The influence of assistance in home-based exercise programmes for individuals with intellectual disabilities.

BACKGROUND: Regular physical activity (PA) decreases the risk of comorbidities associated with a sedentary lifestyle in individuals with intellectual disabilities (IDs). They also may experience additional barriers that may prevent PA, including access, proper instruction and support. At-home PA programming is a feasible alternative to long-term adherence. This study aimed to determine (1) how an at-home DVD programme affects PA adherence and (2) the extent to which caregiver support influences PA. METHODS: Thirty-one adolescent or adult-aged participants with mild or moderate ID were randomised into a DVD or control group exercise intervention. Participants were given autonomy to choose what type of PA modality from the intervention they would like to participate in. Caregiver support during the PA was also measured. RESULTS: The two-way repeated-measures MANOVA demonstrated that the intervention DVD group was statistically significant, with a large effect size in PA minutes (P = 0.014, ηP2 = 0.236) and rate of perceived exertion (P = 0.002, ηP2 = 0.342) compared with the control group. CONCLUSIONS: The findings demonstrated that using an adapted DVD increased PA minutes and the rate of perceived exertion without high levels of caregiver support.

Factors affecting short-term precision of musculoskeletal measures using peripheral quantitative computed tomography (pQCT).

UNLABELLED: Few studies have investigated factors influencing the precision of peripheral quantitative computed tomography (pQCT) measures. This study found time between repeat scans and subject anthropometric characteristics to influence short-term precision of pQCT-derived measures in the lower leg. These findings have implications for both investigators and clinicians utilizing pQCT outcomes. INTRODUCTION: Peripheral quantitative computed tomography (pQCT) is increasingly being used to investigate musculoskeletal changes associated with age, disease and/or intervention. Precision of pQCT measures is of paramount importance in this endeavor. This study aimed to establish the short-term precision of pQCT-derived musculoskeletal measures of the lower leg and investigate factors influencing this precision. METHODS: Thirty healthy subjects had a series of six pQCT scans of the lower leg (66% of tibial length proximal from its distal end) performed on two separate days by two different testers. The influences of different testers, time between repeat scans, and subject anthropometric characteristics on precision were explored. RESULTS: Overall precision error (root mean square) increased from bone (<1%) to muscle (<1.5%) to fat (3%). The two testers were equally precise in performing pQCT measures; however, precision error increased when repeat scans were repeated 1 week apart as opposed to on the same day. Subject anthropometric characteristics influenced precision errors with the general finding being that an increase in subject size was associated with less precise pQCT measures. CONCLUSIONS: pQCT is a relatively precise technique for the assessment of bone and muscle, but precision is influenced by time between repeat scans and subject anthropometric characteristics. Investigators and clinicians need to be aware of these factors influencing pQCT outcomes as they may influence statistical power in clinical studies and the characterization of change in individual patients.

Long-term safety of recombinant human growth hormone in children.

BACKGROUND: Between 1985 and 2006, the National Cooperative Growth Study (NCGS) monitored the safety and efficacy of recombinant human growth hormone (rhGH) in 54,996 children. METHODS: Enrolled patients were followed until rhGH discontinuation. Investigators submitted adverse event reports for targeted events or those potentially rhGH-related. RESULTS: Early concerns about de novo leukemia in patients without risk factors have not been substantiated--three observed vs. 5.6 expected in age-matched general population based on years at risk [standard incidence ratio (SIR), 0.54; 95% confidence interval (CI), 0.11-1.58]. De novo malignancies (intracranial and extracranial) were not significantly increased in patients without risk factors (29 confirmed vs. 26 expected; SIR, 1.12; 95% CI, 0.75-1.61). Second neoplasms occurred in 49 patients, of whom 37 had irradiation for their initial tumors (including five of 16 retinoblastoma patients, three of whom had bilateral retinoblastoma) consistent with an increased risk with rhGH. Thirty-three patients developed type 1 diabetes mellitus (DM) (37 expected; SIR, 0.90; 95% CI, 0.62-1.26). Type 2 DM and nonspecified DM were reported in 20 and eight patients, respectively. Two deaths were reported in patients with Prader-Willi syndrome and five deaths from aortic dissection in patients with Turner syndrome. In patients with organic GH deficiency and idiopathic panhypopituitarism, 11 events of acute adrenal insufficiency occurred, including four deaths, consistent with a reported increased risk for adrenal insufficiency in hypopituitary patients with or without rhGH treatment. CONCLUSION: After more than 20 yr, leukemia, a major safety issue initially believed associated with GH, has not been confirmed, but other signals, including risk of second malignancies in patients previously treated with irradiation, have been detected or confirmed through the NCGS. These data further clarify the events associated with rhGH and, although confirming a favorable overall safety profile, they also highlight specific populations at potential risk.

