Although it is self-evident that the study of human nutrition has as its goal the optimal nutrition of man, the nutritional status of the body best suited to optimal performance, i.e., optimal nutrition, has unfortunately not yet been satisfactorily defined. Body composition of animals may be measured by direct chemical analysis and correlated with dietary intake and with the various aspects of performance; studies of body composition of living man, on the other hand, must rely on indirect measure ments. The following two reports, which give an account of the current status of the attack on the difficult task of measuring body composition in living man, are sponsored by the Committee on Nutrition to call attention to the resurgence of effort in this field during recent years. A fuller knowledge of the gross composition of the human body and its relation to preceding diet will constitute a significant step towards realization of the ultimate goal of nutritional science. Even then, a particular body composition will be of importance primarily in terms of functional performance. The availability of newer techniques should do much to stimulate physicians and nutritionists in defining body composition as an essential step in arriving at a more exact definition of optimal nutrition.

https://pediatrics.aappublications.org/content/pediatrics/29/3/476.full.pdf

Human body composition

Background
Duchenne muscular dystrophy (DMD) is the most common muscular dystrophy of childhood. This incurable disease is characterised by muscle wasting and loss of walking ability leading to complete wheelchair dependence by 13 years of age. Prolongation of walking is one of the major aims of treatment.

Objectives
The aim of this review was to assess whether glucocorticoid corticosteroids stabilize or improve muscle strength and walking in boys with DMD.

Search methods
This is an update of the Cochrane systematic review first published in 2004 (Manzur 2004). We searched the Cochrane Neuromuscular Disease Group Trials Register (August 2006) using the term 'Duchenne muscular dystrophy'. We also searched MEDLINE (January 1966 to July 2007), EMBASE (January 1980 to August 2006), CINAHL and LILACS (January 1982 to August 2006). We wrote to authors of published studies and other experts in this disease to help identify other trials, checked the references in the identified trials and hand searched the abstracts of relevant journals.

Selection criteria
Types of studies: randomised or quasi-randomised trials. 
Types of participants: all patients with a definite diagnosis of Duchenne muscular dystrophy. 
Types of interventions: glucocorticoids such as prednisone, prednisolone, deflazacort or others, with a minimum treatment period of three months. 
Primary outcome measure: prolongation of walking (independent walking without long leg calipers). 
Secondary outcome measures: strength outcome measures, manual muscle strength testing using Medical Research Council strength scores, functional outcome measures and adverse events.

Data collection and analysis
We identified six randomised controlled trials that met the inclusion criteria for our review, and one of these (Beenakker 2005) is a new addition to this update, as it was published subsequent to our first review (Manzur 2004). Two review authors independently selected the trials for the review and assessed methodological quality. Data extraction and inputting were double-checked.

Main results
Primary outcome measure: data from one small study used prolongation of walking as an outcome measure and did not show significant benefit.

Secondary outcome measures: The meta-analysis of the results from four randomised controlled trials with altogether 249 participants showed that glucocorticoid corticosteroids improved muscle strength and function over six months. Improvements were seen in time taken to rise from the floor (Gowers' time), nine metres walking time, four-stair climbing time, ability to lift weights, leg function grade and forced vital capacity. One randomised controlled trial with altogether 28 participants showed that glucocorticoid corticosteroids stabilize muscle strength and function for up to two years. The most effective prednisolone regime appears to be 0.75 mg/kg/day, given in a daily dose regime. Not enough data were available to compare efficacy of prednisone with deflazacort.

Adverse effects: Excessive weight gain, behavioural abnormalities, cushingoid appearance and excessive hair growth were all more common with glucocorticoid corticosteroids than placebo. Long-term adverse effects of glucocorticoid therapy could not be evaluated because of the short-term duration of the randomised studies.

Non-randomised studies: A number of non-randomised studies with important efficacy and adverse effects data are tabulated and discussed.

Authors' conclusions
There is evidence from randomised controlled studies that glucocorticoid corticosteroid therapy in Duchenne muscular dystrophy improves muscle strength and function in the short-term (six months to two years). The most effective prednisolone regime appears to be 0.75 mg/kg/day, given daily. In the short term, adverse effects were significantly more common but not clinically severe. Long-term benefits and hazards of glucocorticoid treatment cannot be evaluated from the currently published randomised studies. Non-randomised studies support the conclusions of functional benefits but also identify clinically significant adverse effects of long-term treatment. These benefits and adverse effects have implications for future research studies and clinical practice.

