Safety and tolerability of 6-month supplementation with a vitamin D, calcium and leucine-enriched whey protein medical nutrition drink in sarcopenic older adults.

AIMS: Safety and tolerability of prolonged supplementation with a vitamin D, calcium and leucine-enriched whey protein medical nutrition drink (WP-MND) was evaluated in sarcopenic older adults. METHODS: A 13-week double-blinded, randomized, isocaloric placebo-controlled trial (PROVIDE study; n = 380) was extended with a voluntary 13-week open-label extension (OLE). OLE participants were randomized to receive daily 1 or 2 servings of WP-MND (21 g protein, 3 g leucine, 10 µg vitD and 500 mg calcium per serving). Gastro-intestinal tolerability, kidney function and serum levels of calcidiol, parathyroid hormone (PTH) and calcium were evaluated at week 0, 13 and 26. RESULTS AND DISCUSSION: In response to the high daily protein intake (median1.5; IQR: 1.3, 1.7 g/kg BW/day), the estimated glomerular filtration rate (eGFR) increased in the test group during the RCT (p = 0.013). The same trend was observed for those participants with moderate chronic kidney disease. During OLE no eGFR change was observed in any of the groups. Serum calcidiol and calcium reached a plateau after 13-week WP-MND supplementation. As expected, PTH significantly changed in the opposite direction, decreasing during RCT in the test group (T vs C: p < 0.001) and during OLE in former control groups. During RCT, 20/366 participants with normal baseline calcidiol reached levels ≥ 100 nmol/L (T: n = 18; C: n = 2) and 6 developed albumin-corrected calcium levels > 2.55 mmol/L (T: n = 3; C: n = 3), without associated adverse events. CONCLUSION: A 6 months intervention with up to 2 servings of WP-MND did neither result in kidney function deterioration nor symptoms of vitamin D or calcium toxicity. The product was overall well tolerated.

The prevalence and health burden of malnutrition in Belgian older people in the community or residing in nursing homes: results of the NutriAction II study.

INTRODUCTION: In 2008, the NutriAction study showed that (risk of) malnutrition was highly prevalent (57%) among Belgian older people living in the community or in a nursing home. In 2013, this study was repeated to re-evaluate the occurrence of malnutrition, as well as mobility problems and dependence in activities of daily living (ADL). METHODS: Health care professionals (HCPs) associated with homecare organizations and nursing homes across Belgium were invited to screen their patients and complete an online questionnaire. Nutritional status, presence of pre-specified comorbidities, mobility, and ADL dependency were assessed. RESULTS: In total, 3299 older patients were analysed: 2480 (86.3 ± 6.3 years) nursing home (NH) residents and 819 (82.7 ± 6.1 years) community dwelling (CD). Overall, 12% was malnourished (MNA-SF score < 8) and 44% was at risk of malnutrition (MNA-SF 8-11). The highest prevalence of (risk of) malnutrition was observed in NHs (63%) and in patients with dementia (CD: 68%; NH: 82%) or depression (CD: 68%; NH: 79%). Of all malnourished individuals, 49% was recognized as malnourished by HCPs and 13% of the malnourished recognized themselves as such. Mobility (stair climbing and walking) and ADL dependency (Belgian KATZ score) were impaired in older people with (risk of) malnutrition in comparison with individuals with normal nutritional status (p < 0.001). DISCUSSION: Despite public awareness initiatives, the prevalence of malnutrition remained stable among Belgian older people seen by HCPs in the period 2008-2013. Moreover, malnutrition is not well recognized. CONCLUSION: Under-recognition of malnutrition is problematic, because associated loss of mobility and independence may accelerate the transformation of frailty into disability in older people.

Correction to: The prevalence and health burden of malnutrition in Belgian older people in the community or residing in nursing homes: results of the NutriAction II study.

In the original publication, table row alignment was incorrectly formatted for all the tables. The corrected tables are given below.

Thirteen weeks of supplementation of vitamin D and leucine-enriched whey protein nutritional supplement attenuates chronic low-grade inflammation in sarcopenic older adults: the PROVIDE study.

