Expression of the death gene Bik/Nbk promotes sensitivity to drug-induced apoptosis in corticosteroid-resistant T-cell lymphoma and prevents tumor growth in severe combined immunodeficient mice.

Members of the Bcl-2 gene family have been implicated in the regulation of cell death induced by cytostatic drugs. In some malignancies such as B-cell lymphoma, there is evidence that high expression of Bcl-2 is an independent negative prognostic marker and the overexpression of Bcl-2 has been shown to confer resistance to cytotoxic drugs by preventing drug-induced apoptosis. This function of Bcl-2 can be antagonized by apoptosis-promoting members of the Bcl-2 family. We previously showed that overexpression of Bax restores the chemosensitivity of Bax-deficient breast cancer cell lines. Therefore, we investigated whether the death-promoting Bcl-2 homologue Bik/Nbk can enhance cytostatic drug-induced apoptosis. As a model, we used the T-cell leukemia H9 (CD3(+) and CD4(+)CD8(-)), which is resistant to corticosteroid-induced cell death and does not express endogenous Bik/Nbk. Sensitivity for drug-induced apoptosis was increased 10- to 39-fold in cells transfected with the full-length coding sequence of Bik/Nbk. In addition, apoptosis induced via CD95/Fas or heat shock was increased to a similar extent. These data show that Bik/Nbk, which, unlike Bax, carries only a BH3 but no BH1 or BH2 domain may be a target to enhance chemosensitivity. The complete suppression of tumor growth in a severe combined immunodeficient mouse xenotransplant model suggests that, in analogy to Bax, Bik/Nbk may function as a tumor suppressor gene.     

Thyrotropin-releasing hormone has profound presynaptic action on cultured spinal cord neurons

Thyrotropin-releasing hormone (TRH) receptors are widely distributed throughout the nervous system. In particular, both the dorsal and the ventral horn (VH) neurons contain a rich distribution of TRH receptors, and TRH application to these sites has profound physiological effects. Currently the mechanism of action of TRH is not known. We examined the effect of TRH on ventral horn neurons using intracellular and patch-clamp techniques. Our results indicate that TRH application profoundly increases the firing rate of VH cells by decreasing membrane conductance. More importantly, TRH causes a significant increase in frequency and amplitude of postsynaptic potentials. Under voltage-clamp condition, TRH reduces holding current and causes a significant increase in the rate of occurrence and the amplitude of excitatory postsynaptic currents (EPSCs), an effect that lasts for more than 5 minutes. This effect of TRH is not observed in cultured neurons pretreated with tetanus toxin. TRH also fails to alter the characteristics of the EPSCs when it is applied to a region of the cell that is sparsely innervated. These results provide strong evidence that presynaptic mechanisms have a significant role in the excitatory effect of TRH on the VH neurons. Because there is evidence that trophic factors are released from presynaptic terminals, by increasing synaptic activity, TRH can have a trophic influence on the spinal cord neurons. In addition, because there are a significant number of TRH containing neurons within the spinal cord, it is likely that TRH has a major role in information processing within the spinal cord.     

Evaluation of Coomassie dye binding method for microprotein assay in diabetic proteinuria

A simple and relatively cheap method for quantitating diabetic microproteinuria with Coomassie brilliant blue dye binding method was evaluated. It provides a proportional reactivity to urinary albumin as measured by the more expensive immunoassay. The significant correlation between haemoglobin A1 and microproteinuria shows that the quantity of urinary protein is affected by metabolic control of diabetes.     

Intensive care unit delirium is an independent predictor of longer hospital stay: a prospective analysis of 261 non-ventilated patients

Introduction

Delirium occurs in most ventilated patients and is independently associated with more deaths, longer stay, and higher cost. Guidelines recommend monitoring of delirium in all intensive care unit (ICU) patients, though few data exist in non-ventilated patients. The study objective was to determine the relationship between delirium and outcomes among non-ventilated ICU patients.