Reduced variability of neoral pharmacokinetic studies in pediatric renal transplantation.

In adult renal transplant recipients the Neoral area under the curve (AUC) displays less inter- and intra-individual variability than Sandimmune, and those renal transplant recipients with reduced intra-individual variability of the AUC have a lower risk for chronic rejection. As variability of Neoral pharmacokinetic (Pk) parameters has not been investigated in pediatric renal transplant recipients, we retrospectively analyzed 453 Pk profiles in 14 pediatric patients who were switched from Sandimmune to Neoral and compared the inter- and intra-individual variability of the Pk profiles on both formulations. After the switch, we observed less inter- and intra-individual variability of AUC, the 2-h concentration, and the oral clearance. As clearance with both formulations is supposedly equal, the significantly lower intra-individual variability of oral clearance is most likely an effect of less variable absorption. While the lower inter-individual variability of the Pk parameters suggests increased success in keeping cyclosporine concentrations on target, the lower intra-individual variability leads to the hypothesis that with Neoral, a lower incidence of chronic rejection might be achieved.

A limited sampling strategy for the estimation of Neoral AUCs in pediatric patients.

The improved pharmacokinetics of Neoral allows the development of an accurate estimate of the full area under the concentration time curve (AUC) from a limited sampling strategy. As no such strategy has been derived from pharmacokinetic data obtained from children on 12-hourly dosing, and as patient convenience demands shorter sampling times, we derived a limited sampling strategy from 45 AUCs obtained from 19 pediatric renal transplant patients by stepwise forward multiple regression, and prospectively tested them on a separate group of 49 AUCs obtained from 18 pediatric renal transplant patients. Full cyclosporine (CsA) AUCs were obtained from samples drawn pre dose (C0) and at 2, 4, 6, 8 and 12 h post dose (C2, C4, C6, C8, and C12). High-precision predictions of full AUC were obtained based on the formula: AUC = 444 + 3.69 x C0 + 1.77 x C2 + 4. 1 x C4 (mean prediction error +/- SD = 0.3 +/- 6.4%, 95% confidence interval=-1.7% to 1.9%.) In conclusion, CsA exposure in pediatric renal transplant patients on 12-hourly Neoral dosing can be reliably predicted by an early time point-based limited sampling strategy in children. This formula has the advantage of obtaining trough as well as AUC from one brief, convenient sampling period.

Changing patterns in the histopathology of idiopathic nephrotic syndrome in children.

BACKGROUND: It is widely accepted that minimal change nephrotic syndrome (MCNS) is the most common cause of nephrosis in children. Recent studies have demonstrated an increasing incidence of focal segmental glomerulosclerosis (FSGS) in adults. METHODS: To determine possible changes in the etiology of childhood nephrosis, the clinical charts of 152 pediatric patients diagnosed with idiopathic nephrotic syndrome between 1978 and 1997 were reviewed. Histopathological diagnosis was available in 105 patients. RESULTS: MCNS was present in 35% of all biopsies, whereas FSGS was observed in 31%. Even if we assume that all patients without a histological diagnosis had MCNS (presumptive MCNS), the total incidence of MCNS (biopsy proven + presumptive) in our population was only 55%. We observed a dramatic increase in the incidence of FSGS during recent years. Before 1990, FSGS was diagnosed in 23% of all renal biopsies but increased to 47% afterward (P = 0.02). This pattern was observed in all ethnic groups. In African Americans, there was a trend for an increase in the incidence of FSGS from 38% before 1990 to 69% after 1990. A similar trend was observed in Caucasians (from 20 to 45%) and Hispanics (from 8 to 33%) Hispanics had the highest incidence of MCNS (biopsy proven + presumptive: 73%), followed by Caucasians (53%) and African Americans (37%). The mean age for presentation of nephrotic syndrome in African Americans (8.0 +/- 0.9 years) was higher than in Caucasians (4.1 +/- 0.05) and Hispanics (3.3 +/- 0.5). CONCLUSIONS: Our study showed that the incidence of FSGS in children with idiopathic nephrotic syndrome has increased recently. Furthermore, in African American children. FSGS is the most common cause of nephrotic syndrome. These findings may have significant implications in the management of childhood nephrotic syndrome.

