Klaas W. van Kralingen

A single night of partial sleep deprivation induces insulin resistance in multiple metabolic pathways in healthy subjects.

BACKGROUND Subsequent nights with partial sleep restriction result in impaired glucose tolerance, but the effects on insulin sensitivity have not been characterized. OBJECTIVE The aim of this study was to evaluate the effect of a single night of partial sleep restriction on parameters of insulin sensitivity. RESEARCH DESIGN AND METHODS Nine healthy subjects (five men, four women) were studied once after a night of normal sleep duration (sleep allowed from 2300 to 0730 h), and once after a night of 4 h of sleep (sleep allowed from 0100 to 0500 h). Sleep characteristics were assessed by polysomnography. Insulin sensitivity was measured by hyperinsulinemic euglycemic clamp studies (from 1130 to 1430 h) with infusion of [6,6-(2)H(2)]glucose. RESULTS Sleep duration was shorter in the night with sleep restriction than in the unrestricted night (226 +/- 11 vs. 454 +/- 9 min; P< 0.0001). Sleep restriction did not affect basal levels of glucose, nonesterified fatty acids, insulin, or endogenous glucose production. Sleep restriction resulted in increased endogenous glucose production during the hyperinsulinemic clamp study compared to the unrestricted night (4.4 +/- 0.3 vs. 3.6 +/- 0.2 micromol x kg lean body mass(-1) x min(-1); P = 0.017), indicating hepatic insulin resistance. In addition, sleep restriction decreased the glucose disposal rate during the clamp (32.5 +/- 3.6 vs. 40.7 +/- 5.1 micromol x kg lean body mass(-1) x min(-1); P = 0009), reflecting decreased peripheral insulin sensitivity. Accordingly, sleep restriction decreased the rate of glucose infusion by approximately 25% (P = 0.001). Sleep restriction increased plasma nonesterified fatty acid levels during the clamp study (68 +/- 5 vs. 57 +/- 4 micromol/liter; P = 0.005). CONCLUSIONS Partial sleep deprivation during only a single night induces insulin resistance in multiple metabolic pathways in healthy subjects. This physiological observation may be of relevance for variations in glucoregulation in patients with type 1 and type 2 diabetes.

MVA.85A Boosting of BCG and an Attenuated, phoP Deficient M. tuberculosis Vaccine Both Show Protective Efficacy Against Tuberculosis in Rhesus Macaques

Background Continuous high global tuberculosis (TB) mortality rates and variable vaccine efficacy of Mycobacterium bovis Bacille Calmette-Guérin (BCG) motivate the search for better vaccine regimes. Relevant models are required to downselect the most promising vaccines entering clinical efficacy testing and to identify correlates of protection. Methods and Findings Here, we evaluated immunogenicity and protection against Mycobacterium tuberculosis in rhesus monkeys with two novel strategies: BCG boosted by modified vaccinia virus Ankara expressing antigen 85A (MVA.85A), and attenuated M. tuberculosis with a disrupted phoP gene (SO2) as a single-dose vaccine. Both strategies were well tolerated, and immunogenic as evidenced by induction of specific IFNγ responses. Antigen 85A-specific IFNγ secretion was specifically increased by MVA.85A boosting. Importantly, both MVA.85A and SO2 treatment significantly reduced pathology and chest X-ray scores upon infectious challenge with M. tuberculosis Erdman strain. MVA.85A and SO2 treatment also showed reduced average lung bacterial counts (1.0 and 1.2 log respectively, compared with 0.4 log for BCG) and significant protective effect by reduction in C-reactive protein levels, body weight loss, and decrease of erythrocyte-associated hematologic parameters (MCV, MCH, Hb, Ht) as markers of inflammatory infection, all relative to non-vaccinated controls. Lymphocyte stimulation revealed Ag85A-induced IFNγ levels post-infection as the strongest immunocorrelate for protection (spearmans rho: −0.60). Conclusions Both the BCG/MVA.85A prime-boost regime and the novel live attenuated, phoP deficient TB vaccine candidate SO2 showed significant protective efficacy by various parameters in rhesus macaques. Considering the phylogenetic relationship between macaque and man and the similarity in manifestations of TB disease, these data support further development of these primary and combination TB vaccine candidates.

