Severe Protein Depletion Research Articles

Dysfunction in the mitochondrial Fe-S assembly machinery leads to formation of the chemoresistant truncated VDAC1 isoform without HIF-1α activation.

Biogenesis of iron-sulfur clusters (ISC) is essential to almost all forms of life and involves complex protein machineries. This process is initiated within the mitochondrial matrix by the ISC assembly machinery. Cohort and case report studies have linked mutations in ISC assembly machinery to severe mitochondrial diseases. The voltage-dependent anion channel (VDAC) located within the mitochondrial outer membrane regulates both cell metabolism and apoptosis. Recently, the C-terminal truncation of the VDAC1 isoform, termed VDAC1-ΔC, has been observed in chemoresistant late-stage tumor cells grown under hypoxic conditions with activation of the hypoxia-response nuclear factor HIF-1α. These cells harbored atypical enlarged mitochondria. Here, we show for the first time that depletion of several proteins of the mitochondrial ISC machinery in normoxia leads to a similar enlarged mitochondria phenotype associated with accumulation of VDAC1-ΔC. This truncated form of VDAC1 accumulates in the absence of HIF-1α and HIF-2α activations and confers cell resistance to drug-induced apoptosis. Furthermore, we show that when hypoxia and siRNA knock-down of the ISC machinery core components are coupled, the cell phenotype is further accentuated, with greater accumulation of VDAC1-ΔC. Interestingly, we show that hypoxia promotes the downregulation of several proteins (ISCU, NFS1, FXN) involved in the early steps of mitochondrial Fe-S cluster biogenesis. Finally, we have identified the mitochondria-associated membrane (MAM) localized Fe-S protein CISD2 as a link between ISC machinery downregulation and accumulation of anti-apoptotic VDAC1-ΔC. Our results are the first to associate dysfunction in Fe-S cluster biogenesis with cleavage of VDAC1, a form which has previously been shown to promote tumor resistance to chemotherapy, and raise new perspectives for targets in cancer therapy.

Body composition changes in female adolescents with anorexia nervosa

Background: Body weight provides limited information about nutritional status of patients with anorexia nervosa (AN).Objectives: Our objectives were to determine body composition (BC) changes, to find clinical predictors and endocrine correlates of total body protein (TBPr) depletion, and to compare results on fat mass (FM) obtained with anthropometry (skinfold measurements) and dual-energy X-ray absorptiometry (DXA) in patients with AN.Design: Body weight, body mass index (BMI; in kg/m2), BC (with DXA and skinfold measurements), and TBPr [with in vivo neutron activation analysis (IVNAA)] was assessed in 50 AN patients (15.2 y) and 40 healthy sex- and age-matched controls. In 47 AN patients and 22 controls, hormone concentrations were measured.Results: In AN patients, body weight (44.4 ± 5.5 kg), BMI (16.7 ± 1.6), and FMDXA (7.0 ± 3.4 kg) were lower than in controls. Lean tissue mass by DXA (LTMDXA) was similar in AN patients and controls (35.7 ± 4.3 compared with 35.8 ± 4.5 kg), but TBPr was 87% of that of controls (8.1 ± 1.0 compared with 9.2 ± 1.2 kg; P < 0.001). Cortisol was high, testosterone was unchanged, and estradiol and insulin-like growth factor I were low. Severe protein depletion measured by IVNAA seen in 17 AN patients could not be identified with simpler methods. All except 1 of 26 AN patients with a BMI > 16.5 had normal TBPr. The difference in individual percentage of body fat measured with DXA and skinfold measurements came up to 9%.Conclusion: The severe protein depletion in 34% of AN patients was not accurately identified by LTMDXA or simpler methods, but a BMI > 16.5 indicated normal TBPr. Future studies need to compare DXA and skinfold measurements with a reference technique to assess FM in AN patients.

