Comprehensive cancer predisposition testing within the prospective MASTER trial identifies hereditary cancer patients and supports treatment decisions for rare cancers.

BACKGROUND: Germline variant evaluation in precision oncology opens new paths toward the identification of patients with genetic tumor risk syndromes and the exploration of therapeutic relevance. Here, we present the results of germline variant analysis and their clinical implications in a precision oncology study for patients with predominantly rare cancers. PATIENTS AND METHODS: Matched tumor and control genome/exome and RNA sequencing was carried out for 1485 patients with rare cancers (79%) and/or young adults (77% younger than 51 years) in the National Center for Tumor Diseases/German Cancer Consortium (NCT/DKTK) Molecularly Aided Stratification for Tumor Eradication Research (MASTER) trial, a German multicenter, prospective, observational precision oncology study. Clinical and therapeutic relevance of prospective pathogenic germline variant (PGV) evaluation was analyzed and compared to other precision oncology studies. RESULTS: Ten percent of patients (n = 157) harbored PGVs in 35 genes associated with autosomal dominant cancer predisposition, whereof up to 75% were unknown before study participation. Another 5% of patients (n = 75) were heterozygous carriers for recessive genetic tumor risk syndromes. Particularly, high PGV yields were found in patients with gastrointestinal stromal tumors (GISTs) (28%, n = 11/40), and more specifically in wild-type GISTs (50%, n = 10/20), leiomyosarcomas (21%, n = 19/89), and hepatopancreaticobiliary cancers (16%, n = 16/97). Forty-five percent of PGVs (n = 100/221) supported treatment recommendations, and its implementation led to a clinical benefit in 40% of patients (n = 10/25). A comparison of different precision oncology studies revealed variable PGV yields and considerable differences in germline variant analysis workflows. We therefore propose a detailed workflow for germline variant evaluation. CONCLUSIONS: Genetic germline testing in patients with rare cancers can identify the very first patient in a hereditary cancer family and can lead to clinical benefit in a broad range of entities. Its routine implementation in precision oncology accompanied by the harmonization of germline variant evaluation workflows will increase clinical benefit and boost research.

Skin pigmentation and vitamin D-folate interactions in vascular function: an update.

PURPOSE OF REVIEW: Vitamin D and folate promote vascular endothelial health and may therefore help mitigate the development of cardiovascular disease (CVD). Ultraviolet radiation (UVR) exposure stimulates cutaneous vitamin D synthesis but degrades the bioactive metabolite of folate, 5-methyltetrahydrofolate (5-MTHF). Skin melanin absorbs UVR, thereby modulating the impact of UVR exposure on vitamin D and 5-MTHF metabolism. This review presents recent findings regarding the inter-relations among UVR, skin pigmentation, folate and vitamin D, and endothelial function. RECENT FINDINGS: Evidence for roles of folic acid or vitamin D supplementation on CVD endpoints is inconsistent, although preclinical and clinical studies have demonstrated the efficacy of both micronutrients for improving endothelial function. Vitamin D deficiency is most prevalent in darkly pigmented individuals living in relatively low-UVR environments. Conversely, there is a negative relation between accumulated UVR exposure and serum folate concentration in lightly pigmented adults. The interactions among UVR and bioavailable folate and vitamin D differentially impact endothelial function in differently pigmented skin. SUMMARY: UVR exposure disparately impacts folate and vitamin D metabolism in differently pigmented skin depending upon regional UVR intensity and seasonality. These findings present new clinical research questions regarding the interactions among UVR, skin pigmentation, folate and vitamin D bioavailability, and endothelial health.

Four weeks of vitamin D supplementation improves nitric oxide-mediated microvascular function in college-aged African Americans.

