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1.  Is the Optimal Level of Protein Intake for Older Adults Greater Than the Recommended Dietary Allowance? 
Protein is a macronutrient essential for growth, muscle function, immunity and overall tissue homeostasis. Suboptimal protein intake can significantly impact physical function and overall health in older adults.
This article reviews the literature on the recommendations for protein intake in older adults in light of the new evidence linking protein intake with sarcopenia and physical function. Challenges and opportunities for optimal protein nutrition in older persons are discussed.
Recent metabolic and epidemiological studies suggest that the current recommendations of protein intake may not be adequate for maintenance of physical function and optimal health in older adults. Methodological limitations and novel concepts in protein nutrition are also discussed.
We conclude that new research and novel research methodologies are necessary to establish the protein needs and optimal patterns of protein intake for older persons.
PMCID: PMC3660117  PMID: 23183903
2.  Is there a maximal anabolic response to protein intake with a meal? 
Several recent publications indicate that the maximum stimulation of muscle protein fractional synthetic rate occurs with intake of 20 to 30 gms protein. This finding has led to the concept that there is a maximal anabolic response to protein intake with a meal, and that the normal amount of protein eaten with dinner will generally exceed the maximally-effective intake of protein.
However, protein breakdown has not been taken into account when evaluating the anabolic response to protein intake. Protein anabolism occurs only when protein synthesis exceeds breakdown protein breakdown.
Higher protein intakes when protein synthesis is maximized is characterized by suppressed protein breakdown and via that mechanism leads to a greater anabolic response. This explains why when net protein synthesis is measured, the relationship between amino acid availability and net gain remains linear, without any apparent plateau of effect at higher levels of availability.
We conclude that there is no practical upper limit to the anabolic response to protein or amino acid intake in the context of a meal.
PMCID: PMC3595342  PMID: 23260197
protein; anabolic response; meal; muscle protein synthesis
3.  Muscle protein synthesis in cancer patients can be stimulated with a specially formulated medical food☆ 
Maintenance of muscle mass is crucial to improving outcome and quality of life in cancer patients. Stimulating muscle protein synthesis is the metabolic basis for maintaining muscle mass, but in cancer patients normal dietary intake has minimal effects on muscle protein synthesis. Adding leucine to high protein supplements stimulates muscle protein synthesis in healthy older subjects. The objective was to determine if a specially formulated medical food, high in leucine and protein, stimulates muscle protein synthesis acutely in individuals with cancer to a greater extent than a conventional medical food.
A randomized, controlled, double-blind, parallel-group design was used in 25 patients with radiographic evidence of cancer. Patients were studied before their cancer treatment was started or 4 weeks after their treatment was completed or halted. The fractional rate of muscle protein synthesis (FSR) was measured using the tracer incorporation technique with L-[ring-13C6]-phenylalanine. The experimental group (n = 13) received a medical food containing 40 g protein, based on casein and whey protein and enriched with 10% free leucine and other specific components, while the control group (n = 12) was given a conventionally used medical food based on casein protein alone (24 g). Blood and muscle samples were collected in the basal state and 5h hours after ingestion of the medical foods.
The cancer patients were in an inflammatory state, as reflected by high levels of C-reactive protein (CRP), IL-1β and TNF-α, but were not insulin resistant (HOMA). After ingestion of the experimental medical food, plasma leucine increased to about 400 μM as compared to the peak value of 200 μM, after the control medical food (p < 0.001). Ingestion of the experimental medical food increased muscle protein FSR from 0.073 (SD: 0.023) to 0.097 (SD: 0.033) %/h (p = 0.0269). In contrast, ingestion of the control medical food did not increase muscle FSR; 0.073 (SD: 0.022) and 0.065 (SD: 0.028) %/h.
In cancer patients, conventional nutritional supplementation is ineffective in stimulating muscle protein synthesis. This anabolic resistance can be overcome with a specially formulated nutritional supplement.
PMCID: PMC3964623  PMID: 21683485
Muscle; Protein synthesis; Casein; Whey; Cancer; Leucine; Medical food
4.  Insulin sensitivity is related to fat oxidation and protein kinase C activity in children with acute burn injury 
Impaired fatty acid oxidation occurs with type 2 diabetes and is associated with accumulations of intracellular lipids, which may increase diacylglycerol, stimulate protein kinase C activity and inactivate insulin signaling. Glucose and fat metabolism are altered in burn patients, but have never been related to intracellular lipids or insulin signaling.
Thirty children sustaining >40% total body surface area burns were studied acutely with glucose and palmitate tracer infusions and a hyper-insulinemic euglycemic clamp. Muscle triglyceride, diacylglycerol, fatty acyl CoA and insulin signaling were measured. Liver and muscle triglyceride levels were measured with magnetic resonance spectroscopy. Muscle samples from healthy children were controls for diacylglycerol concentrations.
Insulin sensitivity was reduced and correlated with whole body palmitate β-oxidation (P=0.004). Muscle insulin signaling was not stimulated by hyper-insulinemia. Tissue triglyceride concentrations and activated protein kinase C-β were elevated, whereas the concentration of diacylglycerol was similar to the controls. Free fatty acid profiles of muscle triglyceride did not match diacylglycerol.
Insulin resistance following burn injury is accompanied by decreased insulin signaling and increased protein kinase C-β activation. The best metabolic predictor of insulin resistance in burned patients was palmitate oxidation.
