Adenosine A1 receptor activation attenuates cardiac hypertrophy and fibrosis in response to α1 -adrenoceptor stimulation in vivo.

BACKGROUND AND PURPOSE: Adenosine has been proposed to exert anti-hypertrophic effects. However, the precise regulation and the role of the different adenosine receptor subtypes in the heart and their effects on hypertrophic signalling are largely unknown. We aimed to characterize expression and function of adenosine A1 receptors following hypertrophic stimulation in vitro and in vivo. EXPERIMENTAL APPROACH: Pro-hypertrophic stimuli and adenosine A1 receptor stimulation of neonatal rat cardiomyocytes and male C57/Bl6 mice, sc. drug administration, real-time PCR, (3) [H]-leucine-incorporation assay, immunostaining, tissue staining, Western blots, gravimetric analyses and echocardiography were applied in this study. KEY RESULTS: In neonatal rat cardiomyocyte cultures, phenylephrine, but not angiotensin II or insulin-like growth factor 1 (IGF1), up-regulated adenosine A1 receptors concentration-dependently. The hypertrophic phenotype (cardiomyocyte size, sarcomeric organization, total protein synthesis, c-fos expression) mediated by phenylephrine (10 µM), but not that by angiotensinII (1 µM) or IGF1 (20 ng·mL(-1) ), was counteracted by the selective A1 receptor agonist, N6-cyclopentyladenosine. In C57/BL6 mice, continuous N6-cyclopentyladenosine infusion (2 mg·kg(-1) ·day(-1) ; 21 days) blunted phenylephrine (120 mg·kg(-1) ·day(-1) ; 21 days) induced hypertrophy (heart weight, cardiomyocyte size and fetal genes), fibrosis, MMP 2 up-regulation and generation of oxidative stress - all hallmarks of maladaptive remodelling. Concurrently, phenylephrine administration increased expression of adenosine A1 receptors. CONCLUSIONS AND IMPLICATIONS: We have presented evidence for a negative feedback mechanism attenuating pathological myocardial hypertrophy following α1 -adrenoceptor stimulation. Our results suggest adenosine A1 receptors as potential targets for therapeutic strategies to prevent transition from compensated myocardial hypertrophy to decompensated heart failure due to chronic cardiac pressure overload.

Take action to prevent diabetes--the IMAGE toolkit for the prevention of type 2 diabetes in Europe.

When we ask people what they value most, health is usually top of the list. While effective care is available for many chronic diseases, the fact remains that for the patient, the tax payer and the whole of society: prevention is better than cure. Diabetes and its complications are a serious threat to the survival and well-being of an increasing number of people. It is predicted that one in ten Europeans aged 20-79 will have developed diabetes by 2030. Once a disease of old age, diabetes is now common among adults of all ages and is beginning to affect adolescents and even children. Diabetes accounts for up to 18 % of total healthcare expenditure in Europe. The good news is that diabetes is preventable. Compelling evidence shows that the onset of diabetes can be prevented or delayed greatly in individuals at high risk (people with impaired glucose regulation). Clinical research has shown a reduction in risk of developing diabetes of over 50 % following relatively modest changes in lifestyle that include adopting a healthy diet, increasing physical activity, and maintaining a healthy body weight. These results have since been reproduced in real-world prevention programmes. Even a delay of a few years in the progression to diabetes is expected to reduce diabetes-related complications, such as heart, kidney and eye disease and, consequently, to reduce the cost to society. A comprehensive approach to diabetes prevention should combine population based primary prevention with programmes targeted at those who are at high risk. This approach should take account of the local circumstances and diversity within modern society (e.g. social inequalities). The challenge goes beyond the healthcare system. We need to encourage collaboration across many different sectors: education providers, non-governmental organisations, the food industry, the media, urban planners and politicians all have a very important role to play. Small changes in lifestyle will bring big changes in health. Through joint efforts, more people will be reached. The time to act is now.

A European evidence-based guideline for the prevention of type 2 diabetes.