Rapid activation of the alternative pathway of complement by extracorporeal membrane oxygenation.

Extracorporeal membrane oxygenation (ECMO) is an effective therapy for patients with severe respiratory distress syndromes. However, an inflammatory response has been observed with the use of this therapy. We measured complement activation in vivo in two adults receiving ECMO for acute respiratory distress syndrome (ARDS). Production of complement activation fragments C4d, Bb, iC3b, and SC5b-9 was determined using commercial ELISA kits. In both patients there was intense activation of complement that peaked 1 hour (mean SC5b-9 increase to 1135% of baseline) after the start of ECMO and occurred predominantly via the alternative pathway (Bb production). Early and acute complement activation may be responsible for the initiation of the inflammatory response that has been observed in patients treated with ECMO.

Chronic rejection and chronic cyclosporin toxicity in renal allografts.

Recent evidence indicates that growth factors are critically important in both chronic rejection and chronic cyclosporin A toxicity, suggesting that these two entities share a common pathophysiological pathway, leading to progressive allograft failure. Here, Manuel Pascual and colleagues discuss the relevance of growth factors to chronic allograft nephropathy, and the implications for therapy in view of the great choice of immunosuppressive drugs now available.

Dialysis membrane adsorption during CRRT.

Experimental and clinical studies have suggested that dialysis membrane biocompatibility may influence the morbidity and mortality of patients with acute renal failure. Complement activation by dialysis membranes may also prolong the recovery from acute renal failure. In this article, we review the concept of dialysis membrane adsorption, with particular attention to adsorption/inhibition of factor D, a highly specific serine protease of the alternative pathway of complement. The adsorptive properties of some dialysis membranes may be useful during continuous renal replacement therapies (CRRT) in critically ill patients.

Acute renal failure: role of dialysis membrane biocompatibility.

Recent clinical studies of acute renal failure in adults have focused attention on the biocompatibility of the dialysis membrane as a possible factor influencing patient morbidity and mortality. In this article, we review the concept of dialysis membrane biocompatibility and highlight the difficulty of finding an ideal definition. We then expand on the possible roles of complement and neutrophil activation by dialysis membranes, which may prolong the recovery from acute renal failure. The results of several clinical studies analyzing the impact of dialysis membranes on the course and outcome of acute renal failure are discussed. Finally, the possible relevance of biocompatibility in continuous renal replacement therapies is emphasized.

Acute effects of delayed reperfusion on myocardial infarct shape and left ventricular volume: a potential mechanism of additional benefits from thrombolytic therapy.

The purpose of this study was to characterize the effects of late reperfusion on myocardial infarct shape and to quantitate associated changes in left ventricular volume. Reperfusion was delayed until there was no salvage of ischemic myocardium. Dogs underwent 6.5 h of left anterior descending coronary artery occlusion (n = 5) or 5.5 h of occlusion and 1 h of reperfusion (n = 5). Infarct shape was measured with pairs of ultrasonic crystals implanted circumferentially in the mid myocardium. Infarct stiffness was determined from end-diastolic pressure-segment length curves produced by aortic clamping. Left ventricular volume was measured with three pairs of endocardial ultrasonic crystals and the effect of infarct shape change on left ventricular volume was determined. Infarct size, expressed as a percent of the area at risk, was similar in reperfused (97 +/- 1%) and nonreperfused (98 +/- 1%) hearts. After coronary artery occlusion, infarct segments became akinetic and functional dilation, measured as end-diastolic ultrasonic crystal separation, increased to a similar extent in reperfused (24 +/- 7%) and nonreperfused (19 +/- 3%) hearts. In 13 additional dogs that underwent reperfusion and instrumentation with endocardial ultrasonic crystals for volume measurement, left ventricular volume increased 42 +/- 6% over the preocclusion level (p less than 0.001). Within minutes of reperfusion, the infarct stiffened, infarct dilation decreased to 1 +/- 4% over the baseline preocclusion level (p less than 0.05 vs. prereperfusion) and left ventricular volume decreased to 16 +/- 11% over the baseline level (p less than 0.01 vs. postocclusion). Thus, coronary artery reperfusion reverses initial infarct dilation. Changes in infarct dilation occur immediately after reperfusion and are accompanied by infarct stiffening and a decrease in left ventricular volume. Reperfusion can affect infarct shape and stiffness at a point in time when myocardial salvage is no longer possible.

