Arsenite modulates cardiac substrate preference by translocation of GLUT4, but not CD36, independent of mitogen-activated protein kinase signaling.

The protein thiol-modifying agent arsenite, a potent activator of stress signaling, was used to examine the involvement of MAPKs in the regulation of cardiac substrate uptake. Arsenite strongly induced p38 MAPK phosphorylation in isolated rat cardiac myocytes but also moderately enhanced phosphorylation of p42/44 ERK and p70 S6K. At the level of cardiomyocytic substrate use, arsenite enhanced glucose uptake dose dependently up to 5.1-fold but failed to stimulate long-chain fatty acid uptake. At the substrate transporter level, arsenite stimulated the translocation of GLUT4 to the sarcolemma but failed to recruit CD36 or FABPpm. Because arsenite did not influence the intrinsic activity of glucose transporters, GLUT4 translocation is entirely responsible for the selective increase in glucose uptake by arsenite. Moreover, the nonadditivity of arsenite-induced glucose uptake and insulin-induced glucose uptake indicates that arsenite recruits GLUT4 from insulin-responsive intracellular stores. Inhibitor studies with SB203580/SB202190, PD98059, and rapamycin indicate that activation of p38 MAPK, p42/44 ERK, and p70 S6K, respectively, are not involved in arsenite-induced glucose uptake. In addition, all these kinases do not play a role in regulation of cardiac glucose and long-chain fatty acid uptake by insulin. Hence, arsenite's selective stimulation of glucose uptake appears unrelated to its signaling actions, suggesting that arsenite acts via thiol modification of a putative intracellular protein target of arsenite within insulin-responsive GLUT4-containing stores. Because of arsenite's selective stimulation of cardiac glucose uptake, identification of this putative target of arsenite within the GLUT4-storage compartment may indicate whether it is a target for future strategies in prevention of diabetic cardiomyopathy.     

Feasibility of withholding antibiotics in selected febrile neutropenic cancer patients.

PURPOSE: To investigate the feasibility of withholding antibiotics and early discharge for patients with chemotherapy-induced neutropenia and fever at low risk of bacterial infection by a new risk assessment model. PATIENTS AND METHODS: Outpatients with febrile neutropenia were allocated to one of three groups by a risk assessment model combining objective clinical parameters and plasma interleukin 8 level. Patients with signs of a bacterial infection and/or abnormal vital signs indicating sepsis were considered high risk. Based on their interleukin-8 level, remaining patients were allocated to low or medium risk for bacterial infection. Medium-risk and high-risk patients received standard antibiotic therapy, whereas low-risk patients did not receive antibiotics and were discharged from hospital after 12 hours of a febrile observation. End points were the feasibility of the treatment protocol. RESULTS: Of 196 assessable episodes, 76 (39%) were classified as high risk, 84 (43%) as medium risk, and 36 (18%) as low risk. There were no treatment failures in the low-risk group (95% CI, 0% to 10%). Therefore, sensitivity of our risk assessment model was 100% (95% CI, 90% to 100%), the specificity, positive, and negative predictive values were 21%, 13%, and 100%, respectively. Median duration of hospitalization was 3 days in the low-risk group versus 7 days in the medium- and high-risk groups (P < .0001). The incremental costs of the experimental treatment protocol amounted to a saving of 471 (US $572) for every potentially low-risk patient. CONCLUSION: This risk assessment model appears to identify febrile neutropenic patients at low risk for bacterial infection. Antibiotics can be withheld in well-defined neutropenic patients with fever.     

Prognostic stratification using dobutamine stress 99mTc-tetrofosmin myocardial perfusion SPECT in elderly patients unable to perform exercise testing.

