Pentoxifylline reduces pro-inflammatory and increases anti-inflammatory activity in patients with coronary artery disease - A randomized placebo-controlled study

The balance between different immunological stimuli is essential in the progression and stabilization of atherosclerotic plaques. Immune regulation has been suggested as potential target for the treatment of atherosclerotic disease. We sought to determine whether treatment with pentoxifylline, a phosphodiesterase inhibitor with immunomodulating properties, could reduce the pro-inflammatory response observed in patients with acute coronary syndromes (ACS) and increase anti-inflammatory activity. In a double-blind, prospective, placebo-controlled study, 64 patients with ACS were randomized to receive pentoxifylline 400 mg TID or placebo for 6 months. Analysis of the pro-inflammatory markers, Greactive protein (CRP), interleukin (IL)-6, IL-12, interferon-gamma and tumor necrosis factor (TNF)-alpha and the anti-inflammatory cytokines, transforming growth factor (TGF)-beta 1 and IL-10 were done at baseline, 1 and 6 months. Pentoxifylline treatment significantly reduced the adjusted levels of CRP and TNF-alpha compared to placebo after 6 months (P=0.04 and P < 0.01, respectively). IL-12 increase was significantly less pronounced with pentoxifylline (P=0.04). The levels of the anti-inflammatory cytokine, IL-10, also declined significantly less in the pentoxifylline group compared to placebo (P < 0.01) with a trend towards a higher increase of TGF-beta 1 in the former group (P=0.16). Pentoxifylline reduces pro-inflammatory and increases anti-inflammatory response in patients with ACS and may have beneficial clinical effects on cardiovascular events. (c) 2006 Elsevier Ireland Ltd. All rights reserved.

VALIDATION OF THE LONDON CHEST ACTIVITY OF DAILY LIVING SCALE IN PATIENTS WITH HEART FAILURE

Background: The Minnesota Living with Heart Failure Questionnaire (MLHFQ) is a well-validated, commonly-used tool to assess quality of life in patients with heart failure. However, it lacks specific information concerning breathlessness during daily activities. Objective: To determine the validity of the London Chest Activity of Daily Living (LCADL) scale for use in patients with heart failure. Methods: Forty-seven patients with heart failure (57% males, mean age 50 years (standard deviation 9), mean left ventricle ejection fraction 29% (SD 6), New York Heart Association (NYHA) functional class I-III) were included. All subjects first performed a cardiopulmonary exercise test and then responded to the LCADL and the MLHFQ, with guidance from the same investigator. The re-test for the LCADL was applied one week later. Results: LCADL was correlated with MLHFQ (r=0.88; p < 0.0001). LCADL and MLHFQ were also correlated with exercise capacity (r=-0.75 and r=-0.73, respectively; both p < 0.0001). The LCADL was shown to be reproducible (r(i)=0.98). There was a significant difference (p < 0.05) in the LCADL scores between NYHA functional classes I and II, as well as classes I and III, hut not between classes II and III. Conclusion: The LCADL was shown to be a valid measurement of dyspnoea during daily activities in patients with heart failure. This scale could be an additional useful tool for the assessment of patients` dyspnoea during activities of daily living.

Physical activity profile in heart failure patients from a Brazilian tertiary cardiology hospital

Background: Physical activity (PA) has proven benefits in the primary prevention of heart diseases such as heart failure (HF). Although it is well known, HF PA habits and physicians` advice have been poorly described. The aim of this study was to investigate if physicians were advising HF patients to exercise and to quantify patients` exercise profiles in a complex cardiology hospital. Methods: All 131 HF patients (80 male, average age 53 +/- 10 years, NYHA class I-V, left ventricular ejection fraction 35 +/- 11%, 35 ischemic, 35 idiopatic , 32 hypertensive and 29 with Chagas disease) went to the hospital for a HF routine check-up. On this occasion, after seeing the physician, we asked the patients if the physician had advised them about PA. Then, we asked them to fill in the international physical activity questionnaire (IPQA) Short Form to classify their PA level. Results: Our data showed a significant difference between patients who had received any kind of PA advice from physicians (36%) and those who had not (64%, p<0.0001). Using the IPAQ criteria, of the 36% of patients who had received advice, 12.4% were classified as low and 23.6% as moderate. Of the 64% of patients who did not receive advice, 26.8% were classified as lowand 37.2% as moderate. Etiology (except Chagas), functional class, ejection fraction, sex and age did not influence the PA profile. Conclusions: Physicians at a tertiary cardiology hospital were not giving patients satisfactory advice as to PA. Our data supports the need to strengthen exercise encouragement by physicians and for complementary studies on this area. (Cardiol J 2010; 17, 2: 143-148)