PMCID: PMC3905468  PMID: 18535477
Insulin Sensitivity; fat metabolism; Protein Kinase C; Burn Trauma
5.  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 
Nutrition Journal  2014;13:9.
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.
Utilizing a randomized, controlled, double blind study design, healthy older adults received a single bolus of a high whey protein, leucine-enriched supplement (EXP: 20g whey protein, 3g total leucine, 150kcal; 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.
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).
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.
PMCID: PMC3909458  PMID: 24450500
Muscle; Protein synthesis; Older people; Leucine; Whey; Exercise
6.  Blood Pressure Levels and Mortality Risk among Hemodialysis Patients: Results from the Dialysis Outcomes and Practice Patterns Study 
Kidney international  2012;82(5):570-580.
KDOQI practice guidelines recommend pre-dialysis blood pressure (BP) <140/90 mm Hg. However, most prior hemodialysis studies found elevated mortality with low, not high, systolic blood pressure (SBP), possibly due to unmeasured confounders affecting BP and mortality such as severity of comorbidities. To lessen this bias, we analyzed facility-level BP practices, relating patient-level survival to the fraction of patients in BP categories at each dialysis facility in Cox regression models adjusted for patient and facility characteristics. Analyses included 24,525 patients in the Dialysis Outcomes and Practice Patterns Study. Compared with pre-dialysis SBP 130–159 mm Hg, mortality was 13% higher in facilities with 20% more patients at SBP 110–129 mm Hg and 16% higher in facilities with 20% more patients at SBP ≥160 mm Hg. For patient-level SBP, mortality was elevated at low (<130 mm Hg), not high (up to ≥180 mm Hg) SBP. For pre-dialysis diastolic BP, mortality was lowest at 60–99 mm Hg, a wide range suggesting less chance to improve outcomes. Higher mortality at SBP <130 mm Hg is consistent with prior studies and may be due to excessive BP-lowering during dialysis. The lowest risk facility SBP range of 130–159 mm Hg indicates this range may be optimal, but may have been influenced by unmeasured facility practices. While additional study is needed, the findings contrast with KDOQI BP targets, and provide guidance on optimal BP range in absence of definitive clinical trial data.
PMCID: PMC3891306  PMID: 22718187
7.  Impaired glucose tolerance in pediatric burn patients at discharge from the acute hospital stay 
Hyperglycemia, secondary to the hypermetabolic stress response, is a common occurrence after thermal injury. This stress response has been documented to persist up to 9 months post burn. The purpose of this study was to measure insulin sensitivity in severely burned children prior to discharge when wounds are 95% healed.
Twenty-four children, aged 4–17 years, with burns ≥ 40% total body surface area (TBSA) underwent a 2 hour oral glucose tolerance test (OGTT) prior to discharge from the acute pediatric burn unit. Plasma glucose and insulin levels, as well as the Homeostasis Model Assessment for Insulin Resistance (HOMAIR) were compared to published OGTT data from healthy, non-burned children.
There was a significant difference between severely burned children and non-burned, healthy children with respect to the HOMAIR. Severely burned children had a HOMAIR of 3.53±1.62 compared to the value in non-burned healthy children was 1.28±0.16 (p<0.05).
Insulin resistance secondary to the hypermetabolic stress response persists in severely burned children when burn wounds are at least 95% healed. The results of this study warrant future investigations into therapeutic options for the burned child during the rehabilitative phase of their care after injury.
PMCID: PMC3884511  PMID: 20634704
Burns; Pediatrics; Children; Insulin Resistance; Oral Glucose Tolerance Test
8.  Acute hyperinsulinemia and reduced plasma free fatty acid levels decrease intramuscular triglyceride synthesis 
To investigate the effect of acute hyperinsulinemia and the resulting decrease in plasma free fatty acid (FFA) concentrations on intramuscular TG synthesis.
U-13C16-palmitate was infused for 3 hours in anesthetized rabbits after overnight food deprivation. Arterial blood and leg muscle were sampled during the tracer infusion. Plasma samples were analyzed for free and TG-bound palmitate enrichments and concentrations. The enrichments and concentrations of palmitoyl-CoA and palmitoyl-carnitine as well as the enrichment of palmitate bound to TG were measured in muscle samples. Fractional synthetic rate (FSR) of intramuscular TG was calculated using the tracer incorporation method. The rabbits were divided into a control group and a hyperinsulinemic euglycemic clamp group.
Insulin infusion decreased the rate of appearance of plasma free palmitate (2.00 ± 0.15 vs. 0.68 ± 0.20 µmol . kg−1 . min−1; p<.001), decreased plasma FFA concentration (327 ± 61 vs. 72 ± 25 nmol/mL; p<.01), decreased the total concentration of intramuscular fatty acyl-CoA plus fatty acyl-carnitine (12.1 ± 1.6 vs. 7.0 ± 0.7 nmol/g; p<.05), and decreased intramuscular TG FSR (0.48 ± 0.05 vs. 0.21 ± 0.06 %/h; p<.01) in comparison with the control group. Intramuscular TG FSR was correlated (p<.01) with both plasma FFA concentrations and intramuscular fatty acyl-CoA concentrations.
Fatty acid availability is a determinant of intramuscular TG synthesis. Insulin infusion decreases plasma and intramuscular fatty acid availability and thereby decreases TG synthesis.