BACKGROUND: The prevalence and socioeconomic burden of type 2 diabetes (T2DM) and associated co-morbidities are rising worldwide. AIMS: This guideline provides evidence-based recommendations for preventing T2DM. METHODS: A European multidisciplinary consortium systematically reviewed the evidence on the effectiveness of screening and interventions for T2DM prevention using SIGN criteria. RESULTS: Obesity and sedentary lifestyle are the main modifiable risk factors. Age and ethnicity are non-modifiable risk factors. Case-finding should follow a step-wise procedure using risk questionnaires and oral glucose tolerance testing. Persons with impaired glucose tolerance and/or fasting glucose are at high-risk and should be prioritized for intensive intervention. Interventions supporting lifestyle changes delay the onset of T2DM in high-risk adults (number-needed-to-treat: 6.4 over 1.8-4.6 years). These should be supported by inter-sectoral strategies that create health promoting environments. Sustained body weight reduction by >or= 5 % lowers risk. Currently metformin, acarbose and orlistat can be considered as second-line prevention options. The population approach should use organized measures to raise awareness and change lifestyle with specific approaches for adolescents, minorities and disadvantaged people. Interventions promoting lifestyle changes are more effective if they target both diet and physical activity, mobilize social support, involve the planned use of established behaviour change techniques, and provide frequent contacts. Cost-effectiveness analysis should take a societal perspective. CONCLUSIONS: Prevention using lifestyle modifications in high-risk individuals is cost-effective and should be embedded in evaluated models of care. Effective prevention plans are predicated upon sustained government initiatives comprising advocacy, community support, fiscal and legislative changes, private sector engagement and continuous media communication.

Analysis of symptoms and endoscopic findings in 117 patients with histological diagnoses of eosinophilic esophagitis.

BACKGROUND AND STUDY AIMS: Although eosinophilic esophagitis has been increasingly diagnosed over recent years, little is known about this disease. In this study, symptoms, accompanying allergic disorders, and endoscopic findings in 117 patients with eosinophilic esophagitis were analyzed retrospectively. PATIENTS AND METHODS: The physicians who had treated the 117 patients (mean age 42.2 years; 9 children, 108 adults; male patients 71.8%) with the histological diagnosis of eosinophilic esophagitis were asked to provide data on symptoms, accompanying allergic disorders, and endoscopic findings. RESULTS: In 82.2% of the patients symptoms appeared in adulthood, predominantly between the ages of 21 and 30 years. The average duration of symptoms until final diagnosis of eosinophilic esophagitis was 4.2 years (range 0-44 years). The most frequent symptom was dysphagia (70.1%), followed by heartburn (47%), chest pain (29%), epigastric pain (29%), and a combination of dysphagia and heartburn (29%). Allergic disorders were seen in 48.7% of our patients. The most frequent endoscopic findings were stipple-like exudates (25.6%), linear fissures (25.6%), and reddening (25.6%), followed by rings (18.8%) and strictures (16.2%) of the esophagus. The esophageal mucosa was regarded as "normal" in 24.8% of the patients. CONCLUSION: Dysphagia in the second or third decade of life may suggest eosinophilic esophagitis. Symptoms of eosinophilic esophagitis may be indistinguishable from those of gastroesophageal reflux disease. The endoscopic appearance is not specific. Biopsies taken from multiple locations in the esophageal mucosa are essential for diagnosis of eosinophilic esophagitis.

Influence of exercise training on physiological and performance changes with weight loss in men.

PURPOSE: The purpose of this study was to examine the physiological effects of a weight-loss dietary regimen with or without exercise. METHODS: Thirty-five overweight men were matched and randomly placed into either a control group (C; N = 6) or one of three dietary groups; a diet-only group (D; N = 8), a diet group that performed aerobic exercise three times per week (DE; N = 11); and a diet group that performed both aerobic and strength training three times per week (DES; N = 10). RESULTS: After 12 wk, D, DE, and DES demonstrated a similar and significant (P < or = 0.05) reduction in body mass (-9.64, -8.99, and -9.90 kg, respectively) with fat mass comprising 69, 78, and 97% of the total loss in body mass, respectively. The diet-only group also demonstrated a significant reduction in fat-free mass. Maximum strength, as determined by 1-RM testing in the bench press and squat exercise was significantly increased for DES in both the bench press (+19.6%) and squat exercise (+32.6%). Absolute peak O2 consumption was significantly elevated in DE (+24.8%) and DES (+15.4%). There were no differences in performance during a 30-s Wingate test for the DE and DES, whereas D demonstrated a significant decline in peak and mean power output. Resting metabolic rate (RMR) (kcal x d(-1)) was not significantly different for any of the groups except for the DE group. There were no significant changes in basal concentrations of serum glucose, BUN, cortisol, testosterone, and high density lipoprotein (HDL) cholesterol for any of the groups. Serum total cholesterol and low density lipoprotein (LDL) cholesterol were significantly decreased for all dietary groups. Serum triglycerides were significantly reduced for D and DES at week 6 and remained lower at week 12 for D, while triglycerides returned to baseline values for DES. CONCLUSIONS: These data indicate that a weight-loss dietary regimen in conjunction with aerobic and resistance exercise prevents the normal decline in fat-free mass and muscular power and augments body composition, maximal strength, and maximum oxygen consumption compared with weight-loss induced by diet alone.