Reduced nitric oxide (NO)-mediated cutaneous vasodilation, secondary to increased oxidative stress, presents in young African American (AA) compared with European American (EA) adults and may be modulated by vitamin D status. We assessed cutaneous microvascular function in 18 young, healthy (21 ± 2 yr; 9 men, 9 women) subjects before (pre, 8 AA, 10 EA) 4 wk of 2,000 IU/day oral vitamin D supplementation and in 13 subjects after (post, 7 AA, 6 EA) 4 wk of 2,000 IU/day oral vitamin D supplementation. Serum vitamin D concentrations [25(OH)D] were measured at each visit. Three intradermal microdialysis fibers placed in the ventral forearm were randomized for treatment with 10 µM Tempol, 100 µM apocynin, or lactated Ringer's solution (control). Local heating (39°C) induced cutaneous vasodilation; red cell flux was measured at each site (laser-Doppler flowmetry), and cutaneous vascular conductance (CVC = flux/MAP) was expressed as a percentage of maximum (28 mM sodium nitroprusside, +43°C) for each phase of local heating. After stable elevated blood flow was attained, 15 mM NG-nitro-l-arginine methyl ester (l-NAME; NO synthase inhibitor) was perfused at all sites to quantify the NO contribution to cutaneous vasodilation (%NO), calculated as the difference between local heating and l-NAME plateaus. Serum [25(OH)D], the magnitude of the local heating response, and %NO were all lower in AAs versus EAs (P < 0.01). Tempol (P = 0.01), but not apocynin (P ≥ 0.19), improved the local heating response and %NO. Four weeks of supplementation improved serum [25(OH)D], the local heating response, and %NO in AAs (P ≤ 0.04) but not in EAs (P ≥ 0.41). Vitamin D supplementation mitigated endothelial dysfunction, an antecedent to overt cardiovascular disease (CVD), in otherwise healthy, young AA adults.NEW & NOTEWORTHY Endothelial dysfunction, an antecedent to overt cardiovascular disease (CVD), is observed earlier and more frequently in otherwise healthy African Americans (AAs) when compared with other ethnic groups. Vitamin D may modulate endothelial function, and darkened skin pigmentation increases risk of vitamin D deficiency. We show that 4 wk of 2,000 IU/day vitamin D supplementation improves microvascular responses to local heating in AAs. Ensuring adequate vitamin D status may mitigate development of cardiovascular dysfunction in this at-risk population.

Age-related differences in water and sodium handling after commercial hydration beverage ingestion.

Aging is associated with altered water, electrolyte, and glucose handling. Alternative beverages to those containing carbohydrate (CHO) should be considered for older adults. We hypothesized that reduced sodium (CNa+) and/or water (CH2O) clearance would underlie greater beverage retention in older compared with young adults, secondary to reduced glomerular filtration rate (GFR). We further hypothesized that amino acid (AA)- and CHO-based beverages would promote retention better than water. Over five visits, 12 young (23 ± 3 yr; 7 men, 5 women) and 12 older (67 ± 6 yr; 5 men, 7 women) subjects consumed 1 liter of distilled water or beverages with 6% CHO, 0.46 g/l Na+ [Gatorade (GAT)]; 2.5% CHO, 0.74 g/l Na+ [Pedialyte (PED)]; 5 AA, 1.04 g/l Na+ [enterade (ENT)-5]; or 8 AA, 1.38 g/l Na+ (ENT-8) over 30 min. Blood and urine were collected every hour for 4 h after ingestion; retention, CH2O, and CNa+ were calculated at 2 and 4 h. Additional calculations adjusted CH2O and CNa+ for estimated GFR (eGFR). Water yielded the lowest retention in both groups ( P ≤ 0.02). Retention was higher in older vs. young adults except for ENT-8 at 4 h ( P = 0.73). CH2O was higher for older vs. young adults for GAT at 2 h ( P < 0.01) and GAT and PED at 4 h ( P < 0.01) after ingestion but was otherwise similar between groups. CNa+ was lower in older vs. young adults except for ENT-8 ( P ≥ 0.19). Adjusting for eGFR resulted in higher CH2O for all beverages in older vs. young adults ( P < 0.05) but did not influence CNa+. Older adults may better retain beverages with less Na+ than young adults because of reduced CNa+. AA- and CHO-based electrolyte-rich beverages may similarly promote beverage retention. NEW & NOTEWORTHY Commercially available amino acid (AA)-containing beverages may provide an alternative to traditional carbohydrate (CHO)-containing beverages, particularly for older adults with attenuated water, electrolyte, and glucose handling. We compared beverage retention and free water and sodium clearance between young and older adults after ingestion of water, two CHO-based beverages, and two AA-based beverages. Our data suggest that older adults better retain beverages with less sodium compared with young adults and that AA-based and CHO-based electrolyte-containing beverages similarly promote retention.