PMCID: PMC3518684  PMID: 22898252
stable isotopes; fatty acyl-carnitine; fatty acyl-CoA
9.  Intensive insulin therapy improves insulin sensitivity and mitochondrial function in severely burned children 
Critical care medicine  2010;38(6):10.1097/CCM.0b013e3181de8b9e.
To institute intensive insulin therapy protocol in an acute pediatric burn unit and study the mechanisms underlying its benefits.
Prospective, randomized study.
An acute pediatric burn unit in a tertiary teaching hospital.
Children, 4–18 yrs old, with total body surface area burned ≥40% and who arrived within 1 wk after injury were enrolled in the study.
Patients were randomized to one of two groups. Intensive insulin therapy maintained blood glucose levels between 80 and 110 mg/dL. Conventional insulin therapy maintained blood glucose ≤215 mg/dL.
Measurements and Main Results
Twenty patients were included in the data analysis consisting of resting energy expenditure, whole body and liver insulin sensitivity, and skeletal muscle mitochondrial function. Studies were performed at 7 days post-burn (pretreatment) and at 21 days postburn (posttreatment). Resting energy expenditure significantly increased posttreatment (1476 ± 124 to 1925 ± 291 kcal/m2·day; p = .02) in conventional insulin therapy as compared with a decline in intensive insulin therapy. Glucose infusion rate was identical between groups before treatment (6.0 ± 0.8 conventional insulin therapy vs. 6.8 ± 0.9 mg/kg·min intensive insulin therapy; p = .5). Intensive insulin therapy displayed a significantly higher glucose clamp infusion rate posttreatment (9.1 ± 1.3 intensive insulin therapy versus 4.8 ± 0.6 mg/kg·min conventional insulin therapy, p = .005). Suppression of hepatic glucose release was significantly greater in the intensive insulin therapy after treatment compared with conventional insulin therapy (5.0 ± 0.9 vs. 2.5 ± 0.6 mg/kg·min; intensive insulin therapy vs. conventional insulin therapy; p = .03). States 3 and 4 mitochondrial oxidation of palmitate significantly improved in intensive insulin therapy (0.9 ± 0.1 to 1.7 ± 0.1 μm O2/CS/mg protein/min for state 3, p = .004; and 0.7 ± 0.1 to 1.3 ± 0.1 μm O2/CS/mg protein/min for state 4, p < .002), whereas conventional insulin therapy remained at the same level of activity (0.9 ± 0.1 to 0.8 ± 0.1.μm O2/CS/mg protein/min for state 3, p = .4; 0.6 ± 0.03 to 0.7 ± 0.1 μm O2/CS/mg protein/min, p = .6).
Controlling blood glucose levels ≤120 mg/dL using an intensive insulin therapy protocol improves insulin sensitivity and mitochondrial oxidative capacity while decreasing resting energy expenditure in severely burned children.
PMCID: PMC3826175  PMID: 20400899
burns; child; pediatrics; insulin; hyperinsulinism; hyperglycemia; critical care
10.  Clinical manifestations and long-term follow-up in pediatric patients living at altitude with an isolated pulmonary artery of ductal origin 
Pediatric Cardiology  2012;33(5):775-781.
The study aim was to define the clinical manifestations and long-term outcome of pediatric patients living at altitude with isolated pulmonary artery of ductal origin. This was a retrospective cohort study of 17 consecutive cases of isolated pulmonary artery of ductal origin at a single center. All patients lived at modest altitude (median, range; 2050 m, 1700–3050 m). Fifteen children (88%) were symptomatic at presentation. High altitude pulmonary edema was present in 2 patients (12%) at diagnosis and only 1 patient had episodes of hemoptysis during follow-up. Fourteen patients (82%) demonstrated evidence of pulmonary arterial hypertension (PAH). Among 14 patients with PAH, 11 patients had surgical interventions. PAH resolved in 5 of 11 patients (45%) undergoing surgical rehabilitation. One patient died during follow-up and 7 patients are receiving oral vasodilator therapies due to residual PAH; 14 patients remained asymptomatic. Our study showed that early intervention in patients with isolated pulmonary artery of ductal origin at modest altitude can potentially rehabilitate the isolated pulmonary artery and reverse the PAH. Whether surgery is indicated for patients with this disorder in the absence of PAH is unknown.
PMCID: PMC3360790  PMID: 22430374
isolated pulmonary artery of ductal origin; unilateral absence of pulmonary artery; altitude; high altitude pulmonary edema; pulmonary arterial hypertension
11.  Whey protein and essential amino acids promote the reduction of adipose tissue and increased muscle protein synthesis during caloric restriction-induced weight loss in elderly, obese individuals 
Nutrition Journal  2012;11:105.
Excess adipose tissue and sarcopenia presents a multifaceted clinical challenge that promotes morbidity and mortality in the obese, elderly population. Unfortunately, the mortality risks of muscle loss may outweigh the potential benefits of weight loss in the elderly. We have previously demonstrated the effectiveness of whey protein and essential amino acids towards the preservation of lean tissue, even under the conditions of strict bedrest in the elderly.