Glucocorticoid corticosteroids for Duchenne muscular dystrophy

BACKGROUND: Duchenne muscular dystrophy (DMD) is the most common muscular dystrophy of childhood. Untreated, this incurable disease, which has an X-linked recessive inheritance, is characterised by muscle wasting and loss of walking ability, leading to complete wheelchair dependence by 13 years of age. Prolongation of walking is a major aim of treatment. Evidence from randomised controlled trials (RCTs) indicates that corticosteroids significantly improve muscle strength and function in boys with DMD in the short term (six months), and strength at two years (two-year data on function are very limited). Corticosteroids, now part of care recommendations for DMD, are largely in routine use, although questions remain over their ability to prolong walking, when to start treatment, longer-term balance of benefits versus harms, and choice of corticosteroid or regimen.

We have extended the scope of this updated review to include comparisons of different corticosteroids and dosing regimens.


OBJECTIVES: To assess the effects of corticosteroids on prolongation of walking ability, muscle strength, functional ability, and quality of life in DMD; to address the question of whether benefit is maintained over the longer term (more than two years); to assess adverse events; and to compare efficacy and adverse effects of different corticosteroid preparations and regimens.


SEARCH METHODS: On 16 February 2016 we searched the Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, EMBASE, CINAHL Plus, and LILACS. We wrote to authors of published studies and other experts. We checked references in identified trials, handsearched journal abstracts, and searched trials registries.

SELECTION CRITERIA: We considered RCTs or quasi-RCTs of corticosteroids (e.g. prednisone, prednisolone, and deflazacort) given for a minimum of three months to patients with a definite DMD diagnosis. We considered comparisons of different corticosteroids, regimens, and corticosteroids versus placebo.

DATA COLLECTION AND ANALYSIS: The review authors followed standard Cochrane methodology.


MAIN RESULTS: We identified 12 studies (667 participants) and two new ongoing studies for inclusion. Six RCTs were newly included at this update and important non-randomised cohort studies have also been published. Some important studies remain unpublished and not all published studies provide complete outcome data.

Primary outcome measure: one two-year deflazacort RCT (n = 28) used prolongation of ambulation as an outcome measure but data were not adequate for drawing conclusions.

Secondary outcome measures: meta-analyses showed that corticosteroids (0.75 mg/kg/day prednisone or prednisolone) improved muscle strength and function versus placebo over six months (moderate quality evidence from up to four RCTs). Evidence from single trials showed 0.75 mg/kg/day superior to 0.3 mg/kg/day on most strength and function measures, with little evidence of further benefit at 1.5 mg/kg/day. Improvements were seen in time taken to rise from the floor (Gowers' time), timed walk, four-stair climbing time, ability to lift weights, leg function grade, and forced vital capacity. One new RCT (n = 66), reported better strength, function and quality of life with daily 0.75 mg/kg/day prednisone at 12 months. One RCT (n = 28) showed that deflazacort stabilised muscle strength versus placebo at two years, but timed function test results were too imprecise for conclusions to be drawn.

One double-blind RCT (n = 64), largely at low risk of bias, compared daily prednisone (0.75 mg/kg/day) with weekend-only prednisone (5 mg/kg/weekend day), finding no overall difference in muscle strength and function over 12 months (moderate to low quality evidence). Two small RCTs (n = 52) compared daily prednisone 0.75 mg/kg/day with daily deflazacort 0.9 mg/kg/day, but study methods limited our ability to compare muscle strength or function.

Adverse effects: excessive weight gain, behavioural abnormalities, cushingoid appearance, and excessive hair growth were all previously shown to be more common with corticosteroids than placebo; we assessed the quality of evidence (for behavioural changes and weight gain) as moderate. Hair growth and cushingoid features were more frequent at 0.75 mg/kg/day than 0.3 mg/kg/day prednisone. Comparing daily versus weekend-only prednisone, both groups gained weight with no clear difference in body mass index (BMI) or in behavioural changes (low quality evidence for both outcomes, one study); the weekend-only group had a greater linear increase in height. Very low quality evidence suggested less weight gain with deflazacort than with prednisone at 12 months, and no difference in behavioural abnormalities. Data are insufficient to assess the risk of fractures or cataracts for any comparison.