Protein status and metabolic expenditure determine the response to intravenous nutrition - a new classification of surgical malnutrition

To determine whether nutritional and metabolic factors affect the response to intravenous nutrition (IVN) 146 surgical patients were classified according to their protein and metabolic status using direct measurements of body protein and metabolic expenditure. The patients were grouped into four categories: category I, moderate to severe protein depletion without raised metabolic expenditure; category II, moderate to severe protein depletion with raised metabolic expenditure; category III, mild protein depletion without raised metabolic expenditure; and category IV, mild protein depletion with raised metabolic expenditure. After 2 weeks of IVN patients in category I gained a mean(s.e.m.) of 0.43(0.06) kg of body protein (P less than 0.001) and had significant rises in both plasma transferrin and prealbumin (P less than 0.05); patients in category II gained 0.30(0.11) kg of protein (P less than 0.005) and also had significant rises in transferrin and prealbumin (P less than 0.05). Patients in category III lost 0.24(0.11) kg protein (P less than 0.05) and had no changes in either transferrin or prealbumin and patients in category IV lost 0.51(0.13) kg of body protein (P less than 0.001) and although there was a significant rise in plasma prealbumin there was no significant change in plasma transferrin. When postoperative patients were examined separately, they did not differ significantly from preoperative patients except in category I, where their protein gain was only 0.19(0.10) kg, an amount not significantly different from that gained by patients in category II. In each of the four categories described, the changes in total body protein occurring with 2 weeks of IVN were determined by the relative effects of two competing processes; protein depletion and raised metabolic expenditure. With moderate to severe protein depletion (approximately 30 per cent depletion of body protein stores) there was a marked tendency to gain protein with IVN. When the patient had a raised metabolic expenditure or was postoperative this tendency of depleted patients to gain protein was still present but it was less. With only mild protein depletion (approximately 10 per cent depletion) increases in metabolic expenditure made it difficult, if not impossible, to prevent continuing protein loss in spite of aggressive nutritional support. The patient categories we have described determine the response to IVN and form the basis of a new clinical classification of surgical malnutrition.

Free Radical–Induced Contractile Protein Dysfunction in Endotoxin-Induced Sepsis

Recent studies have indicated that sepsis is associated with enhanced generation of several free-radical species (nitric oxide [NO], superoxide, hydrogen peroxide) in skeletal muscle. It is also known that this enhanced free-radical generation results in reductions in skeletal muscle force-generating capacity, but the precise mechanism(s) by which free radicals exert this effect in sepsis has not been determined. We postulated that free radicals might react directly with the contractile proteins in this condition, altering contractile protein force-generating capacity. To test this theory, we compared the force generation of single Triton-skinned diaphragmatic fibers (Triton skinning exposes the contractile apparatus, permitting direct assessment of contractile protein function) from the following groups of rats: (1) control animals; (2) endotoxin-treated animal; (3) animals given endotoxin plus polyethylene glycol- superoxide dismutase (PEG-SOD), a superoxide scavenger; (4) animals given endotoxin plus N(omega)-nitro-L-arginine methylester (L-NAME), a NO synthase inhibitor; (5 ) animals given only PEG-SOD or L-NAME; and (6 ) animals given endotoxin plus denatured PEG-SOD. We found that endotoxin administration produced both a reduction in the maximum force-generating capacity (Fmax) (i.e., a decrease in Fmax) of muscle fibers and a reduction in fiber calcium sensitivity (i.e., an increase in the Ca2+ concentration required to produce half-maximal activation [Ca50]). L-NAME and PEG-SOD administration preserved Fmax and Ca50 in endotoxin-treated animals; neither drug affected these parameters in non-endotoxin treated animals. Denatured PEG-SOD failed to inhibit endotoxin-related alterations in contractile protein function. Sodium dodecyl sulfate polyacrylamide gel electrophoresis of skinned fibers from endotoxin-treated animals revealed a selective depletion of several proteins; administration of L-NAME or PEG-SOD to endotoxin-treated animals prevented this protein depletion, paralleling the effect of these two agents to prevent a reduction in contractile protein force-generating capacity. These data indicate that free radicals (superoxide, NO, or daughter species of these radicals) play a central role in altering skeletal muscle contractile protein force-generating capacity in endotoxin-induced sepsis.