BACKGROUND: A chronic low-grade inflammatory profile (CLIP) is associated with sarcopenia in older adults. Protein and Vitamin (Vit)D have immune-modulatory potential, but evidence for effects of nutritional supplementation on CLIP is limited. AIM: To investigate whether 13 weeks of nutritional supplementation of VitD and leucine-enriched whey protein affected CLIP in subjects enrolled in the PROVIDE-study, as a secondary analysis. METHODS: Sarcopenic adults (low skeletal muscle mass) aged ≥ 65 years with mobility limitations (Short Physical Performance Battery 4-9) and a body mass index of 20-30 kg/m2 were randomly allocated to two daily servings of active (n = 137, including 20 g of whey protein, 3 g of leucine and 800 IU VitD) or isocaloric control product (n = 151) for a double-blind period of 13 weeks. At baseline and after 13 weeks, circulating interleukin (IL)-8, IL-1 receptor antagonist (RA), soluble tumor-necrosis-factor receptor (sTNFR)1, IL-6, high-sensitivity C-reactive protein, pre-albumin and 25-hydroxyvitamin(OH)D were measured. Data-analysis included repeated measures analysis of covariance (corrected for dietary VitD intake) and linear regression. RESULTS: IL-6 and IL-1Ra serum levels showed overall increases after 13 weeks (p = 0.006 and p < 0.001, respectively). For IL-6 a significant time × treatment interaction (p = 0.046) was observed, with no significant change over time in the active group (p = 0.155) compared to control (significant increase p = 0.012). IL-8 showed an overall significant decrease (p = 0.03). The change in pre-albumin was a significant predictor for changes in IL-6 after 13 weeks. CONCLUSIONS: We conclude that 13 weeks of nutritional supplementation with VitD and leucine-enriched whey protein may attenuate the progression of CLIP in older sarcopenic persons with mobility limitations.

Supplementing Breakfast with a Vitamin D and Leucine-Enriched Whey Protein Medical Nutrition Drink Enhances Postprandial Muscle Protein Synthesis and Muscle Mass in Healthy Older Men.

Background: A promising strategy to help older adults preserve or build muscle mass is to optimize muscle anabolism through providing an adequate amount of high-quality protein at each meal.Objective: This "proof of principle" study investigated the acute effect of supplementing breakfast with a vitamin D and leucine-enriched whey protein medical nutrition drink on postprandial muscle protein synthesis and longer-term effect on muscle mass in healthy older adults.Methods: A randomized, placebo-controlled, double-blind study was conducted in 24 healthy older men [mean ± SD: age 71 ± 4 y; body mass index (in kg/m2) 24.7 ± 2.8] between September 2012 and October 2013 at the Unit of Human Nutrition, University of Auvergne, Clermont-Ferrand, France. Participants received a medical nutrition drink [test group; 21 g leucine-enriched whey protein, 9 g carbohydrates, 3 g fat, 800 IU cholecalciferol (vitamin D3), and 628 kJ] or a noncaloric placebo (control group) before breakfast for 6 wk. Mixed muscle protein fractional synthesis rate (FSR) was measured at week 0 in the basal and postprandial state, after study product intake with a standardized breakfast with the use of l-[2H5]-phenylalanine tracer methodology. The longer-term effect of the medical nutrition drink was evaluated by measurement of appendicular lean mass, representing skeletal muscle mass at weeks 0 and 6, by dual-energy X-ray absorptiometry.Results: Postprandial FSR (0-240 min) was higher in the test group than in the control group [estimate of difference (ED): 0.022%/h; 95% CI: 0.010%/h, 0.035%/h; ANCOVA, P = 0.001]. The test group gained more appendicular lean mass than the control group after 6 wk (ED: 0.37 kg; 95% CI: 0.03, 0.72 kg; ANCOVA, P = 0.035), predominantly as leg lean mass (ED: 0.30 kg; 95% CI: 0.03, 0.57 kg; ANCOVA, P = 0.034).Conclusions: Supplementing breakfast with a vitamin D and leucine-enriched whey protein medical nutrition drink stimulated postprandial muscle protein synthesis and increased muscle mass after 6 wk of intervention in healthy older adults and may therefore be a way to support muscle preservation in older people. This trial was registered at www.trialregister.nl as NTR3471.

Arginine infusion in patients with septic shock increases nitric oxide production without haemodynamic instability.