Non-randomised studies support RCT evidence in showing improved functional benefit from corticosteroids. These studies suggest sustained benefit for up to 66 months. Adverse effects were common, although generally manageable. According to a large comparative longitudinal study of daily or intermittent (10 days on, 10 days off) corticosteroid for a mean period of four years, a daily regimen prolongs ambulation and improves functional scores over the age of seven, but with a greater frequency of side effects than an intermittent regimen.

AUTHORS' CONCLUSIONS: Moderate quality evidence from RCTs indicates that corticosteroid therapy in DMD improves muscle strength and function in the short term (twelve months), and strength up to two years. On the basis of the evidence available for strength and function outcomes, our confidence in the effect estimate for the efficacy of a 0.75 mg/kg/day dose of prednisone or above is fairly secure. There is no evidence other than from non-randomised trials to establish the effect of corticosteroids on prolongation of walking. In the short term, adverse effects were significantly more common with corticosteroids than placebo, but not clinically severe. A weekend-only prednisone regimen is as effective as daily prednisone in the short term (12 months), according to low to moderate quality evidence from a single trial, with no clear difference in BMI (low quality evidence). Very low quality evidence indicates that deflazacort causes less weight gain than prednisone after a year's treatment. We cannot evaluate long-term benefits and hazards of corticosteroid treatment or intermittent regimens from published RCTs. Non-randomised studies support the conclusions of functional benefits, but also identify clinically significant adverse effects of long-term treatment, and a possible divergence of efficacy in daily and weekend-only regimens in the longer term. These benefits and adverse effects have implications for future research and clinical practice.

/pdf/corticosteroids-for-the-treatment-of-duchenne-muscular-49gx4jk7lc.pdf

Corticosteroids for the treatment of Duchenne muscular dystrophy.

https://www.kidney-international.org/article/S0085-2538(15)34940-1/pdf

Renal, metabolic and hormonal responses to ingestion of animal and vegetable proteins

Insulin is as a major postprandial hormone with profound effects on carbohydrate, fat, and protein metabolism. In the absence of exogenous insulin, patients with type 1 diabetes exhibit a variety of metabolic abnormalities including hyperglycemia, glycosurea, accelerated ketogenesis, and muscle wasting due to increased proteolysis. We analyzed plasma from type 1 diabetic (T1D) humans during insulin treatment (I+) and acute insulin deprivation (I-) and non-diabetic participants (ND) by 1H nuclear magnetic resonance spectroscopy and liquid chromatography-tandem mass spectrometry. The aim was to determine if this combination of analytical methods could provide information on metabolic pathways known to be altered by insulin deficiency. Multivariate statistics differentiated proton spectra from I- and I+ based on several derived plasma metabolites that were elevated during insulin deprivation (lactate, acetate, allantoin, ketones). Mass spectrometry revealed significant perturbations in levels of plasma amino acids and amino acid metabolites during insulin deprivation. Further analysis of metabolite levels measured by the two analytical techniques indicates several known metabolic pathways that are perturbed in T1D (I-) (protein synthesis and breakdown, gluconeogenesis, ketogenesis, amino acid oxidation, mitochondrial bioenergetics, and oxidative stress). This work demonstrates the promise of combining multiple analytical methods with advanced statistical methods in quantitative metabolomics research, which we have applied to the clinical situation of acute insulin deprivation in T1D to reflect the numerous metabolic pathways known to be affected by insulin deficiency.

/pdf/quantitative-metabolomics-by-1h-nmr-and-lc-ms-ms-confirms-3417jtwle7.pdf

Quantitative Metabolomics by 1H-NMR and LC-MS/MS Confirms Altered Metabolic Pathways in Diabetes

Urinary excretion of the post-translationally modified amino-acid 3-methylhistidine, derived from the contractile proteins actin and myosin, was measured in patients with conditions associated with nitrogen loss. The ratio of 3-methylhistidine:creatinine excretion, a measure of the fractional catabolic rate of myofibrillar protein was increased in severe injury, thyrotoxicosis, neoplastic disease, prednisolone administration, and sometimes Duchenne muscular dystrophy. In myxoedema, osteomalacia, and hypothermia the ratio was decreased; and starvation, elective operations, and rheumatoid arthritis had little effect. Provided that the diet is meat free, measurement of urinary 3-methylhistidine may provide useful information on the cause of protein loss.

https://www.bmj.com/content/bmj/282/6261/351.full.pdf

Clinical usefulness of urinary 3-methylhistidine excretion in indicating muscle protein breakdown.