Response to Cyclophosphamide Therapy in Saudi Children with Idiopathic Nephrotic Syndrome

Thirty-three children with idiopathic nephrotic syndrome received an eight-week course of 2.5 to 3.0 mg/kg of body weight of cyclophosphamide. Twenty-five (76%) were in remission 12 to 28 months la...

Preoperative total parenteral nutrition and surgical outcome in patients with inflammatory bowel disease

Further trials are needed to identify the preoperative patient who will have a significantly improved postoperative outcome with the use of total parenteral nutrition. Better nutritional markers are needed to evaluate the response to total parenteral nutrition and to help identify the irreducible minimum that should be given. In our series, patients who received preoperative total parenteral nutrition for at least 5 days had significantly fewer postoperative complications (p < 0.05) than those who did not. All patients with postoperative complications had either a preoperative serum albumin level less than 3.5 g/dl or a serum transferrin level less than 150 mg/dl. Preoperative total parenteral nutrition for at least 5 days is strongly recommended in patients with inflammatory bowel disease who have severe protein depletion.

The Relation between Insulin Secretion Glucose Tolerance, Growth Hormone, and Serum Proteins in Protein-Calorie Malnutrition

Extract: Data on serum immunoreactive insulin (IRI), glucose tolerance, serum growth hormone (HGH), and amino acid levels obtained during previous studies of 35 children suffering from protein-calorie malnutrition (PCM) have been reviewed. In all children intravenous glucose tolerance tests (1 g/kg glucose) were performed after 24 hr of carbohydrate feeding and before protein was introduced into the diets. In 19 of the 35 cases the tests were repeated 24–72 hr after either an albumin or amino acid infusion or milk feeding, and in 29 after 3–6 weeks of refeeding. It was found that the IRI response to glucose paralleled the severity of malnutrition, being low on admission, and improving with recovery. There was a correlation between peak IRI response and both serum albumin and serum alanine levels on admission, but acutely induced increase of albumin and infusions of alanine containing amino acids during therapy did not result in a consistent improvement of insulin secretion. Correlation between peak IRI and the branch chain amino acids barely reached significance on admission. There did not appear to be a direct relation between IRI peak or area and either basal HGH levels or the degree of HGH suppressibility. The glucose intolerance appeared to be related to the poor insulin response, although there were numerous exceptions which indicated that factors other than those recorded in this study are likely to be involved in the production of the glucose intolerance of PCM. Speculation: The impaired insulin response to glucose characteristic of PCM is associated with severe protein depletion. It is unlikely that the insulin deficiency or the glucose intolerance are related to a single abnormality; they are more likely part of widespread metabolic disturbance or adaptation which varies in importance in each individual.

The Relation between Insulin Secretion Glucose Tolerance, Growth Hormone, and Serum Proteins in Protein-Calorie Malnutrition

Extract: Data on serum immunoreactive insulin (IRI), glucose tolerance, serum growth hormone (HGH), and amino acid levels obtained during previous studies of 35 children suffering from protein-calorie malnutrition (PCM) have been reviewed. In all children intravenous glucose tolerance tests (1 g/kg glucose) were performed after 24 hr of carbohydrate feeding and before protein was introduced into the diets. In 19 of the 35 cases the tests were repeated 24–72 hr after either an albumin or amino acid infusion or milk feeding, and in 29 after 3–6 weeks of refeeding.It was found that the IRI response to glucose paralleled the severity of malnutrition, being low on admission, and improving with recovery. There was a correlation between peak IRI response and both serum albumin and serum alanine levels on admission, but acutely induced increase of albumin and infusions of alanine containing amino acids during therapy did not result in a consistent improvement of insulin secretion. Correlation between peak IRI and the branch chain amino acids barely reached significance on admission. There did not appear to be a direct relation between IRI peak or area and either basal HGH levels or the degree of HGH suppressibility.The glucose intolerance appeared to be related to the poor insulin response, although there were numerous exceptions which indicated that factors other than those recorded in this study are likely to be involved in the production of the glucose intolerance of PCM.Speculation: The impaired insulin response to glucose characteristic of PCM is associated with severe protein depletion. It is unlikely that the insulin deficiency or the glucose intolerance are related to a single abnormality; they are more likely part of widespread metabolic disturbance or adaptation which varies in importance in each individual.

