Severe Traumatic Brain Injury in Austria VI: Effects of guideline-based management

OBJECTIVES: The goal of this paper is to report relations between health outcomes and implementation of individual recommendations of the guidelines. PATIENTS AND METHODS: Data sets from 405 patients included by 5 Austrian hospitals were available. The analysis focused on the compliance of treatment modalities to TBI guidelines recommendations. Compliance was evaluated based on scores developed specifically for this purpose. To evaluate the relations between the TBI guidelines compliance and outcomes the estimation of odds ratios was computed using multiple as well as logistic regression with age, ISS and initial GCS used to control confounding. RESULTS: The option on prehospital resuscitation was followed in 84%, the guideline on early resuscitation was followed in 79%. The guideline on intracranial pressure treatment threshold was the most closely followed one (89%). The option on cerebral perfusion pressure was followed in less than 30% of patients. Only the scores on resuscitation of blood pressure and oxygenation and on cerebral perfusion pressure were positively and statistically significantly related to ICU survival. Positive relations were also found for adherence to the recommendations on the type of monitoring, hyperventilation (guideline), prophylactic use of anti-seizure drugs, and the total of scores. The other recommendations were negatively related to ICU survival, but computed odds ratios were statistically not significant. Analysis of relations between compliance scores and length of ICU and hospitals stay in survivors showed that adherence to the recommendations on type of monitoring was related to a reduction of length of stay in ICU and hospital, adherence to the hyperventilation guideline was related to shortened ICU, but increased hospital stay, and adherence to the guideline on mannitol was related to reduced days in hospital, but not to days in ICU. Implementing the standard on corticosteroid use was related to a reduction of days both in hospital and ICU. Using the standard on prophylactic use of anti-seizure drugs was related to a reduction in ICU days. If all the recommendations were closely followed an increase of days in ICU would be observed, while the length of stay in hospital would be reduced. CONCLUSIONS: The relatively strong relation between initial resuscitation in the hospital and ICU survival provides a firm basis for future efforts of emergency teams. The positive influence of some of the recommendations on reduction of ICU or hospital days may provide economic incentives to promote guidelines implementation.     

Pharmacogenomics: a clinician's primer on emerging technologies for improved patient care

Pharmacogenomics is a term recently coined to embody the concept of individualized and rational drug selection based on the genotype of a particular patient. Customization of drug therapy offers the potential for optimal safety and efficacy in an individual patient. Such a process contrasts current prescribing practices, which use medications shown to be safe and effective in patient populations or based on anecdotal experiences. Within patient populations, medications vary in their efficacy among individual patients. More importantly, a medication that is safe and effective in one patient may be ineffective or even harmful in another. Underlying many of these phenotypic differences are genotypic variants (polymorphisms) of key enzymes and proteins that affect the safety and efficacy of a drug in an individual patient. An understanding of these polymorphisms has the potential to enhance patient care by allowing physicians to customize the selection of medication to meet individual patient needs. Pharmacogenomics may also lead to improved compliance and shorter time to optimal disease management, thereby reducing morbidity and mortality. Significant cost savings could result from reductions in polypharmacy as well as from fewer physician encounters and hospitalizations for exacerbations of underlying illness and because of adverse drug reactions.     

预防治疗2型糖尿病药物分子作用靶点的相关研究与进展

目的:综合分析2型糖尿病新药研究的分子靶点。资料来源:应用计算机检索Springer1990-01/2005-02和Pubmed2000-01/2005-08有关预防和治疗2型糖尿病药物的文献,检索词“diabetes,drug,target”,并限定文献语言种类为English。资料选择:对检索到的有关预防和治疗2型糖尿病药物的相关信息进行整理,筛选针对性强、影响因子较大、最近几年发表的论文。资料提炼:共检索到相关文献49篇,其中15篇符合要求,排除34篇。排除的文章中6篇是关于2型糖尿病的病理生理及生化方面的基础研究,其余为2型糖尿病预防和治疗效果方面的文献。资料综合:综合文献资料发现,以往研制的治疗糖尿病的药物或者因缺乏明确的分子靶点,或者因对疾病本身的病理反应不清楚,因而存在各种弊端。有关预防和治疗2型糖尿病和代谢综合征的分子靶点为抗糖尿病药物的研发展示了光明的前景,涉及的药物包括经典受体的小分子调节剂、酶作用靶点、蛋白质制剂和反义寡核苷酸等。结论:根据2型糖尿病和代谢综合征特异的病理反应机制作为筛选药物的分子基础是未来抗糖尿病药物研发的主攻方向。     

The effects of the novel,reversible epidermal growth factor receptor/ErbB-2 tyrosine kinase inhibitor,GW2016, on the growth of human normal and tumor-derived cell lines in vitro and in vivo

