Residual effects of prior exercise and recovery on subsequent exercise-induced metabolic responses

Abstract Data on the metabolic responses to repeated endurance exercise sessions are limited. Thus, the aims of this study were to examine (1) the impact of prior exercise on metabolic responses to a subsequent exercise session and (2) the effect of different recovery periods between two daily exercise sessions on metabolic responses to the second bout of exercise. Nine male elite athletes participated in four 25-h trials: one bout of exercise (ONE), two bouts of exercise separated by 3 h of rest and one meal (SHORT), two bouts of exercise separated by 6 h of rest and two meals (LONG), and a trial with no exercise (REST). All exercise bouts consisted of 10 min cycling at 50% followed by 65 min at 75% of maximal O₂ uptake. Compared to no prior exercise (ONE), a previous bout of exercise (SHORT) was followed by higher mean O₂ uptake, heart rate (HR), rectal temperature (T_R), excess post-exercise oxygen consumption and lower respiratory exchange ratio (R) during and after a similar exercise session 3 h later. A longer rest interval between the two exercise bouts (6 h versus 3 h) and an additional meal resulted in a decrease in O₂ uptake, HR, T_R and an increase in R during the second bout of exercise, but no effects on post-exercise metabolism were found. Thus, augmented metabolic stress was observed when strenuous exercise was repeated after only 3 h of recovery, but this was attenuated when a longer recovery period including an additional meal was provided between the exercise sessions.     

Disease-stabilizing treatment with all-trans retinoic acid and valproic acid in acute myeloid leukemia: serum hsp70 and hsp90 levels and serum cytokine profiles are determined by the disease, patient age, and anti-leukemic treatment

Heat shock protein (HSP) 70 and HSP90 are released by primary human acute myeloid leukemia (AML) cells during stress-induced spontaneous in vitro apoptosis. The AML cells also show constitutive release of several cytokines and the systemic serum levels of several soluble mediators are altered in patients with untreated AML. In the present study, we have investigated serum levels of HSP70/HSP90 and the serum cytokine profiles of patients with untreated AML and patients receiving AML-stabilizing palliative treatment based on all-trans retinoic acid (ATRA) plus valproic acid. Patients with untreated AML showed increased HSP90 levels and a distinct serum cytokine profile when compared with healthy controls, and low pre-therapy HSP90 levels were associated with a prolonged survival during treatment with ATRA + valproic acid + theophyllin. Hierarchical cluster analysis showed a close association between HSP70, HSP90, IL-1 receptor antagonist (IL-1ra), and hepatocyte growth factor (HGF) levels. Furthermore, disease-stabilizing therapy altered the serum-cytokine profile, but the correlations between HSP70/HSP90/IL-1ra/HGF were maintained only when ATRA + valproic acid were combined with theophyllin but not when combined with cytarabine. We conclude that both HSP levels and serum cytokine profiles are altered and may represent possible therapeutic targets or prognostic markers in human AML.     

Magnetic resonance imaging evaluation after implantation of a titanium cervical disc prosthesis: a comparison of 1.5 and 3 Tesla magnet strength

Purpose

Cervical disc prostheses induce significant amount of artifact in magnetic resonance imaging which may complicate radiologic follow-up after surgery. The purpose of this study was to investigate as to what extent the artifact, induced by the frequently used Discover^® cervical disc prosthesis, impedes interpretation of the MR images at operated and adjacent levels in 1.5 and 3 Tesla MR.

Methods

Ten subsequent patients were investigated in both 1.5 and 3 Tesla MR with standard image sequences one year following anterior cervical discectomy with arthroplasty.

Outcome measures

Two neuroradiologists evaluated the images by consensus. Emphasis was made on signal changes in medulla at all levels and visualization of root canals at operated and adjacent levels. A “blur artifact ratio” was calculated and defined as the height of the artifact on T1 sagittal images related to the operated level.

Results

The artifacts induced in 1.5 and 3 Tesla MR were of entirely different character and evaluation of the spinal cord at operated level was impossible in both magnets. Artifacts also made the root canals difficult to assess at operated level and more pronounced in the 3 Tesla MR. At the adjacent levels however, the spinal cord and root canals were completely visualized in all patients. The “blur artifact” induced at operated level was also more pronounced in the 3 Tesla MR.

Conclusions

The artifact induced by the Discover^® titanium disc prosthesis in both 1.5 and 3 Tesla MR, makes interpretation of the spinal cord impossible and visualization of the root canals difficult at operated level. Adjusting the MR sequences to produce the least amount of artifact is important.     