Arginine deficiency in sepsis may impair nitric oxide (NO) production for local perfusion and add to the catabolic state. In contrast, excessive NO production has been related to global haemodynamic instability. Therefore, the aim of the present study was to investigate the dose-response effect of intravenous arginine supplementation in post-absorptive patients with septic shock on arginine-NO and protein metabolism and on global and regional haemodynamics. Eight critically ill patients with a diagnosis of septic shock participated in this short-term (8 h) dose-response study. L-Arginine-HCl was continuously infused [intravenously (IV)] in three stepwise-increasing doses (33, 66 and 99 µmol·kg-1·h-1). Whole-body arginine-NO and protein metabolism were measured using stable isotope techniques, and baseline values were compared with healthy controls. Global and regional haemodynamic parameters were continuously recorded during the study. Upon infusion, plasma arginine increased from 48±7 to 189±23 µmol·l-1 (means±S.D.; P<0.0001). This coincided with increased de novo arginine (P<0.0001) and increased NO production (P<0.05). Sepsis patients demonstrated elevated protein breakdown at baseline (P<0.001 compared with healthy controls), whereas protein breakdown and synthesis both decreased during arginine infusion (P<0.0001). Mean arterial and pulmonary pressure and gastric mucosal-arterial partial pressure of carbon dioxide difference (Pr-aCO2) gap did not alter during arginine infusion (P>0.05), whereas stroke volume (SV) increased (P<0.05) and arterial lactate decreased (P<0.05). In conclusion, a 4-fold increase in plasma arginine with intravenous arginine infusion in sepsis stimulates de novo arginine and NO production and reduces whole-body protein breakdown. These potential beneficial metabolic effects occurred without negative alterations in haemodynamic parameters, although improvement in regional perfusion could not be demonstrated in the eight patients with septic shock who were studied.

Micronutrient intakes and potential inadequacies of community-dwelling older adults: a systematic review.

Micronutrient deficiencies and low dietary intakes among community-dwelling older adults are associated with functional decline, frailty and difficulties with independent living. As such, studies that seek to understand the types and magnitude of potential dietary inadequacies might be beneficial for guiding future interventions. We carried out a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Observational cohort and longitudinal studies presenting the habitual dietary intakes of older adults (≥65 years) were included. Sex-specific mean (and standard deviation) habitual micronutrient intakes were extracted from each article to calculate the percentage of older people who were at risk for inadequate micronutrient intakes using the estimated average requirement (EAR) cut-point method. The percentage at risk for inadequate micronutrient intakes from habitual dietary intakes was calculated for twenty micronutrients. A total of thirty-seven articles were included in the pooled systematic analysis. Of the twenty nutrients analysed, six were considered a possible public health concern: vitamin D, thiamin, riboflavin, Ca, Mg and Se. The extent to which these apparent inadequacies are relevant depends on dynamic factors, including absorption and utilisation, vitamin and mineral supplement use, dietary assessment methods and the selection of the reference value. In light of these considerations, the present review provides insight into the type and magnitude of vitamin and mineral inadequacies.

Macronutrient Intake and Inadequacies of Community-Dwelling Older Adults, a Systematic Review.

BACKGROUND: Anorexia of ageing may predispose older adults to under-nutrition and protein energy malnutrition. Studies, however, report a large variation in nutrient inadequacies among community-dwelling older adults. SUMMARY: This systematic review provides a comprehensive overview of the energy and macronutrient intakes and possible inadequacies in community-dwelling older adults. PubMed and EMBASE were screened up to December 2013; data from national nutrition surveys were added. Forty-six studies were included, following the PRISMA guideline. KEY MESSAGES: Mean daily energy intake was 8.9 MJ in men and 7.3 MJ in women. Mean daily carbohydrate and protein intakes were 46 and 15 En% in men and 47 and 16 En% in women, respectively. Mean daily total fat, saturated fatty acid (SFA), mono-unsaturated fatty acid (MUFA) and poly-unsaturated fatty acid intakes were respectively 34, 13, 13 and 5-6 En%. The carbohydrates and MUFA intakes are below the acceptable macronutrient distribution ranges (AMDR). Fat intake is relatively high, and SFA intake exceeds the upper-AMDR. Based on the estimated average requirement (EAR) cut-point method, 10-12% of older adults do not meet the EAR for protein. To interpret a possible energy imbalance additional information is needed on physical activity, energy expenditure and body weight changes. This systematic review indicates a suboptimal dietary macronutrient distribution and a large variation in nutrient intakes among community-dwelling older adults.

Postprandial muscle protein synthesis is higher after a high whey protein, leucine-enriched supplement than after a dairy-like product in healthy older people: a randomized controlled trial.