Impact of gender on benefits of exercise training on sympathetic nerve activity and muscle blood flow in heart failure

We compared the effects of exercise training on neurovascular control and functional capacity in men and women with chronic heart failure (HF). Forty consecutive HF outpatients from the Heart Institute, University of Sao Paulo, Brazil were divided into the following four groups matched by age: men exercise-trained (n = 12), men untrained (n = 10), women exercise-trained (n = 9), women untrained (n = 9). Maximal exercise capacity was determined from a maximal progressive exercise test on a cycle ergometer. Forearm blood flow was measured by venous occlusion plethysmography. Muscle sympathetic nerve activity (MSNA) was recorded directly using the technique of microneurography. There were no differences between groups in any baseline parameters. Exercise training produced a similar reduction in resting MSNA (P = 0.000002) and forearm vascular resistance (P = 0.0003), in men and women with HF. Peak VO(2) was similarly increased in men and women with HF (P = 0.0003) and VE/VCO(2) slope was significantly decreased in men and women with HF (P = 0.0007). There were no significant changes in left-ventricular ejection fraction in men and women with HF. The benefits of exercise training on neurovascular control and functional capacity in patients with HF are independent of gender.

Muscle sympathetic nerve activity in patients with Chagas` disease

Background: The progression of heart failure in Chagas` disease has been explained by remodeling, leading to neurohumoral activation, or by the direct parasite damage to parasympathetic neurons during acute phase, leading to early sympathetic activation and progressive heart failure. To help distinguish between these hypotheses we studied muscle sympathetic nerve activity (MSNA) at rest and during handgrip exercise (30% of maximal voluntary contraction) in patients with Chagas` disease and normal ejection fraction vs. patients with heart failure. Methods: A consecutive study of 72 eligible out-patients/subjects was conducted between July 1998 and November 2004. The participants were classified in three advanced heart failure groups (New York Heart Association Functional Classes II-III): Chagas` disease (n-15), ischemic (n=15) and idiopathic cardiomyopathy (n-15). Twelve Chagas` disease patients without heart failure and normal ejection fraction, and 15 normal controls were also studied. MSNA was recorded directly from the peroneal nerve by microneurography technique. Results: MSNA was greater in heart failure patients when compared with Chagas` disease patients without heart failure (51 +/- 3 vs. 20 +/- 2 bursts/min P=0.0001). MSNA in Chagas` patients with normal ejection fraction and normal controls was not different. During exercise, MSNA was similar in all 3 heart failure groups. And, was lower in the Chagas` patients with normal ejection fraction than in patients with Chagas` disease and heart failure (28 +/- 1 vs. 63 +/- 5 bursts/min, respectively). Conclusion: MSNA is not elevated in patients with Chagas` disease with normal ejection fraction. These findings support the concept of remodeling and neurohumoral activation as a common pathway following significant cardiac injury. (C) 2008 Elsevier Ireland Ltd. All rights reserved.

