Increased turnover of Gc-globulin in patients with hepatic encephalopathy

BACKGROUND: A low serum level (< 100 mg/L) of the actin-scavenger Gc-globulin is a prognostic marker of non-survival in fulminant hepatic failure (FHF). It is unknown whether decreased production or increased consumption (or both) is responsible for the low Gc-globulin levels. METHODS: Ten patients with FHF and four patients with acute or chronic liver disease (AOCLD) with hepatic encephalopathy (HE) grades II-IV were included. Eight patients with cirrhosis (chronic liver disease, CLD) without HE served as controls. Total, free, and actin-bound Gc-globulin were measured in samples from an artery, a central vein, and a hepatic vein. In 12 patients (9 FHF, 3 AOCLD), concentrations were measured before and after high volume plasmapheresis (HVP). RESULTS: Total Gc-globulin was reduced to 21%, 40%, and 43% of the normal level in the FHF, AOCLD, and CLD groups, respectively, whereas bound Gc-globulin was within normal range in all patients. The Gc:actin complex ratio was increased 3.8, 2.5, and 1.9-fold compared with normal levels. Total, free, and bound serum Gc-globulin levels did not differ among arterial, systemic venous, or hepatic venous blood. Total Gc-globulin rose to >100 mg/L in all patients after HVP, whereas bound Gc-globulin remained unchanged. The Gc-globulin production rate in FHF and AOCLD patients was increased to 4.1 +/- 1.3 mg/min compared to literature values of 0.6 mg/min in healthy individuals. The estimated half-life of total Gc-globulin was shorter in the patients compared to healthy individuals (127 +/- 56 min and 870 min, respectively). CONCLUSIONS: Gc-globulin levels were reduced in patients with FHF and AOCLD because a 7-fold increase of Gc-globulin production rate could not compensate for the accelerated clearance. Bound Gc-globulin was maintained within normal levels in all circumstances studied, indicating a possible regulatory role of this parameter in the clearance of actin.     

Targeting of heat shock protein 32 (Hsp32)/heme oxygenase-1 (HO-1) in leukemic cells in chronic myeloid leukemia: a novel approach to overcome resistance against imatinib

Resistance toward imatinib and other BCR/ABL tyrosine kinase inhibitors remains an increasing clinical problem in the treatment of advanced stages of chronic myeloid leukemia (CML). We recently have identified the heat shock protein 32 (Hsp32)/heme oxygenase-1 (HO-1) as a BCR/ABL-dependent survival molecule in CML cells. We here show that silencing Hsp32/HO-1 in CML cells by an siRNA approach results in induction of apoptosis. Moreover, targeting Hsp32/HO-1 by either pegylated zinc protoporphyrine (PEG-ZnPP) or styrene maleic acid-micelle-encapsulated ZnPP (SMA-ZnPP) resulted in growth inhibition of BCR/ABL-transformed cells. The effects of PEG-ZnPP and SMA-ZnPP were demonstrable in Ba/F3 cells carrying various imatinib-resistant mutants of BCR/ABL, including the T315I mutant, which exhibits resistance against all clinically available BCR/ABL tyrosine kinase inhibitors. Growth-inhibitory effects of PEG-ZnPP and SMA-ZnPP also were observed in the CML-derived human cell lines K562 and KU812 as well as in primary leukemic cells obtained from patients with freshly diagnosed CML or imatinib-resistant CML. Finally, Hsp32/HO-1-targeting compounds were found to synergize with either imatinib or nilotinib in producing growth inhibition in imatinib-resistant K562 cells and in Ba/F3 cells harboring the T315I mutant of BCR/ABL. In summary, these data show that HO-1 is a promising novel target in imatinib-resistant CML.     

Independent validation of the ICU requirement score in a cohort of acutely poisoned adults

Objective: To independently validate the predictive value of the intensive care requirement score (IRS) in unselected poisoned patients.

Design: Retrospective chart review.

Patients and methods: Five hundred and seventeen out of 585 admissions for acute intoxications could be analyzed. Eleven were excluded for a condition already requiring intensive care unit (ICU) support at admission (e.g., preclinical intubation). A further 57 admissions were excluded due to missing data. The IRS was calculated using a point-scoring system including age, Glasgow Coma Scale, heart rate, type of intoxication, and preexisting conditions. It was then compared to a composite endpoint indicating an ICU requirement (death in hospital, vasopressors, need for ventilation). The endpoint and the point-scoring system were identical to the original publication of the score.

