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PubMed1999

Therapeutic antibodies elicited by immunization against TNF-alpha.

Tumor necrosis factor-alpha (TNF-alpha) is critically involved in the pathogenesis of several chronic inflammatory diseases. Monoclonal antibodies against TNF-alpha are currently used for the treatment of rheumatoid arthritis and Crohn's disease. This report describes a simple and effective method for active immunization against self TNF-alpha. This vaccination approach leads to a T-cell-dependent polyclonal and sustainable anti-TNF-alpha autoantibody response that declines upon discontinuation of booster injections. The autoantibodies are elicited by injecting modified recombinant TNF-alpha molecules containing foreign immunodominant T-helper epitopes. In mice immunized with such molecules, the symptoms of experimental cachexia and type II collagen-induced arthritis are ameliorated. These results suggest that vaccination against TNF-alpha may be a useful approach for the treatment of rheumatoid arthritis and other chronic inflammatory diseases.

Animals↗
PubMedDate not supplied

Cachectin and tumour necrosis factor as two sides of the same biological coin.

In response to invasive stimuli macrophages secrete cachectin, a multipotent protein. Prominent among its biological effects is the ability to induce wasting (cachexia) as well as a lethal state of shock. The identity of cachectin and tumour necrosis factor has led to a new view of its therapeutic potential.

Amino Acid Sequence↗
PubMed2001

Localized Igf-1 transgene expression sustains hypertrophy and regeneration in senescent skeletal muscle.

Aging skeletal muscles suffer a steady decline in mass and functional performance, and compromised muscle integrity as fibrotic invasions replace contractile tissue, accompanied by a characteristic loss in the fastest, most powerful muscle fibers. The same programmed deficits in muscle structure and function are found in numerous neurodegenerative syndromes and disease-related cachexia. We have generated a model of persistent, functional myocyte hypertrophy using a tissue-restricted transgene encoding a locally acting isoform of insulin-like growth factor-1 that is expressed in skeletal muscle (mIgf-1). Transgenic embryos developed normally, and postnatal increases in muscle mass and strength were not accompanied by the additional pathological changes seen in other Igf-1 transgenic models. Expression of GATA-2, a transcription factor normally undetected in skeletal muscle, marked hypertrophic myocytes that escaped age-related muscle atrophy and retained the proliferative response to muscle injury characteristic of younger animals. The preservation of muscle architecture and age-independent regenerative capacity through localized mIgf-1 transgene expression suggests clinical strategies for the treatment of age or disease-related muscle frailty.

Animals↗
PubMed1976

Purification of a cytotoxic factor from human and rat tissues.

Human and rat normal tissues and tumours have been studied for the presence of toxic substances, possibly of importance in the development of cachexia in patients with cancer and other chronic diseases. The toxic effect of tissue extracts was gauged by measuring the inhibition of growth of mouse L-cells in 1-ml cultures, as revealed by reduced incorporation of [14C]leucine into cell protein. A common cytotoxic substance of mol. wt. approximately 700 daltons was isolated from all rat and human tissues tested, including tumours. The isolation procedure involved tissue homogenization, followed by pressure dialysis, gel filtration of concentrated pressure dialysates, cation exchange chromatography, and thin layer chromatography. Amounts isolated from different tissues varied by a factor of 3. The purified substance reacted with ninhydrin and a few other reagents for amino groups. It was completely resistant to acid and enzymatic hydrolysis. The evidence thus suggests that the substance is an amine. It is toxic to L-cells, HeLa cells and normal rat fibroblasts in concentrations of 10-20 muM, producing cell death and lysis during incubation overnight.

Animals↗
PubMed1995

Perturbations of triglycerides but not of cholesterol metabolism are prevented by anti-tumour necrosis factor treatment in rats bearing an ascites hepatoma (Yoshida AH-130).

