of 0.51 and 0.53 v 1.10 U/mL, respectively. External calcium was necessary for maximal 20K phosphorylation, since EDTA inhibited this by 30%. The 40K phosphorylation was not affected by EDTA. Platelet activation by thrombin thus induced biochemical changes well before one second. The quenched-flow approach may help to reveal relationships between phospholipase activation, calcium fluxes, and protein phosphorylation during these early periods of platelet function.     

Diagnostic role of an immunoassay-detected polymorphism of factor IX for potential carriers of hemophilia B

In hemophilia B, assays based on a monoclonal antifactor IX specific for the Thr-148 variant of an exonic polymorphism have diagnosed carriers in selected families by either establishing linkage or by indicating the presence or absence of a given normal factor IX. The sensitivity of the immunoassays for detecting heterozygous women was explored by comparing results from immunoassays with solid-phase polyclonal v the monoclonal antifactor IXs. Factor IX with the normal Ala-148 variant gave a flat dilution curve, qualitatively distinct from factor IX with the Thr-148 variant in the monoclonal assay. The two were indistinguishable in the polyclonal assay. Mixtures of equal amounts of the two types gave an intermediate result, about half as reactive in the monoclonal as compared with the polyclonal assay system. Whereas mixtures with 10% Ala-148 and 90% Thr-148 factor IXs could not readily be distinguished from Thr-148 factor IX plasma, as little as 1% of the Thr-148 protein was detected in Ala-148 factor IX plasma. The frequency of the Ala-148 variant varied in individuals with different ethnic backgrounds; it was found in 29% of white, 12% of black, and none of Asian blood donors' factor IX genes in Seattle. Only 4% of samples from South African black men were nonreactive (ie, Ala- 148). The Thr/Ala-148 dimorphism is in strong linkage disequilibrium with Taql restriction fragment length polymorphisms (RFLPs). Three recombinations were noted in normal white genes and one in a normal black factor IX gene (less than 2% of those examined). In 34 white families with at least one woman being a possible carrier, genetically, the immunoassay results were informative in 18. RFLP analyses were informative in eight of the 15 families tested. In five families each, assignment of carrier status was made to a woman by only DNA or only immunoassay results, whereas the other approach was noninformative. The immunoassays provide a rapid, inexpensive screening test and complement DNA analysis in white women who are potential carriers of hemophilia B.     

Pembrolizumab with R-CHOP in previously untreated diffuse large B-cell lymphoma: potential for biomarker driven therapy

Tumor programmed death-ligand 1 (PD-L1) expression in diffuse large B-cell lymphoma (DLBCL) is associated with inferior outcomes. The first-line immunologically-replete setting may be an opportune time for PD-1 inhibition. We evaluated pembrolizumab in combination with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) in untreated patients with DLBCL. Eligible patients were age 18 or older, had adequate organ function, and had DLBCL requiring full-course therapy. Patients received pembrolizumab 200 mg/cycle with R-CHOP, primarily to assess toxicity. Response assessment utilized standard criteria, and PD-L1 staining was performed at a validated central laboratory. Among 30 patients, toxicity was comparable to standard R-CHOP but with two grade ≥3 immune related adverse events (rash, pneumonitis). The overall and complete response rate was 90% and 77%. With 25·5 months of median follow-up, 2-year progression-free survival (PFS) is 83%. PD-L1 expression was associated with non-GCB subtype, and improved PFS and survival. Pembrolizumab can safely be added to R-CHOP, and is associated with a high CR rate and 2-year PFS. Improved PFS with PR-CHOP in PD-L1 expressing tumors contradicts historical data in R-CHOP treated patients, supporting evaluation of PD-L1 as a biomarker to identify DLBCL patients who may benefit from this first-line strategy.     

抗血管生成因子Angiostatin与Endostatin作用下肿瘤血管生成的二维数值模拟

目的数值模拟抗血管生成因子Angiostatin和Endostatin对肿瘤血管生成的影响。方法建立肿瘤内外血管生成的二维离散数学模型。模型耦合两种抗血管生成因子Angiostatin和Endostatin的抑制效应,数值模拟在促血管生成因子诱导下肿瘤微血管网生成,讨论血管生成抑制因子的影响。结果抗血管生成因子Angiostatin对肿瘤内外血管网络生成的速度和成熟度有抑制作用。抗血管生成因子Angiostatin和Endostatin耦合作用时,在肿瘤血管生成的早期有明显的抑制效应;在肿瘤血管生成的中后期,它们可以降低肿瘤血管化程度。结论本文模型能够较好的模拟抗血管生成因子Angiostatin和Endostatin对内皮细胞迁移和增殖的抑制作用。     

Increased Radioresistance to Lethal Doses of Gamma Rays in Mice and Rats after Exposure to Microwave Radiation Emitted by a GSM Mobile Phone Simulator

The aim of this study was to investigate the effect of pre-irradiation with microwaves on the induction of radioadaptive response. In the 1^st phase of the study, 110 male mice were divided into 8 groups. The animals in these groups were exposed/sham-exposed to microwave, low dose rate gamma or both for 5 days. On day six, the animals were exposed to a lethal dose (LD). In the 2^nd phase, 30 male rats were divided into 2 groups of 15 animals. The 1^st group received microwave exposure. The 2^nd group (controls) received the same LD but there was no treatment before the LD. On day 5, all animals were whole-body irradiated with the LD. Statistically significant differences between the survival rate of the mice only exposed to lethal dose of gamma radiation before irradiation with a lethal dose of gamma radiation with those of the animals pre-exposed to either microwave (p=0.02), low dose rate gamma (p=0.001) or both of these physical adapting doses (p=0.003) were observed. Likewise, a statistically significant difference between survival rates of the rats in control and test groups was observed. Altogether, these experiments showed that exposure to microwave radiation may induce a significant survival adaptive response.     

