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PubMed2002

Roles of nutrition and physical activity in musculoskeletal complications before and after liver transplantation.

End-stage liver disease (ESLD) affects thousands of people in the United States annually. Improvements in survival after liver transplantation have broadened the indications for its use as a proven therapy for ESLD, rapidly increasing the number of transplant candidates. However, the number of patients awaiting transplantation far surpasses the donor supply, resulting in lengthy waiting times. During this wait, these patients experience progressive disease-related decompensation that is often accompanied by malnutrition and reduced physical activity. This chronic disease triad can have profound effects on musculoskeletal complications, such as cachexia and osteoporosis. In the absence of proper interventional strategies before transplantation, these complications can intensify after the transplantation, as a result of continued poor nutrition intake, bed rest, and pharmacotherapies. This article discusses levels of physical functioning and nutrition status in both the pre-and post-transplant populations, the risks associated with current levels, and the roles that diet and activity therapies can have to improve outcomes.

Cachexia↗
PubMedDate not supplied

Insights into novel biological mediators of clinical manifestations in cancer.

A myriad of novel mediators in neoplastic development and progression are currently being explored. Of significance are those that directly explain clinical manifestations of cancer, because understanding these may lead to new diagnostic, preventive, and therapeutic strategies. This review focuses on novel mediators that address how cancer, before it is treated, can induce cachexia, pain, hematological, and immune alterations. It highlights two concepts: first, that a synergy between tumor and stromal cells may be partly responsible for these manifestations, and second, that soluble factors, and in particular cytokines are being identified as major players in tumor-induced local and systemic effects.

Cachexia↗
PubMed1998

Catabolic proinflammatory cytokines.

Catabolic proinflammatory cytokines play a key role in mediating biochemical changes associated with many pathophysiological states. The present review emphasizes the role of this type of cytokine in inflammation and cachexia. Additionally, it reviews the role of one of these mediators in the induction of insulin resistance by dealing with some of the most recent publications on this topic.

Animals↗
PubMed2005

Inhibition of albumin synthesis in chronic diseases: molecular mechanisms.

The albumin gene is expressed specifically in the liver after birth, and this expression is regulated predominantly at the transcriptional level. Regulatory proteins occupy specific DNA sequences within the promoter and enhancer of the albumin gene. The interaction between the CCAAT/enhancer binding protein (C/EBP)-beta and the albumin DNA is critical for albumin synthesis. Cachexia-induced hypoalbuminemia is mediated by tumor necrosis factor (TNF)-alpha. In turn, TNF-alpha stimulates oxidative stress, NO synthesis, and phosphorylation of C/EBP-beta within its nuclear localization signal (NLS). Consequently, C/EBP-beta is exported from the nucleus, preventing it to act as a transcriptional factor on the albumin gene. Antioxidants, NOS inhibitors. and dominant negative, nonphosphorylatable C/EBP-beta peptides block phosphorylation of C/EBP-beta within the NLS and its nuclear export as well as rescue the abnormal albumin gene expression, suggesting potential therapeutic interventions.

Albumins↗
PubMed2005

Branched-chain amino acids: the best compromise to achieve anabolism?

PURPOSE OF REVIEW: The anorexia-cachexia syndrome is highly prevalent in patients suffering from acute and chronic diseases, including cancer, chronic renal failure and liver cirrhosis. Once it has developed, it significantly influences the clinical course of the underlying disease, simultaneously impinging on patients' quality of life. Unfortunately, currently available therapeutic strategies do not appear to greatly impact on patients' morbidity, mortality and quality of life. More effective therapies are needed to promote appetite and food intake, to preserve lean body mass, and to ameliorate patients' psychological distress. RECENT FINDINGS: Branched-chain amino acids are neutral amino acids with interesting and clinically relevant metabolic effects. Their potential role as antianorexia and anticachexia agents was proposed many years ago, but only recent experimental studies and clinical trials have tested their ability to stimulate food intake and counteract muscle wasting in anorectic, weight-losing patients. By interfering with brain serotonergic activity and by inhibiting the overexpression of critical muscular proteolytic pathways, branched-chain amino acids have been shown to induce beneficial metabolic and clinical effects under different pathological conditions. SUMMARY: Based on the available data, branched-chain amino acids appear to exert significant antianorectic and anticachectic effects, and their supplementation may represent a viable intervention not only for patients suffering from chronic diseases, but also for those individuals at risk of sarcopenia due to age, immobility or prolonged bed rest, including trauma, orthopedic or neurologic patients.

