Muscle metabolites and performance during high-intensity, intermittent exercise

Six men were studied during four 30-s all-out exercise bouts on an air-braked cycle ergometer. The first three exercise bouts were separated by 4 min of passive recovery; after the third bout, subjects rested for 4 min, exercised for 30 min at 30-35% peak O-2 consumption, and rested for a further 60 min before completing the fourth exercise bout. Peak power and total work were reduced (P < 0.05) during bout 3 [765 +/- 60 (SE) W; 15.8 +/- 1.0 kJ] compared with bout 1 (1,168 +/- 55 mT, 23.8 +/- 1.2 kJ), but no difference in exercise performance was observed between bouts 1 and 4 (1,094 +/- 64 W, 23.2 +/- 1.4 kJ). Before bout 3, muscle ATP, creatine phosphate (CP), glycogen, pH, and sarcoplasmic reticulum (SR) Ca2+ uptake were reduced, while muscle lactate and inosine 5'-monophosphate were increased. Muscle ATP and glycogen before bout 4 remained lower than values before bout I (P < 0.05), but there were no differences in muscle inosine 5'-monophosphate, lactate, pH, and SR Ca2+ uptake. Muscle CP levels before bout 4 had increased above resting levels. Consistent with the decline in muscle ATP were increases in hypoxanthine and inosine before bouts 3 and 4. The decline in exercise performance does not appear to be related to a reduction in muscle glycogen. Instead, it may be caused by reduced CP availability, increased H+ concentration, impairment in SR function, or some other fatigue-inducing agent.

Acute intermittent porphyria: alternative splicing of hydroxymethylbilane synthase mRNA excludes exons 3 and 12

The hydroxymethylbilane synthase (HMBS) mRNAs from 44 control individuals and 30 patients suffering from acute intermittent porphyria (AIP), were screened for length differences by reverse transcriptase polymerase chain reaction (RT-PCR) and any abnormalities were characterized by direct sequencing. Examination of the mRNAs extracted from the peripheral blood lymphocytes of the samples revealed varying degrees of alternative splicing, involving the removal of exons 3 and 12. Approximately 10-50% of the mRNA molecules were affected, despite the absence of genomic splice site mutations or any major deviance from consensus splice sequence values. The preliminary data obtained from this study suggest that this event is a normal occurrence in peripheral blood lymphocytes, and may not be associated with the molecular pathology responsible for AIP. (C) 1998 Academic Press Limited.

Intermittent target inhibition with dasatinib 100 mg once daily preserves efficacy and improves tolerability in imatinib-resistant and -intolerant chronic-phase chronic myeloid leukemia

Purpose Dasatinib is a BCR-ABL inhibitor, 325-fold more potent than imatinib against unmutated BCR-ABL in vitro. Phase II studies have demonstrated efficacy and safety with dasatinib 70 mg twice daily in chronic-phase (CP) chronic myelogenous leukemia (CML) after imatinib treatment failure. In phase I, responses occurred with once-daily administration despite only intermittent BCR-ABL inhibition. Once-daily treatment resulted in less toxicity, suggesting that toxicity results from continuous inhibition of unintended targets. Here, a dose-and schedule-optimization study is reported. Patients and Methods In this open-label phase III trial, 670 patients with imatinib-resistant or -intolerant CP-CML were randomly assigned 1: 1: 1: 1 between four dasatinib treatment groups: 100 mg once daily, 50 mg twice daily, 140 mg once daily, or 70 mg twice daily. Results With minimum follow-up of 6 months (median treatment duration, 8 months; range, = 1 to 15 months), marked and comparable hematologic (complete, 86% to 92%) and cytogenetic (major, 54% to 59%; complete, 41% to 45%) response rates were observed across the four groups. Time to and duration of cytogenetic response were similar, as was progression-free survival (8% to 11% of patients experienced disease progression or died). Compared with the approved 70-mg twice-daily regimen, dasatinib 100 mg once daily resulted in significantly lower rates of pleural effusion (all grades, 7% v 16%; P = .024) and grade 3 to 4 thrombocytopenia (22% v 37%; P = .004), and fewer patients required dose interruption (51% v 68%), reduction (30% v 55%), or discontinuation (16% v 23%). Conclusion Dasatinib 100 mg once daily retains the efficacy of 70 mg twice daily with less toxicity. Intermittent target inhibition with tyrosine kinase inhibitors may preserve efficacy and reduce adverse events.

