Effect Of Modest Changes Research Articles

Underpowered Studies in Muscle Metabolism Research: Determinants and Considerations

Biomedical research frequently employs null hypothesis testing to determine whether an observed difference in a sample is likely to exist in the broader population. Null hypothesis testing generally assumes that differences between groups or interventions are non-existent, unless proven otherwise. Because biomedical studies with human subjects are often limited by financial and logistical resources, they tend to have low statistical power, i.e. a low probability of statistically confirming a true difference. As a result, small but potentially clinically important differences may be overseen or ignored simply due to the absence of a statistically significant difference. This absence is often misinterpreted as ‘equivalence’ of treatments. In this educational paper, we will use practical examples related to the effects of exercise and nutrition on muscle protein metabolism to illustrate the most important determinants of statistical power, as well as their implications for both investigators and readers of scientific articles.Changes in muscle mass occur at a relatively slow rate, making it practically challenging to detect differences between treatment groups in a long-term setting. One way to make it ‘easier’ to differentiate between groups and hence increase statistical power is to have a sufficiently long study duration to allow treatment effects to become apparent. This is especially relevant when comparing treatments with relatively small expected differences such as the effect of modest changes in daily protein intake. Secondly, one could try to minimize the variance and response heterogeneity within groups, for example by using strict inclusion criteria and standardization protocols (e.g., meal provision), by using cross-over designs, or even within-subject designs where two interventions are compared simultaneously (e.g., studying an exercised limb vs a contralateral control limb) although this might limit the generalizability of the findings (e.g. such single-limb exercise training is not common in practice). In terms of data interpretation, investigators should obviously refrain from drawing strong conclusions from underpowered studies. Yet, such studies still provide valuable data for meta-analyses. Finally, because muscle protein synthesis rates are highly responsive to anabolic stimuli, acute metabolic studies are more sensitive to detect potentially clinically relevant differences in the anabolic response between treatments. Apart from further elaborating on these topics, this educational article encourages readers to more critically question null findings and scientists to more clearly discuss limitations that may have compromised statistical power.

The effect of modest changes in sleep on dietary intake and eating behavior in children: secondary outcomes of a randomized crossover trial

BackgroundInsufficient sleep duration increases obesity risk in children, but the mechanisms remain unclear. ObjectivesThis study seeks to determine how changes in sleep influence energy intake and eating behavior. MethodsSleep was experimentally manipulated in a randomized, crossover study in 105 children (8–12 y) who met current sleep guidelines (8–11 h/night). Participants went to bed 1 h earlier (sleep extension condition) and 1 h later (sleep restriction condition) than their usual bedtime for 7 consecutive nights, separated by a 1-wk washout. Sleep was measured via waist-worn actigraphy. Dietary intake (2 24-h recalls/wk), eating behaviors (Child Eating Behavior Questionnaire), and the desire to eat different foods (questionnaire) were measured during or at the end of both sleep conditions. The type of food was classified by the level of processing (NOVA) and as core or noncore (typically energy-dense foods) foods. Data were analyzed according to ‘intention to treat’ and ‘per protocol,’ an a priori difference in sleep duration between intervention conditions of ≥30 min. ResultsThe intention to treat analysis (n = 100) showed a mean difference (95% CI) in daily energy intake of 233 kJ (−42, 509), with significantly more energy from noncore foods (416 kJ; 6.5, 826) during sleep restriction. Differences were magnified in the per-protocol analysis, with differences in daily energy of 361 kJ (20, 702), noncore foods of 504 kJ (25, 984), and ultraprocessed foods of 523 kJ (93, 952). Differences in eating behaviors were also observed, with greater emotional overeating (0.12; 0.01, 0.24) and undereating (0.15; 0.03, 0.27), but not satiety responsiveness (−0.06; −0.17, 0.04) with sleep restriction. ConclusionsMild sleep deprivation may play a role in pediatric obesity by increasing caloric intake, particularly from noncore and ultraprocessed foods. Eating in response to emotions rather than perceived hunger may partly explain why children engage in unhealthy dietary behaviors when tired.This trial was registered at Australian New Zealand Clinical Trials Registry; ANZCTR as CTRN12618001671257.