NMDA receptor antagonists suppress behaviors but not norepinephrine turnover or locus coeruleus unit activity induced by opiate withdrawal.

Pretreatment with the non-competitive NMDA (N-methyl-D-aspartate) antagonist MK801 (0.5, 1.0 mg/kg, s.c.) suppressed the behavioral signs of withdrawal in morphine-dependent rats. However, the same doses of MK801 that suppressed morphine withdrawal also simultaneously produced phencyclidine (PCP)-like behaviors. Pretreatment with the competitive NMDA antagonist LY274614 (25, 50, 100 mg/kg i.p.) also suppressed the behavioral signs of withdrawal in morphine-dependent rats but did not produce PCP-like behavioral effects. Single unit recordings were made from noradrenergic neurons in the locus coeruleus (LC) and, at doses that suppressed morphine withdrawal behaviors, neither MK801 nor LY274614 blocked the withdrawal-induced activation of LC neurons. Biochemical analysis indicated that, at the same behaviorally relevant doses, neither MK801 nor LY274614 blocked the withdrawal-induced increase in norepinephrine turnover in the hippocampus, cerebral cortex, or hypothalamus. These results indicate that NMDA antagonists attenuate the behavioral signs of morphine withdrawal without blocking the withdrawal-induced increase in norepinephrine turnover or the withdrawal-induced increase in LC unit activity. In addition, non-competitive NMDA antagonists, like MK801, may not be useful to alleviate opiate withdrawal symptoms in man because of their PCP-like side effects. However, competitive NMDA antagonists, like LY274614, could be of great benefit for alleviating opiate withdrawal symptoms in man.

Regional left ventricular filling: does it reflect diastolic abnormalities in contiguous areas of myocardium?

To test the hypothesis that regional left ventricular filling reflects diastolic changes in contiguous areas of myocardium, we performed radionuclide ventriculograms on normal subjects, patients with left anterior descending coronary artery disease, and patients with anteroseptal myocardial infarctions. We reasoned that because diastolic properties of the anteroseptal myocardium should be different in the three groups of patients, regional filling in the anteroseptal area of the left ventricle should also be different, if regional filling does, indeed, reflect diastolic changes in the adjacent myocardium. While anteroseptal regional filling in the normal subjects was different than regional filling in the two patient groups, the degree of filling abnormality was similar in patients with and without myocardial infarctions. Our results suggest that regional left ventricular filling is not exclusively determined by diastolic changes in contiguous areas of myocardium.

Effect of coronary artery bypass grafting on left ventricular diastolic function.

Because left ventricular (LV) diastolic function is abnormal in patients with coronary artery disease (CAD), pulsed Doppler echocardiography was used to evaluate LV filling before and after coronary artery bypass grafting (CABG). Filling was evaluated by Doppler in 2 studies: (1) in a group of 41 unpaired patients (11 with angiographically normal coronary arteries, 14 with CAD but without CABG and 16 at 1 week after CABG) and (2) in a group of 12 patients with CAD before and 1 week after CABG. Doppler sampling at the level of the mitral anulus was analyzed for the deceleration half-time and for the ratio of peak late (A) to peak early (E) filling velocity, measures reflecting early ventricular filling and the relative contribution of atrial contraction to ventricular filling. In the first study the deceleration half-time was significantly prolonged in both CAD and CABG groups. The late to early peak transmitral velocity ratio, however, was significantly prolonged only in the nonrevascularized CAD patients. In the second group of CAD patients studied before and 1 week after surgical revascularization, both the late to early peak transmitral velocity ratio and the deceleration half-time showed significant postoperative improvement. Thus, patients with CAD showed impairment in early LV filling and a compensatory increase in the proportion of filling with active atrial contraction. Successful CABG appears to result in normalization of early filling and decreased reliance on active atrial transport.