BACKGROUND: Decreased ability of muscles to respond to anabolic stimuli is part of the underlying mechanism for muscle loss with aging. Previous studies suggest that substantial amounts of essential amino acids (EAA), whey protein and leucine are beneficial for stimulation of acute muscle protein synthesis in older adults. However, these studies supplied only proteins, and no bolus studies have been done with dairy products or supplements that contained also fat and carbohydrates besides proteins. The aim of this study was to evaluate whether a specifically designed nutritional supplement in older adults stimulates muscle protein synthesis acutely to a greater extent than a conventional dairy product. Moreover, the combined effect with resistance exercise was studied by using a unilateral resistance exercise protocol. METHODS: Utilizing a randomized, controlled, double blind study design, healthy older adults received a single bolus of a high whey protein, leucine-enriched supplement (EXP: 20 g whey protein, 3g total leucine, 150 kcal; n = 9) or an iso-caloric milk protein control ( CONTROL: 6g milk protein; n = 10), immediately after unilateral resistance exercise. Postprandial mixed muscle protein fractional synthesis rate (FSR) was measured over 4h using a tracer infusion protocol with L-[ring-¹³C6]-phenylalanine and regular blood and muscle sampling. RESULTS: FSR was significantly higher overall after EXP (0.0780 ± 0.0070%/h) vs CONTROL (0.0574 ± 0.0066%/h (EMM ± SE)) (p = 0.049). No interaction between treatment and exercise was observed (p = 0.519). Higher postprandial concentrations of EAA and leucine are possible mediating factors for the FSR response, while plasma insulin increase did not dictate the FSR response. Moreover, when the protein intake from the supplements was expressed per kg leg lean mass (LLM), a significant correlation was observed with resting postprandial FSR (r = 0.48, P = 0.038). CONCLUSIONS: Ingestion of a high whey protein, leucine-enriched supplement resulted in a larger overall postprandial muscle protein synthesis rate in healthy older subjects compared with a conventional dairy product. This acute effect is promising for long-term effects on parameters of muscle mass, strength and function in sarcopenic older people, which requires further study. TRIAL REGISTRATION: This trial is registered in the Dutch Trial Register under number NTR1823.

Stimulated nitric oxide production and arginine deficiency in children with cystic fibrosis with nutritional failure.

OBJECTIVE: To determine whether upregulated whole body de novo arginine synthesis and protein breakdown are present as a compensatory mechanism to meet the increased demand for arginine and nitric oxide (NO) production in pediatric patients with cystic fibrosis (CF) and nutritional failure. STUDY DESIGN: In 16 children with CF, studied at the end of antibiotic treatment for a pulmonary exacerbation, and 17 healthy controls, whole body arginine, citrulline (Cit), and protein turnover were assessed by stable isotope methodology and de novo arginine synthesis, arginine clearance, NO synthesis, protein synthesis and breakdown, and net protein balance were calculated. The plasma isotopic enrichments and amino acid concentrations were measured by liquid chromatography-tandem mass spectrometry. RESULTS: Increased arginine clearance was found in patients with CF (P < .001), whereas whole body NO production rate and plasma arginine levels were not different. Whole body arginine production (P < .001), de novo arginine synthesis, and protein breakdown and synthesis (P < .05) were increased in patients with CF, but net protein balance was comparable. Patients with CF with nutritional failure (n = 7) had significantly higher NO production (P < .05), de novo arginine synthesis, Cit production (P < .001), and plasma Cit concentration (P < .05) and lower plasma arginine concentration (P < .05) than those without nutritional failure (n = 9). CONCLUSIONS: Nutritional failure in CF is associated with increased NO production. However, up-regulation of de novo arginine synthesis and Cit production was not sufficient to meet the increased arginine needs leading to arginine deficiency.

Muscle Protein Synthesis with a Hybrid Dairy and Plant-Based Protein Blend (P4) Is Equal to Whey Protein in a Murine Ageing Model after Fasting.