Rats transplanted with the ascites hepatoma Yoshida AH-130 developed a severely progressive cachexia, characterised by marked alterations in protein and lipid metabolism. In particular, high levels of serum triglycerides and free fatty acids were associated with altered levels and distribution of plasma cholesterol, with increased total and very low-density lipoprotein-low-density lipoprotein (VLDL-LDL) cholesterol and reduced high-density lipoprotein (HDL) cholesterol. The tumour cells showed high rates of cholesterol synthesis and elevated content of free and esterified cholesterol, whereas total cholesterol synthesis was reduced in the host liver. To determine whether these perturbations could be related to the elevation of tumour necrosis factor alpha (TNF-alpha) previously shown in the AH-130 bearers (Tessitore L, Costelli P, Baccino FM 1993, Br J Cancer, 67, 15-23), either anti-TNF polyclonal antibodies or non-immune IgGs were injected daily after tumour transplantation. The anti-TNF treatment neither affected tumour growth nor prevented the serum cholesterol changes, while attenuating the hypertriglyceridaemia and the elevated serum free fatty acid levels. These data indicate that TNF does not appear to be directly involved in the altered cholesterol metabolism in AH-130 hosts, thus supporting the view that cholesterol metabolism and lipid metabolism are regulated differently during tumour growth.

Animals↗
PubMed1997

Mechanism of the anti-tumour effect of 2,3,5-trimethyl-6-(3-pyridylmethyl) 1,4-benzoquinone (CV-6504).

2,3,5-Trimethyl-6-(3-pyridylmethyl) 1,4-benzoquinone (CV-6504), an inhibitor of 5-lipoxygenase, effectively suppressed growth of the MAC16 tumour in vivo and prevented the accompanying cachexia, when administered daily at a dose of 10 mg kg(-1). There was a reduction in the tumour concentration of linoleic (LA), arachidonic (AA), oleic, stearic and palmitic acid. In order to elucidate the mechanism of the anti-tumour action, the effect of CV-6504 on the metabolism of AA through the 5-, 12- and 15-lipoxygenase pathways has been determined in cell lines sensitive (MAC16, MAC13, MAC26 and Caco-2) and resistant (A549 and DU-145) to CV-6504. Incubation of all cell lines with [3H]AA led to the appearance of [3H]5-, 12- and 15-HETE. Preincubation of MAC16, MAC13, MAC26 and Caco-2 with 10 microM CV-6504 inhibited the conversion of AA to 5-, 12- and 15-HETE, while in A549 and DU-145 cells there was no effect on metabolism through any lipoxygenase pathway. Two other cell lines, MDA-MB-231 and PC-3, sensitive to growth inhibition by CV-6504, are known to require LA for growth, while DU-145, which was insensitive to growth inhibition by CV-6504, showed no growth response to LA. These results suggest that some tumours are dependent on lipoxygenase metabolites of LA and AA for their continual growth, and interference with this pathway produces a specific growth inhibition.

Animals↗
PubMed1997

Changes in nutritional status associated with unresectable pancreatic cancer.

Weight loss is common in patients with pancreatic cancer; however, the nature and progress of their nutritional depletion are not well documented. In this study, pre-illness weight and duration of weight loss were recorded in 20 patients with histologically confirmed unresectable cancer of the pancreas. Patients then underwent nutritional analysis at monthly intervals until death. The median period of assessment was 27 weeks (interquartile range 22.5-38.0 weeks). At the time of diagnosis, all patients had lost weight [median 14.2% (10.0-20.0%) of pre-illness stable weight], and this weight loss was progressive, increasing to a median of 24.5% by the time of the last assessment (P =0.0004). Body mass index was significantly reduced from a pre-illness median value of 24.9 kg m-2 (22.4-27.4 kg m-2) to 20.7 kg m-2 (19.5-23.6 kg m-2) at the time of diagnosis and further to 17.7 kg m-2 (16.6-23.1 kg m-2) just before death (P =0.0003). Further evidence of tissue depletion was evident from the significant reductions in lean body mass [43.4 kg (36.9-53.0 kg) to 40.1 kg (33.5-50.7 kg) P =0.008] and fat mass [12.5 kg (8.9-17.8 kg) to 9.6 kg (6.3-15.1 kg) P =0.03). This study confirms that the majority of patients with unresectable pancreatic cancer have already undergone significant weight loss by the time of diagnosis and that the natural history of this process is one of inexorable progression. These results highlight the need for selective non-toxic therapeutic intervention to attenuate cachexia and indicate that such interventions should be instituted early in the course of the disease.

Anthropometry↗
PubMed1998

Mechanism of muscle protein degradation induced by a cancer cachectic factor.