Sugar-sweetened Beverages and Hypertension

Consumption of sugar-sweetened beverages has been associated with the development and maintenance of obesity, as well as the risk for multiple obesity-related comorbidities. Some experts have hypothesized that the effect is entirely associated with excess caloric intake, while others suggest that a component of sweeteners may have a physiologic impact on the development of hypertension, insulin resistance and nonalcoholic fatty liver disease. Chen et al. have presented the first, large-scale clinical trial, assessing the direct effect of modest changes in sweetened drink consumption on blood pressure in a racially diverse population. The study team utilized data from the PREMIER: Lifestyle Interventions for Blood Pressure Control trial, in which 810 adult subjects were randomized to three groups: advice only; comprehensive lifestyle modification aimed at weight loss, increased exercise and dietary sodium reduction; or comprehensive lifestyle modification with incorporation of the Dietary Approach to Stop Hypertension (DASH) diet. Sweetened drink intake was estimated from 24-h subject recall, assessed by unscheduled phone calls to subjects at baseline, 6 months and 18 months. Over the duration of the study, a reduction of one 12-oz serving of sugar-sweetened beverages per day was associated with an average of 1.8 mmHg reduction in systolic blood pressure and an average of 1.1 mmHg reduction in diastolic blood pressure.

Effect of modest changes in BMI on cardiovascular disease risk markers in severely obese, minority adolescents

African American and Hispanic adolescents have disproportionately higher rates of obesity compared to white adolescents. In adults, modest weight loss of five percent improves CVD risk marker levels. Less is known about the effects of modest changes in BMI on CVD risk markers in adolescents, particularly newer markers such as C reactive protein (CRP), lipoprotein (a) and homocysteine. To examine the effect of modest BMI change on CVD risk marker levels in a group of severely obese, African American and Hispanic adolescents. A six-month longitudinal analysis. Eighty-three African American and Hispanic adolescents were recruited (mean age ± sd: 15.1 ± 2.0 years); 50 (60%) were reevaluated at 6 ± 2 months. At baseline, mean BMI was 42.3 ± 7.8 kg/m(2). BMI directly correlated with CRP (p = < 0.001); homocysteine (p = 0.02); insulin (p = 0.05); and systolic and diastolic blood pressures (both p = <0.001). BMI remained significantly associated with CRP and insulin after adjusting for age, sex and ethnicity (p = 0.001). At six-month follow up, there was a significant p for trend between the three groups of BMI change (those with a ≥5% BMI decrease, those who maintained BMI within 5% and those with ≥5% BMI increase) and CRP (p = 0.05) and insulin (p = 0.04). A modest decrease in BMI is associated with improvement in CRP and insulin levels. Obese adolescents should be encouraged to continue with modest weight loss goals as they result in improvement in cardiovascular disease risk markers.

Whole genome microarray analysis of gene expression in an imprinting center deletion mouse model of Prader–Willi syndrome

Prader-Willi syndrome (PWS) is caused by loss of paternally expressed genes in the 15q11-q13 region. To further characterize alterations in gene expression in this classical obesity syndrome we used whole genome microarrays to study a PWS mouse model resulting from a paternally derived imprinting center (IC) deletion (PWS IC deletion). These mice die generally within 2-3 days of life (reflective of failure to thrive in infants with PWS) and therefore, the analysis was performed on RNA extracted from the whole brain of PWS IC deletion mice and normal littermates at less than 24 hr after birth. Of more than 45,000 probes examined, 26,471 (59%) were detected for further analysis, and 69 had a significant change in expression of at least 1.5-fold and a false discovery rate (FDR) of 5%. Eight of the genes with differential expression were imprinted and from the PWS critical region (PWSCR). The three genes with the highest expression in the PWS IC mice were pro-opiomelanocortin (Pomc) and two transcripts of unknown function. Pomc knockout mice have been shown to develop obesity. Therefore, elevated Pomc RNA in PWS IC deletion neonatal mice may be an important genetic factor in the survival of these mice as it may affect eating behavior. Interestingly, Mc5r, a melanocortin receptor known to directly respond to Pomc expression changes, was upregulated as well. Mc5r is known to be involved with thermoregulation which is reportedly abnormal in PWS infants. These observations support a role for Pomc and the network of genes involved in regulating energy homeostasis in the early clinical findings of failure to thrive observed in PWS. Other notable patterns include three previously unstudied transcripts that are expressed only from the paternal allele under regulatory control of the IC and include AK013560, BB3144814, and BB182944 (whose genes are located in the mouse PWSCR on chromosome 7B). As expected, all the known paternally expressed genes from the PWSCR had detection signals below the threshold in the PWS IC deletion mice but were clearly detectable in control littermates. Several of the genes in this study were further examined by quantitative reverse transcription-PCR (RT-PCR) to confirm their expression status. Further analysis of gene expression in these mice may lead to novel pathways affected in PWS. These results, along with other recent reports, suggest that the cumulative effect of modest changes in expression of many genes, especially genes involved in energy metabolism, contribute to the failure to thrive of infants with PWS.

