Aerobic exercise reduces cardiomyocyte hypertrophy and increases contractility,Ca2+ sensitivity and SERCA-2 in rat after myocardial infarction

OBJECTIVE: Although it is generally accepted that endurance training improves cardiac function after myocardial infarction the sub-cellular mechanisms are uncertain. The present study reports the effects of aerobic endurance training on myocardial mass, myocyte dimensions, contractile function, Ca2+ handling, and myofilament responsiveness to Ca2+ in cardiomyocytes from healthy and failing rat hearts. METHODS: Adult female Sprague-Dawley rats ran on a treadmill 1.5 h/day, 5 days a week for 8 weeks. Exercise intervals alternated between 8 min at 85-90% of V(O(2max)) and 2 min at 50-60%. Training started 4 weeks after ligation of the left coronary artery (TR-INF, n=11) or sham operation (TR-SHAM, n=6). Sedentary animals (SED-SHAM, n=6; SED-INF, n=13) were controls. RESULTS: After 6 weeks V(O(2max)) in TR-INF and TR-SHAM leveled off 65% above sedentary controls. In TR-SHAM, left and right ventricle weights were approximately 25% higher than in SED-SHAM, myocytes were approximately 13% longer; width remained unchanged. At physiological stimulation frequencies, relative myocyte shortening was markedly higher whereas peak systolic [Ca2+] and t(1/2) of Ca2+ transient decay were 10-20% lower, indicating higher Ca2+ sensitivity in cardiomyocytes from trained rats, compared to respective controls. In TR-INF the left and right ventricular weights, and myocyte length and width were 15, 23, 12, and 20% less than in SED-INF. Endurance training significantly increased the myocardial SR Ca2+ pump (SERCA-2) and sarcolemmal Na+-Ca2+-exchanger (NCX) protein levels to the extent that TR-INF did not differ from SED-SHAM. CONCLUSION: This is the first study to show that aerobic endurance training attenuates the ventricular and cellular hypertrophy in failing hearts. Furthermore, training consistently restores contractile function, intracellular Ca2+ handling, and Ca2+-sensitivity in cardiomyocytes from rats with myocardial infarction.     

Uveal melanoma survival in Sweden from 1960 to 1998

PURPOSE: To investigate the crude and relative survival rates in patients with uveal melanoma in Sweden during the period from 1960 to 1998. METHODS: A population-based national survey revealed 2997 cases of uveal melanoma in the Swedish Cancer Registry. The survival rates were calculated by the Hakulinen life-table method, using relative survival as an estimate for deaths due to uveal melanoma. The excess mortality rates were calculated with confidence intervals for the first 15 years after diagnosis. Multivariate regression analysis was undertaken to evaluate the influence of gender, age, and calendar period on relative survival the first 5 years after diagnosis. The underlying causes of deaths in the patients with uveal melanoma, as found in the Cause of Death Registry were also investigated. RESULTS: Up to December 31, 1998, 2003 patients had died. The 5-year crude survival rate was 60.3% and the relative survival 70.1%. After 10 years, the rates were 42.5% and 59.4%, respectively. Significant excess mortality existed up to 5.5 years after diagnosis. In the multivariate model, younger age (P < 0.001) and later calendar period (P = 0.002), but not gender (P = 0.117), were associated with better relative survival. Deaths due to uveal melanoma were misclassified in the Cause of Death Registry in more than half of the cases. CONCLUSIONS: This study, covering more than 95% of the uveal melanoma cases in the Swedish population revealed an improvement in relative survival rates for patients with uveal melanoma over time and a significant excess mortality up to 5.5 years after diagnosis.     

Structural and functional probing of the biogenic amine transporters by fluorescence spectroscopy

Fluorescence spectroscopy techniques have proven extremely powerful for probing the molecular structure and function of membrane proteins. In this review, it will be described how we have applied a series of these techniques to the biogenic amine transporters, which are responsible for the clearance of dopamine, norepinephrine, and serotonin from the synaptic cleft. In our studies, we have focused on the serotonin transporter (SERT) for which we have established a purification procedure upon expression of the transporter in Sf-9 insect cells. Importantly, the purified transporter displays pharmacological properties in detergent micelles similar to that observed in membranes suggesting that the overall tertiary structure is preserved upon purification. Using this purified SERT preparation and the fluorescent cocaine analogue RTI-233 as a molecular reporter, we have been able to characterize the microenvironment of the cocaine-binding pocket. In current follow-up studies, we are attempting to map the relative position of this binding pocket using fluorescence resonance energy transfer (FRET) between RTI-233 and an acceptor fluorophore covalently attached to endogenous cysteines in the transporter. Finally, it will be described how we recently initiated the implementation of single-molecule confocal fluorescence spectroscopy techniques in our studies of the SERT.     