Amino Acids, Branched-Chain↗
PubMed2004

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE): a disease of two genomes.

BACKGROUND: Mitochondrial encephalomyopathies are clinically and genetically heterogeneous because mitochondria are the products of 2 genomes: mitochondrial DNA (mtDNA) and nuclear DNA (nDNA). Among the mendelian-inherited mitochondrial diseases are defects of intergenomic communication, disorders due to nDNA mutations that cause depletion and multiple deletions of mtDNA. REVIEW SUMMARY: Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disorder of intergenomic communication and is defined clinically by 1) severe gastrointestinal dysmotility; 2) cachexia; 3) ptosis, ophthalmoparesis, or both; 4) peripheral neuropathy; and 5) leukoencephalopathy. Skeletal muscle biopsies of patients have revealed abnormalities of mtDNA and mitochondrial respiratory chain enzymes. The disease is caused by mutations in the thymidine phosphorylase (TP) gene. TP protein catalyzes phosphorolysis of thymidine to thymine and deoxyribose 1-phosphate. In MNGIE patients, TP enzyme activity is reduced drastically, and plasma thymidine and deoxyuridine are elevated dramatically. We have hypothesized that alterations of nucleoside metabolism cause an imbalanced mitochondrial nucleotide pool that leads to depletion and deletions of mtDNA. CONCLUSIONS: MNGIE is a recognizable clinical syndrome caused by mutations in TP. The diagnosis can be confirmed by measuring TP activity in buffy coat or plasma levels of thymidine and deoxyuridine. Reduction of circulating thymidine and deoxyuridine in MNGIE patients may be therapeutic.

Adolescent↗
PubMed2004

Pellagra: a rare disease observed in a victim of mental and physical abuse.

Lesions of the brain stem and cerebellum due to nutritional deficiencies are mostly seen in chronic alcohol abuse and more rarely in severe malnutrition. We report the case of a 27-year-old woman, found dead in the family flat. She presented cachexia (167 cm, 25 kg) and multiple hematomas of the limbs. Postmortem examination revealed lesions due to peritonitis. Neuropathological examination showed severe atrophy of the corpus callosum and central neuronal chromatolysis, which are observed in pellagra. Inflammatory colitis or celiac disease was not found. Toxicological analysis was negative, in particular no alcohol absorption. Pellagra, which is due to nicotinamide deficiency, is a disease rarely seen in this country. In this case, nutritional deficiency was the consequence of failure to eat in a context of abuse. The woman was born of an incestuous relationship and presented intellectual retardation due to poor affective relations with her mother.

Adult↗
PubMed2004

Ghrelin: integrative neuroendocrine peptide in health and disease.

OBJECTIVE: Ghrelin is a novel gastric hormone recognized in 1999 as a mediator of growth hormone release. Since growth hormone is anabolic, an important function of ghrelin may be to coordinate energy needs with the growth process. Newly discovered biologic roles of ghrelin imply that it may have other important physiological functions as well. This is a review of recent clinically relevant, yet less well-known, physiologic actions of ghrelin. SUMMARY BACKGROUND DATA: Ghrelin has profound orexigenic, adipogenic, and somatotrophic properties, increasing food intake and body weight. Secreted predominantly from the stomach, ghrelin is the natural ligand for the growth hormone secretagogue receptor in the pituitary gland, thus fulfilling criteria of a brain-gut peptide. The brain-gut axis is the effector of anabolism by regulating growth, feeding, and metabolism via vagal afferents mediating ghrelin signaling. However, the wide tissue distribution of ghrelin suggests that it may have other functions as well. METHODS: Systematic literature review of all PubMed citations between 1999 and August 2003 focusing on clinically relevant biochemical and physiological characteristics of ghrelin. RESULTS: Ghrelin is an important component of an integrated regulatory system of growth and metabolism acting via the vagus nerve, and is implicated in a variety of altered energy states such as obesity, eating disorders, neoplasia, and cachexia. It also enhances immune responses and potentially down-regulates anti-inflammatory molecules. Ghrelin's role as a brain-gut peptide emphasizes the significance of afferent vagal fibers as a major pathway to the brain, serving the purpose of maintaining physiologic homeostasis. CONCLUSIONS: The discovery of ghrelin has increased our understanding of feeding regulation, nutritional homeostasis, and metabolic processes. Further characterization of ghrelin's functions will likely generate new pharmacological approaches to diagnose and treat different disease entities including those related to the over-nutrition of obesity and the catabolic response to surgical trauma.