Results and conclusion: Twenty-three out of 517 patients had a complicated clinical course as defined by meeting the endpoint definition. Twenty-one out of 23 complicated courses had a positive IRS (defined as greater or equal 6 points), as compared to 255/494 patients with an uncomplicated clinical course (p?相似文献   

Disaster Training in 24 Hours: Evaluation of a Novel Medical Student Curriculum in Disaster Medicine

Background

Over a decade ago, the Association of American Medical Colleges called for incorporation of disaster medicine training into the education of medical students in the United States. Despite this recommendation, similar suggestions by other professional organizations, and significant interest from medical students and educators, few medical schools explicitly include robust disaster training in their curricula.

Evaluation of the likelihood of a selective CHK1 inhibitor (LY2603618) to inhibit CYP2D6 with desipramine as a probe substrate in cancer patients

LY2603618 is a selective inhibitor of deoxyribonucleic acid damage checkpoint kinase 1 (CHK1) and has been in development for the enhancement of chemotherapeutic agents. The study described was to assess the potential interaction between LY2603618 and cytochrome P450 isoform 2D6 (CYP2D6) substrate desipramine in patients with cancer. Before clinical investigation, in silico simulations (using Simcyp®) were conducted. An open‐label, two‐period, fixed‐sequence study was planned in 30 patients with advanced or metastatic cancers, in which a 50 mg oral dose of desipramine was administered alone and in combination with 275 mg of LY2603618 (i.v. infusion). An interim analysis was planned after 15 patients completed both periods. Ratios of geometric least squares means (LSMs) of primary pharmacokinetic (PK) parameters and 90% repeated confidence intervals (RCIs) between desipramine plus LY2603618 and desipramine alone were calculated. Lack of an interaction was declared if the 90% RCI fell between 0.8 and 1.25. The LSM ratios (90% RCI) for areas under the plasma concentration–time curve from time zero to t_last (AUC_[0‐tlast]) and to infinity (AUC_[0‐∞]) and maximum plasma concentration (C_max) were 1.14 (1.04, 1.25), 1.09 (0.99, 1.21) and 1.16 (1.05, 1.29). In silico simulations were predictive of clinical results. Single doses of 275 mg LY2603618 administered with 50 mg desipramine were generally well tolerated. In conclusion, no clinically significant interaction was observed between LY2603618 and desipramine in patients with cancer. In silico predictions of clinical results demonstrated that mechanistic and physiologically based PK approaches may inform clinical study design in cancer patients. Copyright © 2014 John Wiley & Sons, Ltd.     

Ebola Risk Perception in Germany, 2014

Ebola virus disease (EVD) outbreaks have occurred during the past 5 decades, but none has affected European countries like the 2014 epidemic in West Africa. We used an online questionnaire to investigate risk perceptions in Germany during this epidemic peak. Our questionnaire covered risk perceptions, knowledge about transmission routes, media use, reactions to the outbreak, attitudes toward measures to prevent the spread of EVD and vaccination against EVD, and willingness to volunteer for aid missions. Of 974 participants, 29% indicated that they worried about EVD, 4% correctly stated virus transmission routes, and 75% incorrectly rated airborne transmission and transmission by asymptomatic patients as possible. Many indicated that if a patient were flown to Germany for treatment in a nearby hospital, they would adapt preventive behavior. Although most participants were not worried about EVD at the current stage of the epidemic, misperceptions regarding transmission were common and could trigger inappropriate behavior changes.     