Increased muscle sympathetic nerve activity predicts mortality in heart failure patients

Background: Previous studies have associated neurohumoral excitation, as estimated by plasma norepinephrine levels, with increased mortality in heart failure. However, the prognostic value of neurovascular interplay in heart failure (HF) is unknown. We tested the hypothesis that the muscle sympathetic nerve activity (MSNA) and forearm blood flow would predict mortality in chronic heart failure patients. Methods: One hundred and twenty two heart failure patients, NYHA II-IV, age 50 +/- 1 ys, LVEF 33 +/- 1%, and LVDD 7.1 +/- 0.2 mm, were followed up for one year. MSNA was directly measured from the peroneal nerve by microneurography. Forearm blood flow was obtained by venous occlusion plethysmography. The variables were analyzed by using univariate, stepwise multivariate Cox proportional hazards analysis, and Kaplan-Meier analysis. Results: After one year, 34 pts died from cardiac death. The univariate analysis showed that MSNA, forearm blood flow, LVDD, LVEF, and heart rate were significant predictors of mortality. The multivariate analysis showed that only MSNA (P = 0.001) and forearm blood flow (P = 0.003) were significant independent predictors of mortality. On the basis of median levels of MSNA, survival rate was significantly lower in pts with >49 bursts/min. Similarly, survival rate was significantly lower in pts with forearm blood flow <1.87 ml/min/100 ml (P = 0.002). Conclusion: MSNA and forearm blood flow predict mortality rate in patients with heart failure. It remains unknown whether therapies that specifically target these abnormalities will improve survival in heart failure. (C) 2008 Elsevier Ireland Ltd. All rights reserved.

Endostatin gene therapy enhances the efficacy of IL-2 in suppressing metastatic renal cell carcinoma in mice

We investigated whether the administration of IL-2 combined with endostatin gene therapy was able to produce additive or even synergistic immunomodulatory activity in a mouse model of metastatic renal carcinoma. Renca cells were injected into the tail vein of BALB/c mice. After 24 h, the animals were randomly divided into four groups (5 mice/group). One group of mice was the control, the second group received treatment with 100,000 UI of Recombinant IL-2 (Proleukin, Chiron) twice a day, 1 day per week during 2 weeks (IL-2), the third group received treatment with a subcutaneous inoculation of 3.6 x 10(6) endostatin-producing cells, and the fourth group received both therapies (IL-2 + ES). Mice were treated for 2 weeks. In the survival studies, 10 mice/group daily, mice were monitored daily until they died. The presence of metastases led to a twofold increase in endostatin levels. Subcutaneous inoculation of NIH/3T3-LendSN cells resulted in a 2.75 and 2.78-fold increase in endostatin levels in the ES and IL-2 + ES group, respectively. At the end of the study, there was a significant decrease in lung wet weight, lung nodules area, and microvascular area (MVA) in all treated groups compared with the control group (P < 0.001). The significant difference in lung wet weight and lung nodules area between groups IL-2 and IL-2 + ES revealed a synergistic antitumor effect of the combined treatment (P < 0.05). The IL-2 + ES therapy Kaplan-Meier survival curves showed that the probability of survival was significantly higher for mice treated with the combined therapy (log-rank test, P = 0.0028). Conjugated therapy caused an increase in the infiltration of CD4, CD8 and CD49b lymphocytes. An increase in the amount of CD8 cells (P < 0.01) was observed when animals received both ES and IL-2, suggesting an additive effect of ES over IL-2 treatment. A synergistic effect of ES on the infiltration of CD4 (P < 0.001) and CD49b cells (P < 0.01) was also observed over the effect of IL-2. Here, we show that ES led to an increase in CD4 T helper cells as well as cytotoxic lymphocytes, such as NK cells and CD8 cells, within tumors of IL-2 treated mice. This means that ES plays a role in supporting the actions of T cells.