Information on the prognostic value of noninvasive stress imaging techniques in the elderly is relatively scarce. This study assessed the prognostic value of dobutamine stress (99m)Tc-tetrofosmin SPECT for the prediction of mortality and cardiac events in elderly patients. METHODS: Clinical information and SPECT results were analyzed for 272 consecutive patients > or = 65 y old (mean age, 71 +/- 5 y; range, 65-87 y) with limited exercise capacity. Follow-up was complete in 270 patients (99.3%); 23 underwent revascularization within 60 d of the scintigraphy and were excluded. Abnormal findings were defined as the presence of a fixed or reversible perfusion defect. A summed stress score was obtained to estimate the extent and severity of perfusion defects. The incremental prognostic value of SPECT over clinical data was evaluated according to 3 multivariate models, which included any SPECT abnormality, the presence of a fixed or reversible defect, and the summed stress score. RESULTS: During the follow-up (3.3 +/- 1.4 y), 59 patients died (29 cardiac deaths), 16 had a nonfatal infarction, and 49 underwent late revascularization. Abnormal scan findings were present for 140 patients (57%). The annual event rates for total mortality, cardiac death, and cardiac death or nonfatal infarction were, respectively, 3.2%, 0.2%, and 0.7% when scan findings were normal and, respectively, 9.5%, 4.3%, and 8% when scan findings were abnormal (all P < 0.0001). Multivariate analysis showed that abnormal scan findings, the presence of a fixed or reversible defect, and the summed stress score provided incremental prognostic information over clinical data. The presence of abnormal scan findings was independently associated with an increased risk for total mortality, cardiac death, and cardiac death or nonfatal infarction (respectively, hazard ratio 3.4 [95% CI, 1.8-6.5], 12.1 [95% CI, 2.9-51.5], and 9.0 [95% CI, 2.8-29.6]). CONCLUSION: Dobutamine stress (99m)Tc-tetrofosmin SPECT provides incremental prognostic information for the prediction of total mortality and cardiac events in elderly patients.     

The effect of acute exercise on glycogen synthesis rate in obese subjects studied by 13C MRS

In obesity, insulin-stimulated glucose uptake in skeletal muscle is decreased. We investigated whether the stimulatory effect of acute exercise on glucose uptake and subsequent glycogen synthesis was normal. The study was performed on 18 healthy volunteers, 9 obese (BMI?=?32.6?±?1.2?kg/m², mean?±?SEM) and 9 lean (BMI?=?22.0?±?0.9?kg/m²), matched for age and gender. All participants underwent a euglycemic hyperinsulinemic clamp, showing reduced glucose uptake in the obese group (P?=?0.01), during which they performed a short intense local exercise (single-legged toe lifting). Dynamic glucose incorporation into glycogen in the gastrocnemius muscle before and after exercise was assessed by ¹³C magnetic resonance spectroscopy combined with infusion of [1-¹³C]glucose. Blood flow was measured to investigate its potential contribution to glucose uptake. Before exercise, glycogen synthesis rate tended to be lower in obese subjects compared with lean (78?±?14 vs. 132?±?24???mol/kg muscle/min; P?=?0.07). Exercise induced highly significant rises in glycogen synthesis rates in both groups, but the increase in obese subjects was reduced compared with lean (112?±?15 vs. 186?±?27???mol/kg muscle/min; P?=?0.03), although the relative increase was similar (184?±?35 vs. 202?±?51%; P?=?0.78). After exercise, blood flow increased equally in both groups, without a temporal relationship with the rate of glycogen synthesis. In conclusion, this study shows a stimulatory effect of a short bout of acute exercise on insulin-induced glycogen synthesis rate that is reduced in absolute values but similar in percentages in obese subjects. These results suggest a shared pathway between insulin- and exercise-induced glucose uptake and subsequent glycogen synthesis.     

Should children at risk for familial adenomatous polyposis be screened for hepatoblastoma and children with apparently sporadic hepatoblastoma be screened for APC germline mutations?