A proteolysis-inducing factor (PIF) isolated from a cachexia-inducing murine tumour (MAC16) produced a decrease in body weight (1.6 g, P < or = 0.01 compared with control subjects) within 24 h after i.v. administration to non-tumour-bearing mice. Weight loss was associated with significant decreases in the weight of the spleen and soleus and gastrocnemius muscles, with no effect on the weight of the heart or kidney and with an increase in weight of the liver. Protein degradation in isolated soleus muscle was significantly increased in mice bearing the MAC16 tumour. To define which proteolytic pathways contribute to this increase, soleus muscles from mice bearing the MAC16 tumour and non-tumour-bearing animals administered PIF were incubated under conditions that modify different proteolytic systems. In mice bearing the MAC16 tumour, there were increases in both cathepsin B and L, and the Ca2+-dependent lysosomal and ATP-dependent pathways were found to contribute to the increased proteolysis; whereas, in PIF-injected animals, there was activation only of the ATP-dependent pathway. Further studies in mice bearing the MAC16 tumour have provided evidence for increased levels of ubiquitin-conjugated proteins and increased mRNA levels for the 14 kDa ubiquitin carrier protein E2 and the C9 proteasome subunit in gastrocnemius muscle, suggesting activation of the ATP-ubiquitin-dependent proteolytic pathway. A monoclonal antibody to PIF attenuated the enhanced protein degradation in soleus muscle from mice bearing the MAC16 tumour, confirming that PIF is responsible for the loss of skeletal muscle in cachectic mice.

Animals↗
PubMed2003

Increased expression of the ubiquitin-proteasome pathway in murine myotubes by proteolysis-inducing factor (PIF) is associated with activation of the transcription factor NF-kappaB.

Proteolysis-inducing factor (PIF), isolated from a cachexia-inducing murine tumour, has been shown to stimulate protein breakdown in C(2)C(12) myotubes. The effect was attenuated by the specific proteasome inhibitor lactacystin and there was an elevation of proteasome 'chymotrypsin-like' enzyme activity and expression of 20S proteasome alpha-subunits at concentrations of PIF between 2 and 16 nM. Higher concentrations of PIF had no effect. The action of PIF was attenuated by eicosapentaenoic acid (EPA) (50 microM). At a concentration of 4 nM, PIF induced a transient decrease in IkappaBalpha levels after 30 min incubation, while no effect was seen at 20 nM PIF. The level of IkappaBalpha, an NF-kappaB inhibitory protein, returned to normal after 60 min. Depletion of IkappaBalpha from the cytosol was not seen in myotubes pretreated with EPA, suggesting that the NF-kappaB/IkappaB complex was stabilised. At concentrations between 2 and 8 nM, PIF stimulated an increased nuclear migration of NF-kappaB, which was not seen in myotubes pretreated with EPA. The PIF-induced increase in chymotrypsin-like enzyme activity was also attenuated by the NF-kappaB inhibitor peptide SN50, suggesting that NF-kappaB may be involved in the PIF-induced increase in proteasome expression. The results further suggest that EPA may attenuate protein degradation induced by PIF, at least partly, by preventing NF-kappaB accumulation in the nucleus.

Animals↗
PubMed1999

Increased lipid utilization in weight losing and weight stable cancer patients with normal body weight.

OBJECTIVE: Cachexia and weight loss are frequently seen in cancer patients. We investigated lipid metabolism to elucidate a metabolic basis for adequate nutrition of cancer patients. DESIGN: Lipid metabolism was assessed by indirect calorimetry and triglyceride clearance rates after randomised injection of a lipid bolus (long-chain triglycerides (LCT) or medium-chain triglycerides (MCT) during an euglycemic clamp protocol in cancer patients. SETTING: Rudolf-Virchow Krankenhaus, Berlin, Germany. SUBJECTS: Eighteen patients were included. Twelve patients had upper gastrointestinal cancer: a weight stable cancer group (Caws, n = 6) with a body mass index (BMI) of 22.9 +/- 1.7 kg/m2 and a weight losing cancer group (Cawl, n = 6) with a mean weight loss of 7.4 +/- 3.1 kg or 11% of the initial body weight during the previous three months (present BMI 21.8 +/- 0.8 kg/m2). The data were compared with six control patients with benign gastrointestinal diseases (BMI = 25.0 +/- 0.8 kg/m2). MAIN OUTCOME: Cancer patients had an increased basal lipid oxidation rate that was more pronounced in Cawl (+92% vs +42% in Caws; P < 0.01 and 0.05 vs controls, respectively). Utilisation of LCT was increased in cancer patients, this was most pronounced in Cawl (+150 vs +65% in Caws; P < 0.01 and 0.05, respectively). Metabolically, there were no differences in the utilisation of LCT and MCT/LCT containing lipid emulsions. CONCLUSIONS: Cancer patients have an increased lipid oxidation and an enhanced utilisation of exogeneous lipids. This is most pronounced in Cawl. To prevent further weight loss or to increase body weight, they should increase their fat intake. In contrast, fat-reduced or prudent diets seem to be inadequate for the nutrition of cancer patients.