Neural activity changes to emotional stimuli in healthy individuals under chronic use of clomipramine

Previous functional magnetic resonance imaging (fMRI) studies examined neural activity responses to emotive stimuli in healthy individuals after acute/subacute administration of antidepressants. We now report the effects of repeated use of the antidepressant clomipramine on fMRI data acquired during presentation of emotion-provoking and neutral stimuli on healthy volunteers. A total of 12 volunteers were evaluated with fMRI after receiving low doses of clomipramine for 4 weeks and again after 4 weeks of washout. Fear-, happiness-, anger-provoking and neutral pictures from the International Affective Picture System (IAPS) were used. Data analysis was performed with statistical parametric mapping (P < 0.05). Paired t-test comparisons for each condition between medicated and unmedicated states showed, to negative valence paradigms, decrease in brain activity in the amygdala when participants were medicated. We also demonstrated, across both positive and negative valence paradigms, consistent decreases in brain activity in the medicated state in the anterior cingulate gyrus and insula. This is the first report of modulatory effects of repeated antidepressant use on the central representation of somatic states in response to emotions of both negative and positive valences in healthy individuals. Also, our results corroborate findings of antidepressant-induced temporolimbic activity changes to emotion-provoking stimuli obtained in studies of subjects treated acutely with such agents.

Progesterone, estrogen and pregnancy do not decrease colon myoelectric activity in rats: An in vivo study

Background: Progesterone, estrogen and the hormonal complex of pregnancy have been responsible for some degree of colon hypomotility in human pregnancy. Objective: To find out if estrogen, progesterone and the hormonal complex of pregnancy decrease colon myoelectric activity. Methods: The study was performed in 37 healthy female rats in which electrodes were implanted on the serosa of the proximal ascendent, distal ascendent, transverse, and descendent colon. We analyzed the records of colon myoelectric activity in vivo in five groups: control, ovariectomized, ovariectomized and treated with estrogen, ovariectomized and treated with progesterone, and pregnant rats. Results: We found a great variation in myoelectric activity in all groups studied. The mean of electric activity did not show statistical difference among the five groups, but pregnant rats had a statistically significant higher duration of maximum electric activity in all distances from the cecocolon junction. Conclusion: Pregnant rats had a statistically higher duration of maximum electric activity. If we could transpose these results to humans, this increase in duration of colon myoelectric activity could explain, in part, the slight constipation that some pregnant women have. Copyright (C) 2008 S. Karger AG, Basel.

How can and do Australian doctors promote physical activity?

Background. Physical inactivity is recognized as an important public health issue. Yet little is known about doctors' knowledge, attitude, skills, and resources specifically relating to the promotion of physical activity. Our survey assessed the current practice, perceived desirable practice, confidence, and barriers related to the promotion of physical activity in family practice, Methods. A questionnaire was developed and distributed to all 1,228 family practitioners in Perth, Western Australia. Results. We received a 71% response (n = 789). Family practitioners are most likely to recommend walking to sedentary adults to improve fitness and they are aware of the major barriers to patients participating in physical activity. Doctors are less confident at providing specific advice on exercise and may require further skills, knowledge, and experience, Although they promote exercise to patients through verbal advice in the consultation, few use written materials or referral systems, Conclusions. There are significant differences between self-reports of current practice and perceived desirable practice in the promotion of physical activity by doctors, Future strategies need to address the self-efficacy of family physicians and involve resources of proven effectiveness. The potential of referral systems for supporting efforts to increase physical activity by Australians should be explored. (C) 1997 Academic Press.

Insulin-like growth factor-I induced and constitutive arginase activity differs among isolates of Leishmania derived from patients with diverse clinical forms of Leishmania braziliensis infection

Arginase activity has been related to leishmaniasis development, thus we studied the constitutive and insulin-like growth factor (IGF) I-induced arginase activity of Leishmania (Viannia) braziliensis isolates from patients with different clinical forms of American tegumentary leishmaniasis (ATL). Isolates from mucosal leishmaniasis presented higher basal levels of arginase activity than isolates from other clinical forms of ATL. Isolates from disseminated leishmaniasis that present mucosal lesion in some cases reached the arginase activity similar to that of isolates from mucosal leishmaniasis upon IGF-I stimulation. Differences in arginase activity may influence disease outcomes such as evolution to mucosal lesion in patients with L (V.) braziliensis infection. (C) 2010 Royal Society of Tropical Medicine and Hygiene. Published by Elsevier Ltd. All rights reserved.

Platelet GSK3B activity in patients with late-life depression: Marker of depressive episode severity and cognitive impairment?

