NOTCH1 activation in breast cancer confers sensitivity to inhibition of SUMOylation.

Breast cancer is genetically heterogeneous, and recent studies have underlined a prominent contribution of epigenetics to the development of this disease. To uncover new synthetic lethalities with known breast cancer oncogenes, we screened an epigenome-focused short hairpin RNA library on a panel of engineered breast epithelial cell lines. Here we report a selective interaction between the NOTCH1 signaling pathway and the SUMOylation cascade. Knockdown of the E2-conjugating enzyme UBC9 (UBE2I) as well as inhibition of the E1-activating complex SAE1/UBA2 using ginkgolic acid impairs the growth of NOTCH1-activated breast epithelial cells. We show that upon inhibition of SUMOylation NOTCH1-activated cells proceed slower through the cell cycle and ultimately enter apoptosis. Mechanistically, activation of NOTCH1 signaling depletes the pool of unconjugated small ubiquitin-like modifier 1 (SUMO1) and SUMO2/3 leading to increased sensitivity to perturbation of the SUMOylation cascade. Depletion of unconjugated SUMO correlates with sensitivity to inhibition of SUMOylation also in patient-derived breast cancer cell lines with constitutive NOTCH pathway activation. Our investigation suggests that SUMOylation cascade inhibitors should be further explored as targeted treatment for NOTCH-driven breast cancer.

Are women appropriately represented and assessed in clinical trials submitted for marketing authorization? A review of the database of the European Medicines Agency.

OBJECTIVE: There is concern that patients included in trials do not represent the true patient population and women in particular may selectively be excluded. We looked at trial data submitted to the European Medicines Agency (EMEA) by drug companies to achieve marketing authorization in Europe between 2000 and 2003. METHODS: We reviewed the EMEA database and included the main studies for the risk/benefit assessment (pivotal trials) submitted between 2000 and 2003. RESULTS: In pivotal trials submitted to the EMEA there was no, or generally clinically negligible, evidence for gender bias; however, women were underrepresented in hypertension, diabetes and hepatitis B trials, and overrepresented in rheumatoid arthritis and allergic conjunctivitis. CONCLUSIONS: In trials submitted for marketing authorization to the EMEA gender bias was not a serious problem.

Bed rest for acute uncomplicated myocardial infarction.

BACKGROUND: Bed rest is prescribed to all patients with acute myocardial infarction (AMI), but to a variable extent. Current guidelines (American College of Cardiology/ American Heart Association) recommend at least 12 hours bed rest in patients with uncomplicated ST-elevation myocardial infarction, however the basis for this recommendation is unclear. OBJECTIVES: To compare the effects of short versus longer bed rest in patients with uncomplicated AMI. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 2, 2005), MEDLINE (January 1966 - August 2005), EMBASE (January 1988 - August 2005), PASCAL BioMed (January 1996 - August 2005); PsycINFO (January 1966 - August 2005) and BIOSIS Previews (January 1990 - August 2005). SELECTION CRITERIA: Randomised and quasi-randomised controlled trials of short versus longer bed rest in patients with uncomplicated AMI were sought. DATA COLLECTION AND ANALYSIS: Study selection was performed independently by at least two investigators according to the predefined inclusion criteria. Data were extracted by two investigators independently and in duplicate. Authors were contacted to obtain missing information. MAIN RESULTS: We found 15 trials with 1487 patients assigned to a short period of bed rest (median 6 days) and 1471 patients assigned to longer bed rest (median 13 days). Generally the studies were outdated and appeared to be of moderate to poor methodological reporting quality. There was no evidence that shorter bed rest was more harmful than longer bed rest in terms of all cause mortality (RR=0.85 (95%CI 0.68 to 1.07), cardiac mortality (RR=0.81 (95%CI 0.54 to 1.19), or reinfarction (RR=1.07 (95%CI 0.79 to 1.44)). AUTHORS' CONCLUSIONS: Bed rest ranging from 2 to 12 days appears to be as safe as longer periods of bed rest. The quality of most trials is unsatisfactory. Current bed rest recommendations are not supported by the existing evidence as the optimal duration of bed rest is unknown. The lack of adequate trials is surprising, considering the large size of several studies to compare effectiveness of drugs on people with AMI.