Prospective cardiopulmonary screening program to detect chronic thromboembolic pulmonary hypertension in patients after acute pulmonary embolism

Background Chronic thromboembolic pulmonary hypertension after pulmonary embolism is associated with high morbidity and mortality. Understanding the incidence of chronic thromboembolic pulmonary hypertension after pulmonary embolism is important for evaluating the need for screening but is also a subject of debate because of different inclusion criteria among previous studies. We determined the incidence of chronic thromboembolic pulmonary hypertension after acute pulmonary embolism and the utility of a screening program for this disease. Design and Methods We conducted a cohort screening study in an unselected series of consecutive patients (n=866) diagnosed with acute pulmonary embolism between January 2001 and July 2007. All patients who had not been previously diagnosed with pulmonary hypertension (PH) and had survived until study inclusion were invited for echocardiography. Patients with echocardiographic suspicion of PH underwent complete work-up for chronic thromboembolic pulmonary hypertension, including ventilation-perfusion scintigraphy and right heart catheterization. Results After an average follow-up of 34 months of all 866 patients, PH was diagnosed in 19 patients by routine clinical care and in 10 by our screening program; 4 patients had chronic thromboembolic pulmonary hypertension, all diagnosed by routine clinical care. The cumulative incidence of chronic thromboembolic pulmonary hypertension after all cause pulmonary embolism was 0.57% (95% confidence interval [CI] 0.02–1.2%) and after unprovoked pulmonary embolism 1.5% (95% CI 0.08–3.1%). Conclusions Because of the low incidence of chronic thromboembolic pulmonary hypertension after pulmonary embolism and the very low yield of the echocardiography based screening program, wide scale implementation of prolonged follow-up including echocardiography of all patients with pulmonary embolism to detect chronic thromboembolic pulmonary hypertension does not seem to be warranted.

EBUS-TBNA for the diagnosis of central parenchymal lung lesions not visible at routine bronchoscopy

BACKGROUND Obtaining a tissue diagnosis of malignancy is challenging in patients with suspected lung cancer presenting with centrally located intrapulmonary masses. OBJECTIVE (1) To evaluate the yield of endobronchial ultrasound with real-time guided transbronchial needle aspiration (EBUS-TBNA) for diagnosing centrally located lesions after a non-diagnostic conventional bronchoscopy. (2) To assess the impact of EBUS-TBNA on patient management for this indication. STUDY DESIGN AND PATIENTS A retrospective analysis of a series of patients with a central parenchymal lung lesion suspected to be lung cancer who had been referred to three university hospitals for EBUS-TBNA to obtain a tissue diagnosis was undertaken. If EBUS-TBNA did not result in a formal pathological diagnosis of malignancy, patients were subsequently referred for a transthoracic needle aspiration biopsy or a surgical diagnostic procedure. RESULTS Sixty patients were investigated with EBUS-TBNA. The majority (82%) had a prior (non-diagnostic) flexible bronchoscopy. EBUS-TBNA was performed in an out-patient setting in 97%. With ultrasound, the primary lung lesion was observed in all cases. EBUS-TBNA confirmed lung cancer in 46 (77%). A final reference pathology diagnosis was available in 59 (98%) cases. The sensitivity of EBUS-TBNA for diagnosing lung cancer was 82% (95% confidence intervals (CI) 69-91%) with a negative predictive value of 23% (95%CI 5-53%). Based on the EBUS-TBNA findings, transthoracic needle aspiration biopsy or a surgical diagnostic procedure was cancelled in 47% and 30% of patients, respectively. No serious procedure-related complications were reported. CONCLUSION EBUS-TBNA is a sensitive tool for the diagnosis of centrally located primary lung cancer not visible at conventional bronchoscopy. Therefore, EBUS-TBNA can impact on patient management in this setting. However, the low negative predictive value indicates that a negative EBUS-TBNA result should be confirmed by other methods. IMPLICATION EBUS-TBNA can be considered as a diagnostic test in patients with a centrally located lung lesion after a previous non-diagnostic conventional bronchoscopy.

Patient outcomes after acute pulmonary embolism. A pooled survival analysis of different adverse events.

RATIONALE There is a lack of information on the long-term prognosis of patients with acute pulmonary embolism (PE). OBJECTIVES To assess the long-term risk for adverse events after PE. METHODS Consecutive patients diagnosed with PE between January 2001 and July 2007, and patients in whom PE was ruled out from a previous study were followed until July 2008 for the occurrence of adverse clinical events: mortality, symptomatic recurrent venous thromboembolism, cancer, arterial cardiovascular events and chronic thromboembolic pulmonary hypertension. Hazard ratios (HR) for all endpoints and a combined endpoint were calculated and adjusted for potential confounders. MEASUREMENTS AND MAIN RESULTS Three hundred eight patients with unprovoked, 558 with provoked, and 334 without PE were studied with a median follow-up period of 3.3 years. Patients with unprovoked PE had a lower overall risk for mortality than patients with provoked PE (HR, 0.59; 95% confidence interval [CI], 0.43-0.82), but a higher risk for nonmalignancy-related mortality (HR, 1.8; 95% CI, 1.3-2.5), recurrent venous thromboembolism (HR, 2.1; 95% CI, 1.3-3.1), cancer (HR, 4.4; 95% CI, 2.0-10), cardiovascular events (HR, 2.6; 95% CI, 1.5-3.8) and chronic thromboembolic pulmonary hypertension (1.5 vs. 0%). The risk for the combined endpoint did not differ between both groups (HR, 0.98; 95% CI, 0.82-1.1). Patients without PE had similar risks for malignancy and cardiovascular events than patients with provoked PE, but lower risks for the remaining outcomes. The fraction of both patients with provoked and unprovoked PE without events after 1 year was only 70% and decreased to fewer than 60% after 2 years and fewer than 50% after 4 years, whereas this latter was 84% for the control patients. CONCLUSIONS The clinical course of acute PE is complicated by high rates of serious adverse events, which occur in half of the patients within 4 years.