Asymmetrical dimethylarginine: the Uber marker?

The traditional risk factors of hypercholesterolemia, hypertension, diabetes mellitus, and tobacco exposure identify a subset of patients at greater cardiovascular risk. A variety of clinical phenotypes, biochemical markers, and genetic polymorphisms have been proposed to explain the variance in risk not explained by the traditional factors. Notably, all of the traditional risk factors, as well as the great majority of new risk markers, are associated with endothelial vasodilator dysfunction. Because the end points (endothelial dysfunction leading to plaque formation, progression, and rupture) are the same, it follows that diverse risk factors ultimately share common pathways(s) of pathobiology. We and others have provided evidence for a ubiquitous mechanism of endothelial pathobiology shared by all risk factors and markers examined to date. This mechanism of endothelial derangement is mediated by an endogenous inhibitor of nitric oxide synthase (NOS), a molecule known as asymmetrical dimethylarginine (ADMA). Risk factors impair endothelial vasodilator function by causing the accumulation of ADMA. Furthermore, by blocking NO generation, ADMA initiates and promotes processes involved in atherogenesis, plaque progression. and plaque rupture. This review examines the burgeoning body of literature that supports ADMA as an “Uber marker,” a biochemical factor mediating the adverse vascular effects of many other risk factors and markers. Endothelial NOS converts the amino acid l-arginine into l-citrulline and NO. The importance of NO in vascular homeostasis has been discussed elsewhere.1 In addition to its vasodilator activity, NO inhibits key processes involved in vascular disease, including leukocyte adhesion, platelet aggregation, and vascular smooth muscle cell proliferation. In animal models, alterations in vascular NO synthesis profoundly influence the progression of atherosclerosis and restenosis.2–6 These experimental observations have gained greater significance with recent reports that impairment of the NOS pathway independently predicts cardiovascular events.7–11 Major causes of impairment of the NOS pathway are …

Brown adipose tissue and liver development during early postnatal life in hand-reared and ewe-reared lambs

This study examined the effects of modest changes in ambient temperature in hand-reared lambs (experiment one) and in ewe-reared lambs (experiment two). Lambs were killed at either 8 or 31 days of age and perirenal adipose tissue was identified as being brown adipose tissue (BAT) from measurements of thermogenic activity (i.e. GDP binding to uncoupling protein in isolated mitochondria) or thermogenic capacity (i.e. detection of uncoupling protein by immunoblotting). In addition, type I and II iodothyronine 5' monodeiodonase (5'MDI) activities were assayed in perirenal adipose tissue, plus type I 5'MDI activity in liver. Plasma samples were also taken for measurements of glucose, lactate, insulin, triiodothyronine (T3) and thyroxine (T4) concentrations. In experiment one, lambs were hand-reared at either warm (WR; 25 degrees C) or cool (CR; 10-15 degrees C) ambient temperatures. Mean growth rate over the first 8 days of life in CR lambs was 88 g/day and increased to 128 g/day over the first month of life. Growth rate in WR lambs was constant at 141 g/day. Thermogenic activity of BAT was significantly higher in CR than WR lambs, but total weight and tissue lipid content of perirenal adipose tissue were significantly lower in the CR group. In both WR and CR lambs, the thermogenic activity of BAT fell by an average of 71% between 8 and 31 days. At 31 days of age, uncoupling protein in mitochondria could be detected only by immunoblotting in adipose tissue sampled from CR lambs. There was no effect of ambient temperature on type I or type II 5'MDI activity in BAT or liver; it decreased in adipose but not liver tissue between 8 and 31 days of age. The plasma concentrations of glucose, insulin and T3 tended to decline with age in CR but not in WR lambs. In ewe-reared lambs perirenal adipose tissue weight and tissue lipid content more than doubled between 8 and 31 days of age, but the level of GDP binding decreased from 85 to 5 pmol/mg mitochondrial protein over this period. Liver weight increased by 55% between 8 and 31 days of age, but hepatic 5'MDI activity remained unchanged. The plasma concentrations of T3, T4 and lactate, but not glucose or insulin, increased between 8 and 31 days of age. It is concluded that hand-rearing lambs at a cool ambient temperature significantly delays postnatal development, to the extent that BAT characteristics are retained. Ewe-rearing lambs enhances the rate at which BAT adopts the characteristics of white adipose tissue, and it prevents the postnatal decline in plasma concentrations of thyroid hormones.