Immunoadsorption in severe C4d-positive acute kidney allograft rejection: a randomized controlled trial.

Antibody-mediated rejection (AMR) frequently causes refractory graft dysfunction. This randomized controlled trial was designed to evaluate whether immunoadsorption (IA) is effective in the treatment of severe C4d-positive AMR. Ten out of 756 kidney allograft recipients were included. Patients were randomly assigned to IA with protein A (N = 5) or no such treatment (N = 5) with the option of IA rescue after 3 weeks. Enrolled recipients were subjected to tacrolimus conversion and, if indicated, 'anti-cellular' treatment. All IA-treated patients responded to treatment. One death unrelated to IA occurred after successful reversal of rejection. Four control subjects remained dialysis-dependent. With the exception of one patient who developed graft necrosis, non-responders were subjected to rescue IA, however, without success. Because of a high graft loss rate in the control group the study was terminated after a first interim analysis. Even though limited by small patient numbers, this trial suggests efficiency of IA in reversing severe AMR.

Impact of parathyroidectomy on neutrophil cytosolic calcium in chronic kidney disease patients: a prospective parallel group trial.

OBJECTIVES: Polymorphonuclear leucocytes (PMNs) of chronic kidney disease (CKD) patients display elevated basal cytosolic calcium concentrations (iCa(2+)). As parathyroid hormone is considered to substantially contribute to the inappropriate cellular entry of calcium in uraemia, we hypothesized that parathyroidectomy lowers PMN iCa(2+). DESIGN AND SETTING: Prospective parallel group trial at a tertiary care centre. SUBJECTS, INTERVENTION AND MAIN OUTCOME MEASURES: Two patient cohorts (cohort 1: 14 CKD patients; cohort 2: 14 renal transplant recipients) underwent parathyroidectomy for uncontrolled secondary hyperparathyroidism. We assessed PMN iCa(2+) (primary objective) spectrofluorimetrically 1 day before and 20 days after intervention (secondary objective: PMN glucose uptake). Data were compared with those of 16 matched maintenance haemodialysis patients (cohort 3), and to 15 healthy subjects (cohort 4), by generalized estimating equations. RESULTS: PMN iCa(2+) of cohort 1 decreased over time and was significantly higher than that of cohort 3 before but not after parathyroidectomy [mean difference before/after parathyroidectomy: 19.1 nmol L(-1) (95% confidence interval: 9.4-22.4), P =0.0003/-3.2 (-20.9-14.5), P = 0.71]. PMN iCa(2+) of cohort 2 decreased over time, but we found no significant difference in comparison with cohort 3 [mean difference before/after parathyroidectomy: 6.5 nmol L(-1) (-9.4-22.4), P = 0.4/-15.8 (-43.6-12.0), P = 0.25]. PMN iCa(2+) of all CKD patients was substantially higher in comparison with that of healthy subjects [cohort 4 vs. 3: -35.3 (-48.9-21.6), P < 0.001]. PMN glucose uptake increased significantly in both interventional cohorts in comparison with cohort 3. CONCLUSIONS: Parathyroidectomy lowers, but does not normalize PMN iCa(2+) of CKD patients. Further variables, possibly uraemic retention solutes, control both PMN iCa(2+) and functional responses.

Vasopressors for shock.