Area Under Curve↗
PubMed2004

Modulation of the liver export protein synthetic response to feeding by an n-3 fatty-acid-enriched nutritional supplement is associated with anabolism in cachectic cancer patients.

The acute-phase protein response is associated with accelerated weight loss and shortened survival in cancer. This may be due to hepatic protein synthesis increasing demand for amino acids. An n -3 fatty-acid-enriched nutritional supplement will moderate aspects of cachexia in cancer patients. The present study examined the effect of such a supplement on hepatic synthesis of albumin and fibrinogen. Albumin and fibrinogen synthesis were measured in the fed and fasting state in eight weight-losing patients with pancreatic cancer by an intravenous flooding dose technique. Tracer incorporation into proteins was measured by GC/MS. Patients were restudied after 3 weeks of oral supplement enriched with fish oil (providing 2510 kJ/day and 2 g of eicosapentaenoic acid/day). At baseline, all patients were losing weight (median, 2.4 kg/month). After 3 weeks of consumption of the fish-oil-enriched nutritional supplement, patients' weight stabilized (median change, +1 kg; P = 0.01). At baseline, albumin and fibrinogen synthesis rates were stimulated in the fed compared with the fasting state [14.2 compared with 11.3 g/day (29% rise; P = 0.01) and 4.5 compared with 3.3 g/day (38% rise; P = 0.01) respectively]. After 3 weeks of the supplement, this stimulation in the fed state was no longer observed for albumin and was reduced for fibrinogen [11.2 compared with 10.5 g/day (3% rise; P = 0.21) and 3.7 compared with 2.9 g/day (17% rise; P = 0.01) respectively]. After 3 weeks, the combined albumin plus fibrinogen synthetic rate tended to fall in the fasting state (14.7 compared with 12.3 g/day; P = 0.09) and was significantly reduced in the fed state (18.7 compared with 14.6 g/day; P = 0.01). Modulation of hepatic export protein synthesis with feeding may have contributed to the net whole-body anabolism observed with administration of the n -3 fatty-acid-enriched oral supplement.

Aged↗
PubMed2000

Characteristics of patients with pancreatic cancer expressing a novel cancer cachectic factor.

BACKGROUND: Recently a novel tumour-derived cachectic factor was identified in the murine MAC16 colonic adenocarcinoma model of cachexia. This factor, provisionally named proteolysis-inducing factor (PIF), was subsequently identified in the urine of weight-losing patients with cancer but not in the urine of weight-stable patients with cancer or weight-losing controls with benign disease. This study determined the nutritional characteristics of patients with pancreatic cancer who excrete PIF in the urine and investigated the relationship between PIF and the acute-phase protein response. METHODS: PIF was isolated from urine by precipitation and ultrafiltration and was then identified by Western blotting of nitrocellulose membranes using a previously developed monoclonal antibody. Full nutritional assessment of patients was undertaken at the same time as urine collection. RESULTS: PIF was detected in the urine of 80 per cent of patients (n = 55). These patients had a significantly greater total weight loss and rate of weight loss than patients whose urine did not contain PIF (median 12.5 (range 4-43) kg versus 4.5 (0-14) kg; P < 0.0002). No association was evident between the presence of PIF in patients' urine and serum C-reactive protein (CRP) concentration. Furthermore, the accelerated weight loss associated with PIF expression also appeared to be independent of the acute-phase response. Overall the presence of PIF was not associated with reduced survival, although the previously reported association between raised CRP concentration and poor prognosis was confirmed. CONCLUSION: PIF is associated with an accelerated rate of weight loss in patients with a tumour of the pancreatic head. This observation appears to be independent of the effect of an increased hepatic acute-phase protein response.

Aged↗
PubMed2001

Opsonizing antibodies (IgG1) up-regulate monocyte proinflammatory cytokines tumour necrosis factor-alpha (TNF-alpha) and IL-6 but not anti-inflammatory cytokine IL-10 in mycobacterial antigen-stimulated monocytes-implications for pathogenesis.