Specific isolation of disseminated cancer cells: a new method permitting sensitive detection of target molecules of diagnostic and therapeutic value

Molecular studies of rare cells, such as circulating cancer cells, require efficient pre-enrichment steps to obtain a pure population of target cells for further characterization. We have developed a two-step approach, starting with immunomagnetic enrichment, followed by specific isolation of individual, easily identifiable bead-rosetted target cells using a new semi-automated CellPick system. With this procedure, 1–50 live target cells can now be isolated. As a model system, we spiked a small number of tumor cells into millions of normal mononuclear cells (MNCs). Efficient isolation of pure target cells was obtained by use of the CellPick system, and the nature of isolated, bead-rosetted cells was verified by use of FISH. Single breast cancer cells were picked directly into an RNA preserving lysis buffer, reverse transcribed, and PCR amplified with two cDNA specific primer sets. With the isolated cells we consistently obtained both ubiquitously expressed and tumor cell specific PCR products. We also performed a successful mutation analysis of single cells using PCR and cycling temperature capillary electrophoresis (CTCE). This may have significant clinical implications in cancer and in other diseases, e.g. in characterizing micrometastatic cancer cells in blood and lymph nodes to help identifying patients who most likely will respond to therapies like tyrosine kinase inhibitors and compounds targeting specific mutations. By use of the CellPick system it is possible to specifically isolate bead-rosetted or otherwise labelled target cells from a heterogeneous cell population for further molecular characterization.     

Effect of beta-adrenergic blockade on hormonal responses during continuous and intermittent exercise

Summary The modifying effect on exercise performance and neuroendocrine response of the nonselective beta blocker timolol (10 mg b.i.d. for 5 days) and the beta₁-selective beta blocker metoprolol (100 mg b.i.d. for 5 days) was studied. The hormones studied were growth hormone, prolactin, cortisol, renin, epinephrine, dopamine, and norepinephrine. The response was studied during short-term maximal dynamic exercise, using two different exercise protocols; continuous (n=11) and intermittent (n=9) bicycle ergometry, in normal healthy young men. Accumulated work on placebo was nearly identical in the two studies, but was significantly reduced by 10.4% and 6.6% with timolol and by 4.7% and 6.7% with metoprolol, during continuous and intermittent exercise, respectively. During continuous exercise, accumulated work was 5.8% lower (p<0.05) with timolol than with metoprolol. The hormonal plasma concentrations of all hormones except renin were higher during continuous exercise than during intermittent exercise. Beta blockade had no effect on baseline hormonal levels, but the response was markedly changed during exercise. Maximum epinephrine, cortisol, and prolactin responses increased after beta blockade; dopamine remained nearly unchanged; while the renin responses were attenuated. Norepinephrine concentrations were slightly increased during continuous exercise by beta blockade and rose in direct proportion to the increase in workload. During intermittent exercise, maximum norepinephrine levels were significantly reduced by beta blockade compared with placebo. Thus the effect of beta₁-selective and nonselective beta receptor blockade on circulating hormones does not seem to explain the reduced exercise capacity following beta blockade.     

The arsenic-based cure of acute promyelocytic leukemia promotes cytoplasmic sequestration of PML and PML/RARA through inhibition of PML body recycling

Arsenic in the form of arsenic trioxide (ATO) is used as a therapeutic drug for treatment of acute promyelocytic leukemia (APL). The mechanism by which this agent cures this disease was previously shown to involve direct interactions between ATO and the promyelocytic leukemia protein (PML), as well as accelerated degradation of the APL-associated fusion oncoprotein PML/retinoic acid receptor α (RARA). Here we investigated the fate of PML-generated nuclear structures called PML bodies in ATO-treated cells. We found that ATO inhibits formation of progeny PML bodies while it stabilizes cytoplasmic precursor compartments, referred to as cytoplasmic assemblies of PML and nucleoporins (CyPNs), after cell division. This block in PML body recycling is readily detected at pharmacologic relevant ATO concentrations (0.02-0.5μM) that do not cause detectable cell-cycle defects, and it does not require modification of PML by SUMOylation. In addition, PML and PML/RARA carrying mutations previously identified in ATO-resistant APL patients are impeded in their ability to become sequestered within CyPNs. Thus, ATO may inhibit nuclear activities of PML and PML/RARA in postmitotic cells through CyPN-dependent cytoplasmic sequestration.     