EBUS-TBNA for the clarification of PET positive intra-thoracic lymph nodes-an international multi-centre experience

Introduction: To determine the sensitivity and accuracy of endobronchial ultrasound guided transbronchial needle aspiration (EBUS-TBNA) for clarification of the nature of fluorodeoxyglucose-positron emission tomography (18FDG) positive hilar and/or mediastinal lymph nodes in patients with (suspected) lung cancer. Methods: All consecutive patients who had undergone EBUS-TBNA alone for assessment of abnormal 18FDG-uptake in hilar and/or mediastinal lymph nodes between January 2005 and August 2007 were reviewed. Results: One-hundred-nine patients underwent EBUS-TBNA of 127 positron emission tomography positive lymph nodes. Hilar (station 10 or 11) nodes (N1 or N3) were aspirated in 26 patients and mediastinal (stations 2, 4, 7) nodes (N2 or N3) in 90 patients. In 7 patients both hilar and mediastinal nodes were sampled. There were no procedure-related complications. Malignancy was detected in 77 (71%) cases. Thirty-two patients were tumor negative by EBUS-TBNA; subsequent surgical biopsy in 19 showed malignancy in 7. In four cases the false negative result was due to sampling error and in three cases due to detection error. In 13 cases surgical staging was not performed although long term follow-up in 3 showed no evidence of malignancy. The sensitivity and accuracy of EBUS-TBNA for malignancy in patients with reference pathology was 91% and 92%, respectively. The negative predictive value was 60%. If the 10 cases for which confirmatory surgical staging was not performed are assumed to be false negative results, overall sensitivity and accuracy were 82% and 84%, respectively. Conclusions: EBUS-TBNA offers an effective accurate, minimally invasive strategy for evaluating FDG avid hilar and mediastinal lymph nodes. However, negative findings should be confirmed by surgical staging.

Screening for Small-Cell Lung Cancer: A Follow-Up Study of Patients With Lambert-Eaton Myasthenic Syndrome

PURPOSE A small-cell lung carcinoma (SCLC) is found in 50% of patients with Lambert-Eaton myasthenic syndrome (LEMS). We evaluated screening to optimize screening strategy for SCLC. It is important to detect these tumors early in newly diagnosed patients with LEMS to offer optimal patient treatment. PATIENTS AND METHODS A large nationwide cohort study of consecutive patients in the Netherlands, seen between 1990 and 2007, were screened for the presence of a tumor using chest x-ray, computed tomography of the thorax (CT-thorax), [(18)F]fluorodeoxyglucose positron emission tomography (FDG-PET), bronchoscopy, and/or mediastinoscopy. RESULTS SCLC was found in 54 patients, and in 46 patients, no tumor was found during a median follow-up of 8 years (range, 3 to 26 years). All patients with SCLC had a positive smoking history and 86% were still smoking at diagnosis. SCLC was found in 92% of these patients within 3 months and in 96% within a year. At first screening, CT-thorax detected an SCLC in 45 patients (83%), whereas chest x-ray found the tumor in only 23 patients (51%). An SCLC was found during secondary screening in another nine patients (median, 3 months; range, 1 to 41 months). In six patients, a lung tumor was found by CT-thorax or FDG-PET, and in three patients, extrapulmonary metastases were found, initially without identifiable tumor mass on CT-thorax. CONCLUSION In almost all patients (96%), the SCLC was found within 1 year of diagnosis. CT-thorax scans detected most of the tumors (93%) and was far more sensitive than chest x-ray (51%). FDG-PET may have additive value in selected cases. We propose a screening protocol based on CT-thorax and FDG-PET.