Cachexia is one of the prominent features of advanced tuberculosis (TB) seen in association with increased expression of the monokine TNF-alpha. Several mycobacterial proteins, including PPD, stimulate TNF-alpha secretion from monocytes. Host factors that may play a role in cytokine expression from monocytes remain largely unknown. One such factor is the opsonizing antibodies. Monocytes have high-affinity receptors (FcgammaI and FcgammaIII) for IgG1 and IgG3 antibodies that mediate antigen uptake. We have reported selective up-regulation of IgG1 (which bind to Fcgamma receptors) in advanced TB and have recently shown the ability of PPD-specific IgG1 antibodies to augment TNF-alpha expression in PPD-stimulated monocytes. These observations have now been extended to other cytokines with semipurified fractions from secreted antigens of Mycobacterium tuberculosis (containing 30 kD and 58 kD) that were devoid of lipids, glycolipids and carbohydrates. In the presence of heat-inactivated TB plasma containing known amounts of antigen-specific IgG1 antibodies, these fractions induced significantly increased TNF-alpha, IL-6 and IL-10 secretion. Absorption of IgG1 with Protein 'A' removed the augmenting activity for TNF-alpha and IL-6 secretion from the TB plasma samples. In the case of IL-10, removal of IgG1 resulted in increased rather than decreased IL-10 secretion. These results suggest a possible pathogenic role for antibodies in TB by enhancing proinflammatory and blocking down-regulatory cytokines such as IL-10 cytokines during the chronic phase of TB.

Antigens, Bacterial↗
PubMed2000

Serum tumour necrosis factor-alpha levels in cancer patients are discontinuous and correlate with weight loss.

BACKGROUND: Tumour necrosis factor-alpha (TNF) has been regarded as a potential mediator of cancer cachexia. Assessment of TNF circulating levels in cancer patients and their correlation with weight loss has led to controversial results. MATERIALS AND METHODS: We measured TNF circulating levels in 28 patients with gastrointestinal cancer and 29 controls with benign gastrointestinal diseases at different times (08.00 h, 14.00 h, 20.00 h) before operation. RESULTS: TNF activity was not detected in any of controls at any times. In cancer patients, TNF circulating levels were detectable in 18 cases (64.3%) and appeared to be discontinuous. TNF levels above the limit of detection were present in 15 patients (53.6%) at 08.00 h, in 14 (50%) at 014.00 h and in nine (32.1%) at 20.00 h. Mean TNF levels were 14.3 +/- 4 pg mL(-1) at 08.00 h, 16.7 +/- 4.6 pg mL(-1) at 14.00 h (P = 0.05) and 18.5 +/- 10.2 pg mL(-1) at 20.00 h (P < 0.05 vs. 08.00 h and 14.00 h). According to Spearman's analysis, the sum of TNF concentrations at the three times significantly correlated with the severity of weight loss (Spearman's correlation coefficient = - 0.420; P = 0.026). TNF concentrations were consistently and significantly higher in patients with severe weight loss than in those with moderate or light weight loss at 08.00 h (26.3 +/- 8.3, 8.9 +/- 4.2, 3.8 +/- 2.1, respectively; P = 0.04 at one-way ANOVA). TNF levels were higher in anorectic than in nonanorectic patients at any hour, but the differences were not statistically significant. CONCLUSIONS: The present study demonstrates that TNF is intermittently or discontinuously detectable in patients with gastrointestinal cancer and that its levels correlate with the severity of weight loss.

Anorexia↗
PubMed2003

Metastatic gastric adenocarcinoma and diffuse hyperplastic gastritis resembling human Menétrier's disease in a camel (Camelus ferus bactrianus).

A captive 16-year-old male camel (Camelus ferus bactrianus) was euthanized after a prolonged period of inappetence leading to cachexia. At necropsy, there was a 7 cm large, tan, firm, well-demarcated nodule in the tunica muscularis and serosa of the distal region of C3. Histologically, a gastric adenocarcinoma was diagnosed. Numerous metastases were found in the liver and the hepatic lymph nodes, in the wall of the portal vein and the aorta, in the lung, heart, and pleura parietalis. Osseous metaplasia was found within the pleural and aortic metastases. In the mucosa of the glandular region of the C3 compartment a diffuse marked hypertrophy of rugae resembling cerebral convolutions was observed. The lesion was characterized by glandular hyperplasia and stromal inflammation and oedema. These changes closely resembled Menétrier's disease described in humans. To our knowledge, this is the first report of concomitant metastatic gastric adenocarcinoma and gastric hyperplasia in a camel.