Objective. Increased GSK3B activity has been reported as a state marker of major affective episodes in patients with depression and bipolar disorder. No study so far has addressed GSK3B activity in late-life depression. The aims of the present study were to determine GSK3B activity in platelets of elderly patients with major depression, and the association between GSK3B activity and the severity of depressive symptoms and cognitive impairment. Methods. Forty drug-free elderly patients with major depressive episode were compared to healthy older adults (n == 13). Severity of the depressive episode and current cognitive state were determined by the Hamilton Depression Scale (HAM-D) and the Cambridge Cognitive Test (CAMCOG), respectively. Total- and ser-9-phosphorylated GSK3B (tGSK3B and pGSK3B) were determined in platelets by enzyme immunometric assays (EIA). GSK3B activity was indirectly inferred by the GSK3B ratio (i.e. pGSK3B/tGSK3B). Results. Elderly depressed patients had significantly lower pGSK3B levels (P == 0.03) and GSK3B ratio (P == 0.03), indicating higher GSK3B activity. Higher GSK3B activity were observed in patients with severe depressive episode (HAM-D scores > 22, P == 0.03) and with cognitive impairment (CAMCOG scores < 86, P == 0.01). Conclusion. The present findings provide additional evidence of the involvement of GSK3B in the pathophysiology of late-life major depression. Higher GSK3B activity may be more relevant in those patients with more severe depressive symptoms and cognitive impairment.

Muscle sympathetic nervous activity in depressed patients before and after treatment with sertraline

Background Sympathetic hyperactivity is one of the mechanisms involved in the increased cardiovascular risk associated with depression, and there is evidence that antidepressants decrease sympathetic activity. Objectives We tested the following two hypotheses: patients with major depressive disorder with high scores of depressive symptoms (HMDD) have augmented muscle sympathetic nervous system activity (MSNA) at rest and during mental stress compared with patients with major depressive disorder with low scores of depressive symptoms (LMDD) and controls; sertraline decreases MSNA in depressed patients. Methods Ten HMDD, nine LMDD and 11 body weight-matched controls were studied. MSNA was directly measured from the peroneal nerve using microneurography for 3 min at rest and 4 min during the Stroop color word test. For the LMDD and HMDD groups, the tests were repeated after treatment with sertraline (103.3 +/- 40 mg). Results Resting MSNA was significantly higher in the HMDD [29.1 bursts/min (SE 2.9)] compared with LMDD [19.9 (1.6)] and controls [22.2 (2.0)] groups (P=0.026 and 0.046, respectively). There was a significant positive correlation between resting MSNA and severity of depression. MSNA increased significantly and similarly during stress in all the studied groups. Sertraline significantly decreased resting MSNA in the LMDD group and MSNA during mental stress in LMDD and HMDD groups. Sertraline significantly decreased resting heart rate and heart rate response to mental stress in the HMDD group. Conclusion Moderate-to-severe depression is associated with increased MSNA. Sertraline treatment reduces MSNA at rest and during mental challenge in depressed patients, which may have prognostic implications in this group. J Hypertens 27:2429-2436 (c) 2009 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.

Conditioning training and retrieval increase phospholipase A(2) activity in the cerebral cortex of rats

In rats, phospholipase A(2) (PLA(2)) activity was found to be increased in the hippocampus immediately after training and retrieval of a contextual fear conditioning paradigm (step-down inhibitory avoidance [IA] task). In the present study we investigated whether PLA(2) is also activated in the cerebral cortex of rats in association with contextual fear learning and retrieval. We observed that IA training induces a rapid (immediately after training) and long-lasting (3 h after training) activation of PLA(2) in both frontal and parietal cortices. However, immediately after retrieval (measured 24 h after training), PLA(2) activity was increased just in the parietal cortex. These findings suggest that PLA(2) activity is differentially required in the frontal and parietal cortices for the mechanisms of contextual learning and retrieval. Because reduced brain PLA(2) activity has been reported in Alzheimer disease, our results suggest that stimulation of PLA(2) activity may offer new treatment strategies for this disease.