Lymphangiosarcomas in cats: a retrospective study of 12 cases.

Clinical, macroscopic, and histologic features of 12 lymphangiosarcomas in cats are described. Nine tumors were located in the subcutaneous tissue at the caudoventral abdominal wall (eight cats) or in the neck (one cat). The remaining three cats had lymphangiosarcomas around the cranial mesenteric artery (two cats) or precardial in the mediastinum (one cat). Macroscopically, the tumors were noncircumscribed, white, edematous, and intermixed with fat tissue. Histologic features varied from cleft-forming and cavernous growth to papilliform and solid patterns. Follow-up data were available for seven cats with subcutaneous lymphangiosarcomas. All these cats died or were euthanatized within 6 months after surgery because of poor wound healing, local recurrence, or distant metastases. The cats with abdominal or thoracic masses were either euthanatized at surgery or within 6 months after the first surgery because of recurrent chylothorax, chyloperitoneum, or distant metastases.

Physiological adaptations to a weight-loss dietary regimen and exercise programs in women.

Thirty-one women (mean age 35.4 +/- 8.5 yr) who were overweight were matched and randomly placed into either a control group (Con; n = 6), a diet-only group (D; n = 8), a diet+aerobic endurance exercise training group (DE; n = 9), or a diet+aerobic endurance exercise training+strength training group (DES; n = 8). After 12 wk, the three dietary groups demonstrated a significant (P

Simultaneous derivation of clothing-specific heat exchange coefficients.

Clothing adds resistance to heat exchange between the wearer and the environment. If clothing-specific heat exchange coefficients are known, a combined rational/empirical approach can be used to describe thermal exchange between clothed humans and the environment. However, during exercise these coefficients--typically calculated using thermal manikins--change, primarily due to wetting of the fabric during intense sweating and body movement. A procedure is described that allows for the simultaneous determination of both total insulation (IT) and resistance to water vapor permeation (Re) on exercising clothed subjects without the need to directly measure skin water vapor pressure or continuously weigh the subjects. Two tests are performed by each subject in each clothing ensemble. In one test, ambient water vapor pressure (Pa) is systematically increased in stepwise fashion while dry-bulb temperature (Tdb) is held constant; in the second test protocol Pa is held constant while Tdb is increased. Heat exchange data are collected at the time at which core temperature is forced out of equilibrium by the environment (according to the assumption that heat production is balanced by heat loss immediately prior to this critical environmental limit). Previous studies using similar approaches have typically estimated IT a priori and used this value in the subsequent derivation of Re for each clothing ensemble or condition tested. In the proposed method, IT and Re are derived from the solution of two simultaneous equations based on heat balance data from both tests. This paper describes and critiques this methodology via an error analysis, and compares the coefficients obtained with those from similar trials using other physiological and nonphysiological approaches.

Fat-free mass in relation to stature: ratios of fat-free mass to height in children, adults, and elderly subjects.