Atrial Coronary Arteries in Areas Involved in Atrial Fibrillation Catheter Ablation

Background-The proximity to vascular structures is a limiting factor during radiofrequency ablation. However, little or no attention has been given to the atrial arterial circulation during the development of atrial fibrillation (AF) catheter ablation techniques. Methods and Results-We examined the atrial arterial circulation in areas involved in AF ablation in 24 heart specimens by colored resin injection and careful dissection. The sinus node artery (SNA) arose from the circumflex artery in 42% of case; proximal to the LA appendage in 29%, crossing the left atrium (LA) anterior wall; and after the LA appendage in the remaining 13%, crossing the mitral isthmus and passing close to the left pulmonary veins (PVs), the LA roof, and the right superior PV. In 58%, the SNA arose from the right coronary artery. Major arteries (>= 1 mm in external diameter) were found in the mitral isthmus in 54%, at the LA roof in 54%, and at the LA anterior wall in 29%. Around the left PV ostia, there were areas with major arteries in up to 37% (at the roof and inferior segments) and around the right PV ostia in up to 29% (at the roof segment). Conclusions-Major atrial coronary arteries, including the SNA, were commonly found in the areas involved in AF ablation and could cause difficulties in obtaining transmural lesions and electric isolation or even lead to ischemic sinus node or atrial dysfunction. (Circ Arrhythm Electrophysiol. 2010;3:600-605.)

Hemodynamic Changes during Myocardial Revascularization without Extracorporeal Circulation

Background and objectives: Cardiac positioning and stabilization during myocardial revascularization without extracorporeal circulation (ECC) may cause hemodynamic changes dependent to the surgical site. The objective of this study was to evaluate these changes during distal coronary anastomosis. Methods: Twenty adult patients undergoing myocardial revascularization without ECC were monitored by pulmonary artery catheter and transesophageal Echo Doppler. Hemodynamic data were collected at the following times before removing the stabilizer wall: (1) after volume adjustments, (2) at the beginning of distal anastomosis, and (3) after 5 minutes. Treated coronary arteries were grouped according to their location in the lateral, anterior, or posterior wall. Two-way ANOVA with repetition and Newman-Keuls post-test were used in the analysis. A p value < 0.05 was considered statically significant. Results: During myocardial revascularization without ECC, pulmonary artery wedge pressure showed elevation from 17.7 +/- 6.1 to 19.2 +/- 6.5 (p < 0.001) and 19.4 +/- 5.9 mmHg (p < 0.001), while the central venous pressure went from 13.9 +/- 5.4 to 14.9 +/- 5.9 mmHg (p = 0.007) and 15.1 +/- 6.0 mmHg (p = 0.006). Intermittent cardiac output was reduced from 4.70 +/- 1.43 to 4.23 +/- 1.22 (p < 0.001) and 4.26 +/- 1.25 L.min(-1) (p < 0.001). According to transesophageal Doppler, a significant group-time interaction was observed in cardiac output, which was reduced in the lateral group from 4.08 +/- 1.99 to 2.84 +/- 1.82 (p = 0.02) and 2.86 +/- 1.73 L.min(-1) (p = 0.02), and aortic blood flow, which went from 2.85 +/- 1.39 to 1.99 +/- 1.26 (p = 0.02) and 2.00 +/- 1.21 L.min(-1) (p = 0.02). Other hemodynamic changes were not observed during anastomoses. Conclusions: A significant hemodynamic deterioration was observed during myocardial revascularization without ECC. Transesophageal Doppler detected a decrease in cardiac output only in the lateral group.

Prevalence of Metabolic Syndrome in Patients With Intermittent Claudication and its Correlation With the Segment of Arterial Obstruction

The metabolic syndrome (MetS) is associated with increased cardiovascular morbidity and mortality. Intermittent claudication reflects the presence of peripheral arterial disease (PAD). The aim of this study is to determine the prevalence of the MetS in claudicants and its correlation with age, gender, localization of arterial obstruction, and symptomatic coronary disease. Patients (n = 170) with intermittent claudication were studied. The mean age was 65 years (33-89). Metabolic syndrome was diagnosed in 98 patients (57.6%). The mean age of patients with MetS was 63.5 years compared with 67.0 years for patients without MetS (P = .027). Considering patients aged >= 65 years, MetS was present in 46 (48.9%) individuals and in 52 (68.4%) patients younger than 65 years (P = .011). Metabolic syndrome must be actively searched for in claudicant patients.