Application of theoretical methods to increase succinate production in engineered strains.

Computational methods have enabled the discovery of non-intuitive strategies to enhance the production of a variety of target molecules. In the case of succinate production, reviews covering the topic have not yet analyzed the impact and future potential that such methods may have. In this work, we review the application of computational methods to the production of succinic acid. We found that while a total of 26 theoretical studies were published between 2002 and 2016, only 10 studies reported the successful experimental implementation of any kind of theoretical knowledge. None of the experimental studies reported an exact application of the computational predictions. However, the combination of computational analysis with complementary strategies, such as directed evolution and comparative genome analysis, serves as a proof of concept and demonstrates that successful metabolic engineering can be guided by rational computational methods.

[Declared dead? Recommendations regarding integrated care from the perspective of German statutory health insurance]. / Totgesagte leben länger : Empfehlungen zur Integrierten Versorgung aus Sicht der gesetzlichen Krankenkassen.

The traditional separation of health care into sectors in Germany causes communication problems that hinder continuous, patient-oriented care. This is most evident in the transition from inpatient to outpatient care. That said, there are also breaks in the flow of information, a lack of supply, or even incorrect information flowing within same-sector care. The transition from a division of functions into sectors to a patient-oriented process represents a change in the paradigm of health care that can only be successfully completed with considerable effort. Germany's statutory health insurance (SHI) funds play a key role here, as they are the contracting parties as well as the financiers of integrated care, and are strategically located at the center of the development process.The objective of this article is to explore how Germany's SHI funds view integrated care, what they regard as being the drivers of and barriers to transitioning to such a system, and what recommendations they can provide with regard to the further development of integrated care. For this purpose semi-structured interviews with board members and those responsible for implementing integrated care into the operations of ten SHI funds representing more than half of Germany's SHI-insured population were conducted. According to the interviewees, a better framework for integrated care urgently needs to be developed and rendered more receptive to innovation.Only in this way will the widespread stagnation of the past several years be overcome. The deregulation of § 140a-d SGB V and the establishment of a uniform basis for new forms of care in terms of a new innovation clause are among the central recommendations of this article. The German federal government's innovation fund was met with great hope, but also implied risks. Nonetheless, the new law designed to strengthen health care overall generated high expectations.

[Delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage: prevention, diagnostics and therapy]. / "Delayed cerebral ischemia" nach aneurysmatischer Subarachnoidalblutung : Prävention, Diagnostik und Therapie.

Delayed cerebral ischemia (DCI) is the second most important impacting factor for functional outcome after aneurysmal subarachnoid hemorrhage (SAH) following the initial severity of the bleeding. In contrast to the initial SAH severity the presence and consequences of DCI can be managed with prophylactic and therapeutic interventions. The previous notion of treatment of angiographically observed vasospasm has not been shown to be successful.This article covers prevention, monitoring and therapeutic concepts for patients with SAH with emphasis on the efficacy for DCI and current and ongoing research projects.

[Health care system facing change: physician networks: driving force for integrated care?]. / Gesundheitssystem im Umbruch : Ärztenetze: Treiber für integrierte Versorgung?

The German health care system is faced with enormous challenges: population ageing, more chronic diseases and multimorbidity. The fragmentation of medical care into disconnected parts-ambulant and clinical services, pharmaceutical provision, nursing care etc.-is inefficient and inhibits coordinated courses of treatment. Instead of this new types of organizational structures and processes are needed. By means of different health care acts the German government has supported innovative medical care structures for many years. In the meantime, 30,000 doctors have joined 400 physician networks. Their aims are to improve the coordination of services, to facilitate collaboration among providers and to ensure better health care to the population. Furthermore, those interdisciplinary networks are crucial prerequisites for integrated health care. But there is still a lot of work to do. The successful integration of the components of health care into functioning process chains depends on political, economic and sociocultural parameters.