In the context of caloric restriction-based weight loss, we hypothesized that a similar formulation given as a meal replacement (EAAMR) would foster the retention of lean tissue through an increase in the skeletal muscle fractional synthesis rate (FSR). We also proposed that EAAMR would promote the preferential loss of adipose tissue through the increased energy cost of skeletal muscle FSR. We recruited and randomized 12 elderly individuals to an 8 week, caloric restriction diet utilizing equivalent caloric meal replacements (800 kcal/day): 1) EAAMR or a 2) competitive meal replacement (CMR) in conjunction with 400 kcal of solid food that totaled 1200 kcal/day designed to induce 7% weight loss. Combined with weekly measurements of total body weight and body composition, we also measured the acute change in the skeletal muscle FSR to EAAMR and CMR.
By design, both groups lost ~7% of total body weight. While EAAMR did not promote a significant preservation of lean tissue, the reduction in adipose tissue was greater in EAAMR compared to CMR. Interestingly, these results corresponded to an increase in the acute skeletal muscle protein FSR.
The provision of EAAMR during caloric restriction-induced weight loss promotes the preferential reduction of adipose tissue and the modest loss of lean tissue in the elderly population.
PMCID: PMC3546025  PMID: 23231757
Obesity; Fat; Protein
12.  Plasma triglycerides are not related to tissue lipids and insulin sensitivity in elderly following PPARα agonist treatment 
Mechanisms of ageing and development  2007;128(10):558-565.
Increases in plasma lipids, tissue triglycerides and decreases in mitochondrial function have been linked to insulin resistance and aging. In animals, peroxisome proliferator-activated receptor-α (PPARα) agonists decrease plasma lipids, intramyocellular fat (IMCL) and liver fat (LFAT) and improve mitochondrial β- oxidative function and insulin sensitivity, but the effects in elderly were not known. Insulin sensitivity was assessed with a 2-hour oral glucose tolerance test, magnetic resonance spectroscopy was used to asses IMCL, LFAT and plasma lipids were measured before and after 6, 11 and 61 days of PPAR-α agonist (fenofibrate) administration in 19 elderly (age 70±1 years) volunteers. Volunteers were stratified into healthy (N=7) and insulin resistant (N=12) groups. The baseline insulin sensitivity index (8.1±1.2 vs. 3.8±0.5, healthy vs. insulin resistant; P<0.001) was significantly higher in the healthy group. Fenofibrate treatment induced significant reductions in plasma triglycerides (P<0.001) and total cholesterol (P<0.001) in both groups. Nonetheless, neither fasted free fatty acids, glucose, insulin, nor insulin sensitivity improved in either group (Day 1 vs. day 61, 8.1±1.2 vs. 8.1±0.9, healthy; and 3.8±0.5 vs. 4.2±0.05, insulin resistant). Furthermore, there was no change in IMCL or LFAT. These results indicate that whereas fenofibrate significantly lowers plasma lipids it does not affect insulin sensitivity nor intracellular lipids in elderly.
PMCID: PMC3503242  PMID: 17904198
Intramuscular triglyceride; liver fat; aging; insulin resistance; plasma lipids
13.  Insulin resistance, secretion and breakdown are increased 9 months following severe burn injury 
Insulin resistance in the acute burn period has been well described, however, it is unknown if alterations in glucose metabolism persist beyond discharge from the acute injury. To measure the duration of insulin resistance following recovery from the acute burn injury, we performed a prospective cross-sectional study with a standard two hour oral glucose tolerance test in 46 severely burned children at 6, 9 or 12 months following initial injury. Glucose uptake and insulin secretion were assessed following the glucose load. Results were compared to those previously published in healthy children. At 6 months post-burn, the 2 hour glucose concentration was significantly (P<0.001) greater than controls, and the area under the curve (AUC) of glucose was significantly higher compared to 12 months and to healthy children (P=0.027 and P<0.001, respectively). The 9 month AUC glucose was higher than controls (P<0.01). The 6 month 2 hour insulin in was significantly higher than controls, as was the AUC of insulin in all time points post-burn. The AUC of C-peptide was significantly greater at 6 months post-injury compared to 9 and 12 months (P<0.01 for both). Increased 2 hour and AUC glucose and insulin indicate that glucose metabolism is still altered at 6 and 9 months post-injury, and coincides with previously documented defects in bone and muscle metabolism at these time points. Insulin breakdown is also still increased in this population. Further study of this population is warranted to determine if specific treatment is needed.
PMCID: PMC3503248  PMID: 18672331
Burns; insulin resistance; OGTT; pediatrics
14.  Human mitochondrial oxidative capacity is acutely impaired following burn trauma 
American journal of surgery  2008;196(2):234-239.
Mitochondrial proteins and genes are damaged after burn injury in animals but have not previously been assessed in human burn patients.
The rates of maximal muscle mitochondrial oxidative capacity(ATP production) and uncoupled oxidation(heat production) for both palmitate and pyruvate were measured in muscle biopsies from 40 children sustaining burns >40% body surface area and from 13 healthy children controls.
Maximal mitochondrial oxidation of pyruvate and palmitate were reduced in burn patients compared to controls (4.0±0.2:1.9±0.1 µmolO2/citrate synthase activity/mg protein/min pyruvate; Control:Burn;P<0.001 and 3.0±0.1:0.9±0.03 µmolO2/citrate synthase activity/mg protein/min palmatyl CoA; Control:Burn;P=0.003). Uncoupled oxidation was the same between groups.