Partial Sleep Restriction Decreases Insulin Sensitivity in Type 1 Diabetes

OBJECTIVE Sleep restriction results in decreased insulin sensitivity and glucose tolerance in healthy subjects. We hypothesized that sleep duration is also a determinant of insulin sensitivity in patients with type 1 diabetes. RESEARCH DESIGN AND METHODS We studied seven patients (three men, four women) with type 1 diabetes: mean age 44 ± 7 years, BMI 23.5 ± 0.9 kg/m2, and A1C 7.6 ± 0.3%. They were studied once after a night of normal sleep duration and once after a night of only 4 h of sleep. Sleep characteristics were assessed by polysomnography. Insulin sensitivity was measured by hyperinsulinemic euglycemic clamp studies with an infusion of [6,6-2H2]glucose. RESULTS Sleep duration was shorter in the night with sleep restriction than in the unrestricted night (469 ± 8.5 vs. 222 ± 7.1 min, P = 0.02). Sleep restriction did not affect basal levels of glucose, nonesterified fatty acids (NEFAs), or endogenous glucose production. Endogenous glucose production during the hyperinsulinemic clamp was not altered during the night of sleep restriction compared with the night of unrestricted sleep (6.2 ± 0.8 vs. 6.9 ± 0.6 μmol · kg lean body mass−1 · min−1, NS). In contrast, sleep restriction decreased the glucose disposal rate during the clamp (25.5 ± 2.6 vs. 22.0 ± 2.1 μmol · kg lean body mass−1 · min−1, P = 0.04), reflecting decreased peripheral insulin sensitivity. Accordingly, sleep restriction decreased the rate of glucose infusion by ∼21% (P = 0.04). Sleep restriction did not alter plasma NEFA levels during the clamp (143 ± 29 vs. 133 ± 29 μmol/l, NS). CONCLUSIONS Partial sleep deprivation during a single night induces peripheral insulin resistance in these seven patients with type 1 diabetes. Therefore, sleep duration is a determinant of insulin sensitivity in patients with type 1 diabetes.

Quality of Life in Long-term Survivors of Acute Pulmonary Embolism

BACKGROUND To our knowledge, studies evaluating the quality of life (QoL) in patients with a history of acute pulmonary embolism (PE) are not available, even though QoL is a key outcome component of medical care and a predictor of disease-specific prognosis. METHODS As part of a large follow-up study, the Short Form 36 (SF-36) was presented to consecutive patients who had survived one or more episodes of acute PE. The results of all nine subscales of the SF-36 were compared with sex- and age-adjusted Dutch population norms. Single and multivariate analyses were performed to identify independent determinants of the QoL in our study population. RESULTS The SF-36 was completed by 392 patients. Except for the health change subscale, patients had substantially lower QoL than population norms on all eight remaining subscales. After multivariate analysis, the time interval between the last thromboembolic episode and study inclusion was inversely related to QoL, and significant determinants of poor QoL were prior PE, age, obesity, active malignancy, and cardiopulmonary comorbid conditions. Regression models that included all identified significant determinants proved to be quite modest predictors for QoL in the individual patient. Awareness of illness, coping mechanisms, and self-management behavior might be additional important indicators of QoL in our study population but require further investigation. CONCLUSION We identified several PE- and non-PE-related determinants of QoL in patients with a history of acute PE, which is impaired compared with sex- and age-adjusted population norms. QoL after acute PE should be studied more extensively and added as a standard measure to outcome studies.

Illness perceptions and quality of life in Japanese and Dutch patients with non-small-cell lung cancer

This study examined quality of life (QOL) and illness perceptions in Dutch and Japanese patients with non-small-cell lung cancer, thereby extending the body of knowledge on cultural differences and psychosocial aspects of this illness. 24 Dutch and 22 Japanese patients with non-small-cell lung cancer filled out questionnaires on three occasions: immediately before chemotherapy, 1 week later, and 8 weeks after the initial chemotherapy. The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) assessed QOL, and the Brief Illness Perception Questionnaire (B-IPQ) illness perceptions. Scores on several QOL measures indicated (a) major impact of first chemotherapy sessions, and (b) some tendency to returning to baseline measures at 8 weeks. Differences between Japanese and Dutch samples were found on five EORTC QLQ-C30 dimensions: global health status, emotional functioning, social functioning, constipation, and financial difficulties, with the Dutch patients reporting more favorable scores. Regarding illness perceptions, Japanese patients had higher means on perceived treatment control and personal control, expressing a higher sense of belief in the success of medical treatment than Dutch patients. In both Japanese and Dutch patients, impact of chemotherapy on QOL was evident. Some differences in illness perceptions and QOL between the two samples were observed, with implications for integral medical management. Both samples reported illness perceptions that reflect the major consequences of non-small-cell lung cancer. Incorporating symptom reports, illness perceptions, and QOL into medical management may have positive consequences for patients with non-small-cell lung cancer.