Brain↗
PubMed1997

In vivo effect of recombinant human leukemia inhibitory factor in primates.

Leukemia inhibitory factor (LIF) is known to be a causative factor for cachexia and thrombocytosis in nude mice bearing human cancer cells. In the present study, we investigated whether recombinant human (rh) LIF can induce these biological activities in a primate model. rhLIF was synthesized by the expression of LIF protein in Escherichia coli. rhLIF (5, 20, or 80 micrograms/kg) was administered subcutaneously twice daily to cynomolgus monkeys for 14 consecutive days. A remarkable decrease of body weight (10%) was observed in the 80 micrograms/kg/day group. Approximately two-fold increases in platelet counts were observed at doses higher than 5 micrograms/kg/day when compared with control counts. These biological effects disappeared soon after the cessation of rhLIF treatment. Macroscopically, a remarkable reduction in subcutaneous fatty tissues and severe splenomegaly were observed. The results of this study demonstrate that rhLIF induces weight loss and thrombocytosis in a primate model.

Alanine Transaminase↗
PubMed2004

Emotions, the meaning of food and heart failure: a grounded theory study.

BACKGROUND: Many patients with heart failure have generalized wasting, referred to as cardiac cachexia. This leads to skeletal muscle wasting, impaired mobility, reduced functional capacity and poor prognosis. Patients with heart failure have symptoms that can affect their food intake, for example breathing difficulties, fatigue, nausea, loss of appetite, early feeling of fullness and ascites. These dietary problems and patients' nutritional status, can be significantly improved by means of simple nursing interventions. AIM: This paper reports a grounded theory study which developed a theoretical model of experiences of food and food intake among patients with heart failure. METHODS: A descriptive and exploratory design, with a grounded theory analysis, was used. Data were collected in 2002 through interviews with 11 patients with heart failure. FINDINGS: Two core categories emerged: emotions and the meaning of food. Psychosocial meaning could be associated with positive feelings of well-being, or negative feelings of sorrow. Physiological meaning could be associated with positive feelings of comfort or negative feelings of burden. Patients' experiences of food and eating changed during the development of the disease. Feelings of fatigue and lack of appetite gave rise to a feeling of deprivation because of missing both eating and the related social environment. This could lead to a loss of personal identity. DISCUSSION: Although the findings of a qualitative study cannot be generalized, they raise important clinical nursing issues. With increasingly shorter hospital stays, these problems will need to be addressed by community healthcare staff and family carers. Therefore, all healthcare professionals need knowledge about heart disease and information techniques if they are to be able to give appropriate care to this group. CONCLUSION: Ignorance about food and eating can easily lead to malnourishment, with an increased risk of the patients falling into a vicious circle. Implications of the study for health care practice and research are identified.

Aged↗
PubMed1985

The Groll-Hirschowitz syndrome.

Two sisters showed a similar disorder with cachexia, sensory deafness, and upper gastrointestinal abnormalities. The family pedigree suggests autosomal recessive inheritance of the disorder. Demyelinization demonstrated by a peripheral nerve biopsy may explain the basis for the manifestations. Only one family with this unique syndrome has been reported in the literature. The term "The Groll-Hirschowitz Syndrome" has been suggested, named after the two physicians who first described this condition.