Effects of carbohydrate supplementation on competitive runners undergoing overload training followed by a session of intermittent exercise

This study evaluated the effects of a micro cycle of overload training (1st-8th day) on metabolic and hormonal responses in male runners with or without carbohydrate supplementation and investigated the cumulative effects of this period on a session of intermittent high-intensity running and maximum-performance-test (9th day). The participants were 24 male runners divided into two groups, receiving 61% of their energy intake as CHO (carbohydrate-group) and 54% in the control-group (CON). The testosterone was higher for the CHO than the CON group after the overload training (694.0 +/- A 54.6 vs. CON 610.8 +/- A 47.9 pmol/l). On the ninth day participants performed 10 x 800 m at mean 3 km velocity. An all-out 1000 m running was performed before and after the 10 x 800 m. Before, during, and after this protocol, the runners received solution containing CHO or the CON equivalent. The performance on 800 m series did not differ in either group between the first and last series of 800 m, but for the all-out 1000 m test the performance decrement was lower for CHO group (5.3 +/- A 1.0 vs. 10.6 +/- A 1.3%). The cortisol concentrations were lower in the CHO group in relation to CON group (22.4 +/- A 0.9 vs. 27.6 +/- A 1.4 pmol/l) and the IGF1/IGFBP3 ratio increased 12.7% in the CHO group. During recovery, blood glucose concentrations remained higher in the CHO group in comparison with the CON group. It was concluded that CHO supplementation possibly attenuated the suppression of the hypothalamic-pituitary-gonadal axis and resulted in less catabolic stress, and thus improved running performance.

Acute intermittent porphyria: the in vitro expression of mutant hydroxymethylbilane synthase

Acute intermittent porphyria (AIP) is an inborn error of haem biosynthesis caused by a variety of mutations in the gene coding for hydroxymethylbilane synthase (HMB-S). The entire coding sequence of this gene, from each of three South African AIP patients, was therefore screened for mutations using chemical cleavage mismatch (CCM) analysis and any changes detected characterized by DNA sequencing. Three single base changes were identified; a G(77) to A in exon 3, a C-346 to T in exon 8 and a G(518) to A in exon 10. These missense mutations, previously reported to be present in other populations, are known to be responsible for the structurally deleterious amino acid replacements R26H, R116W and R173Q, respectively. The in vitro expression of the enzymes containing these mutations and the subsequent measurement of their specific activities revealed a reduction to approximately 4% of normal activity. (C) 1997 Academic Press Limited.

Salvage of long-term central venous catheters during an outbreak of Pseudomonas putida and Stenotrophomonas maltophilia infections associated with contaminated heparin catheter-lock solution

objective. To describe the management of patients with long-term central venous catheters (CVCs) during an outbreak of infection due to Pseudomonas putida and Stenotrophomonas maltophilia associated with contaminated heparin catheter-lock solution. design. Descriptive study. setting. Private, 250-bed tertiary-care hospital. methods. In March 2003, we identified 2 febrile cancer patients with P. putida bacteremia. Over 2 days, 7 cases of bacteremia were identified; lots of syringes prefilled with heparin catheter-lock solution, supplied by a compounding pharmacy, were recalled and samples were cultured. More cases of bacteremia appeared during the following days, and any patient who had had a catheter lock infused with the suspect solution was asked to provide blood samples for culture, even if the patient was asymptomatic. Isolates that were recovered from culture were typed by pulsed-field gel electrophoresis. Antimicrobial salvage treatment of long-term CVCs was attempted. results. A total of 154 patients had had their catheter lock infused with solution from the lots that were suspected of being contaminated. Only 48 of these patients had CVCs. By day 7 of the outbreak, 18 of these patients had become symptomatic. Twenty-six of the remaining 30 asymptomatic patients then also provided blood samples for culture, 10 of whom developed fever shortly after samples were collected. Thirty-two patients were identified who had P. putida bacteremia; 9 also had infection due to S. maltophilia. Samples from 1 of the 3 lots of prefilled syringes in use at the time of the outbreak also grew P. putida on culture. Molecular typing identified 3 different clones of P. putida from patients and heparin catheter-lock solution, and 1 clone of S. maltophilia. A total of 27 patients received antimicrobial therapy regimens, some of which included decontamination of the catheter lock with anti- infective lock solution. Of 27 patients, 19 (70%) retained their long-term CVC during the 6-month follow-up period. conclusions. To our knowledge, this is one of the largest prospective experiences in the management of bloodstream infection associated with long-term CVCs. The infections were caused by gram-negative bacilli and were managed without catheter removal, with a high response rate. We emphasize the risks of using intravenous formulations of medications supplied by compounding pharmacies that produce large quantities of drugs.