1. Blood alanine was measured in six patients undergoing total hip replacement and in four normal subjects starved for 4 days. Hypoalaninaemia occurred in both groups and persisted in the surgical patients despite an adequate diet. The blood alanine was also low in four insulin-dependent diabetic patients and in four patients with muscular dystrophy; it was normal in four patients with cirrhotic liver disease. 2. The removal of an intravenous L-alanine load (12 g; 133 mmol) was significantly increased after surgery and in the diabetic patients, unaltered by starvation, and decreased in the cirrhotic patients. 3. Increases in blood glucose were observed when alanine infusion was performed 6 h after surgery and after 3 days' starvation. Increases in blood lactate and pyruvate always occurred after alanine infusion but were most marked 6 h after surgery. 4. These results show that the metabolic response to an alanine load and the ability of the body to remove it alter with change in physiological state, and that the hypoalaninaemia after surgery and in diabetes is related to an increased removal of intravenous alanine, whereas that during starvation is not.

Relationship between the basal blood alanine concentration and the removal of an alanine load in various clinical states in man.

1. To establish whether 3-methylhistidine in food is quantitatively excreted in the urine, five normal adults on a vegetarian diet were given known amounts of 3-methylhistidine in meat or fish. The mean cumulative 5-day increment in 3-methylhistidine excretion in non-hydrolysed urine accounted for an average of 90% of the 3-methylhistidine given during the first 3 days of this period. 2. To define the variation in urinary 3-methylhistidine on a constant mixed intake, the daily 3-methylhistidine excretion was measured for 6 days in four patients on a metabolic "balance" diet. The mean daily variation was less than 10%. 3. The results show that under the conditions of this study the increase in urinary 3-methylhistidine above basal levels can be quantitatively accounted for by the 3-methylhistidine content of additional food; in subjects on a constant diet it should be possible to detect relatively small changes in 3-methylhistidine excretion.

The Effect of 3-Methylhistidine in Food on its Urinary Excretion in Man

1. The amount of 3-methylhistidine (3-MeH) has been measured in eighty-eight samples of tissue taken post-mortem from five adults. 2. The highest concentration (mumol/g fat-free dry weight) of 3-MeH was in skeletal muscle (3.31 +/- 0.05); intermediate values (2-3) were found in cardiac muscle and those tissues containing smooth muscle; and low values (less than 1) occurred in parenchymal tissues such as liver and kidney. 3. There was little variation between the mean 3-MeH content of striated muscles in different individuals, and no significant difference between the 3-MeH concentrations of striated muscles taken from six different sites. 4. The results suggest that it is justifiable to use values obtained from single muscles to calculate the rate of myofibrillar breakdown from urinary 3-MeH excretion.

/pdf/the-3-methylhistidine-content-of-human-tissues-4uqbm9kznr.pdf

The 3-methylhistidine content of human tissues.

1. To investigate the effects of starvation, elective surgery, accidental injury and other clinical conditions on the metabolism of branched-chain amino acids in man, we have measured the basal concentration of leucine and the removal and metabolic effects of infused l-leucine. 2. The blood concentration of leucine was significantly increased by surgery, starvation and accidental injury, and decreased in cirrhosis. It tended to increase in diabetes and was unaffected by muscular dystrophy. 3. The half-life of infused leucine was nearly doubled by 4 days of complete starvation, unaltered by surgery and decreased by severe accidental injury. Infusion with Intralipid, which increased free fatty acid and ketone-body concentrations, had no effect on the removal of a leucine load. The clearance rate of infused leucine was reduced in diabetes and muscular dystrophy and increased in cirrhosis. 4. The effects of infused leucine on blood glucose and ketone bodies differed according to the groups studied. 5. Since the traumatized patients were given sufficient energy and nitrogen and disposed of a leucine load at a different rate from the starved patients, the causes of the increase in blood concentration of leucine in these two conditions are different.

M. Elia

Papers

Clinical usefulness of urinary 3-methylhistidine excretion in indicating muscle protein breakdown.

Relationship between the basal blood alanine concentration and the removal of an alanine load in various clinical states in man.

The Effect of 3-Methylhistidine in Food on its Urinary Excretion in Man

The 3-methylhistidine content of human tissues.

The removal of infused leucine after injury, starvation and other conditions in man.