Adult↗
PubMed2005

Temporal events in the intravenous challenge model for experimental Candida albicans infections in female mice.

We characterized the intravenous (i.v.) challenge model for disseminated Candida albicans infection in female BALB/c and DBA/2 mice. Clearance of fungi from the bloodstream and appearance of fungi in tissues were measured at intervals after challenge with various doses of C. albicans. The wild-type isolate SC5314 and derived strains CAF2-1 and CAI-4 transformed with CIp10 were of equal virulence in the model. Variability in mouse survival times, kidney fungal burdens and cachexia was lowest when challenge inocula were within the range 10(4)-10(5) CFU g(-1) body weight in BALB/c mice, but brain fungal burdens and outcomes in DBA/2 mice were variable for all inocula tested. Critical times in the development of infections in optimally challenged BALB/c mice were at 5-10 h (bloodstream fully cleared of fungi), 24 h (start of exponential fungal growth in kidneys) and 48 h (50% of blood cultures become positive). Differential involvement of right and left kidneys occurred almost exclusively in mice challenged with <2 x 10(4) CFU g(-1). We conclude that the i.v. challenge model in female BALB/c mice is now sufficiently well characterized to permit more refined experimentation in future virulence studies with C. albicans mutants.

Animals↗
PubMed2004

Risk factors relating blood markers of inflammation and nutritional status to survival in cachectic geriatric patients in a randomized clinical trial.

OBJECTIVES: To evaluate the effect of proinflammatory cytokines, their receptors, and nutritional indicators (at baseline and after 12 weeks of megestrol acetate (MA) treatment) upon long-term survival in geriatric cachectic patients without active acute infections, inflammation, or cancer. DESIGN: Randomized clinical trial with placebo or MA treatment for 12 weeks and then follow-up for more than 4 years. SETTING: Veterans Affairs nursing home in Northport, New York. PARTICIPANTS: Nursing home patients with weight loss of 5% of usual body weight over the previous 3 months or body weight 20% below ideal body weight. INTERVENTION: Random assignment of placebo or MA oral suspension 800 mg/d to the eligible patients for 12 weeks. MEASUREMENTS: White blood cell counts, prealbumin, plasma cytokine levels (or their receptors), including tumor necrosis factor receptor (TNFR), soluble subunits (TNFR-p55 and TNFR-p75), interleukin (IL)-6, soluble IL-2 receptor, and C-reactive protein at baseline and 12 weeks after treatment. RESULTS: There was no difference in survival between the MA and placebo groups. Considering possible confounders, initial IL-6, initial TNFR-p75 levels, and final neutrophil percentage were associated with elevated mortality, whereas higher initial prealbumin, initial albumin, final prealbumin, final albumin, and final weight gain were associated with decreased death. CONCLUSION: In geriatric weight-loss patients with cachexia, certain cytokines and nutritional indicators were effective in predicting long-term mortality, regardless of treatment with MA. Interventions to modify levels of these cytokines or their receptors and improvement in nutritional status by weight gain might be helpful in ameliorating undetected chronic inflammation and thus might prolong the survival of these nursing home residents.

Aged↗
PubMed1990

Lingual fibrosarcoma induced by 7, 12-dimethylbenzanthracene in the rat.

A single injection of 5 mg of 7, 12-dimethylbenzanthracene (DMBA) resulted in a high incidence of lingual fibrosarcoma in 67 Wistar rats. No metastases were found. We studied the influence of age and sex on the incidence, latency of tumors, loss of weight and the spontaneous survival of animals. The method described offers an experimental model for the study of cachexia resulting from upper digestive and respiratory tract cancer.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed2006

Transvascular dissemination of Porphyromonas gingivalis from a sequestered site is dependent upon activation of the kallikrein/kinin pathway.