BACKGROUND: Besides reversing the underlying cause, the first line treatment for the symptoms of shock is usually the administration of intravenous fluids. If this method is not successful, vasopressors such as dopamine, dobutamine, adrenaline, noradrenaline and vasopressin are recommended. It is unclear if there is a vasopressor of choice, either for the treatment of particular forms of shock or for the treatment of shock in general. OBJECTIVES: To assess the efficacy of vasopressors for circulatory shock in critically ill patients. Our main aim was to assess whether particular vasopressors reduce overall mortality. We also intended to identify whether the choice of vasopressor influences outcomes such as length-of-stay in the intensive care unit and health-related quality of life. SEARCH STRATEGY: We searched MEDLINE, the Cochrane Central Register of Controlled Trials, EMBASE, PASCAL BioMed, CINAHL, BIOSIS, and PsychINFO:all from inception to November 2003; for randomized controlled trials. We also asked experts in the field and searched meta-registries for ongoing trials. SELECTION CRITERIA: We included randomized controlled trials comparing various vasopressors, vasopressors with placebo or vasopressors with intravenous fluids for the treatment of any kind of circulatory failure (shock). Mortality was the main outcome. DATA COLLECTION AND ANALYSIS: Two reviewers abstracted data independently. Disagreement between two reviewers was discussed and resolved with a third reviewer. We used random effects models for combining quantitative data. MAIN RESULTS: We identified eight randomized controlled trials. Reporting of methodological details was for many items not satisfactory: only two studies reported allocation concealment, and two that the outcome assessor was blind to the intervention. Two studies compared norepinephrine plus dobutamine with epinephrine alone in patients with septic shock (52 patients, relative risk of death 0.98, 95% confidence interval 0.57 to 1.67). Three studies compared norepinephrine with dopamine in patients with septic shock (62 patients, relative risk 0.88, 0.57 to 1.36). Two studies compared vasopressin with placebo in patients with septic shock (58 patients, relative risk 1.04, 0.06 to 19.33). One study compared terlipressin with norepinephrine in patients with refractory hypotension after general anaesthesia but there were no deaths (20 patients). REVIEWERS' CONCLUSIONS: The current available evidence is not suited to inform clinical practice. We were unable to determine whether a particular vasopressor is superior to other agents in the treatment of states of shock.

Effect of pretreatment with statins on the severity of acute ischemic cerebrovascular events.

OBJECTIVE: Treatment with statins reduces the risk of ischemic stroke among patients at increased risk for vascular disease. Recent experimental data suggest neuroprotective properties of statins in acute cerebral ischemia. We investigated whether a premedication with statins is associated with a better outcome in patients with acute ischemic cerebrovascular events. METHODS: Within a cross-sectional study, nested in a cohort we identified 1691 patients with a recent ischemic stroke or transient ischemic attack. Clinical severity of the vascular event was evaluated by the modified Rankin Scale (mRS) after 1 week. By means of multivariate logistic regression modeling, we determined the influence of prior statin use on stroke severity with adjustment for potential confounding factors. RESULTS: Severe stroke, defined as a modified Rankin Scale of 5 or 6 (n=231; 14%), was less frequent in patients receiving statin treatment before the event (6% vs. 14%, OR=0.37; 95% CI 0.19 to 0.74; p=0.004). This association remained significant after adjustment for confounding factors. We found a significant interaction between the presence of diabetes and the effect of pretreatment with statins on stroke outcome. Of the patients with diabetes, none of those on statin treatment but 16% of those without a statin had a bad outcome. After exclusion of the group of diabetic patients with prior statin medication, the protective effect was reduced and not statistically significant anymore. CONCLUSIONS: Pretreatment with statins seems to be associated with reduced clinical severity in patients with acute ischemic cerebrovascular events, particularly in patients with diabetes.

Major bleeding complications after cardiopulmonary resuscitation: impact of thrombolytic treatment.

OBJECTIVE: The risk of bleeding complications caused by thrombolysis in patients with cardiac arrest and prolonged cardiopulmonary resuscitation is unclear. We evaluate the complication rate of systemic thrombolysis in patients with out-of-hospital cardiac arrest caused by acute myocardial infarction, especially in relation to duration of cardiopulmonary resuscitation. DESIGN: The study was designed as retrospective cohort study, the risk factor being systemic thrombolysis and the end-point major haemorrhage, defined as life-threatening and/or need for transfusion. Over 10.5 years, emergency cardiac care data, therapy, major haemorrhage and outcome of 265 patients with acute myocardial infarction admitted to an emergency department after successful cardiopulmonary resuscitation were registered. RESULTS: We observed major haemorrhage in 13 of 132 patients who received thrombolysis (10%, 95% confidence interval 5-15%), five of these survived to discharge, none died because of this complication. Major haemorrhage occurred in seven of 133 patients in whom no thrombolytic treatment had been given (5%, 95% confidence interval 1-9%), two of these survived to discharge. Taking into account baseline imbalances between the groups, the risk of bleeding was slightly increased if thrombolytics were used (odds ratio 2.5, 95% confidence interval 0.9-7.4) but this was not significant (P = 0.09). There was no clear association between duration of resuscitation and bleeding complications (z for trend = 1.52, P = 0.12). Survival was not significantly better in patients receiving thrombolysis (odds ratio 1.6, 0.9-3.0, P = 0.12). CONCLUSIONS: Bleeding complications after cardiopulmonary resuscitation are frequent, particularly in patients with thrombolytic treatment, but do not appear to be related to the duration of resuscitation. In the light of possible benefits on outcome, thrombolytic treatment should not be withheld in carefully selected patients.