Evaluation of interventions to reduce catheter-associated bloodstream infection: Continuous tailored education versus one basic lecture

Background: This study evaluated the impact of 2 models of educational intervention on rates of central venous catheter-associated bloodstream infections (CVC-BSIs). Methods: This was a prospective observational study conducted between January 2005 and June 2007 in 2 medical intensive care units (designated ICU A and ICU B) in a large teaching hospital. The study was divided into in 3 periods: baseline (only rates were evaluated), preintervention (questionnaire to evaluate knowledge of health care workers [HCWs] and observation of CVC care in both ICUs), and intervention (in ICU A, tailored, continuous intervention; in ICU B, a single lecture). The preintervention and intervention periods for each ICU were compared. Results: During the preintervention period, 940 CVC-days were evaluated in ICUA and 843 CVC-days were evaluated in ICU B. During the intervention period, 2175 CVC-days were evaluated in ICUA and 1694 CVC-days were evaluated in ICU B. Questions regarding CVC insertion, disinfection during catheter manipulation, and use of an alcohol-based product during dressing application were answered correctly by 70%-100% HCWs. Nevertheless, HCWs` adherence to these practices in the preintervention period was low for CVC handling and dressing, hand hygiene (6%-35%), and catheter hub disinfection (45%-68%). During the intervention period, HCWs` adherence to hand hygiene was 48%-98%, and adherence to hub disinfection was 82%-97%. CVC-BSI rates declined in both units. In ICUA, this decrease was progressive and sustained, from 12CVC-BSIs/1000 CVC-days at baseline to 0 after 9 months. In ICU B, the rate initially dropped from 16.2 to 0 CVC-BSIs/1000 CVC-days, but then increased to 13.7 CVC-BSIs/1000 CVC-days. Conclusion: Personal customized, continuous intervention seems to develop a ""culture of prevention"" and is more effective than single intervention, leading to a sustained reduction of infection rates.

Test-retest reliability of isokinetic strength and endurance tests in patients with intermittent claudication

The objective was to determine the reliability of isokinetic strength and endurance testing in the ankle joints of patients with intermittent claudication. Twenty-three patients with peripheral artery disease (PAD) and symptoms of intermittent claudication participated in the study. Isokinetic strength and endurance testing of the ankle joint were performed in symptomatic and asymptomatic legs on 3 separate days. Intraclass coefficient correlation of peak torque (PT) and total work (TW) ranged from 0.77 to 0.92 and 0.89 to 0.96, respectively. PT and TW increased significantly and similarly in both legs from day 1 to day 2 (PT: +42 +/- 84% in the symptomatic leg and +33 +/- 51% in the asymptomatic leg, p < 0.05;TW: +38 +/- 26% in the symptomatic leg and +26 +/- 50% in the asymptomatic leg, p < 0.05). In conclusion, isokinetic strength and endurance testing in the ankle joints of patients with PAD presents reliability coefficients ranging from 0.77 to 0.96. However, strength and endurance increased between the first and the other test sessions performed on separate days, suggesting that two test sessions are necessary for the accurate evaluation of strength and endurance in patients with PAD.

Catheter ablation of severe neurally meditated reflex (neurocardiogenic or vasovagal) syncope: cardioneuroablation long-term results