Reduction of monocyte-platelet interaction and monocyte activation in patients receiving antiplatelet therapy after coronary stent implantation

BACKGROUND: Monocyte activation induces different procoagulant and proadhesiveinflammatory responses and thus may play a role in thromboticcomplications after coronary interventions. Monocyte-plateletinteraction may trigger these effects inducing monocyte activation. AIMS: To characterize the effect of antiplatelet vs anticoagulationtherapy on monocyte-platelet interaction and monocyte functionafter intracoronary stenting. METHODS AND RESULTS: Immediately before, and during the first 12 days after successfulcoronary stenting, monocyteplatelet conjugates and monocytefunction were assessed by flow cytometric detection of GPIIb/IIIa(CD41) on monocytes and by monocyte surface exposure of Mac-1(CD11b/ CD18) and L-selectin (CD62L). Twenty patients receivingcombined antiplatelet therapy (ticlopidine, aspirin) were comparedto 20 patients with standard anticoagulation (phenprocoumon,overlapping heparin, aspirin). Before stenting, monocyte-plateletconjugates and Mac-1 surface expression in both groups weresignificantly increased, while L-selectin was significantlydiminished. Anticoagulation did not change these variables significantlyduring the subsequent 12 days. In contrast, antiplatelet therapyreduced platelet-monocyte conjugates by 46±9·3%(mean±SEM, P=0·0019) within 4 days, which wasassociated with a decrease in Mac-1 expression (28±6·7%,P=0·0013) and an increase in L-selectin (56±15·0%,P=0·0061). CONCLUSION: After intracoronary stenting, combined antiplatelet therapy,but not anticoagulation, causes reduction of monocyte-plateletinteraction, which is associated with monocyte deactivation.This may contribute to a decreased risk for thrombotic events.     

Contribution of raloxifene and calcium and vitamin D3 supplementation to the increase of the degree of mineralization of bone in postmenopausal women

Raloxifene has been shown to increase bone mineral density and reduce the risk of vertebral fracture in postmenopausal women with osteoporosis. In this study, we report the results of the first prospective longitudinal study to evaluate the mean degree of mineralization of bone (MDMB) in a group of patients enrolled in the Multiple Outcomes of Raloxifene Evaluation trial. Patients were randomly assigned to one of three treatment groups: placebo (n = 24), raloxifene 60 mg/d (RLX60; n = 22), or raloxifene 120 mg/d (RLX120; n = 18). All patients received daily calcium (500 mg) and vitamin D(3) (400-600 IU) supplementation for the duration of the study. Iliac crest biopsies were taken at baseline and after 2 yr of treatment. Quantitative microradiography was used to analyze the biopsy specimens and revealed a statistically significant (P < 0.05) mean percentage increase in total MDMB of 7.0, 5.3, and 5% for RLX60-, RLX120-, and placebo-treated patients, respectively, compared with baseline. Raloxifene treatment was found to shift the distribution of total bone mineral to higher values of MDMB (RLX60, 29%; RLX120, 8%) with greater heterogeneity, compared with placebo. The profile of MDMB observed in biopsies after treatment with placebo and raloxifene, compared with baseline, closely resembles physiological premenopausal bone.     

Changes in membrane glycoproteins of circulating platelets after coronary stent implantation.

OBJECTIVES: To evaluate platelet function in patients with coronary stents. DESIGN: A non-randomised control trial in 30 patients who had immediate implantation of Palmaz-Schatz coronary stents because of a suboptimal angioplasty result. All patients received a standardised anticoagulation regimen including intravenous heparin (activated partial thromboplastin time (APTT) 80 to 120 s), oral vitamin K antagonist (target international normalised ratio (INR) of 3.5), and 100 mg aspirin twice daily. Platelet surface expression of glycoprotein IIb-IIIa, activated fibrinogen receptor, and P-selectin as well as binding of von Willebrand factor and fibrinogen were determined by flow cytometry in peripheral venous blood samples collected before the intervention and then daily for 4 days after it. The results were compared with those in 30 patients undergoing elective coronary balloon angioplasty. SETTING: University hospital. RESULTS: After coronary stenting surface expression of the activated fibrinogen receptor significantly increased, peaking at day 2 (P < 0.001). Similar results were found for von Willebrand factor binding and P-selectin surface expression, with a maximum at day 2 to 4 after stenting (von Willebrand factor, P < 0.001; P-selectin, P < 0.001). The changes in platelet membrane glycoproteins coincided with a significant drop in peripheral platelet count after stent placement (P < 0.01). No significant change in fibrinogen receptor activity, von Willebrand factor binding, P-selectin surface expression, or platelet count was seen in the control group. CONCLUSIONS: The present study shows that current anticoagulation treatment is inefficient in suppressing platelet activation in patients with coronary stents and, therefore, might not be the best treatment for reducing the incidence of subacute stent thrombosis.