Acute phase reactants in patients with abdominal aortic aneurysm.

BACKGROUND: There is increasing evidence that an inflammatory process is present in abdominal aortic aneurysms (AAAs) to varying degrees. The aim of this study was to compare acute phase reactants in patients with asymptomatic AAA, symptomatic AAA without rupture and ruptured AAA. METHOD: Two hundred and twenty-five consecutive patients treated because of AAA were included in this case-control study. Polynomial logistic regression analysis was applied to compare admission C-reactive protein (CRP) and white blood count (WBC) measured in 111 asymptomatic outpatients, 52 symptomatic patients without rupture and 62 patients with rupture of the aneurysm. We adjusted for the potentially confounding effect of age, sex, haemoglobin levels and aneurysm diameter. RESULTS: Patients with symptomatic AAA and patients with ruptured AAA had significantly elevated CRP (p=0.002) and WBC (p<0.0001) levels compared to asymptomatic patients. There was no statistically significant difference in CRP and WBC between patients with symptomatic AAA and ruptured AAA. Median CRP values of asymptomatic, symptomatic and ruptured AAA were <0.5 (interquartile range (IQR) <0.5-0.85), 1.1(IQR <0.5-4.0) and 2.4 mg/dl (IQR 0.65-8.6), respectively, and median WBC values were 6.5 (IQR 5.5-8.0), 8.7 (IQR 6.8-11.2) and 13.2 (IQR 10.5-17.0), respectively. CONCLUSION: A significant elevation of CRP and WBC could be found in patients who presented with symptoms or rupture of an AAA. These indicators of inflammation were not observed in asymptomatic patients with AAA.

Current strategies of secondary prevention after a cerebrovascular event: the Vienna stroke registry.

BACKGROUND AND PURPOSE: Oral anticoagulation (OAC) and antiplatelet drugs are effective in the secondary prevention of ischemic cerebrovascular events. Only few data exist about the factors influencing the choice of a specific therapy for secondary prevention in patients with a recent stroke or transient ischemic attack (TIA). METHODS: Within a cross-sectional study, nested in a cohort we identified 931 patients with a recent ischemic stroke or TIA who were discharged with OAC or with one of the antiplatelet medications aspirin, clopidogrel, or the combination of aspirin and extended-release dipyridamole. By means of multivariate logistic regression analysis, we determined the influence of several clinical variables on the decision between OAC and overall antiplatelet therapy as well as on the decision between different antiplatelet therapies. RESULTS: A cardioembolic etiology of the index event and atrial fibrillation were independently associated with the use of OAC. Age was inversely associated with the use of OAC. Different estimations of contraindications to OAC were the main reason for the considerable variability among the participating centers. The most important factor promoting the use of clopidogrel was therapy with aspirin before the index event. Patients with large- or small-vessel disease received clopidogrel more often than those with an event of undetermined etiology. We found an extremely high interhospital variability for the use of the combination of aspirin with extended-release dipyridamole. CONCLUSIONS: Current recommendations are applied in clinical practice, but great variability between different centers remains. More clearly defined guidelines for indications for, as well as contraindications against, a specific therapy are necessary.

Clinical application of rapid quantitative determination of cardiac troponin-T in an emergency department setting.