The epidermal growth factor receptor (EGFR) and ErbB-2 transmembrane tyrosine kinases are currently being targeted by various mechanisms in the treatment of cancer. GW2016 is a potent inhibitor of the ErbB-2 and EGFR tyrosine kinase domains with IC50 values against purified EGFR and ErbB-2 of 10.2 and 9.8 nM, respectively. This report describes the efficacy in cell growth assays of GW2016 on human tumor cell lines overexpressing either EGFR or ErbB-2: HN5 (head and neck), A-431 (vulva), BT474 (breast), CaLu-3 (lung), and N87 (gastric). Normal human foreskin fibroblasts, nontumorigenic epithelial cells (HB4a), and nonoverexpressing tumor cells (MCF-7 and T47D) were tested as negative controls. After 3 days of compound exposure, average IC50 values for growth inhibition in the EGFR- and ErbB-2-overexpressing tumor cell lines were < 0.16 microM. The average selectivity for the tumor cells versus the human foreskin fibroblast cell line was 100-fold. Inhibition of EGFR and ErbB-2 receptor autophosphorylation and phosphorylation of the downstream modulator, AKT, was verified by Western blot analysis in the BT474 and HN5 cell lines. As a measure of cytotoxicity versus growth arrest, the HN5 and BT474 cells were assessed in an outgrowth assay after a transient exposure to GW2016. The cells were treated for 3 days in five concentrations of GW2016, and cell growth was monitored for an additional 12 days after removal of the compound. In each of these tumor cell lines, concentrations of GW2016 were reached where outgrowth did not occur. Furthermore, growth arrest and cell death were observed in parallel experiments, as determined by bromodeoxyuridine incorporation and propidium iodide staining. GW2016 treatment inhibited tumor xenograft growth of the HN5 and BT474 cells in a dose-responsive manner at 30 and 100 mg/kg orally, twice daily, with complete inhibition of tumor growth at the higher dose. Together, these results indicate that GW2016 achieves excellent potency on tumor cells with selectivity for tumor versus normal cells and suggest that GW2016 has value as a therapy for patients with tumors overexpressing either EGFR or ErbB-2.     

Gene expression of circulating tumour cells and its correlation with tumour stage in breast cancer patients

Background

Breast cancer (BC) represents one of the leading causes of cancer related deaths worldwide. New tools for diagnostic staging and therapeutic monitoring are needed to improve individualized therapies and improve clinical outcome. The analyses of circulating tumour cells may provide important prognostic information in the clinical setting.

Materials and methods

Circulating tumour cells (CTC) of 63 BC patients were isolated from peripheral blood (PB) through immunomagnetic separation. Subsequently, RT-PCR or mPCR for the genes ga733.2, muc-1, c-erbB2, mgb-1, spdef and c-erbB2 were performed. Subsequently, expression data were correlated with the tumour stages. Fourteen healthy individuals served as controls.

Results

Significant correlations with tumour stages were found in single gene analyses of ga733.2, muc-1 and in multi-gene analyses of ga733.2/muc-1/mgb1/spdef. Furthermore, a significant correlation of Ca 15-3 and all studied genes was also observed.

Conclusion

Herein, we demonstrated a positive correlation of a gene signature consisting of ga733.2, muc-1, mgb1 and spdef and advanced stages of BC. Moreover, all studied genes and gene patterns revealed a significant correlation with Ca 15-3 positive cases.     

Experience with intravenous ribavirin in the treatment of hemorrhagic fever with renal syndrome in Korea

Results of a clinical study using intravenous (IV) ribavirin for treating Department of Defense personnel with hemorrhagic fever with renal syndrome (HFRS) acquired in Korea from 1987 to 2005 were reviewed to determine the clinical course of HFRS treated with IV ribavirin. A total of 38 individuals enrolled in the study had subsequent serological confirmation of HFRS. Four of the 38 individuals received three or fewer doses of ribavirin and were excluded from treatment analysis. Of the remaining 34 individuals, oliguria was present in one individual at treatment initiation; none of the remaining 33 subjects developed oliguria or required dialysis. The mean peak serum creatinine was 3.46 mg/dl and occurred on day 2 of ribavirin therapy. Both the peak serum creatinine and the onset of polyuria occurred on mean day 6.8 of illness. Reversible hemolytic anemia was the main adverse event of ribavirin, with a >or=25% decrease in hematocrit observed in 26/34 (76.5%) individuals. While inability to adjust for all baseline variables prevents comparison to historical cohorts in Korea where oliguria has been reported in 39-69% cases and dialysis required in approximately 40% HFRS cases caused by Hantaan virus, the occurrence of 3% oliguria and 0% dialysis requirement in the treatment cohort is supportive of a previous placebo-controlled HFRS trial in China where IV ribavirin given early resulted in decreased occurrence of oliguria and decreased severity of renal insufficiency.     

Laparoscopic Roux-en-Y gastric bypass surgery: initial results of 120 consecutive patients at a single British Columbia surgical center

BACKGROUND: The prevalence of obesity in Canada is increasing, therefore, it has become imminently important to treat these patients in a timely manner. METHODS: A total of 120 consecutive patients who underwent a laparoscopic Roux-en-Y gastric bypass procedure (2004 to 2006), with a mean postoperative follow-up period of 19 months, were divided into 2 chronologic groups and analyzed retrospectively. RESULTS: The overall postoperative excess weight loss was 78.1% (SD, 14.3%) from the time of inclusion into the study preoperatively (average wait time, 21 mo) to 12 months postoperatively. No preoperative weight loss was recorded. A surgeon-dependent learning curve was shown with a decrease in surgical time as well as surgery-related complications. Obesity-associated comorbidities decreased whereas quality of life increased. CONCLUSIONS: Despite a structured multidisciplinary approach to alter lifestyle and daily caloric intake preoperatively, only laparoscopic Roux-en-Y gastric bypass showed effective weight loss and reduced associated comorbidities.