EFFECT OF DIETARY CALCIUM ON THE DEVELOPMENT OF HYPERTENSION AND HYPERTENSIVE VASCULAR LESIONS IN DOCA-SALT AND TWO-KIDNEY, ONE CLIP HYPERTENSIVE RATS

To examine the effect of modest changes in dietary calcium on systolic blood pressure (SBP) and myocardial and renal vascular lesions in Sprague-Dawley rats. Regular- (0.4%, by weight), high- (0.8%) or low-calcium (0.24%) diets were fed to normotensive control, deoxycorticosterone acetate (DOCA)-salt and two-kidney, one clip (2-K, 1C) hypertensive rats for 8 weeks. Tail-cuff SBP and metabolic balance were measured once a week. At the end of the study the kidneys and hearts were collected for histological study. Dietary calcium had no effect on SBP in the DOCA-salt rats, but loading with calcium accelerated the rise in SBP in 2-K,1C rats (P < 0.01, high- versus regular-calcium diet). The high-calcium diet reduced the percentage medial area of intramyocardial arteries in the DOCA-salt and 2-K,1C hypertensive rats. The DOCA-salt rats on the low-calcium diet had a higher renal vascular lesions score than those on the regular- or high-calcium diet (P < 0.05). A high-calcium diet appears to prevent intramyocardial vascular wall thickening in DOCA-salt and 2-K,1C hypertensive rats, and a low-calcium diet aggravates renal vascular lesions in DOCA-salt hypertensive rats. These effects are not related simply to changes in blood pressure.

The effect of inlet conditions on the performance and flowfield structure of a non-premixed swirl-stabilized distributed reaction

A model reactor is used to investigate the extent to which the overall performance and detailed flowfield structure of a non-premixed swirl-stabilized distributed reaction are sensitive to modest changes in inlet conditions (e.g., fuel injection angle, inlet geometry, and swirl vane solidity). Measurements of combustor performance are based on exhaust plane species concentration profiles (HC, CO 2 , CO, O 2 ), combustion efficiency, and visual observation of combustor stability. The detailed flowfield structure is established by spatially mapping the axial and azimuthal velocity fields using two-component laser anemometry, and the temperature field using a thermocouple probe. The results show that relatively modest changes in inlet conditions can dramatically affect the flowfield structure. As an example, for the model reactor evaluated the addition of a small step at the outer boundary of the swirler yields significantly lower centerline axial velocities and a more uniform thermal structure in the recirculation zone. Furthermore, a modest reduction in swirl vane solidity transforms the aerodynamic structure of the recirculation zone from an off-axis to a central, on-axis structure. These results explain, in part, the contradictory conclusions drawn from data acquired in non-premixed swirl-stabilized distributed reactions, and establish that comparisons and generalizations of such flows require, at a minimum, (1) careful measurements and specification of the inlet conditions, (2) detailed measurements of the flow structure, and (3) an assessment of the effects of modest changes in key operating and configurational variables.