BACKGROUND AND OBJECTIVE: Epidemiological evidence implicates a connection between human periodontitis and systemic diseases. One possible mechanism involves the direct dissemination of periodontopathogens to the target organs through the circulation. The aim of this work was to define the mechanism used by Porphyromonas gingivalis for dissemination from a sequestered infection site. MATERIAL AND METHODS: BALB/c mice were subcutaneously infected with P. gingivalis via use of a mouse chamber model. Tissue fluids from various sites were collected and cultured to determine the presence of P. gingivalis. Evans Blue dye was used to measure the dissemination ability of P. gingivalis. Kinin-associated molecules were introduced into mice, and their effects on bacterial dissemination and mouse pathology were monitored. RESULTS: P. gingivalis strain A7436 caused remote lesions and septicemia with severe cachexia, resulting in animal death. Intrachamber challenge with A7436 resulted in vascular permeability enhancement (VPE), as measured by the systemic infiltration of Evans Blue dye into chamber fluids. VPE was blocked by kininase and kinin receptor antagonist and enhanced by exogenous bradykinin and kininase inhibitor. Live bacteria were recovered from the subcutaneous perichamber and abdominal spaces (spreading), and from the blood (disseminating) of infected mice. Both kininase and kinin receptor antagonist reduced animal mortality as a result of infection with strain A7436 and decreased the number of bacteria recoverable from the blood, but they were not associated with bacterial spreading. CONCLUSIONS: The results suggest that activation of the kinin system is involved in the breach of the vascular barrier that permits dissemination of P. gingivalis.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2002

Premature aging in mice deficient in DNA repair and transcription.

One of the factors postulated to drive the aging process is the accumulation of DNA damage. Here, we provide strong support for this hypothesis by describing studies of mice with a mutation in XPD, a gene encoding a DNA helicase that functions in both repair and transcription and that is mutated in the human disorder trichothiodystrophy (TTD). TTD mice were found to exhibit many symptoms of premature aging, including osteoporosis and kyphosis, osteosclerosis, early greying, cachexia, infertility, and reduced life-span. TTD mice carrying an additional mutation in XPA, which enhances the DNA repair defect, showed a greatly accelerated aging phenotype, which correlated with an increased cellular sensitivity to oxidative DNA damage. We hypothesize that aging in TTD mice is caused by unrepaired DNA damage that compromises transcription, leading to functional inactivation of critical genes and enhanced apoptosis.

Aging↗
PubMed2000

Failure to regulate TNF-induced NF-kappaB and cell death responses in A20-deficient mice.

A20 is a cytoplasmic zinc finger protein that inhibits nuclear factor kappaB (NF-kappaB) activity and tumor necrosis factor (TNF)-mediated programmed cell death (PCD). TNF dramatically increases A20 messenger RNA expression in all tissues. Mice deficient for A20 develop severe inflammation and cachexia, are hypersensitive to both lipopolysaccharide and TNF, and die prematurely. A20-deficient cells fail to terminate TNF-induced NF-kappaB responses. These cells are also more susceptible than control cells to undergo TNF-mediated PCD. Thus, A20 is critical for limiting inflammation by terminating TNF-induced NF-kappaB responses in vivo.

Animals↗
PubMed1992

Experimental infection of severe combined immunodeficient beige mice with Mycobacterium paratuberculosis of bovine origin.

Severe combined immunodeficient beige mice were inoculated orally and intraperitoneally with a bovine strain of Mycobacterium paratuberculosis to explore their potential as laboratory animal models in the study of paratuberculosis (Johne's disease). Control animals were similarly inoculated with heat-killed M. paratuberculosis. In the mice inoculated intraperitoneally, focal lesions and acid-fast bacilli were first detected in the livers (4 weeks postinfection) and later in the spleens and intestines of the test but not the control animals. No bacteria were seen in the hearts, kidneys, or lungs. At 12 weeks postinfection, all test mice had significant losses in body weight compared with those in controls (P less than 0.05), a characteristic sign of bovine paratuberculosis. Tumor necrosis factor alpha was not detected in the serum. Histologic lesions were seen in the intestines, livers, and spleens of the animals in the orally inoculated test group after 26 weeks of infection. Our results suggest that the severe combined immunodeficient beige mouse may be a useful model for the investigation of paratuberculosis and cachexia and the evaluation of antimycobacterial drugs.

Animals↗