Continuous selective intraarterial infusion of nimodipine for therapy of refractory cerebral vasospasm.

BACKGROUND: For endovascular treatment of vasospasm after aneurysmal subarachnoid hemorrhage (aSAH), an intraarterial treatment course with the calcium channel antagonist nimodipine infused for 30 min is proposed. As some patients still show ongoing vasospasm thereafter, we report on our experience with an extended time period of selective intraarterial nimodipine administration. METHODS: In nine patients with aSAH and refractory cerebral vasospasm, we left the catheter in place within the internal carotid artery after angiography. On the neurosurgical ICU, a continuous infusion of intraarterial nimodipine was commenced, combined with intraarterial heparin anticoagulation. Therapy was controlled with extended neuromonitoring techniques. RESULTS: Three patients died from refractory vasospasm and a fourth suffered lethal sepsis. Three patients survived in a good clinical condition, two of them without apparent neurologic deficit. The efficacy of intraarterial nimodipine was best verified with regional CBF monitoring. TCD failed to detect vasospasm in two patients and missed improvement in four. Brain tissue oxygenation increased in all patients, but was not indicative of vasospasm in one. CT perfusion reflected the treatment course adequately in the qualitative scans. CONCLUSION: Selective continuous intraarterial nimodipine treatment for refractory cerebral vasospasm after aSAH seems feasible and may add to the endovascular therapeutic options. Appropriate monitoring technology is essential for further investigation of this novel technique.

Male flight distance and population substructure in the bumblebee Bombus terrestris.

1. Bumblebees are important pollinators in natural as well as agricultural ecosystems. Estimates of foraging range, population size and genetic population structure so far have been based on worker samples alone. Here we include both males and workers in a population genetic analysis to infer the contribution of males to these important ecological parameters. 2. The population genetic (microsatellite) analyses of Bombus terrestris L. populations on the island of Cabrera (Spain) and Halle (Germany) revealed high heterozygosities (0.60 +/- 0.08 to 0.77 +/- 0.13) and neither a deviation from Hardy-Weinberg equilibrium nor linkage disequilibrium. 3. We detected five colonies (census population size) for the island population and 27 to 68 for the German mainland population. The genetic effective population sizes were N(e) = 7.5 for the island and 40.5 to 102 for the mainland population respectively. 4. There was a significant genetic subdifferentiation between the male and the worker population samples, suggesting that males originated from different and/or more distant colonies than workers. 5. Based on the colony numbers, we estimated the flight range of males, which ranged from 2.6 km to 9.9 km, much further than worker flight ranges. Bumblebee-mediated pollen flow will therefore be much further than expected based on the foraging range of workers alone if males also contribute to pollination.

Evolving European guidance on the medical management of neovascular age related macular degeneration.

BACKGROUND: Until recently, only two options were available for the treatment of choroidal neovascularisation (CNV) associated with age related macular degeneration (AMD)-thermal laser photocoagulation and photodynamic therapy with verteporfin (PDT-V). However, new treatments for CNV are in development, and data from phase III clinical trials of some of these pharmacological interventions are now available. In light of these new data, expert guidance is required to enable retina specialists with expertise in the management of AMD to select and use the most appropriate therapies for the treatment of neovascular AMD. METHODS: Consensus from a round table of European retina specialists was obtained based on best available scientific data. Data rated at evidence levels 1 and 2 were evaluated for laser photocoagulation, PDT-V, pegaptanib sodium, and ranibizumab. Other treatments discussed are anecortave acetate, triamcinolone acetonide, bevacizumab, rostaporfin (SnET2), squalamine, and transpupillary thermotherapy. RESULTS: PDT-V is currently recommended for subfoveal lesions with predominantly classic CNV, or with occult with no classic CNV with evidence of recent disease progression and a lesion size

The anti-tumor effect of interleukin-12 is enhanced by mild (fever-range) thermal therapy.

