Sirtuin 6 (SIRT6) regulates redox homeostasis and signaling events in human articular chondrocytes.

The nuclear localized protein deacetylase, SIRT6, has been identified as a crucial regulator of biological processes that drive aging. Among these processes, SIRT6 can promote resistance to oxidative stress conditions, but the precise mechanisms remain unclear. The objectives of this study were to examine the regulation of SIRT6 activity by age and oxidative stress and define the role of SIRT6 in maintaining redox homeostasis in articular chondrocytes. Although SIRT6 levels did not change with age, SIRT6 activity was significantly reduced in chondrocytes isolated from older adults. Using dimedone-based chemical probes that detect oxidized cysteines, we identified that SIRT6 is oxidized in response to oxidative stress conditions, an effect that was associated with reduced SIRT6 activity. Enhancement of SIRT6 activity through adenoviral SIRT6 overexpression specifically increased the basal levels of two antioxidant proteins, peroxiredoxin 1 (Prx1) and sulfiredoxin (Srx) and decreased the levels of an inhibitor of antioxidant activity, thioredoxin interacting protein (TXNIP). Conversely, in chondrocytes derived from mice with cartilage specific Sirt6 knockout, Sirt6 loss decreased Prx1 levels and increased TXNIP levels. SIRT6 overexpression decreased nuclear-generated H2O2 levels and oxidative stress-induced accumulation of nuclear phosphorylated p65. Our data demonstrate that SIRT6 activity is altered with age and oxidative stress conditions associated with aging. SIRT6 contributes to chondrocyte redox homeostasis by regulating specific members of the Prx catalytic cycle. Targeted therapies aimed at preventing the age-related decline in SIRT6 activity may represent a novel strategy to maintain redox balance in joint tissues and decrease catabolic signaling events implicated in osteoarthritis (OA).

Health services utilization, satisfaction, and attachment to a regular source of care among participants in an urban health provider alliance.

This study examines the effect of a provider alliance on service utilization, satisfaction , self efficacy, and attachment to a regular source of care for participating low income urban children and their families. The use of Physician Assistants and community health workers to expand community outreach, primary care services, pediatric sub-specialty care, and service coordination within and between care settings improved health services utilization, satisfaction with health services, parental self efficacy in navigating the health care system for their children, and service convenience for an at-risk population. Also, the use of Physician Assistants to provide pediatric sub-specialty services did not have a negative effect on parental satisfaction with a child's care. Parents were slightly more satisfied with services received from a Physician Assistant in comparison with the physician sub- specialists in cardiology and nephrology clinics.

Sex and race differences in cardiovascular disease risk factor changes in schoolchildren, 1975-1990: the Princeton School Study.

OBJECTIVES: This study was done to assess changes in obesity and risk factors for cardiovascular disease (CVD) in Black and White children from 1975 through 1990. METHODS: A cross-sectional study of body composition and CVD risk factors conducted in a school district as part of the Lipid Research Clinics (LRC) Program Prevalence Study (1973-1975) was compared with a later study (1989-1990) conducted in the same school district, which remained demographically stable. The studies included 1456 third- and fifth-grade students and 300 LRC subjects within the same age ranges. RESULTS: Students in the 1989-1990 study had a significantly higher mean body mass index (BMI), total blood cholesterol concentration, and systolic and diastolic blood pressures and marginally higher resting heart rates than those in the earlier study. The prevalence of obesity increased from 12.5% to 25.3%, and of hypercholesterolemia from 8.0% to 14.8%. Black females had the largest increase in BMI and resting heart rate and the highest prevalence of elevated total cholesterol in the 1989-1990 study. CONCLUSIONS: The results of this study suggest a secular trend toward increased obesity in children and portend the potential development of a public health problem that could reverse the recent decline in morbidity from CVD.

[Cycloergometric exercise test in normal children: comparison of an Italian and a North American population]. / La prova da sforzo al cicloergometro in bambini normali: confronto tra una popolazione italiana e nord americana.

The need for a more complete protocol for bicycle ergometer exercise testing in children in our country, induced the Authors to apply the F.W. James protocol to healthy Italian children and then compare the results with a study on a similar american sample population. A total of 102 children, 67 males and 35 females, age range 4.4 - 17 years (mean 10.3 yrs), were examined following the F.W. James protocol. The Authors report the anthropometric and ergometric data obtained, the comparison with James' results and the linear correlation coefficients. Normal reference data were obtained. There were no significant differences between the results obtained from the Italian and American groups, and the correlation coefficients were satisfactory. The results will enable us to benefit from a simple and complete protocol which can be applied to healthy and sick children alike in our country.