P4, a specific combination of dairy proteins (whey and casein) and plant-based protein isolates (pea and soy), has been shown to provide a more balanced amino acid (AA) profile than its single constituent proteins; however, less is known about how this translates to muscle protein synthesis (MPS). The aim of this study was to investigate the effect of P4 compared to whey or casein against fasted control on MPS. C57BL/6J mice, aged 25 months, were fasted overnight, followed by oral gavage of either whey, P4, casein, or water as a fasted control. Thirty minutes after ingestion, puromycin (0.04 µmol∙g-1 bodyweight) was subcutaneously injected; 30-min thereafter, mice were sacrificed. MPS was measured by the SUnSET method, and signalling proteins were determined in the left-tibialis anterior (TA) muscle by the WES technique. AA composition was determined in plasma and right-TA muscle. Dried blood spots (DBS) were analysed for postprandial AA dynamics at 10, 20, 45, 60 min. MPS was 1.6-fold increased with whey (p = 0.006) and 1.5-fold with P4 compared to fasted (p = 0.008), while no change was seen with casein. This was confirmed by a significant increase of phosphorylated/total ratio of 4E-BP1 for both whey (p = 0.012) and P4 (p = 0.001). No changes were observed in p70S6K and mTOR phosphorylation/total ratio with whey or P4. Intramuscular leucine levels were lower for P4 (0.71 µmol∙g dry weight-1) compared to whey (0.97 µmol∙g dry weight-1) (p = 0.0007). Ten minutes postprandial, DBS showed significantly increased blood AA levels of BCAAs, histidine, lysine, threonine, arginine, and tyrosine for P4 versus fasted. In conclusion, a hybrid mix of dairy and plant-based proteins (P4) resulted in a MPS response that was similar to whey protein in aged mice after fasting. This suggests that other anabolic triggers beyond leucine or the well-balanced amino acid profile and bioavailability of the blend benefit stimulation of MPS.

Arginine de novo and nitric oxide production in disease states.

Arginine is derived from dietary protein intake, body protein breakdown, or endogenous de novo arginine production. The latter may be linked to the availability of citrulline, which is the immediate precursor of arginine and limiting factor for de novo arginine production. Arginine metabolism is highly compartmentalized due to the expression of the enzymes involved in arginine metabolism in various organs. A small fraction of arginine enters the NO synthase (NOS) pathway. Tetrahydrobiopterin (BH4) is an essential and rate-limiting cofactor for the production of NO. Depletion of BH4 in oxidative-stressed endothelial cells can result in so-called NOS3 "uncoupling," resulting in production of superoxide instead of NO. Moreover, distribution of arginine between intracellular transporters and arginine-converting enzymes, as well as between the arginine-converting and arginine-synthesizing enzymes, determines the metabolic fate of arginine. Alternatively, NO can be derived from conversion of nitrite. Reduced arginine availability stemming from reduced de novo production and elevated arginase activity have been reported in various conditions of acute and chronic stress, which are often characterized by increased NOS2 and reduced NOS3 activity. Cardiovascular and pulmonary disorders such as atherosclerosis, diabetes, hypercholesterolemia, ischemic heart disease, and hypertension are characterized by NOS3 uncoupling. Therapeutic applications to influence (de novo) arginine and NO metabolism aim at increasing substrate availability or at influencing the metabolic fate of specific pathways related to NO bioavailability and prevention of NOS3 uncoupling. These include supplementation of arginine or citrulline, provision of NO donors including inhaled NO and nitrite (sources), NOS3 modulating agents, or the targeting of endogenous NOS inhibitors like asymmetric dimethylarginine.

Vitamin D status modulates mitochondrial oxidative capacities in skeletal muscle: role in sarcopenia.

Skeletal muscle mitochondrial function is the biggest component of whole-body energy output. Mitochondrial energy production during exercise is impaired in vitamin D-deficient subjects. In cultured myotubes, loss of vitamin D receptor (VDR) function decreases mitochondrial respiration rate and ATP production from oxidative phosphorylation. We aimed to examine the effects of vitamin D deficiency and supplementation on whole-body energy expenditure and muscle mitochondrial function in old rats, old mice, and human subjects. To gain further insight into the mechanisms involved, we used C2C12 and human muscle cells and transgenic mice with muscle-specific VDR tamoxifen-inducible deficiency. We observed that in vivo and in vitro vitamin D fluctuations changed mitochondrial biogenesis and oxidative activity in skeletal muscle. Vitamin D supplementation initiated in older people improved muscle mass and strength. We hypothesize that vitamin D supplementation is likely to help prevent not only sarcopenia but also sarcopenic obesity in vitamin D-deficient subjects.

Bacterial translocation is reduced by a specific nutritional combination in mice with chemotherapy-induced neutropenia.