Advanced life support performance with manual and mechanical chest compressions in a randomized,multicentre manikin study

Aim of the studyClinical mechanical chest compression studies report diverging outcomes. Confounding effects of variability in hands-off fraction (HOF) and timing of necessary tasks during advanced life support (ALS) may contribute to this divergence. Study site variability in these factors coupled to randomization of cardiopulmonary resuscitation (CPR) method was studied during simulated cardiac arrest prior to a multicentre clinical trial.MethodAmbulance personnel from four sites were tested in randomized, simulated cardiac arrest scenarios with manual CPR or load-distributing band CPR (LDB-CPR) on manikins. Primary emphasis was on HOF and time spent before necessary predefined ALS task (ALS milestones). Results are presented as mean differences (confidence interval).ResultsAt the site with lowest HOF during manual CPR, HOF deteriorated with LDB-CPR by 0.06 (0.005, 0.118, p = 0.04), while it improved at the two sites with highest HOF during manual CPR by 0.07 (0.019, 0.112, p = 0.007) and 0.08 (0.004, 0.165, p = 0.042). Initial defibrillation was 29 (3, 55, p = 0.032) s delayed for LDB-CPR vs. manual CPR. Other ALS milestones trended toward earlier completion with LDB-CPR; only significant for intravenous access, mean difference 70 (24, 115, p = 0.003) s.ConclusionIn this manikin study, HOF for manual vs. mechanical chest compressions varied between sites. Study protocol implementation should be simulation tested before launching multicentre trials, to optimize performance and improve reliability and scientific interpretation.     

Vitamins A and E in serum in relation to weight and lung function in patients with advanced pulmonary disease

The objective of the study was to examine whether serum concentrations of retinol (vitamin A) and alpha-, beta-, and gamma-tocopherols (vitamin E) are affected by underweight and weight gain. The analysis was carried out in underweight (n = 42, of whom 24 had chronic obstructive pulmonary disease) and normal-weight (n = 29, of whom 16 had chronic obstructive pulmonary disease) candidates for lung transplantation before and after dietary intervention for weight gain. In all the patients, serum concentrations of retinol at baseline and changes in retinol were positively associated with body mass index (unstandardized regression coefficient, b = 0.03; p = 0.05) and an increase in weight (b = 0.09, p = 0.02) after dietary intervention, respectively. At baseline, serum retinol concentrations were positively correlated with forced vital capacity (b = 0.24, p < 0.05) and forced expiratory volume in one second (b = 0.17, p < 0.05). In patients with chronic obstructive pulmonary disease (COPD), tocopherols were higher in the underweight patients than in the normal-weight ones, while it was an opposite tendency in patients with other lung diseases. Only in patients with lung diseases other than COPD was there found a positive association between tocopherols and lung gas diffusion. In patients with other diagnoses compared with patients with COPD, a positive change in serum tocopherol status after weight gain was suggested.     

Cytologic features of ductal carcinoma in situ in fine-needle aspiration of the breast mirror the histopathologic growth pattern heterogeneity and grading

BACKGROUND: Approximately 20% of the breast carcinoma cases detected on mammography screening represent ductal carcinoma in situ (DCIS). Cytopathologists are exposed to cytologic material from DCIS when nonpalpable, mammographic lesions are aspirated during the workup of organized and opportunistic mammography screening. METHODS: The material in the current study was comprised of 225 representative fine-needle aspiration cytology (FNAC) smears from histologically confirmed DCIS of the breast that were diagnosed between 1990-2003. Smears were rescreened to search for the following features: nuclear size (grading), monolayer sheets, solid and cribriform epithelial aggregates, micropapillary and true papillary structures, comedo-type necrosis, microcalcifications, myoepithelial cells, and discohesion. RESULTS: There were 174 high-grade lesions (77% were Grade 3) and 51 nonhigh-grade lesions (Grades 1 and 2). The concordance between the cytologic and histologic grading was 97% in the Grade 3 lesions and 94% in the Grade 1/2 lesions. Smears from Grade 3 DCIS contained solid and/or cribriform epithelial aggregates in > 93%% of the cases, whereas smears from Grade 1/2 lesions were found to contain cribriform aggregates in 94% of the cases. Pure subtypes were virtually nonexistent. Monolayer sheets were found in 49% of nonhigh-grade DCIS and in 16% of high-grade DCIS. Myoepithelial cells were demonstrated in 51% of the nonhigh-grade DCIS lesions and 27% of the Grade 3 lesions. Microcalcifications were found on the smears from 96% of nonhigh-grade lesions and 84% of high-grade lesions. Approximately 47% of high-grade DCIS and 31% of nonhigh-grade DCIS were found to harbor a distinct single cell population. CONCLUSIONS: The findings on FNAC from DCIS of the breast completely mirror the histologic heterogeneity of growth pattern subtypes. Primary cytologic grading can effectively separate the high-grade lesions from the nonhigh-grade lesions.