Regional myocardial blood flow and cardiac mechanics in dog hearts with CO2 laser-induced intramyocardial revascularization.

Laser-induced intramyocardial revascularization (LIR) has been used to promote direct communications between blood within the ventricular cavity and that of the existing myocardial vasculature in an attempt to increase perfusion in patients with ischemic heart disease. This study was conducted to measure the effects of LIR channels on regional myocardial flood flow (microspheres), cardiac mechanics (sonomicrometers), and myocardial tissue pressures in 18 dogs. Under baseline hemodynamic conditions (mean HR = 165.2 +/- 11.4 bpm, LVP = 123.6 +/- 22.9/4.0 +/- 1.8 mm Hg, AoP = 112.8 +/- 27.1/77.0 +/- 22.5 mm Hg), myocardial blood flow in laser-treated tissue (mean = 1.11 +/- .10 cc/min/gm before laser; .71 +/- .19 cc/min/gm after laser) was reduced as compared to blood flow in control tissue (mean = 1.12 +/- .15 cc/min/gm before laser; 1.25 +/- .22 cc/min/gm after laser). Regional myocardial systolic shortening (11.32% +/- 3.82% before laser; 7.49% +/- 2.86% after laser) was decreased by 33%. During simultaneous reversible ligation of the LAD and LCCA for 2 min, when intramyocardial channels represented the only tissue access for the injected microspheres, blood flow in laser-treated tissue was not increased above that of the control non-lasered tissue. However, regional blood flow was greater in laser-treated ischemic tissue (mean = .61 +/- .12 cc/min/gm) than in untreated ischemic areas (mean = .04 +/- .03 cc/min/gm) when left ventricular pressure (LVP) was acutely elevated (mean SLVP = 207.0 +/- 16.1 mm Hg). Using these measurements, a model is proposed to predict regional systolic pressure gradients between the left ventricular cavity and coronary intramyocardial vasculature required to permit restoration of blood flow to ischemic myocardium. We conclude that improved perfusion via laser-induced intramyocardial channels does not occur in otherwise normal myocardium exposed to acute coronary ligation and only small improvements in perfusion are noted when LVP is significantly elevated. Consideration of further clinical application of this approach is seriously cautioned awaiting additional experimental studies.

Cardiac performance in children with pectus excavatum.

Fourteen children with pectus excavatum and 14 normal control patients underwent graded exercise testing using a cycle ergometer and the James protocol. All the subjects were preoperative. The children were exercised to exhaustion during the test. The pectus and control groups were broken down into subgroups consisting of subjects less than or equal to 10 years of age and subjects greater than or equal to 11 years of age (pectus and controls less than or equal to 10 years old, PI and CI, respectively; pectus and controls greater than or equal to 11 years old, PII and CII, respectively). Maximal workload, oxygen consumption, cardiac output, and stroke volume were not significantly different when comparing the total groups or when each of the respective subgroups were compared. However, maximal diastolic BP was significantly elevated when the entire pectus and control groups were compared. When the subgroups were compared, maximal diastolic BP was elevated only in the older pectus patients (PII) and remained so until five minutes after exercise. Additionally, left ventricular systolic time intervals were measured immediately after exercise in all the children. The ratio of preejection period to left ventricular ejection time (P/L) was significantly shortened in the total pectus group. When the subgroups were compared, the P/L ratio was significantly decreased only in the older patients. Also, the preejection period (PEP) was significantly shortened in the older pectus patients. It appears that children with pectus excavatum have a normal exercise tolerance and oxygen transport. However, older pectus children develop an increased diastolic BP and a shortened P/L and PEP in response to exercise.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood pressure and cardiac output during exercise: a longitudinal study of children undergoing repair of coarctation.

Data were examined from 21 children who underwent graded exercise studies prior to and within 5 years after repair of coarctation. A control group of 10 normal children was also studied longitudinally on two occasions. The exercise was performed on an upright bicycle ergometer using a continuous graded exercise protocol. Parameters measured were heart rate, systolic and diastolic blood pressure at rest, and these pressures at the maximal voluntary exercise level. In addition, a subset of patients and controls had measurement of cardiac output by a modified acetylene rebreathing technique. Results indicate that coarctation patients had significant elevation of systolic and diastolic blood pressures at rest (p less than 0.001 for both) and with exercise (p less than 0.02 for both) prior to surgery. The group mean values for systolic and diastolic blood pressure did not differ from control values after surgery; however, some individuals continued to have hypertension at rest when compared to population-based norms. Heart rate, cardiac index, and stroke volume index did not differ from those of control subjects either at rest or during exercise before or after surgery. In conclusion, a group of coarctation patients studied longitudinally demonstrated marked improvement in both systolic and diastolic hypertension after surgery. The findings of normal cardiac output and stroke volume indices may have implications for the etiology of postoperative hypertension.