The maximal coupled mitochondrial oxidative capacity is severely impaired after burn injury, although there are no alterations in the rate of uncoupled oxidative capacity. It may be that the ratio of these indicates that a larger portion of energy production in trauma patients is wasted through uncoupling, rather than used for healing.
PMCID: PMC3480314  PMID: 18639661
Trauma; burn; mitochondria; muscle
15.  Adult patients are more catabolic than children during acute phase after burn injury: a retrospective analysis on muscle protein kinetics 
Intensive Care Medicine  2011;37(8):1317-1322.
This study was performed to determine if there is an age-related specificity in the response of muscle protein metabolism to severe burn injury during acute hospitalization. This is a retrospective analysis of previously published data. Methods: Nineteen adult and 58 pediatric burn-injured patients (age 43.3 ± 14.3 vs. 7.2 ± 5.3 years, adult vs. children) participated in stable isotope [ring-2H5]phenylalanine (Phe) infusion studies. Femoral arterial and venous blood samples and muscle biopsy samples were collected throughout the study. Data are presented as means ± standard deviation (SD). A p value less than 0.05 was considered statistically significant.
Muscle net protein balance (NB) was higher in children (adult vs. children, -43 ± 61 vs. 8 ± 68 nmol Phe/min/100 ml leg volume, p < 0.05). Muscle protein fractional synthesis rate (FSR) was higher in children (adult vs. children, 0.11 ± 0.05 vs. 0.16 ± 0.10 %/h, p < 0.05). Leg muscle protein breakdown was not different between the groups (adult vs. children, 179 ± 115 vs. 184 ± 124 nmol Phe/ min/100 ml leg volume, p < 0.05; synthesis rate was 134 ± 96 and 192 ± 128 nmol Phe/min/100 ml leg volume in adults and children, respectively (p = 0.07). Age significantly correlated with muscle protein NB (p = 0.01) and FSR (p = 0.02); but not with breakdown (p = 0.67) and synthesis (p = 0.07) rates measured by using a three-pool model.
In burn injury, the muscle protein breakdown may be affected to the same extent in adults and children, whereas synthesis may have age-related specificities, resulting in a better but still low NB in children.
PMCID: PMC3280820  PMID: 21647721
Burn; Muscle protein metabolism; Age
16.  Spectrum of Cancer Risk among U.S. Solid Organ Transplant Recipients: The Transplant Cancer Match Study 
Jama  2011;306(17):1891-1901.
Solid organ transplant recipients have elevated cancer risk due to immunosuppression and oncogenic viral infections. Since most prior research has concerned kidney recipients, large studies that include recipients of differing organs can inform cancer etiology.
Describe the overall pattern of cancer among solid organ transplant recipients.
Cohort study using linked data from the U.S. Scientific Registry of Transplant Recipients (1987–2008) and 13 state/regional cancer registries.
Participants and Setting
Solid organ transplant recipients in the U.S.
Main Outcome Measure
Standardized incidence ratios (SIRs) and excess absolute risks (EARs) assessing relative and absolute cancer risk in transplant recipients compared to the general population.
Registry linkages yielded data on 175,732 solid organ transplants (58.4% kidney, 21.6% liver, 10.0% heart, 4.0% lung). Overall cancer risk was elevated (N=10,656 cases, incidence 1374.7 per 100,000 person-years; SIR 2.10, 95%CI 2.06–2.14; EAR 719.3, 95%CI 693.3–745.6, per 100,000 person-years). Risk was increased (p<0.001) for 32 different malignancies, some related to known infections (e.g., anal cancer, Kaposi sarcoma) and others unrelated (e.g., melanoma, thyroid and lip cancers). The most common malignancies with elevated risk were non-Hodgkin lymphoma (N=1504, incidence 194.0; SIR 7.54, 95%CI 7.17–7.93; EAR 168.3, 95%CI 158.6–178.4) and cancers of the lung (N=1344, incidence 173.4; SIR 1.97, 95%CI 1.86–2.08; EAR 85.3, 95%CI 76.2–94.8), liver (N=930, incidence 120.0; SIR 11.56, 95%CI 10.83–12.33; EAR 109.6, 95%CI 102.0–117.6), and kidney (N=752, incidence 97.0; SIR 4.65, 95%CI 4.32–4.99; EAR 76.1, 95%CI 69.3–83.3). Lung cancer risk was most elevated in lung recipients (SIR 6.13, 95%CI 5.18–7.21) but also increased among other recipients (SIR 1.46, 95%CI 1.34–1.59 for kidney; 1.95, 1.74–2.19 for liver; 2.67, 2.40–2.95 for heart). Liver cancer was elevated only among liver recipients (SIR 43.83, 95%CI 40.90–46.91), who manifested exceptional risk in the first 6 months (SIR 508.97, 95%CI 474.16–545.66) and continuing two-fold excess for 10–15 years (SIR 2.22, 95%CI 1.57–3.04). Among kidney recipients, kidney cancer was elevated (SIR 6.66, 95%CI 6.12–7.23) and bimodal in onset. Kidney cancer was also increased in liver and heart recipients (SIR 1.80, 95%CI 1.40–2.29, and 2.90, 2.32–3.59, respectively).
Recipients of a kidney, liver, heart, or lung transplant have an increased risk for diverse infection-related and unrelated cancers, compared with the general population.