Aims Neurally meditated reflex or neurocardiogenic or vasovagal syncope (NMS) is usually mediated by a massive vagal reflex. This study reports the long-term outcome of NMS therapy based on endocardial radiofrequency (RF) catheter ablation of the cardiac vagal nervous system aiming permanent attenuation or elimination of the cardioinhibitory reflex (cardioneuroablation). Methods and results A total of 43 patients (18F/25M, 32.9+/-15 years) without apparent cardiopathy (left ventricular ejection fraction=68.6+/-5%) were included. All had recurrent NMS (4.7+/-2 syncope/patient) with important cardioinhibition (pauses=13.5+/-13 s) at head-up tilt test (HUT), normal electrocardiogram (ECG), and normal atropine test (AT). The patients underwent atrial endocardial RF ablation using spectral mapping to track the neurocardiac interface (AF Nest Mapping). The follow-up (FU) consisted of clinical evaluation, ECG (1 month/every 6 months/or symptoms), Holter (every 6 months/or symptoms), HUT (>= 4 months/or symptoms), and AT (end of ablation and >= 6 months). A total of 44 ablations (48+/-9 points/patient) were performed. Merely three cases of spontaneous syncope occurred in 45.1+/-22 months (two vasodepressor, one undefined). Only four partial cardioinhibitory responses occurred in post-ablation HUT without pauses or asystole (sinus bradycardia). Long-term AT (21.7+/-11 months post) was negative in 33 (76.7%, P<0.01), partially positive in 7(16.3%), and normal in three patients only (6.9%) reflecting long-term vagal denervation (AT-Delta% HR pre 79.4% x 23.2% post). The post-ablation stress test and Holter showed no abnormalities. No major complications occurred. Conclusion Endocardial RF catheter ablation of severe neurally meditated reflex syncope prevented pacemaker implantation and showed excellent long-term results in well selected patients. Despite no action in vasodepression it seems to cause enough long-term vagal reflex attenuation, eliminating the cardioinhibition, and keeping most patients asymptomatic. Indication was based on clinical symptoms, reproduction of severe cardioinhibitory syncope, and normal atropine response.

Metabolic consequences of intermittent hypoxia: Relevance to obstructive sleep apnea

Obstructive sleep apnea (OSA) is recurrent obstruction of the upper airway leading to sleep fragmentation and intermittent hypoxia (IH) during sleep. There is growing evidence from animal models of OSA that IH is independently associated with metabolic dysfunction, including dyslipidemia and insulin resistance. The precise mechanisms by which IH induces metabolic disturbances are not fully understood. Over the last decade, several groups of investigators developed a rodent model of IH, which emulates the oxyhemoglobin profile in human USA. In the mouse model, IH induces dyslipidemia, insulin resistance and pancreatic endocrine dysfunction, similar to those observed in human USA. Recent reports provided new insights in possible mechanisms by which IH affects lipid and glucose metabolism. IH may induce dyslipidemia by up-regulating lipid biosynthesis in the liver, increasing adipose tissue lipolysis with subsequent free fatty acid flux to the liver, and inhibiting lipoprotein clearance. IH may affect glucose metabolism by inducing sympathetic activation, increasing systemic inflammation, increasing counter-regulatory hormones and fatty acids, and causing direct pancreatic beta-cell injury. IH models of USA have improved our understanding of the metabolic impact of USA, but further studies are needed before we can translate recent basic research findings to clinical practice. (C) 2010 Elsevier Ltd. All rights reserved.

Serum Vitamins in Adult Patients With Short Bowel Syndrome Receiving Intermittent Parenteral Nutrition

Background: Short bowel syndrome (SBS) occurs after massive intestinal resection, and parenteral nutrition (PN) therapy may be necessary even after a period of adaptation. The purpose of this study was to determine the vitamin status in adults with SBS receiving intermittent PN. Methods: The study was conducted on hospitalized adults with SBS who were receiving intermittent PN therapy (n = 8). Nine healthy volunteers, paired by age and sex, served as controls. Food ingestion, anthropometry, plasma folic acid, and vitamins B(12), C, A, D, E, and K were evaluated. Results: The levels of vitamins A, D, and B(12) in both groups were similar. SBS patients presented higher values of folic acid (21.3 +/- 4.4 vs 14.4 +/- 5.2, P = .01) and lower values of vitamin C (0.9 +/- 0.4 vs 1.2 +/- 0.3 mg/dL, P = .03), alpha-tocopherol (16.3 +/- 3.4 vs 24.1 +/-+/- 2.7 mu mol/L, P < .001), and phylloquinone (0.6 +/- 0.2 vs 1.0 +/- 0.5 nmol/L, P < .03). Eight-seven percent of patients had vitamin D deficiency, and all patients presented with serum vitamin E levels below reference values. Conclusions: Despite all efforts to offer all the nutrients mentioned above, SBS patients had lower serum levels of vitamins C, E, and K, similar to those observed in patients on home PN. These findings suggest that the administered vitamins were not sufficient for the intermittent PN scheme and that individual adjustments are needed depending on the patient`s vitamin status. (JPEN J Parenter Enteral Nutr. 2011;35:493-498)