Azelastine effects on electrical and mechanical activities of guinea pig papillary muscles.

The effects of azelastine, a new anti-asthmatic drug under clinical investigation, were studied on both normal fast action potentials (APs) and slow APs using conventional microelectrode techniques in guinea pig papillary muscles (superfused with oxygenated Tyrode solution at 37 degrees C). Slow APs were induced by either 10(-7) M isoproterenol, 10(-5) M histamine, db-cAMP (3 mM) or 10 mM TEA, in the presence of 25 mM [K]o to voltage inactive the fast Na+ channels. At 10(-5) M, azelastine depressed the maximum rate of rise (+Vmax) of the slow APs and the force of contraction. At 3 X 10(-5) M, azelastine further reduced +Vmax and the amplitude of the slow APs; complete abolishing of slow APs and contractions occurred at 10(-4) M. Upon washout of the drug, automaticity appeared. In the presence of 10(-4) M azelastine, increasing the [Ca]o concentration from 1.8 to 3.6 and 5.4 mM caused partial recovery of the slow APs and contractions. The fast APs were also depressed by azelastine. At 10(-5) and 3 X 10(-5) M, azelastine reduced +Vmax and the AP duration at 50% repolarization (APD50) of the fast APs. Complete block of the fast APs and suppression of contractions were observed after 30 min at 10(-4) M azelastine. After 3-5 h of washout, excitability recovered; however, +Vmax was depressed and APD90 was prolonged. It is concluded that azelastine inhibits the slow Ca2+ channels and the fast Na+ channels. The slow recovery suggests that the drug may accumulate inside the cells, and exert a prolonged inhibitory effect on contraction.

Hemodynamic response to exercise in patients with sickle cell anemia.

In order to evaluate potential electrocardiographic (ECG) correlates of ST-segment depression during exercise in patients with sickle cell anemia (SS), 43 subjects, aged 5-23 years, underwent submaximal exercise testing. Eight (19%) had ST-segment depression on the exercise ECG during submaximal exercise. These eight patients had significantly lower hemoglobin levels than the 35 subjects without evidence of ST-segment depression. These eight subjects also had significantly higher peak blood pressures and peak heart rates than the 35 subjects without ST-segment depression. The product of peak heart rate and peak systolic blood pressure, the maximal double product, is a correlate of myocardial oxygen consumption and was significantly higher in the patients with ST-segment depression than in the patients without ST-segment depression. These results indicate that patients with SS and evidence of exercise-induced ST-segment depression may have decreased myocardial oxygen supply due to low hemoglobin levels and increased myocardial oxygen demand (elevated double products) when compared to subjects with SS who do not have exercise-induced ST-segment depression.

Comparison of the cardiac output and stroke volume response to upright exercise in children with valvular and subvalvular aortic stenosis.

Cardiac output and stroke volume were evaluated in 17 children (mean age 11.5 +/- 3 years) with discrete, membranous subvalvular (Group I, n = 7) and valvular (Group II, n = 10) aortic stenosis during submaximal and maximal (greater than 75% predicted maximal oxygen consumption) upright cycle ergometry. Patients with valvular aortic stenosis were further subdivided on the basis of their aortic valve gradient at rest determined by cardiac catheterization (Group IIA, gradient less than 40 mm Hg; Group IIB, gradient greater than or equal to 40 mm Hg). These patients were matched with 17 control subjects on the basis of age, sex, height and intensity of exercise during maximal exertion. Cardiac and stroke indexes were determined by the acetylene rebreathing method at each exercise level. Stroke volume index in Group I was significantly greater at rest when compared with that in control subjects (69 +/- 13 versus 53 +/- 11 ml/m2, alpha = 0.01, p less than 0.05) and that in patients in Group II (69 +/- 13 versus 47 +/- 12 ml/m2, alpha = 0.01, p less than 0.05). Patients with subvalvular aortic stenosis were unable to increase their stroke volume index from rest to submaximal exercise and also decreased their stroke volume index at maximal exercise levels. In contrast, patients with mild valvular aortic stenosis (Group IIA) displayed a normal exercise response. Patients with severe valvular aortic stenosis (Group IIB) had a blunted stroke volume response at rest and at each level of exercise, as well as signs of myocardial ischemia (ST segment depression) during maximal exercise.(ABSTRACT TRUNCATED AT 250 WORDS)

Correlates of resting and maximal exercise systolic blood pressure after repair of coarctation of the aorta: a multivariable analysis.