Immune function is compromised in many cancer patients, leading to an increased risk of (infectious) complications. Chemotherapy-induced neutropenia is a common cause of treatment-induced immune suppression. In the present study, the effect of a specific nutritional combination (SNC) on bacterial translocation was studied in a model of chemotherapy-induced neutropenia in C3H/HeN mice colonized with Pseudomonas aeruginosa PAO-1. Dietary intervention started after stable colonization with P. aeruginosa to compare the SNC containing high protein, l-leucine, fish oil, and specific oligosaccharides to an isoenergetic control diet. After 3 wk, the mice were treated with cyclophosphamide to induce neutropenia. This rendered the mice susceptible to Pseudomonas translocation, which was quantified 5 d later. Intervention with the SNC resulted in a reduced incidence and intensity of bacterial translocation to the liver (P < 0.05) and a similar trend in the lungs (P ≤ 0.057). In addition, the SNC reduced the fecal pH (P < 0.05) and decreased P. aeruginosa counts in fecal samples (P < 0.05). Moreover, plasma concentrations of proinflammatory cytokines were correlated with the reduced bacterial translocation to the liver (ρ > 0.78; P < 0.001). In conclusion, dietary intervention with the SNC significantly reduced the incidence and severity of P. aeruginosa translocation in a mouse model of chemotherapy-induced immune suppression. Several mechanisms might have played a role, including the modulation of the intestinal microbiota, an improved gut barrier function, immune function, and a reduced inflammatory state. These results suggest an opportunity to develop new applications in cancer patients, with the aim to reduce infectious and other complications.

Response and Adherence of Nursing Home Residents to a Nutrition/Exercise Intervention.

OBJECTIVES: Interindividual response variability to nutrition and exercise interventions is extensive in older adults. A group of nursing home (NH) residents participated in a combined intervention. The objective of this post-hoc analysis was to identify factors associated with intervention response measured by change in physical function and body composition. DESIGN: Post-hoc analyses in the Older Person's Exercise and Nutrition study, a 2-arm randomized trial. The primary outcomes were 30-second Chair Stand Test and composite scores combining physical function and fat-free mass. A secondary outcome was intervention adherence. A 12-week intervention of sit-to-stand exercises and protein-rich nutritional supplements did not improve chair-stand capacity vs control on intention-to-treat basis. SETTING AND PARTICIPANTS: Residents ≥75 years of age from dementia and somatic units in eight NHs in Sweden. METHODS: Logistic regressions were performed to define factors associated with response (maintenance/improvement) or nonresponse (deterioration) in 30-second Chair Stand Test, and with intervention adherence. Linear regressions were performed to explore factors associated with response in composite scores. RESULTS: Mean age of participants (n = 52 intervention, n = 49 control) was 85.8 years. Sarcopenia was occurring in 74%. Sarcopenia at baseline (P = .005) and high adherence to nutritional supplements (P = .002) increased the odds of response. Higher independence in daily activities increased the odds of adherence to sit-to-stand exercises (P = .027) and the combined intervention (P = .020). Allocation to the intervention group and higher self-perceived health were associated with higher composite scores. CONCLUSIONS AND IMPLICATIONS: NH residents with baseline sarcopenia, better self-perceived health, and high adherence to nutritional supplements benefitted most from a combined nutrition and exercise intervention regarding chair-stand capacity and composite scores of function and fat-free mass. Adherence was related to higher grade of independence. Understanding factors associated with response and adherence to an intervention will help target susceptible residents in most need of support and to optimize the outcome.

Regulation of nitric oxide production in health and disease.

PURPOSE OF REVIEW: The purpose of this review is to highlight recent publications examining nitric oxide production in health and disease and its association with clinical nutrition and alterations in metabolism. RECENT FINDINGS: The role of the cofactor tetrahydrobiopterin in nitric oxide production and its relation with arginine availability is indicated as an important explanation for the arginine paradox. This offers potential for nitric oxide regulation by dietary factors such as arginine or its precursors and vitamin C. Because diets with a high saturated fat content induce high plasma fatty acid levels, endothelial nitric oxide production is often impaired due to a reduction in nitric oxide synthase 3 phosphorylation. Increasing the arginine availability by arginine therapy or arginase inhibition was, therefore, proposed as a potential therapy to treat hypertension. Recent studies in septic patients and transgenic mice models found that inadequate de-novo arginine production from citrulline reduces nitric oxide production. Citrulline supplementation may, therefore, be a novel therapeutic approach in conditions of arginine deficiency. SUMMARY: Both lack and excess of nitric oxide production in diseases can have various important implications in which dietary factors can play a modulating role. Future research is needed to expand our understanding of the regulation and adequate measurement of nitric oxide production at the organ level and by the different nitric oxide synthase isoforms, also in relation to clinical nutrition.