OBJECTIVES: We analysed the clinical use of Troponin-T compared to creatine kinase MB in a non-trauma emergency department setting. BACKGROUND: A newly established single specimen quantitative Troponin T assay allows the clinical application of this parameter. METHODS. Five-hundred Troponin T tests were provided for use by emergency physicians who could combine them with the routine laboratory tests without restriction as to the indication or number of tests per patient. The number of tests per patient, time frame, final diagnosis and additional clinical information gained were recorded. All patients were followed for at least 6 months to verify the diagnosis and to assess the occurrence of cardiac events (nonfatal AMI or cardiac death). The ability of Troponin T and creatine kinase MB tests to predict cardiac events within 6 months were compared. RESULTS: The 500 Troponin T tests were used in 249 patients (median two tests per patient (range 1-5)) within 41 days. The final diagnosis revealed coronary heart disease in 85, non-coronary heart disease in 39, non-cardiac chest pain in 86 and other diagnoses in 39 of the patients. In 14 patients with an elevated creatine kinase MB, myocardial damage could safely be ruled out by a negative Troponin T, in six patients with a normal creatine kinase MB minor myocardial damage could be detected by a positive Troponin T. During follow up 28 cardiac events were recorded. Troponin T had a significantly higher specificity, positive predictive value and proportion of correct prediction for cardiac events within 6 months compared to creatine kinase MB. CONCLUSIONS: Troponin T has proved to be an useful method for diagnosing myocardial damage in routine clinical use in the non-trauma emergency department.

Acute renal failure after successful cardiopulmonary resuscitation.

OBJECTIVE: To assess the frequency and independent predictors of severe acute renal failure in patients resuscitated from out-of-hospital ventricular fibrillation cardiac arrest. DESIGN: A cohort study with a minimum follow-up of 6 months. SETTING: Emergency department of a tertiary care 2200-bed university hospital. PATIENTS AND PARTICIPANTS: Consecutive adult (> 18 years) patients admitted from 1 July 1991 to 31 October 1997 after witnessed ventricular fibrillation out-of-hospital cardiac arrest and successful resuscitation. MEASUREMENTS AND RESULTS: Acute renal failure was defined as a 25% decrease of creatinine clearance within 24 h after admission. Out of 187 eligible patients (median age 57 years, 146 male), acute renal failure occurred in 22 patients (12%); in 4 patients (18%) renal replacement therapy was performed. Congestive heart failure (OR 6.0, 95% CI 1.6-21.7; p = 0.007), history of hypertension (OR 4.4, 95% CI 1.3-14.7; p = 0.02) and total dose of epinephrine administered (OR 1.1, 95% CI 1.0-1.2; p = 0.009) were independent predictors of acute renal failure. Duration of cardiac arrest, pre-existing impaired renal function and blood pressure at admission were not independently associated with renal outcome. CONCLUSIONS: Severe progressive acute renal failure after cardiopulmonary resuscitation (CPR) is rare. Pre-existing haemodynamics seem to be more important for the occurrence of acute renal failure than actual hypoperfusion during resuscitation.

Diamond stents for palliation of malignant bile duct obstruction: a prospective multicenter evaluation.

BACKGROUND AND STUDY AIMS: Various types of self-expandable metal stents have been introduced for biliary drainage in patients with malignant jaundice, showing prolonged patency compared with plastic endoprostheses. However, there has only been prolonged experience with a meaningful number of patients using the Wallstent. We evaluated the Diamond stent, a self-expanding uncoated biliary metal stent, in a prospective uncontrolled multicenter setting. PATIENTS AND METHODS: The eligibility criterion was obstructive jaundice due to inoperable malignant disease. Between August 1995 and January 2000, 126 patients, who received a total of 134 Diamond stents in four European centers, were followed prospectively. RESULTS: Technical and clinical success rates were 96 % and 98 %, respectively. No major procedure-related complications occurred. The 30-day mortality rate was 13 %. Stent occlusion occurred in 28 patients (22 %). Overall median stent patency was 477 days; overall median survival was 173 days. Stent occlusion, confirmed by endoscopic retrograde cholangiopancreatography, was successfully treated with plastic stents in all patients. Cost analysis revealed estimated costs of 3440 euros per patient for palliative treatment with the Diamond stent. CONCLUSIONS: The Diamond stent compares favorably with other biliary metal stents for patients requiring biliary drainage of malignant jaundice.