Method

A prospective cohort investigation of 261 consecutively admitted medical ICU patients not requiring invasive mechanical ventilation during hospitalization at a tertiary-care, university-based hospital between February 2002 and January 2003. ICU nursing staff assessed delirium and level of consciousness at least twice per day using the Confusion Assessment Method for the ICU (CAM-ICU) and Richmond Agitation-Sedation Scale (RASS). Cox regression with time-varying covariates was used to determine the independent relationship between delirium and clinical outcomes.

Results

Of 261 patients, 125 (48%) experienced at least one episode of delirium. Patients who experienced delirium were older (mean ± SD: 56 ± 18 versus 49 ± 17 years; p = 0.002) and more severely ill as measured by Acute Physiology and Chronic Health Evaluation II (APACHE II) scores (median 15, interquartile range (IQR) 10–21 versus 11, IQR 6–16; p < 0.001) compared to their non-delirious counterparts. Patients who experienced delirium had a 29% greater risk of remaining in the ICU on any given day (compared to patients who never developed delirium) even after adjusting for age, gender, race, Charlson co-morbidity score, APACHE II score, and coma (hazard ratio (HR) 1.29; 95% confidence interval (CI) 0.98–1.69, p = 0.07). Similarly, patients who experienced delirium had a 41% greater risk of remaining in the hospital after adjusting for the same covariates (HR 1.41; 95% CI 1.05–1.89, p = 0.023). Hospital mortality was higher among patients who developed delirium (24/125, 19%) versus patients who never developed delirium (8/135, 6%), p = 0.002; however, time to in-hospital death was not significant the adjusted (HR 1.27; 95% CI 0.55–2.98, p = 0.58).

Conclusion

Delirium occurred in nearly half of the non-ventilated ICU patients in this cohort. Even after adjustment for relevant covariates, delirium was found to be an independent predictor of longer hospital stay.     

Apolipoprotein E4 polymorphism as a genetic predisposition to delirium in critically ill patients

OBJECTIVE: To test for an association between apolipoprotein E (APOE) genotypes and duration of intensive care unit delirium. DESIGN: Prospective, observational cohort study. SETTING: A 541-bed, community-based teaching hospital. PATIENTS: Fifty-three mechanically ventilated intensive care unit patients. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: All patients were managed with standardized sedation and ventilator weaning protocols as part of an ongoing clinical trial and were evaluated prospectively for delirium with the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU). DNA was extracted from whole blood samples obtained on enrollment, and APOE genotype was determined using polymerase chain reaction followed by restriction enzyme digestion by investigators blinded to the clinical information. Delirium occurred in 47 (89%) patients at some point during the intensive care unit stay. Of the 53 patients, 12 (23%) had an APOE4 allele (APOE4+) and 41 (77%) had only APOE2 or APOE3 alleles (APOE4-). APOE4+ patients were younger (53.2 +/- 21.9 vs. 65.4 +/- 13.4, p = .08) and less often admitted for pneumonia (0% vs. 29.3%, p = .05) compared with APOE4- patients, yet they had a duration of delirium that was twice as long: median (interquartile range), 4 (3, 4.5) vs. 2 (1, 4) days (p = .05). No other clinical outcomes were significantly different between the APOE4+ and APOE4- patients. Using multivariable regression analysis to adjust for age, admission diagnosis of sepsis or acute respiratory distress syndrome or pneumonia, severity of illness, and duration of coma, the presence of APOE4 allele was the strongest predictor of delirium duration (odds ratio, 7.32; 95% confidence interval, 1.82-29.51, p = .005). CONCLUSIONS: APOE4 allele represents the first demonstrated genetic predisposition to longer duration of delirium in humans.     

Risk factors for post-traumatic stress disorder symptoms following critical illness requiring mechanical ventilation: a prospective cohort study

Introduction  

Post-traumatic stress disorder (PTSD) has been identified in a significant portion of intensive care unit (ICU) survivors. We sought to identify factors associated with PTSD symptoms in patients following critical illness requiring mechanical ventilation.     