The cytokine interleukin 12 (IL-12) has resulted in notable anti-tumor activity in animal models and in patients and as a result there is considerable interest in learning how to maximize its therapeutic potential while at the same time reducing its known toxic side effects. Strategies which could maintain its effectiveness while permitting reduced dosage could be especially valuable. In this study we used BALB/c mice bearing CT26 tumors as a model for testing whether combining murine IL-12 with a mild (fever range) whole body hyperthermia protocol could result in such a strategy. Our data revealed that 100 ng of IL-12/mouse/day used in combination with FR-WBH was as effective as one in which 300 ng of IL-12/mouse/day was used alone. Importantly, the mice receiving the combination treatment exhibited fewer treatment related toxicities compared to those that received high dose IL-12 alone. Initiation of the IL-12 treatment immediately after FR-WBH induced the greatest anti-tumor effect. This effect does not appear to depend on differences in IL-12-induced IFN-gamma, but may involve production of nitric oxide (NO), since treatment of mice with a NOS inhibitor, NG-monomethyl-L-arginine (L-NMA), abolishes the additive anti-tumor effect of the combination treatment. Collectively, these data suggest that modification of physiological parameters in the host by mild fever-like thermal stimuli may be an effective and feasible adjuvant for cytokine-based immunotherapeutic strategies.

Anatomical characters of the phyllode and stem of Acacia podalyriifolia A. Cunn. ex G. Don (Fabaceae)

The Acacia genus has presented various secondary metabolites, such as tannins, flavonoids, alkaloids and gums. Preparations from different species have been applied for diabetes, gastrointestinal disorders and inflammatory diseases in the traditional medicine and have demonstrated cytotoxic, antimicrobial and antiparasitic activities. Acacia podalyriifolia A. Cunn. ex G. Don (Fabaceae) is a small wood, indigenous to Australia and cultivated worldwide for its ornamental feature. This work aimed to characterize the anatomy of the phyllode and stem, in order to contribute to the species identification. The botanical material was fixed, sectioned and prepared according to usual light and scanning microtechniques. The epidermal cells, in surface view, are polygonal and coated with striate and thick cuticle, and filaments of epicuticular wax. Paracytic stomata and unicellular non-glandular trichomes are seen. Palisade and ground parenchymas, and minor collateral bundles with xylem directed alternately to upper and lower sides occur in the blade. The midrib shows two collateral bundles facing each other. The stem, in incipient secondary growth, exhibits epidermis, annular collenchyma, sclerenchymatic sheath and collateral vascular organization. Cells containing phenolic compounds and prisms of calcium oxalate are observed.

[Immunonutritive enteral feeding in the critically ill]. / Stellenwert immunnutritiver enteraler Ernährung in der operativen Intensivmedizin.

Since imbalances in the immune system of the critically ill patient have been demonstrated, the role of the gastrointestinal tract for the pathogenesis of multiple organ failure has been a focus of research in intensive care medicine. Particularly, the integrity of the intestinal barrier function has been studied experimentally and clinically. The enormous number of gram-negative bacteria up to 10(11)/ml intestinal liquid inducing the release of significant amounts of endotoxin, is considered to be a vital threat to the intensive care unit (ICU) patient. Acute failure of the intestinal barrier following various types of severe shock or following parenteral nutrition inducing atrophy of intestinal mucosa may lead to multiple organ dysfunction. Maintenance of hemodynamic stability is a mainstay of therapy of the critically ill. In addition, the intestinal integrity can be preserved by the early onset of enteral nutrition. Moreover, recent concepts of enteral nutrition using immunomodulating nutrients like omega-3-fatty acids, glutamine, arginine, and nucleotides are under clinical evaluation.

A study design to investigate the effect of intense Tai Chi in reducing falls among older adults transitioning to frailty.