Adenocarcinoma↗
PubMed2005

Diagnostic discordance for hepatitis C virus infection in hemodialysis patients.

BACKGROUND: Hepatitis C virus (HCV) infection is associated with an increase in proinflammatory cytokine levels. Similar changes are seen in maintenance hemodialysis patients with malnutrition-inflammation-cachexia syndrome (MICS), which is associated with poor clinical outcomes in this population. We hypothesized that HCV transcription-mediated amplification (TMA), a sensitive qualitative molecular test for HCV RNA, may identify maintenance hemodialysis patients with HCV infection not detected by means of antibody enzyme immunoassay (EIA), particularly in those with MICS. METHODS: We evaluated HCV status in 314 maintenance hemodialysis patients by using HCV antibody EIA (version 2.0; Abbott Laboratories, Abbott Park, IL) and HCV TMA (Bayer Diagnostics Laboratories, Berkeley, CA). RESULTS: Twenty-five patients (8%) were EIA positive (EIA+)/TMA+; 4 patients (1%), EIA+/TMA negative (TMA-), and 22 patients (7%), EIA-/TMA+. In the 47 TMA+ patients, the sensitivity of EIA for HCV infection was only 53%. TMA+ patients had lower albumin levels and higher tumor necrosis factor alpha and serum glutamic oxaloacetic transaminase levels than TMA- patients. EIA+/TMA+ patients were more likely than EIA-/TMA+ or EIA-/TMA- patients to have hypoalbuminemia and higher iron and transaminase levels. Of all TMA+ patients, EIA- patients were more likely to have diabetes, be on dialysis therapy longer, and have lower liver enzyme levels and higher proinflammatory cytokine levels, including tumor necrosis factor alpha and interleukin 6. CONCLUSION: Maintenance hemodialysis patients infected with HCV according to TMA have clinical features suggestive of MICS. In this population, HCV EIA appears to have a low sensitivity for the identification of HCV infection, which may be caused by the confounding effect of MICS or other demographic or clinical factors. These apparently false-negative HCV antibody test results are seen in persons with a longer time on hemodialysis therapy, mirroring observations in other populations with serious progressive conditions, such as human immunodeficiency virus infection.

Adult↗
PubMed2006

Mitochondrial neurogastrointestinal encephalomyopathy: evidence of mitochondrial DNA depletion in the small intestine.

BACKGROUND & AIMS: Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disease clinically defined by gastrointestinal dysmotility, cachexia, ptosis, ophthalmoparesis, peripheral neuropathy, white-matter changes in brain magnetic resonance imaging, and mitochondrial abnormalities. Loss-of-function mutations in thymidine phosphorylase gene induce pathologic accumulations of thymidine and deoxyuridine that in turn cause mitochondrial DNA (mtDNA) defects (depletion, multiple deletions, and point mutations). Our study is aimed to define the molecular basis of gastrointestinal dysmotility in a case of MNGIE. METHODS: By using laser capture microdissection techniques, we correlated histologic features with mtDNA abnormalities in different tissue components of the gastrointestinal wall in a MNGIE patient and ten controls. RESULTS: The patient's small intestine showed marked atrophy and mitochondrial proliferation of the external layer of muscularis propria. Genetic analysis revealed selective depletion of mtDNA in the small intestine compared with esophagus, stomach, and colon, and microdissection analysis revealed that mtDNA depletion was confined to the external layer of muscularis propria. Multiple deletions were detected in the upper esophagus and skeletal muscle. Site-specific somatic point mutations were detected only at low abundance both in the muscle and nervous tissue of the gastrointestinal tract. Analysis of the gastrointestinal tract from 10 controls revealed a non-homogeneous distribution of mtDNA content; the small intestine had the lowest levels of mtDNA. CONCLUSION: Atrophy, mitochondrial proliferation, and mtDNA depletion in the external layer of muscularis propria of small intestine indicate that visceral myopathy is responsible for gastrointestinal dysmotility in this MNGIE patient.

Adult↗
PubMed2005

Control of common, non-pain cancer symptoms.

Despite major advances in cancer biology and therapeutics, cancer and its treatment continue to cause devastating suffering. Patients with advanced cancer most often experience multiple physical and psychological symptom concurrently. We review here some of the common non-pain cancer symptoms, focusing on the assessment and treatment of fatigue, anorexia and cachexia, dyspnea, and symptoms common near the end of life.

Anorexia↗