Repair of coarctation of the aorta may not prevent the subsequent development of elevated systemic blood pressure at rest or with exercise. The correlates of late postoperative resting systolic blood pressure and maximal exercise systolic blood pressure levels were investigated in a retrospective study of 42 patients who had graded exercise tests after correction of coarctation of the aorta. The independent variables studied included height, weight, body surface area, age at surgery, age at exercise testing, the time interval between surgery and exercise testing, the highest systolic blood pressure prior to surgery, gradient across the coarctation at preoperative catheterization, and the residual postoperative gradient across the coarctation. The same combination of independent variables provided the best regression model for explanation of the variance of both postoperative resting and maximal exercise systolic blood pressure. The models included height, highest preoperative systolic blood pressure, and residual gradient. None of the other variables added significant explanatory ability to either model. These findings suggest that the preoperative level of systolic blood pressure may be the best determinant of timing the corrective surgery. It may be possible to defer the operation, as long as blood pressure remains normal, until an age when repair is less likely to result in recurrent coarctation.

A histologic study of laser-induced transmyocardial channels.

Carbon dioxide lasers are reported to provide ischemic myocardium direct access to blood within the ventricular cavity by inducing transmyocardial channels which maintain patency in long-term experiments. We have histologically examined the natural history of channels produced with this technique and compared them with transmyocardial channels created by needle puncture. Immediately after application of the laser, four concentric zones vaporization, carbonization, fixation, and transition could be distinguished along the transmyocardial path. Needle puncture channels were fully occluded within 48 hr, whereas laser-induced channels maintained partial patency for a 2-week period, after which they also became occluded. It appears likely that the instantaneous vaporization produced by the laser may delay the release of factors which mediate the healing process, but occlusion of channels was universal in this study. It remains to be determined whether or not variables such as wattage, beam diameter, or tissue temperature influence long-term channel patency.

Effects of exercise training on insulin sensitivity in adolescents with type I diabetes.

We investigated the influence of a program of exercise training consisting of three weekly sessions, each 45 min long, for 12 wk, on indices of physical fitness, glycemic control, and insulin sensitivity in nine adolescents with type I diabetes; six age-matched adolescents with diabetes of equivalent duration served as nonexercised controls. All subjects were instructed not to change dialy insulin dose or caloric intake. In the exercised group, maximal oxygen uptake during graded cycle ergometry to volitional exhaustion increased by 9 +/- 2.7% (P less than 0.01) and lean body mass increased by 4 +/- 1.8% (P less than 0.05). Insulin sensitivity, assessed via the euglycemic clamp technique at insulin infusion rates of 100 mU/M2/min, showed an increase of insulin-mediated glucose disposal from 274 +/- 33 to 338 +/- 28 mg/M2/min, representing an increase in insulin sensitivity of 23 +/- 5% (P less than 0.01). None of these indices changed in the control group. Despite increased insulin sensitivity, glycohemoglobin levels remained at 12 +/- 1% before and after the 12 wk of exercise training, indicating no improvement in overall glycemic control. No increase in hypoglycemic reactions was reported in either group. We conclude that exercise training may be a valuable adjunct in managing type I diabetes providing there is concomitant attention to diet and insulin. Exercise training alone, however, does not improve glycemic control, although it improves physical fitness and insulin sensitivity.

Concomitant psychological and cardiac improvement during successful treatment of anorexia nervosa.

A patient with anorexia nervosa in whom concurrent nutritional, psychological, and cardiovascular assessments were obtained sequentially during successful treatment is presented. At the time of diagnosis, severe multisystem dysfunction was present including depression, low self-esteem, hypotension, bradycardia, exercise intolerance, and abnormalities of systolic and diastolic cardiac function. Treatment resulted in weight gain and increased skinfold thickness and arm circumference. There were concomitant improvements in the psychometric indices of depression and self-esteem as well as decreased anorectic tendencies. During her recovery, working capacity increased and diastolic function improved. However, echocardiographic evidence of impaired systolic function persisted. Despite the apparent treatment success in this patient, this report suggests a potential need for further studies to determine the extent, if any, of long-term cardiac sequelae.