This paper describes the study design, methodological considerations, and baseline characteristics of a clinical trial to determine if intense (48 weeks, twice per week) Tai Chi practice can reduce the frequency of falls among older adults transitioning to frailty compared to a wellness education program. Twenty facilities will be stratified on socioeconomic status and facility type and randomly assigned to one of the two interventions. Secondary outcome measurements include variables related to function, behavior, and the biomechanics of movement. This study is unique because it represents an effort to offer a novel physical intervention to a large sample of transitional frail adults, a population that has received few formal exercise interventions. In addition to bringing the interventions into facilities, a 1-year follow-up is also included to assess rates of change in outcome measurements.

From tibialis anterior to Tai Chi: biofeedback and beyond.

This keynote presentation highlights events that have contributed to scientific explorations of one research clinician. Steve Wolf traces his scientific roots to early studies in single motor unit control under the guidance of his primary mentor, John Basmajian, MD. This work led to subsequent studies on the role of EMG feedback in predicting successful outcomes in upper extremity use and in ambulatory capabilities among patients with chronic stroke. These findings are contrasted to further efforts to condition entire reflexes rather than individual muscles through use of operant-conditioning paradigms. The findings from applications of EMG biofeedback to stroke patients became the basis for minimal motor criteria in the treatment of the impaired upper extremities of patients with chronic stroke, using "forced use" or "constraint-induced movement therapy." Last, investigations into center of pressure feedback using computerized balance machines resulted in a series of experiments that ultimately led to the finding that Tai Chi as an exercise form for older adults can have a substantially favorable effect in delaying the onset of fall events.

Timing of amino acid-carbohydrate ingestion alters anabolic response of muscle to resistance exercise.

The present study was designed to determine whether consumption of an oral essential amino acid-carbohydrate supplement (EAC) before exercise results in a greater anabolic response than supplementation after resistance exercise. Six healthy human subjects participated in two trials in random order, PRE (EAC consumed immediately before exercise), and POST (EAC consumed immediately after exercise). A primed, continuous infusion of L-[ring-(2)H(5)]phenylalanine, femoral arteriovenous catheterization, and muscle biopsies from the vastus lateralis were used to determine phenylalanine concentrations, enrichments, and net uptake across the leg. Blood and muscle phenylalanine concentrations were increased by approximately 130% after drink consumption in both trials. Amino acid delivery to the leg was increased during exercise and remained elevated for the 2 h after exercise in both trials. Delivery of amino acids (amino acid concentration times blood flow) was significantly greater in PRE than in POST during the exercise bout and in the 1st h after exercise (P < 0.05). Total net phenylalanine uptake across the leg was greater (P = 0.0002) during PRE (209 +/- 42 mg) than during POST (81 +/- 19). Phenylalanine disappearance rate, an indicator of muscle protein synthesis from blood amino acids, increased after EAC consumption in both trials. These results indicate that the response of net muscle protein synthesis to consumption of an EAC solution immediately before resistance exercise is greater than that when the solution is consumed after exercise, primarily because of an increase in muscle protein synthesis as a result of increased delivery of amino acids to the leg.

Hepatocyte growth factor modulates the hepatic acute-phase response in thermally injured rats.