A randomized-controlled trial of arginine infusion in severe sepsis on microcirculation and metabolism.

BACKGROUND & AIMS: Sepsis is hypothesized as an arginine deficient state, with lack of nitric oxide (NO) for adequate microcirculation and local perfusion. This study aimed to investigate if prolonged (72-h) intravenous l-arginine administration in sepsis patients improves microcirculation. Secondly, effects on arginine and protein metabolism, and organ function were studied. METHODS: Critically ill patients with a diagnosis of septic shock participated in a long-term (72 h) randomized double-blind placebo-controlled parallel-group study. l-arginine-HCl (1.2 µmol kg-1 min-1; n = 9) or l-alanine (isocaloric control: 2.4 µmol kg-1 min-1; n = 9) was continuously infused. Primary study outcome was microcirculation, assessed as gastric mucosal perfusion by gastric tonometry (Pr-aCO2 gap) and skin perfusion by Laser Doppler flowmetry. Secondary endpoints were whole body (WB) arginine and protein metabolism, organ function and clinical outcomes. We measured global hemodynamics continuously for safety monitoring. Statistical analyses were performed by mixed model for repeated measures with treatment by time interaction as estimate for between-group difference. RESULTS: Pr-aCO2 increased only in the l-arginine group (p = 0.006), without a significant between-group difference (p = 0.17). We found no significant differences in skin perfusion parameters. l-arginine infusion resulted in a larger increase of plasma arginine and ornithine concentrations (p < 0.01), WB (endogenous) arginine appearance (p < 0.001), WB NO synthesis (p = 0.027) and WB arginine to urea conversion (p < 0.001) than infusion of l-alanine. We found no effect on global hemodynamics, and protein metabolism by l-arginine infusion. Organ function parameters were unaffected, except for a significant difference between groups in intra-abdominal pressure over time (p = 0.029). CONCLUSIONS: Prolonged intravenous l-arginine administration does not improve local perfusion and organ function despite an increase in WB NO synthesis. Administration is safe with regard to global hemodynamics, but the observed increase in Pr-aCO2 and intra-abdominal pressure warrants careful application of l-arginine infusion and further research, especially in the early stage of septic shock.

Effects of Nutritional Interventions on Nutritional and Functional Outcomes in Geriatric Rehabilitation Patients: A Systematic Review and Meta-Analysis.

OBJECTIVES: It has been recognized that nutritional interventions play a role in improving the nutritional and functional status of older persons. This systematic review summarizes the evidence on nutritional and functional outcomes of nutritional interventions alone or in combination with physical exercise in geriatric rehabilitation patients. DESIGN: Eight electronic databases were searched until July 1, 2019 to identify nutritional intervention studies in patients aged ≥60 years who were admitted to geriatric rehabilitation. A meta-analysis was performed to quantify intervention effects on serum albumin, muscle mass, and hand grip strength (HGS). RESULTS: A total of 1962 studies were screened and 13 included in the systematic review. Studies were heterogeneous in interventions (4 nutritional interventions, 6 physical exercise + nutritional intervention, 1 timing of protein provision, 1 exercise + dietary advice, 1 nutrition-related nursing care) and outcomes. Among the 9 interventions that tested oral nutritional supplements (ONS) with protein, with or without exercise, 7 studies reported protein intake and 6 showed increased protein intakes, 2 of 5 studies showed increased albumin levels, and 5 of 9 reported an improvement in functional outcomes (BI, Functional Independence Measure, mobility). Meta-analyses showed no significant intervention effects on albumin [standardized mean difference (SMD) 0.45, 95% confidence interval (CI) -0.14, 1.04 (4 studies)], muscle mass [mean difference (MD) 2.14 kg, 95% CI -2.17, 6.45 (3 studies)], and HGS [SMD -0.04, 95% CI -0.55, 0.63 (3 studies)], but was based on a very limited number of studies. CONCLUSIONS AND IMPLICATIONS: Only a limited number of studies with heterogeneous nutritional interventions and outcomes were available in the geriatric rehabilitation population. Studies that included ONS improved nutritional outcomes, especially protein intake and albumin levels. Functional outcomes improved in the majority of reporting studies. This indicates benefits of protein supplementation, with or without exercise, in this population. Future well-designed and well-powered clinical trials are needed to clarify existing controversial aspects.