PMCID: PMC3310893  PMID: 22045767
17.  Moderating the portion size of a protein-rich meal improves anabolic efficiency in young and elderly 
Ingestion of sufficient dietary protein is a fundamental prerequisite for muscle protein synthesis and maintenance of muscle mass and function. The elderly are often at increased risk for protein-energy malnutrition, sarcopenia and a diminished quality of life. This study sought to compare changes in muscle protein synthesis and anabolic efficiency in response to a single moderate (113 g; 220 kcal; 30 g protein) or large serving (340 g; 660 kcal; 90 g protein) of 90% lean beef. Venous blood and vastus lateralis muscle biopsy samples were obtained during a primed, constant infusion (0.08 μmol/kg/min) of L-[ring-13C6] phenylalanine in healthy young (n=17; 34±3yrs) and elderly (n=17; 68±2yrs) individuals. Mixed muscle fractional synthesis rate (FSR) was calculated during a 3 h post-absorptive period and for 5 h following meal ingestion. Data were analysed using a two-way repeated measures ANOVA with Tukey's pair-wise comparisons. A 113 g serving of lean beef increased muscle protein synthesis by approximately 50% in both young and older volunteers. Despite a 3-fold increase in protein and energy content, there was no further increase in protein synthesis following ingestion of 340 g of lean beef in either age group. Ingestion of more than 30 g of protein in a single meal does not further enhance the stimulation of muscle protein synthesis in young and elderly.
PMCID: PMC3197704  PMID: 19699838
nutrition; stable isotopes; sarcopenia; diet; beef
18.  The Response of Muscle Protein Anabolism to Combined Hyperaminoacidemia and Glucose-Induced Hyperinsulinemia Is Impaired in the Elderly 
Muscle mass declines with aging. Amino acids alone stimulate muscle protein synthesis in the elderly. However, mixed nutritional supplementation failed to improve muscle mass. We hypothesized that the failure of nutritional supplements is due to altered responsiveness of muscle protein anabolism to increased amino acid availability associated with endogenous hyperinsulinemia.
We measured muscle protein synthesis and breakdown, and amino acid transport in healthy young (30 ± 3 yr) and elderly (72 ± 1 yr) volunteers in the basal postabsorptive state and during the administration of an amino acid-glucose mixture, using l-[ring-2H5]phenylalanine infusion, femoral artery and vein catheterization, and muscle biopsies. Basal muscle amino acid turnover was similar in young and elderly subjects. The mixture increased phenylalanine leg delivery and transport into the muscle in both groups. Phenylalanine net balance increased in both groups (young, −27 ± 8 to 64 ± 17; elderly, −16 ± 4 to 29 ± 7 nmol/(min·100 mL); P < 0.0001, basal vs. mixture), but the increase was significantly blunted in the elderly (P = 0.030 vs. young). Muscle protein synthesis increased in the young, but remained unchanged in the elderly [young, 61 ± 17 to 133 ± 30 (P = 0.005); elderly, 62 ± 9 to 70 ± 14 nmol/(min·100 mL) (P = NS)]. In both groups, protein breakdown decreased (P = 0.012) and leg glucose uptake increased (P = 0.0258) with the mixture.
We conclude that the response of muscle protein anabolism to hyperaminoacidemia with endogenous hyperinsulinemia is impaired in healthy elderly due to the unresponsiveness of protein synthesis.
PMCID: PMC3192447  PMID: 11134097
19.  Essential amino acids are primarily responsible for the amino acid stimulation of muscle protein anabolism in healthy elderly adults 
Nutritional supplementation may be used to treat muscle loss with aging (sarcopenia). However, if physical activity does not increase, the elderly tend to compensate for the increased energy delivered by the supplements with reduced food intake, which results in a calorie substitution rather than supplementation. Thus, an effective supplement should stimulate muscle anabolism more efficiently than food or common protein supplements. We have shown that balanced amino acids stimulate muscle protein anabolism in the elderly, but it is unknown whether all amino acids are necessary to achieve this effect.
We assessed whether nonessential amino acids are required in a nutritional supplement to stimulate muscle protein anabolism in the elderly.
We compared the response of muscle protein metabolism to either 18 g essential amino acids (EAA group: n = 6, age 69 ± 2 y; x̄ ± SD) or 40 g balanced amino acids (18 g essential amino acids + 22 g nonessential amino acids, BAA group; n = 8, age 71 ± 2 y) given orally in small boluses every 10 min for 3 h to healthy elderly volunteers. Muscle protein metabolism was measured in the basal state and during amino acid administration via l-[ring-2H5]phenylalanine infusion, femoral arterial and venous catheterization, and muscle biopsies.
Phenylalanine net balance (in nmol · min−1 · 100 mL leg volume−1) increased from the basal state (P < 0.01), with no differences between groups (BAA: from −16 ± 5 to 16 ± 4; EAA: from −18 ± 5 to 14 ± 13) because of an increase (P < 0.01) in muscle protein synthesis and no change in breakdown.
Essential amino acids are primarily responsible for the amino acid–induced stimulation of muscle protein anabolism in the elderly.