Intravenous immunoglobulin application following immunoadsorption: benefit or risk in patients with autoimmune diseases?

OBJECTIVE: To evaluate infection rates, side-effects and autoantibody resynthesis after immunoadsorption with and without intravenous immunoglobulin substitution. METHODS: Thirty-five patients with autoimmune diseases who were on long-term immunoadsorption therapy participated in a prospective, randomized study. Results and conclusions. Infections were rare but similar in frequency in patients receiving combined immunoadsorption and intravenous immunoglobulins (intervention group, n=17, 1.3 infections per patient-year) and in a control group (n=18, 0.9 infections per patient-year) treated by immunoadsorption alone. The reduction in IgG achieved with two immunoadsorptions within 3 days was 95.0+/-2.5%. The extent of removal of pathogenic autoantibodies was similar to the removal of IGG: Substitution of immunoglobulins was not associated with an increased circulating IgG level before the following immunoadsorption. Infusion of immunoglobulins at a dose of 0.14 g/kg (interquartile range 0.12-0.16) body weight in patients in whom circulating immunoglobulins had been depleted was associated with a high incidence of serious side-effects; these necessitated the termination of treatment in 24% of the patients. No evidence was found that immunoglobulin administration had any beneficial effect with respect to autoantibody resynthesis after immunoadsorption.

Different patterns of angioedema in patients with and without angiotensin-converting enzyme inhibitor therapy.

BACKGROUND: There is convincing evidence for a causal relationship between angiotensin converting enzyme inhibitor (ACEI) therapy and angioedema, but the clinical features of the patients remain unclear. The aim of the study was to compare patterns of angioedema in patients under ACEI therapy and those without ACEI therapy. METHODS: One hundred and seventeen consecutive patients with angioedema treated in the emergency department of a 2000-bed tertiary care university hospital were included. A retrospective cohort study was performed, the exposure being ACEI therapy. The pattern of location of angioedema was the primary outcome measure. RESULTS: Of 117 patients with angioedema, 25 (21%) received ACEI therapy. In a multivariate logistic regression model, angioedema of the cheeks, eyelids or nose was independently negatively associated with ACEI therapy [adjusted odds ratio 0.13 (95% confidence interval 0.03 to 0.49), p = 0.003]. Higher age was also significantly associated with ACEI therapy [adjusted odds ratio 1.85 (95% confidence interval 1.23 to 2.80), p = 0.003]. Furthermore, a trend towards an independent negative association between a history of allergies and angioedema under ACEI therapy was seen. CONCLUSION: Patients with angioedema under ACE inhibitor therapy differ significantly from those receiving no ACEI therapy in terms of patterns of angioedema and age. The applicability of this observation as a tool for deciding whether to continue or terminate ACEI therapy requires prospective evaluation.

Comparison of prone positioning and continuous rotation of patients with adult respiratory distress syndrome: results of a pilot study.

OBJECTIVE: To compare prone positioning and continuous rotational therapy with respect to oxygenation and hemodynamics in patients suffering from adult respiratory distress syndrome (ARDS). DESIGN: Randomized, prospective pilot study. SETTING: Intensive care unit at a university hospital. PATIENTS: Twenty-six mechanically ventilated patients with ARDS from nontraumatic causes. INTERVENTIONS: Twelve patients were turned prone (group 1), 14 patients underwent continuous axial rotation from one lateral position to the other with a maximum angle of 124 degrees in specially designed beds (group 2). All patients had received inhaled nitric oxide (NO) therapy before positioning. MEASUREMENTS AND MAIN RESULTS: Gas exchange and hemodynamics were assessed using a pulmonary artery catheter. In both groups, an improvement in PaO2/RFIO2-ratio and intrapulmonary shunt fraction occurred after initiation of NO as well as during the first 72 hrs of positioning therapy. During the study period, seven patients died in group 1 and nine patients in group 2 (p = NS). Comparing the areas under the curve during the first 72 hrs, no significant differences with respect to PaO2/FIO2-ratio, PaCO2, positive end-expiratory and peak inspiratory pressure levels, intrapulmonary shunt fraction, the alveolar-arterial oxygen difference, and oxygen delivery and consumption, as well as cardiac index, pulmonary and arterial blood pressures, and pulmonary arterial occlusion pressure could be detected between the groups. Prone positioning was tolerated well, continuous rotational therapy had to be modified according to hemodynamic instability in three patients. CONCLUSIONS: In severe lung injury, continuous rotational therapy seems to exert effects comparable to prone positioning and could serve as alternative when prone positioning seems inadvisable.