Treatment of refractory adult‐onset pityriasis rubra pilaris with TNF‐alpha antagonists: a case series

Background Pityriasis rubra pilaris (PRP) is a rare inflammatory dermatosis with frequent clinical presentation as erythroderma. Conventional systemic treatment is often unsatisfactory and limited by long‐term toxicity. The use of tumour necrosis factor (TNF) antagonists has been reported previously in single cases, but lacking long‐term follow‐up or comparison between different biological agents. Objectives To assess the long‐term efficacy and safety of TNF‐alpha antagonist, infliximab and etanercept, either in monotherapy or in combination therapy of severe, refractory adult‐onset PRP. Methods Seven patients of adult‐onset PRP, six newly diagnosed type‐I and 1 type‐II, which were resistant or ineligible to conventional systemic treatment, received a single course of infliximab or etanercept therapy, alone or in combination with low‐dose acitretin (>0.25 mg/kg/daily). After complete remission and treatment discontinuation, a follow‐up period of 12 months was evaluated for relapses. Results Six patients obtained complete remission after a single course of anti‐TNF‐alpha therapy: mean therapy duration was 19.3 weeks (range 6–48 weeks). All patients obtained significant clearing (>75% of body surface area) of skin lesions at week 12. Two patients with marked keratoderma developed localized disease recurrence during treatment. During follow‐up, only a single patient, affected by type II PRP, had disease relapse. Conclusions Both TNF‐alpha antagonists proved successful for the treatment of refractory, adult‐onset PRP, yielding complete and persistent clinical responses in type‐I PRP. Infliximab was associated with a more rapid onset of action, while treatment duration was comparable with etanercept. PRP type II warranted long‐term therapy and showed relapse after drug discontinuation.     

Benzo[a]pyrene at an environmentally relevant dose is slowly absorbed by, and extensively metabolized in, tracheal epithelium

While tobacco smoke has been conclusively identified as a lung carcinogen, there is much debate over which smoke constituent(s) are primarily responsible for its carcinogenicity. Previous studies in our laboratory suggested that highly lipophilic carcinogens are slowly absorbed in the thicker epithelium of the conducting airways, potentially allowing for substantial local metabolism. The bioactivation of polycyclic aromatic hydrocarbons in airway epithelium may, hence, be important in tobacco smoke-induced carcinogenesis. In the present study, the hypothesis of slow absorption and substantial local metabolic activation of highly lipophilic carcinogen in airway epithelium was tested in dogs. A single dose of tritiated benzo[a]pyrene (BaP) dissolved in a saline/phospholipid suspension was instilled in the trachea, just anterior to the carina. At intervals of a few minutes up to 30 min over a 3-h period, blood samples were drawn from the azygous vein, which drains the area around the point of instillation, and from the systemic circulation. Tissue samples were taken at the end of the experiment. The concentration of BaP with depth into the tracheal mucosa was determined with autoradiography. BaP was slowly absorbed into the trachea with a half-time of approximately 73 min, which is consistent with diffusion-limited passage through the epithelium and lead to local doses in the tracheal epithelium that were more than a 1000-fold those of other tissues. The long retention of BaP in the epithelium provided the local metabolizing enzymes with high substrate levels over a long period, resulting in extensive metabolism. At 3 h after the exposure, 23% of the BaP-equivalent activity remained in the tracheal mucosa. Of this fraction, 13% was parent compound, 28% was organic extractable, 31% was water-soluble, and 28-7% of the instilled dose was bound to tracheal tissues. These results explain the tendency of highly lipophilic carcinogens, such as BaP, to induce tumors at the site of entry and, furthermore, indicate that the highly lipophilic components of tobacco smoke and polluted air may be the most important contributors to lung tumors of the conducting airways.      

Need for follow up in coeliac disease

The use of follow up studies was evaluated in 128 patients with coeliac disease during their first visit to a department for adults. The original diagnosis had been made in childhood in all patients. Fifty eight (45%) of the subjects were following a gluten free diet, 23 (18%) were following a gluten free diet but with occasional gluten consumption, and 47 (37%) had adopted an unrestricted, gluten containing diet for a mean of 11.2 years. There was no correlation in individual subjects between the presence of symptoms, biochemical and immunological abnormalities, severity of histological findings, and the amount of dietary gluten, despite the greater frequency of symptoms in the group following an unrestricted diet than in the other two groups. Short stature and epilepsy with cerebral calcifications only occurred in patients following an unrestricted diet. As only diagnosis based on two or three biopsy samples and regular follow up correlated positively with dietary compliance, it is suggested that a histologically confirmed diagnosis of coeliac disease and regular lifelong follow up are essential in the management of these patients.     

Effects of bemethyl, ethomersol, and yakton on the liver regeneration after partial hepatectomy

It is experimentally demonstrated for the first time that the new drugs bemithyl, etomerzol, and yakton are capable of accelerating the process of liver regeneration following partial hepatectomy. The drugs produce a hasty gain in the mass of liver, increase in the content of nucleic acids and glycogen, and improve the functional state, as manifested by a decrease in the blood bilirubin and a reduction in the hexenal sleep duration. Bemithyl, etomerzol, and yakton produce a positive effect upon the liver morphology and the intracellular regeneration process. The repair activity of the new drugs exceeds that of a combination of the well-known regeneration stimulants riboxin and potassium orotate, representing derivatives of purine and pyrimidine bases.