Nutritional status and functionality in geriatric rehabilitation patients: a systematic review and meta-analysis.

PURPOSE: Since there is only limited evidence available for geriatric rehabilitation patients, this systematic review and meta-analysis aims to characterize the nutritional status in this population and its relationship with functionality. METHODS: Eight databases were searched for full-text articles reporting baseline nutritional intake and status of adults ≥ 60 years in rehabilitation settings. Pooled estimates were calculated for prevalence of malnutrition and risk of malnutrition based on the Mini Nutritional Assessment (MNA) and for mean body mass index (BMI). Associations between nutritional status (MNA, MNA short form and BMI) and functional status (Barthel Index and Functional Independence Measure) and prevalence of sarcopenia were reviewed. RESULTS: 62 out of 1717 references were eligible for inclusion. Pooled prevalence [95% confidence interval (CI)] of malnutrition and risk of malnutrition were 13 (5-20) % and 47 (40-54) %. Pooled estimate (95% CI) for BMI was 23.8 (23.2-24.5) kg/m2. Existing data suggest a risk for low protein and energy intake and vitamin D deficiency. Functional status differed widely. Seven out of ten studies reported significant associations between reduced nutritional status and reduced functionality, whilst two out of seven studies reported significant associations between higher BMI and functionality. Prevalence of sarcopenia was high with 40-76% in this population. CONCLUSIONS: Although geriatric rehabilitation populations and settings were heterogeneous, a relevant percentage of geriatric rehabilitation patients were affected by a reduced nutritional status. Nutritional status was associated with decreased functionality. This emphasizes the need for screening for malnutrition and targeted nutritional intervention.

Frailty, Sarcopenia, and Malnutrition Frequently (Co-)occur in Hospitalized Older Adults: A Systematic Review and Meta-analysis.

OBJECTIVES: The purpose of this systematic review and meta-analysis was to summarize the prevalence of, and association between, physical frailty or sarcopenia and malnutrition in older hospitalized adults. DESIGN: A systematic literature search was performed in 10 databases. SETTING AND PARTICIPANTS: Articles were selected that evaluated physical frailty or sarcopenia and malnutrition according to predefined criteria and cutoffs in older hospitalized patients. MEASURES: Data were pooled in a meta-analysis to evaluate the prevalence of prefrailty and frailty [together (pre-)frailty], sarcopenia, and risk of malnutrition and malnutrition [together (risk of) malnutrition], and the association between either (pre-)frailty or sarcopenia and (risk of) malnutrition. RESULTS: Forty-seven articles with 18,039 patients (55% female) were included in the systematic review, and 39 articles (8868 patients, 62% female) were eligible for the meta-analysis. Pooling 11 studies (2725 patients) revealed that 84% [95% confidence interval (CI): 77%, 91%, I2 = 98.4%] of patients were physically (pre-)frail. Pooling 15 studies (4014 patients) revealed that 37% (95% CI: 26%, 48%, I2 = 98.6%) of patients had sarcopenia. Pooling 28 studies (7256 patients) revealed a prevalence of 66% (95% CI: 58%, 73%, I2 = 98.6%) (risk of) malnutrition. Pooling 10 studies (2427 patients) revealed a high association [odds ratio (OR): 5.77 (95% CI: 3.88, 8.58), P < .0001, I2 = 42.3%] and considerable overlap (49.7%) between physical (pre-)frailty and (risk of) malnutrition. Pooling 7 studies (2506 patients) revealed a high association [OR: 4.06 (95% CI: 2.43, 6.80), P < .0001, I2 = 71.4%] and considerable overlap (41.6%) between sarcopenia and (risk of) malnutrition. CONCLUSIONS AND IMPLICATIONS: The association between and prevalence of (pre-)frailty or sarcopenia and (risk of) malnutrition in older hospitalized adults is substantial. About half of the hospitalized older adults suffer from 2 and perhaps 3 of these debilitating conditions. Therefore, standardized screening for these conditions at hospital admission is highly warranted to guide targeted nutritional and physical interventions.