OBJECTIVE: Hepatocyte growth factor (HGF) has been shown to modulate the acute-phase response in vitro. The specific in vivo role of HGF in this multifactorial response, however, remains unknown. This study examines the effects of exogenous HGF on the acute-phase response in thermally injured rats. DESIGN: Prospective, randomized, laboratory study. SETTINGS: Shriners Hospital for Children and University of Texas Medical Branch laboratories. SUBJECTS: Fifty-six male Sprague-Dawley rats (weight range, 300-325 g). INTERVENTION: Animals received a 60% total body surface area third-degree scald burn and were randomly divided to receive either 400 microg/kg/day i.v. HGF or saline (control). MEASUREMENTS AND MAIN RESULTS: Serum acute-phase proteins, cytokines, and insulin-like growth factor (IGF)-I concentrations, as well as liver weight, protein and triglyceride content, IGF-I concentrations, and cytokine gene expression were measured 1, 2, 5, or 7 days after burn. Serum albumin was increased on days 2, 5, and 7 after burn, and transferrin was increased on day 7 after burn in HGF-treated rats compared with controls (p<.05). HGF increased alpha2-macroglobulin concentrations on postburn days 2, 5, and 7 compared with controls (p<.05). Serum interleukin-6 and tumor necrosis factor-alpha were significantly higher within 2 days of burn in rats treated with HGF (p<.05). HGF increased the hepatic gene expression of tumor necrosis factor-alpha compared with controls (p<.05). Serum IGF-I decreased in rats receiving HGF 1, 2, and 5 days after burn, whereas liver IGF-I concentrations were higher on days 1 and 7 after burn compared with controls (p<.05). Hepatic protein concentrations were higher in the HGF group compared with controls on postburn days 1, 2, and 7, with a concomitant increase in total liver weight (p<.05). HGF exerted a strong mitogenic effect on hepatocytes 1 and 2 days after thermal injury compared with controls (p<.05). CONCLUSIONS: These findings suggest that HGF modulates the acute-phase response in vivo after burn and causes changes in liver morphology.

An oral essential amino acid-carbohydrate supplement enhances muscle protein anabolism after resistance exercise.

This study was designed to determine the response of muscle protein to the bolus ingestion of a drink containing essential amino acids and carbohydrate after resistance exercise. Six subjects (3 men, 3 women) randomly consumed a treatment drink (6 g essential amino acids, 35 g sucrose) or a flavored placebo drink 1 h or 3 h after a bout of resistance exercise on two separate occasions. We used a three-compartment model for determination of leg muscle protein kinetics. The model involves the infusion of ring-(2)H(5)-phenylalanine, femoral arterial and venous blood sampling, and muscle biopsies. Phenylalanine net balance and muscle protein synthesis were significantly increased above the predrink and corresponding placebo value (P < 0.05) when the drink was taken 1 or 3 h after exercise but not when the placebo was ingested at 1 or 3 h. The response to the amino acid-carbohydrate drink produced similar anabolic responses at 1 and 3 h. Muscle protein breakdown did not change in response to the drink. We conclude that essential amino acids with carbohydrates stimulate muscle protein anabolism by increasing muscle protein synthesis when ingested 1 or 3 h after resistance exercise.

The combination of growth hormone with hepatocyte growth factor alters the acute phase response.

Recombinant human growth hormone (rhGH) and hepatocyte growth factor (HGF) have both been shown to individually modulate hepatic acute phase reactant proteins and cytokine expression following trauma through different pathways. Recombinant hGH has also been shown to decrease serum and hepatic HGF concentrations after a thermal injury. We hypothesized that the combination of rhGH plus HGF improves the burn-induced acute phase response. Fifty-six male Sprague-Dawley rats received a 60% TBSA third-degree scald burn and were randomly divided to receive either rhGH (2.5 mg/kg/day sc.) plus HGF (200 microg/kg i.v. every 12 h) or placebo (saline). Rats were sacrificed on post-burn days 1, 2, 5, or 7 and serum constitutive and acute phase proteins, TNF-alpha, IL-1beta, IL-6 and liver total protein measured. Hepatic cytokine gene expression, triglyceride concentration, and hepatocyte proliferation were also measured. In rats receiving rhGH/HGF, serum albumin increased on days 5 and 7 and transferrin on day 7 after burn compared to placebo (P<0.05). Haptoglobin decreased 5 days after burn compared to placebo (P<0.05). RhGH/HGF increased serum TNF-alpha on day 2 after burn, while it decreased serum IL-1beta on day 1 after burn compared with placebo (P<0.05). RhGH/HGF had no effect on hepatic cytokine gene expression compared with placebo. Liver total protein content and hepatocyte proliferation increased on days 1, 2, 5, and 7 after burn with rhGH/HGF treatment (P<0.05). These findings indicate that rhGH in combination with HGF exert additive effects on constitutive hepatic proteins and partial inhibitory effects on acute phase protein and cytokine expression. RhGH/HGF has a strong mitogenic effect on hepatocytes.