PMCID: PMC3192452  PMID: 12885705
Sarcopenia; aging; protein synthesis; proteolysis; nutritional supplements
20.  Intravitreal Injection of AAV2 Transduces Macaque Inner Retina 
Intravitreally injected AAV2 transduced inner retinal cells in a restricted region at the macaque fovea. Because macaque and human eyes are similar, the results suggest a need to improve transduction methods in gene therapy for the human inner retina.
Adeno-associated virus serotype 2 (AAV2) has been shown to be effective in transducing inner retinal neurons after intravitreal injection in several species. However, results in nonprimates may not be predictive of transduction in the human inner retina, because of differences in eye size and the specialized morphology of the high-acuity human fovea. This was a study of inner retina transduction in the macaque, a primate with ocular characteristics most similar to that of humans.
In vivo imaging and histology were used to examine GFP expression in the macaque inner retina after intravitreal injection of AAV vectors containing five distinct promoters.
AAV2 produced pronounced GFP expression in inner retinal cells of the fovea, no expression in the central retina beyond the fovea, and variable expression in the peripheral retina. AAV2 vector incorporating the neuronal promoter human connexin 36 (hCx36) transduced ganglion cells within a dense annulus around the fovea center, whereas AAV2 containing the ubiquitous promoter hybrid cytomegalovirus (CMV) enhancer/chicken-β-actin (CBA) transduced both Müller and ganglion cells in a dense circular disc centered on the fovea. With three shorter promoters—human synapsin (hSYN) and the shortened CBA and hCx36 promoters (smCBA and hCx36sh)—AAV2 produced visible transduction, as seen in fundus images, only when the retina was altered by ganglion cell loss or enzymatic vitreolysis.
The results in the macaque suggest that intravitreal injection of AAV2 would produce high levels of gene expression at the human fovea, important in retinal gene therapy, but not in the central retina beyond the fovea.
PMCID: PMC3088562  PMID: 21310920
21.  Basal Muscle Amino Acid Kinetics and Protein Synthesis in Healthy Young and Older Men 
Sarcopenia is associated with loss of strength and function, eventually leading to loss of independence. Some studies suggest that basal muscle protein turnover is reduced with aging, but other studies do not confirm this finding.
To determine if aging per se affects basal muscle protein turnover in men.
Design and Setting
Cross-sectional study conducted from June 1997 to July 2000 in a general US community.
Twenty-six young (mean [SE] age, 28 [2] years) and 22 older (mean [SE] age, 70 [1] years) men, who were healthy and independent based on activities of daily living, physical examinations, and screening tests. Subjects were excluded if they had cardiac, pulmonary, liver, or kidney disease; any impairment in activities of daily living; or steroid use.
Main Outcome Measures
We measured basal muscle protein and amino acid kinetics, based on stable isotope techniques with femoral arteriovenous catheterization and muscle biopsies. Three models (arteriovenous balance, three-pool, and fractional synthesis rate) were used to estimate the metabolic parameters.
Mean (SE) total leg volume was 9.60 (0.32) L in older men vs 10.83 (0.43) L in younger men, which suggests muscle loss in the older men. Net muscle protein balance was similar in both groups (older men, −19 [2] nmol/min per 100 mL of leg volume vs younger men, −21 [2] nmol/min per 100 mL of leg volume; P=.51). Small differences were found in mean (SE) muscle protein synthesis in comparisons of older vs younger men: arteriovenous balance, 48 (5) nmol/min per 100 mL of leg volume vs 32 (3) nmol/min per 100 mL of leg volume; P=.004; three-pool, 58 (5) nmol/min per 100 mL of leg volume vs 43 (4) nmol/min per 100 mL of leg volume; P=.04; and fractional synthesis rate, 0.0601 (0.0046) %/h vs 0.0578 (0.0047) %/h; P=.73. Small differences were also found in mean (SE) muscle protein breakdown: arteriovenous balance, 66 (5) nmol/min per 100 mL of leg volume in older vs 53 (4) nmol/min per 100 mL of leg volume in younger men, P=.045; and three-pool, 76 (6) nmol/min per 100 mL of leg volume vs 64 (5) nmol/min per 100 mL of leg volume, P=.14.
Differences in basal muscle protein turnover between older and younger men do not appear to explain muscle loss that occurs with age.
PMCID: PMC3183815  PMID: 11559266
22.  28 day bed-rest with hypercortisolemia induces peripheral insulin resistance and increases intramuscular triglycerides 
Spaceflight represents a unique physiological challenge to humans, altering hormonal profiles and tissue insulin sensitivity. Among these hormonal alterations, hypercortisolemia and insulin insensitivity are thought to negatively affect muscle mass and function with spaceflight. As insulin sensitivity influences the accumulation of muscle triglycerides, we examined this relationship during hypercortisolemia and inactivity. Six young healthy volunteers were confined to bed rest for 28 days. To mimic the stress response observed during spaceflight, hypercortisolemia (20–24mg/dL) was induced and maintained by oral ingestion of hydrocortisone. On days 1 and 28 of bed rest, insulin sensitivity across the leg was assessed with a local (femoral arterial insulin infusion) 2 stage hyperinsulinemic-euglycemic clamp (stage 1: 35 µU/min/ml leg; stage 2: 70 µU/min/ml leg). Intramuscular lipid was measured with magnetic resonance spectroscopy. Following bed rest, there was a decrease in insulin sensitivity, as assessed by glucose uptake during hyperinsulinemia (from 9.1±1.3 (mean ± SEM) mg/kg.leg/min to 5.2±0.7 mg/kg.leg/min (P=0.015)). Intramuscular triglyceride increased from 0.077±0.011 to 0.136±0.018 (signal area of fat/signal area of standard; P=0.009). Intramuscular lipid content correlated with the glucose uptake at day 28, (R= −0.85; P=0.035). These data demonstrate that muscular inactivity and hypercortisolemia are associated with an increase in intramuscular triglyceride and skeletal muscle insulin resistance in previously healthy subjects.