Does bed rest after cervical or lumbar puncture prevent headache? A systematic review and meta-analysis.

BACKGROUND: Headache after cervical or lumbar puncture has long been attributed to early mobilization; however, there is little evidence for this. We performed a systematic literature review and meta-analysis of randomized controlled trials to assess whether longer bed rest is better than immediate mobilization or short bed rest in preventing headache. METHODS: We searched EMBASE (1988 to March 2001), MEDLINE (1966 to May 2001), Pascal Biomed (1996 to February 2001), Current Contents (1997 to September 1999), PsycINFO (1966 to May 2001), the Cochrane Controlled Trial Register (last search May 15, 2001), textbooks and references of the papers selected. Studies were eligible if patients underwent cervical or lumbar puncture for any reason and were randomly assigned to either a long or a short period of bed rest. Data were abstracted independently by 2 investigators to a predefined form. RESULTS: We found 16 randomized controlled trials involving 1083 patients assigned to immediate mobilization or a short period of bed rest (up to 8 hours) and 1128 patients assigned to a longer period of bed rest (0.5 to 24 hours). Puncture was performed for anesthesia (5 trials), myelography (6 trials) and diagnostic reasons (5 trials). None of the trials showed that longer bed rest was superior to immediate mobilization or short bed rest for preventing headache after puncture. When pooling the results of the trials in the myelography group and the diagnostic group, the relative risks of headache after puncture were 0.93 (95% confidence interval [CI] 0.81-1.08) and 0.97 (95% CI 0.79-1.19) respectively. We did not pool the results from the trials in the anesthesia group because of clinical heterogeneity, but shorter bed rest appeared to be superior. INTERPRETATION: There was no evidence that longer bed rest after cervical or lumbar puncture was better than immediate mobilization or short bed rest in reducing the incidence of headache.

Admission for syncope: evaluation, cost and prognosis.

BACKGROUND: Despite extensive in-hospital evaluation the cause of syncope remains unexplained in up to 40% of patients. AIMS: To determine the application and cost of diagnostic tests, cost of hospital stay, success of evaluation and prognosis of patients admitted via the emergency department after syncope. METHODS: A retrospective cohort study including all consecutive patients admitted via the emergency department for evaluation of syncope between 1 January 1994 and 31 December 1998. The findings obtained from clinical history, physical examination and diagnostic tests were reviewed systematically. The costs of specific tests and hospital stay were analysed. Patients were followed until 31 December 1998. RESULTS: 127 patients underwent a median of 4 diagnostic tests (interquartile range, 3 to 6) over 12 days (IQR 8 to 17). The overall median cost of syncope evaluation was 106,728 ATS/7,756 EUR (IQR 70,860 to 143,583 ATS) per patient; the cost of diagnostic tests per patient was 6,863 ATS/499 EUR (IQR 3,345 to 11,969 ATS); hospital maintenance and in-hospital care accounted for the major part of these costs [median 97,680 ATS/7,099 EUR (IQR 65,120 to 138,380 ATS)]. At the time of hospital discharge, syncope remained unexplained in 48 patients (38%). The strength of agreement between the emergency department diagnosis and the discharge diagnosis was moderate (kappa = 0.49, 95% confidence interval 0.36 to 0.61). None of the patients had recurrent syncope or died during the hospital stay. Within the first 30 days after the index event 2 patients (2%) died due to known pre-existing diseases. CONCLUSION: The emergency department diagnosis markedly influenced the work-up of syncope, but not the cost of evaluation. The moderate diagnostic yield, high cost of in-hospital evaluation and good short term prognosis indicate the need for alternative strategies of in-hospital evaluation.