Pharmacokinetic interaction between amprenavir and delavirdine after multiple-dose administration in healthy volunteers

AIMS: To evaluate the safety and the pharmacokinetic interaction between amprenavir and delavirdine after multiple dose administration in healthy volunteers. METHODS: This was a prospective, open-label, randomized, controlled, two-sequence, two-period multiple dose study with 18 healthy subjects. Volunteers were randomly assigned to amprenavir, 600 mg twice a day, or delavirdine, 600 mg twice a day, for 10 days, followed by both drugs for another 10 days with pharmacokinetic evaluation on day 10 and day 20. Adverse events were recorded throughout the study. RESULTS: Amprenavir decreased all the delavirdine pharmacokinetic parameters apart from tmax. Delavirdine C12h dropped from 7,916 to 933 ng ml-1 (median decrease 5,930 ng ml-1, 95% CI 3,013, 8,955 ng ml-1). A decrease in amprenavir t(1/2) was also seen leading to almost identical median amprenavir C24h values. No serious clinical adverse events were observed during the study. The most frequently reported effects were gastrointestinal symptoms, headache, fatigue and rash. CONCLUSIONS: Amprenavir is an effective inducer of delavirdine metabolism, probably through its effect on hepatic CYP3A4. This could have consequences in other drug-drug interaction situations. Delavirdine is an inhibitor of amprenavir metabolism. The regimen of amprenavir 600 mg and delavirdine 600 mg twice a day is not recommended when an antiretroviral effect from delavirdine is required.     

Prolonged signal-averaged P wave duration as a prognostic marker for morbidity and mortality in patients with congestive heart failure

OBJECTIVE: To evaluate the prognostic roles of prolonged signal-averaged P wave duration (SAPWD), raised levels of natriuretic peptides, and clinical characteristics in patients with stable congestive heart failure (CHF). DESIGN: The SAPWD was assessed from a signal-averaged electrocardiogram (SAECG), and the plasma levels of N-terminal pro-atrial natriuretic peptide (Nt-proANP) and N-terminal pro-brain natriuretic peptide (Nt-proBNP) were measured in 43 consecutive patients with stable CHF without prior supraventricular arrhythmia. Echocardiographic and clinical data were also recorded. Time to death, hospitalization due to deteriorated CHF, or ECG-documented atrial fibrillation (AF) was recorded over a 438-day median follow-up. RESULTS: During follow-up, 17 patients met an endpoint defined as death, AF, or hospitalization due to deteriorated CHF. Proportional hazard regression including the variables high age, prolonged SAPWD, raised levels of Nt-proANP and Nt-proBNP, and low ejection fraction (EF) showed that only prolonged SAPWD > or =149 ms was associated with an increased risk of meeting an early endpoint; the hazard ratio 3.94 with 95% confidence interval 1.50-10.42; p = 0.006. CONCLUSION: Prolonged SAPWD appears to predict early death, AF development, or hospitalization due to deterioration of CHF in patients with stable CHF.     

Treatment of Newly Diagnosed Glioblastoma Multiforme with Carmustine,Cisplatin and Etoposide Followed by Radiotherapy. A Phase II Study

A meta-analysis and several studies of patients with grade III and IV gliomas have indicated that the addition of nitrosurea based chemotherapy to surgery and radiation may improve survival. We performed a phase II study of pre-irradiative chemotherapy with BCNU, cisplatin and etoposide. This implies a short total treatment duration and a reliable response evaluation.The treatment schedule was three cycles of BCNU 200mg/m² i.v. on day 1, cisplatin 20mg/m² i.v. on day 1–5 and etoposide (VP-16) 100mg/m² i.v. on day 1–5, given every five weeks and followed by localized radiation, 60Gy in 30 fractions. Twenty-nine patients with newly diagnosed glioblastoma multiforme (GBM), mean age 50 (27–66) and performance status (PS) 0–2 were included.Using the Macdonald criteria 33% had partial remission (PR), 41% stable disease (SD) and 26% progressive disease (PD) after chemotherapy. After additional radiation 44% had PR, 37% SD and 19% PD. Non-hematological toxicity and leukopenia was mild, but thrombocytopenia (TP) frequent. Grade III and IV TP occurred in 25% and 57% respectively, and grade III bleeding in 45%. No severe or fatal complications was seen. Median time to progression (TTP) was 7.6 months (6.0–9.1) and median survival was 11.4 months (10.1–12.7).We conclude that this regimen is effective and feasible in patients with GBM. The short course pre-irradiatory chemotherapy may be less cumbersome than adjuvant chemotherapy and the regimen may be even more active in grade III gliomas.     

Kinematics of fast cervical rotations in persons with chronic neck pain: a cross-sectional and reliability study

Background  

Assessment of sensorimotor function is useful for classification and treatment evaluation of neck pain disorders. Several studies have investigated various aspects of cervical motor functions. Most of these have involved slow or self-paced movements, while few have investigated fast cervical movements. Moreover, the reliability of assessment of fast cervical axial rotation has, to our knowledge, not been evaluated before.