BACKGROUND: Hepatoblastoma (HB) is the most frequent liver tumor in childhood, occurring in the first few years of life. Surgery combined with chemotherapy has resulted in dramatic improvements in prognosis. However, even today, about one quarter of affected children do not survive the disease. Compared to the general population, the risk of HB is 750-7,500 times higher in children predisposed to familial adenomatous polyposis (FAP), an autosomal-dominant cancer predispostion syndrome caused by germline mutations in the tumor suppressor gene APC. Only limited data exist about the frequency of APC germline mutations in cases of apparently sporadic HB without a family history of FAP. PROCEDURE: In our sample of 1,166 German FAP families, all known cases of HB were registered. In addition, 50 patients with apparently sporadic HB were examined for APC germline mutations. RESULTS: In the FAP families, seven unrelated cases of HB are documented; three had been detected at an advanced stage. In patients with apparently sporadic HB, germline mutations in the APC gene were identified in 10%. CONCLUSIONS: These data raise the issue of the appropriate screening for HB in children of FAP patients. To date, the efficiency of surveillance for HB is unclear. In Beckwith-Wiedemann syndrome (BWS), recent studies suggest an earlier detection of both Wilms tumor and HB by frequent screening. We discuss the rationale and implications of a screening program; besides the examination procedure itself, screening for HB in children of FAP patients would have important consequences for the policy of predictive testing in FAP. In a substantial fraction of sporadic HB, the disease is obviously the first manifestation of a de novo FAP. These patients should be identified by routine APC mutation screening and undergo colorectal surveillance thereafter.     

Early insulin sensitivity after restrictive bariatric surgery,inconsistency between HOMA-IR and steady-state plasma glucose levels

BackgroundThe low-grade inflammatory condition present in morbid obesity is thought to play a causative role in the pathophysiology of insulin resistance (IR). Bariatric surgery fails to improve this inflammatory condition during the first months after surgery. Considering the close relation between inflammation and IR, we conducted a study in which insulin sensitivity was measured during the first months after bariatric surgery. Different methods to measure IR shortly after bariatric surgery have given inconsistent data. For example, the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) levels have been reported to decrease rapidly after bariatric surgery, although clamp techniques have shown sustained insulin resistance. In the present study, we evaluated the use of steady-state plasma glucose (SSPG) levels to assess insulin sensitivity 2 months after bariatric surgery.MethodsInsulin sensitivity was measured using HOMA-IR and SSPG levels in 11 subjects before surgery and at 26% excess weight loss (approximately 2 months after restrictive bariatric surgery).ResultsThe SSPG levels after 26% excess weight loss did not differ from the SSPG levels before surgery (14.3 ± 5.4 versus 14.4 ± 2.7 mmol/L). In contrast, the HOMA-IR values had decreased significantly (3.59 ± 1.99 versus 2.09 ± 1.02).ConclusionDuring the first months after restrictive bariatric surgery, we observed a discrepancy between the HOMA-IR and SSPG levels. In contrast to the HOMA-IR values, the SSPG levels had not improved, which could be explained by the ongoing inflammatory state after bariatric surgery. These results suggest that during the first months after restrictive bariatric surgery, HOMA-IR might not be an adequate marker of insulin sensitivity.     

The added value of simultaneous EEG and amplitude-integrated EEG recordings in three newborn infants

Amplitude-integrated electroencephalograms (aEEGs) recorded by cerebral function monitors (CFMs) are used increasingly to monitor the cerebral activity of newborn infants with encephalopathy. Recently, new CFM devices became available which also reveal the original EEG signals from the same leads. To date it was unclear whether this single-lead EEG provides additional information towards interpreting the aEEG traces more accurately. Our report deals with three cases in which the single-lead EEG from the CFM device did indeed reveal important additional information not provided by the aEEG alone. In cases 1 and 3, the aEEGs showed drifting of the baseline to higher amplitudes. The single-lead EEG revealed that this was due to muscle artefacts, high-frequency oscillation ventilation and the electrocardiogram rather than to cerebral activity. Hence, without knowledge of the EEG, the aEEG trace might have been misinterpreted as being fairly normal. Case 2 showed paroxysmal elevation of the lower margin of the amplitude on the aEEG which looked like epileptic activity. However, additional information from the single-lead EEG revealed that it was due to muscle artefacts. Thus, simultaneously recorded EEG can help to interpret seizure-like episodes on the aEEG. CONCLUSION: Simultaneously recorded single-lead EEGs can help to interpret aEEG traces more accurately.