Use of an age-adjusted Doppler E/A ratio in patients with moderate to severe hypertension.

OBJECTIVE: To assess the ratio of early (E) to late atrial (A) mitral Doppler peak flow velocity (Doppler E/A ratio) before and after adjustment for age in patients with moderate to severe hypertension, in whom left ventricular diastolic dysfunction is an early finding. Mitral flow patterns can be used to assess diastolic filling characteristics, and the Doppler E/A ratio is the parameter most commonly used, although it is known to be strongly age dependent. There are no established normal values for this ratio. DESIGN: Retrospective data analysis. SETTING: A 2000-bed tertiary-care teaching hospital. PATIENTS: We studied 190 patients (99 women and 91 men; ages 55 +/- 13 years) with moderate to severe hypertension. INTERVENTIONS: The ratio of early (E) to late atrial (A) mitral Doppler peak flow velocity was measured. As this ratio depends on age, a Z score was calculated to control for this influence. The Z score is the standardized normal deviation of the mean, with a normal value of 0 +/- 2. MAIN OUTCOME MEASURES: Sensitivities and specificities for detecting an age-dependent reduction in Doppler E/A score (Z score less than -2) with a non-age-dependent Doppler E/A ratio (less than 1) were calculated. RESULTS: In 106 of the patients (56%) the Doppler E/A ratio was less than 1.0. Only nine patients (4.7%) had a Z score less than -2. The sensitivity of the Doppler E/A ratio threshold of 1.0 for detecting a Z score less than -2 was 0.89 and the specificity was 0.46. A Z score less than -2 was found only in patients younger than 45 years. CONCLUSIONS: The Doppler E/A ratio was reduced in a large proportion of our patients. However, after correction for age it was decreased in only 4.7% of these patients. The use of a single Doppler E/A ratio threshold value has a weak diagnostic power to detect age-independent changes in mitral flow patterns.

Prevalence and relevance of thyroid dysfunction in 1922 cholesterol screening participants.

Controversy persists about the role of subclinical hypothyroidism in hypercholesterolemia. This study aimed to assess in a clinically healthy, middle-aged population of employees the prevalence of thyroid function disorders and their relation to demographic variables and cardiovascular risk factors. 1922 (former) employees were screened with follow-up of newly identified cases of undiagnosed (subclinical) hypothyroidism and hyperthyroidism. Thyroid stimulating hormone (TSH), prevalence and course of (subclinical) hypo- and hyperthyroidism and their relation to cardiovascular risk factors (cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, smoking, systolic and diastolic blood pressure) were assessed. The prevalence of newly diagnosed subclinical hypothyroidism (cut-off TSH concentration: 4.0 mU/L) was 1.1% (17 women and 5 men) with a mean TSH concentration of 7.37 (95% CI 5.18-9.56) mU/L. No case of overt hypothyroidism could be diagnosed. Elevated levels of antibodies to microsomal or thyroglobulin antigens were detected in six subjects with subclinical hypothyroidism (27.3%). Fifteen subjects (0.8%, 13 women and 2 men) had TSH concentrations below 0.1 mU/L. The cardiovascular risk profile of subjects with mild subclinical hypothyroidism was not different from subjects with normal TSH levels. The prevalence of subclinical hypothyroidism was 0.8% in normocholesterolemic (cholesterol <5.2 mmol/l) and 1.4% in hypercholesterolemic subjects (n.s.). One woman each with the subclinical form of the disease developed hypothyroidism or hyperthyroidism after 21 and 11 months of follow-up, respectively. Subclinical hypothyroidism and subclinical hyperthyroidism were rarely observed in a target group for coronary heart disease prevention. Mild subclinical hypothyroidism was not associated with any adverse cardiovascular risk profile. These results argue against indiscriminate measurements of TSH concentrations in clinically healthy subjects either with normocholesterolemia or hypercholesterolemia.