A cross-sectional relationship of fat-free mass to height expressed as a ratio (FFM:ht) is presented for 1103 people aged 6-86 y. Data are presented for 13 specific age groups by gender. By providing information for normal, healthy individuals, these data may be of comparative value for nutritionists and clinicians concerned with body composition of patients with wasting diseases. The data were collected over 20 y in our laboratory by using the same densitometric procedure. A significant increase in FFM:ht occurs during the preadolescent and adolescent years. The adolescent spurt continues for a longer period for boys than for girls, resulting in a significant gender difference beginning at approximately age 16 y and continuing throughout adulthood. A decline in FFM:ht, not statistically significant, appears to occur in men greater than 60 y of age, and a significant decline occurs among women greater than 50 y of age (alpha less than 0.01). Thus, both gender- and age-related trends that have implications for the interpretation of comparative body-composition status are suggested.

Alpha 1-adrenergic blockade does not alter control of skin blood flow during exercise.

Human skin blood flow (SkBF) is controlled by both an alpha-adrenergic vasoconstrictor system and an active vasodilator system. During upright dynamic exercise, SkBF increases linearly with increasing body core temperature (Tc) until higher (i.e., greater than 38 degrees C) Tcs, beyond which little further increase in SkBF occurs. To examine the role of the two efferent control arms in this attenuated SkBF rise, we tested nine men (aged 25-53 yr) with and without (placebo) orally administered prazosin HCl (an alpha 1-adrenergic antagonist) during 1 h of moderate cycle exercise (100 W) in a warm (36 degrees C, 45% relative humidity) environment. Blockade of reflex vasoconstriction was verified via a cold challenge. During exercise, mean arterial pressure (MAP, brachial auscultation) was significantly lower (P less than 0.03) and heart rate significantly higher (P less than 0.02) during the prazosin trials; plasma catecholamine concentrations were unaffected. Neither esophageal temperature (Tes) nor mean skin temperature was affected by the drug during exercise. Forearm vascular conductance (FVC) was calculated from forearm blood flow (FBF, venous occlusion plethysmography) and MAP (FVC = FBF/MAP). FVC plotted as a function of time or Tes resulted in coincident response patterns for the placebo and prazosin treatments, reaching a plateau at a Tes of about 38 degrees C. The responses of the older men were not selectively altered by prazosin treatment, indicating that the lower FBF responses previously seen in older subjects during exercise in the heat does not appear to be the result of an increased alpha 1-adrenergic tone.(ABSTRACT TRUNCATED AT 250 WORDS)

Age and hypohydration independently influence the peripheral vascular response to heat stress.

Seven young (Y, 22-28 yr) and seven middle-aged (MA, 49-60 yr) normotensive men of similar body size, fatness, and maximal oxygen uptake (VO2max) were exposed to a heat challenge in an environmental chamber (48 degrees C, 15% relative humidity). Tests were performed in two hydration states: hydrated (H, 25 ml water/kg body wt 1 h before the test, 2.5 h before exercise) and hypohydrated (Hypo, after 18-20 h of water deprivation). Each test began with a 90-min rest period during which the transiently increased plasma volume and decreased osmolality after drinking in the H condition returned to base line. This period was followed by 30 min of cycle exercise at a mean intensity of 43% VO2max and a 60-min resting recovery period with water ad libitum. Although prior drinking caused no sustained changes in plasma osmolality, Hypo increased plasma osmolality by 7-10 mosmol/kg in both groups. There were no significant age differences in water intake, urine output or osmolality, overall change in body weight, or sweating rate. In the H state, the percent change in plasma volume was less (P less than 0.01) during exercise for the Y group (-5.9 +/- 0.7%) than for the MA group (-9.4 +/- 0.6%). Esophageal temperature (Tes) was higher in the Hypo condition for both groups with no age-related differences. Throughout the 3-h period, mean skin temperature was higher in the Y group and significantly so (P less than 0.05) in the Hypo condition.(ABSTRACT TRUNCATED AT 250 WORDS)

Zinc sulfate in acne vulgaris.

The effects of orally administered zinc sulfate in 52 patients with mild to moderate acne vulgaris were compared to those of a placebo capsule. The numbers of comedones, papules, pustules, infiltrates, and cysts were counted at each visit over a 12-week period. Forty patients completed the study. Zinc appeared to have a somewhat beneficial effect on pustules but not on comedones, papules, infiltrates, or cysts. Fourteen patients (50%) in the zinc group had side effects of nausea, vomiting, or diarrhea. Six patients (21%) in the zinc group could not tolerate the nausea and withdrew from the study.