A new use for M-mode echocardiography in detecting left ventricular diastolic dysfunction in coronary artery disease.

Regional left ventricular (LV) diastolic function affects the global rate and pattern of LV filling. These changes may be detected by changes in the magnitude and timing of the increase in LV basal diameter during diastole. Because M-mode echocardiography possesses the high temporal and spatial resolution to detect such abnormalities, a group of 8 normal control subjects were compared with a group of 12 patients with coronary artery disease (CAD) to determine differences in the rate and timing of ventricular filling. The CAD patients had lower rates of fast filling expansion than the control subjects. The proportion of LV diastolic expansion during fast filling was lower. During atrial systole the increased rate of LV expansion was not significantly higher in the CAD patients, but the proportion of diastolic expansion occurring with atrial systole was increased. These changes may reflect a decrease in the rate and magnitude of early diastolic filling in the noncompliant ventricle and an increased reliance on active atrial transport. Thus, CAD alters the rate and pattern of LV filling. Changes in LV diameter as measured by M-mode echocardiography may be useful in detecting altered patterns of LV diastolic filling and identifying patients with CAD.

Effect of beta blockade on silent regional left ventricular wall motion abnormalities.

The effect of beta-adrenergic blockade on regional left ventricular wall motion abnormalities was studied in 11 patients with coronary artery disease and silent myocardial ischemia during exercise testing. Four patients were asymptomatic; 7 were asymptomatic after a myocardial infarction. Left ventricular wall motion abnormalities were characterized by reduced regional ejection fraction (EF) during exercise determined by gated left anterior oblique images of the cardiac blood pool. In the 11 patients, 10 anteroseptal and 8 inferoposterior regions were subserved by stenotic coronary arteries. Before beta blockade, regional EF decreased in 15 of 18 regions. After beta blockade, this occurred in only 6 of 18 regions (p less than 0.05); the other 12 regions showed no change or an actual increase in regional EF. Thus, beta-adrenergic blockade effectively improved the reduction in exercise regional EF usually seen in patients with coronary artery disease with silent myocardial ischemia. One probable mechanism of action is a reduction in myocardial oxygen requirement at peak exercise.

Effect of timolol on exercise-induced reduction in regional ejection fraction in patients with coronary artery disease.

In order to evaluate the effects of timolol, a new beta-adrenergic blocking agent, on exercise-induced left ventricular wall motion abnormalities, we studied nine patients with chronic, angiographically-documented coronary artery disease. A computerized technique for determining apical, anteroseptal and inferoposterior regional ejection fractions during gated radionuclide ventriculography was used to assess left ventricular dysfunction. During exercise prior to the administration of timolol, the apical regional ejection fraction fell from 0.62 +/- 0.08 to 0.51 +/- 0.08 (p less than .01). The anteroseptal ejection fraction fell from 0.50 +/- 0.08 to 0.41 +/- 0.05 (p less than .05), and the inferoposterior ejection fraction fell from 0.75 +/- 0.10 to 0.59 +/- 0.06 (p less than .05). Three days after beginning therapy with 10-30 mg of timolol, this reduction was markedly attenuated. The apical ejection fraction fell from 0.59 +/- 0.09 to 0.54 +/- 0.08 (p = NS), the anteroseptal ejection fraction fell from 0.49 +/- 0.07 to 0.47 +/- 0.18 (p = NS) and the inferoposterior ejection fraction fell from 0.62 +/- 0.06 to 0.59 +/- 0.07 (p = NS). Furthermore, several individual regions showed increases in ejection fraction. This study demonstrates a previously unreported and beneficial anti-ischemic effect of timolol.