PMCID: PMC2856785  PMID: 19919871
23.  In vivo imaging of microscopic structures in the rat retina 
The ability to resolve single retinal cells in rodents in vivo has applications in rodent models of the visual system and retinal disease. We have characterized the performance of a fluorescence adaptive optics scanning laser ophthalmoscope (fAOSLO) that provides cellular and subcellular imaging of rat retina in vivo.
Green fluorescent protein (eGFP) was expressed in retinal ganglion cells of normal Sprague Dawley rats via intravitreal injections of adeno-associated viral vectors. Simultaneous reflectance and fluorescence retinal images were acquired using the fAOSLO. fAOSLO resolution was characterized by comparing in vivo images with subsequent imaging of retinal sections from the same eyes using confocal microscopy.
Retinal capillaries and eGFP-labeled ganglion cell bodies, dendrites, and axons were clearly resolved in vivo with adaptive optics (AO). AO correction reduced the total root mean square wavefront error, on average, from 0.30 μm to 0.05 μm (1.7-mm pupil). The full width at half maximum (FWHM) of the average in vivo line-spread function (LSF) was ∼1.84 μm, approximately 82% greater than the FWHM of the diffraction-limited LSF.
With perfect aberration compensation, the in vivo resolution in the rat eye could be ∼2× greater than that in the human eye due to its large numerical aperture (∼0.43). While the fAOSLO corrects a substantial fraction of the rat eye's aberrations, direct measurements of retinal image quality reveal some blur beyond that expected from diffraction. Nonetheless, subcellular features can be resolved, offering promise for using AO to investigate the rodent eye in vivo with high resolution.
PMCID: PMC2873188  PMID: 19578019
24.  Amino acid supplementation decreases plasma and liver triglycerides in elderly 
Hypertriglyceridemia is a risk factor for coronary heart disease. The aim of this study was to determine the effect of AA supplementation on plasma, liver and muscle lipid concentrations and insulin sensitivity in elderly.
Twelve impaired glucose tolerant elderly (67.0 ± 5.6 (SD) years, 7 females, 5 males) ingested 11 g of essential AA + arginine twice a day for 16 weeks, after a 7 week control run in. Diet and activity were not otherwise modified. Plasma lipid concentrations and oral glucose tolerance were measured every 4th week, and tissue lipid concentrations (magnetic resonance spectroscopy) every 8th week.
No changes in plasma lipids were observed during the control run-in. AA supplementation lowered plasma triglyceride (TG) (P < 0.001), total cholesterol (P = 0.048) and very low density lipoprotein (VLDL)-cholesterol (P < 0.001) concentrations. Plasma TG dropped ~20% from the initial value of 1.45 ± 0.18 (SE) mmol/l (128 ± 16 mg/dl), with greatest decrease in the subjects starting out with highest concentrations (r = −0.83). Similarly, liver fat content (liver TG/intralipid standard) decreased ~50% from the initial value of 0.34 ± 0.06 (P = 0.021; n = 9), with greatest decrease in the subjects that initially had highest values (r = −0.86). Intramuscular fat content and insulin sensitivity did not change.
Diet supplementation with AA lowers plasma TG, total cholesterol and VLDL-cholesterol concentrations, and liver lipid content in impaired glucose tolerant elderly. AA supplementation may have a potential role in treatment of hypertriglyceridemia or hepatic steatosis.
PMCID: PMC2696073  PMID: 19041223
elderly; amino acids; plasma lipids; liver lipids; insulin sensitivity
25.  Insulin resistance of muscle protein metabolism in aging 
A reduced response of older skeletal muscle to anabolic stimuli may contribute to the development of sarcopenia. We hypothesized that muscle proteins are resistant to the anabolic action of insulin in the elderly. We examined the effects of hyperinsulinemia on muscle protein metabolism in young (25±2 year) and older (68±1 year) healthy subjects using stable isotope tracer techniques. Leg blood flow was higher in the young at baseline and increased during hyperinsulinemia, whereas it did not change in the elderly. Glucose concentrations and muscle uptake were not different between groups at baseline and during hyperinsulinemia. Leg phenylalanine net balance was not different at baseline and significantly increased in both groups with hyperinsulinemia (P<0.05) but to a greater extent in the young (P<0.05). Muscle protein synthesis increased only in the young during hyperinsulinemia. Muscle protein breakdown did not significantly change in either group, although it tended to decrease in the elderly. Changes in muscle protein synthesis were correlated with changes in leg amino acid delivery (R=0.89; P=0.0001) and blood flow (R=0.90; P<0.0001). In conclusion, skeletal muscle protein synthesis is resistant to the anabolic action of insulin in older subjects, which may be an important contributor to the development of sarcopenia.
PMCID: PMC2804965  PMID: 16464955
skeletal muscle; hyperinsulinemia; leg blood flow; phenylalanine

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