Analysis of positive Edinburgh depression scale referrals to a consultation liaison psychiatry service in a two-year period

Antenatal depression is a depressive episode that begins in pregnancy and is often a predictor of postnatal depression. The main aim of this study was to examine the prevalence of antenatal depression and other psychiatric conditions in women referred to a consultation liaison psychiatry service because of positive scores on the Edinburgh Postnatal Depression Scale. The other aim was to review known risk factors in the women and note any significant findings. An audit of all women referred to the psychiatry team because of positive Edinburgh scores during a 2-year period was completed. Information about Edinburgh scores, clinical diagnoses at the time of the psychiatric appointment, and factors such as relationship status, domestic violence, ethnicity, and substance use was noted. According to the Diagnostic and Statistical Manual of Mental Disorders: Fourth Edition criteria: 36.5% of the women had an adjustment disorder, 13% had a major depression, 10% had dysthymia, 8% had a recurrent depressive disorder, 2% had post-traumatic stress disorder, and 2% had a borderline personality disorder. The findings demonstrated the usefulness of using a screening tool such as the Edinburgh Postnatal Depression Scale in detecting women requiring psychiatric intervention and highlighted the importance of a psychiatric interview assessment to interpret the scores of screened patients in terms of clinically relevant syndromes.     

The sedation of critically ill adults: Part 1: Assessment. The first in a two-part series focuses on assessing sedated patients in the ICU

The prevention or treatment of pain, anxiety, and delirium in the ICU is an important goal. But achieving a balance between sedation and analgesia, especially in critically ill patients on mechanical ventilation, can be challenging. Both under- and oversedation carry serious risks. In 2002 the Society of Critical Care Medicine, along with the American Society of Health-System Pharmacists, updated recommendations in its clinical practice guidelines for the sustained use of sedatives and analgesics in adults. This two-part series examines those recommendations that relate to sedation assessment and management, as well as the current literature. This month Part 1 also reviews pertinent recommendations concerning pain and delirium and discusses tools for assessing pain, delirium, and sedation. In August Part 2 will explore pharmacologic and nonpharmacologic management of anxiety and agitation in critically ill patients. The prevention or treatment of pain, anxiety, and delirium in the ICU is an important goal. But achieving a balance between sedation and analgesia, especially in critically ill patients on mechanical ventilation, can be challenging. Both under- and oversedation carry serious risks. In 2002 the Society of Critical Care Medicine, along with the American Society of Health-System Pharmacists, updated recommendations in its clinical practice guidelines for the sustained use of sedatives and analgesics in adults. This two-part series examines those recommendations that relate to sedation assessment and management, as well as the current literature. This month Part 1 also reviews pertinent recommendations concerning pain and delirium and discusses tools for assessing pain, delirium, and sedation. In August Part 2 will explore pharmacologic and nonpharmacologic management of anxiety and agitation in critically ill patients.     

心肌坏死标记物在检测心肌坏死中的应用与地位

目的:评估各种心肌坏死标记物对判断心肌坏死的价值。资料来源:应用计算机检索LWW全文英文数据库1994-01/2006-08与心肌坏死标记物相关的文献,检索词“Myocardial damage,myocardiolysis,marker”,并限定文章语言种类为“English”。资料选择:对资料进行初审,选对于临床有意义的心肌坏死物进行较详细的总结。选择临床研究的文章,无论有无对照组、是否为随机对照文献均纳入;排除观察对象为动物的基础研究和综述类文献。资料提炼:对收集到的文献进一步查找全文,凡是对于心肌坏死检测快速且可靠的心肌坏死物优先选择,研究内容相似的,以近3年且发表在较权威杂志者优先,最后纳入30篇关于心肌坏死标记物的文章进行综述。资料综合:急性血栓形成及其随后的心肌损伤、坏死是急性心肌梗死的最主要特征,准确、快速、可靠地检测血栓形成和心肌坏死标志物对内科医生诊断急性心肌梗死极具价值。研究表明缺血修饰白蛋白、心肌型脂肪酸结合蛋白、髓过氧化物酶、CK-MB和心肌肌钙蛋白对急性心肌梗死的诊断各具特点,而联合检测更有助于早期、准确诊断急性心肌梗死,为尽早抢救急性心肌梗死创造时机。结论:缺血修饰白蛋白、心肌型脂肪酸结合蛋白、髓过氧化物酶、CK-MB和心肌肌钙蛋白是较敏感的心肌坏死标记物,联合应用诊断价值更大。