Indicanuria after Gastric SurgeryAN EVALUATION IN THE DIAGNOSIS OF THE BLIND-LOOP SYNDROME

The level of indican excreted in the urine per 24 hours has been measured in 127 subjects following gastric surgery (18 Billroth 1 type partial gastrectomies, 63 Polya type partial gastrectomies, and 46 gastroenterostomies). These results have been compared with 141 normal control subjects. In the control group the level of dietary tryptophane intake correlated directly with the level of indicanuria, which may account for the wide variation in normal values reported in the literature. The dietary intake of tryptophane was significantly lower in the post-gastric-surgery subjects than in the matched controls. This may be a factor in the severe protein depletion reported following partial gastrectomy. Twenty-nine (23 per cent) of our post-gastric-surgery group had elevated indican levels; all had had either Polya partial gastrectomy, or gastroenterostomy, both of which entail the creation of a ‘blind’ loop liable to bacterial colonization. By contrast there was no difference in the Biflroth 1 subjects when compared with the control group. The level of indicanuria and the E. coil population of the small intestine have been shown to be related in 10 patients following gastric surgery. The metabolic significance of this was supported by a faecal-fat excretion in 18 subjects significantly related to indican excretion; and by the relation of post-operative weight loss to the levels of indicanuria in the whole group. It is suggested that bacterial colonization of the afferent loop following Polya gastrectomies and gastroenterostomies is underestimated as a cause of steatorrhoea and post-operative weight loss. No relationship was found between indican excretion and serum vitamin B12' serum iron, or the degree of post-operative anaemia. The reasons for these findings are discussed. The level of indican excreted in the urine following gastric operations is proportional to the degree of bacterial colonization of the upper small intestine. It may therefore indicate when further metabolic complications are to be expected.

Albumin metabolism in chronic renal failure.

1. Plasma albumin concentration was measured in fifty-eight patients with chronic renal failure. The mean value was 3·27 g/100 ml (SD 0·44 g/100 ml; range 2·4–4·3 g/100 ml) which is significantly lower (P &amp;lt; 0·001) than normal (mean 3·94 g/100 ml; SD 0·23 g/100 ml; range 3·5–4·4 g/100 ml). In thirty-eight of the fifty-eight patients (65%), plasma albumin concentration was below the normal range. Treatment by maintenance haemodialysis or renal transplantation usually corrected the hypoalbuminaemia. 2. Radioactive iodine-labelled albumin turnover was investigated in twelve patients. Although plasma albumin concentration was reduced in eight of the twelve patients, the plasma half-life (T½) of the labelled albumin was normal or increased in all but one of these patients. Fractional and absolute albumin degradation rates (which include urinary albumin loss) were reduced in six of the twelve patients. In two of the four patients with normal plasma albumin concentrations the fractional albumin degradation rate was reduced. 3. Albumin synthesis was estimated by measuring the rate of incorporation into plasma proteins of 14C in two patients on a 20 g protein diet. The values were low in both. 4. Albumin catabolism and albumin synthesis were normal in two patients who had been on regular haemodialysis for 5 and 8 weeks respectively. 5. We conclude that these abnormalities in albumin metabolism were probably due to severe protein depletion, induced either by prolonged anorexia and vomiting or by deliberate restriction of protein in the diet in the course of treatment.

Relationships between Oesophagostomum columbianum infection and the nutritional status of sheep. III. Serum and tissue protein changes

The infection of young sheep with 1500 infective Oesophagostomum columbianum larvae was associated with the development of hypoproteinaemia resulting basically from a hypoalbuminaemia. Hypogammaglobulinaemia and hyperbetaglobulinaemia also developed in the infected animals. The concentration of α-globulin in the serum was not affected by infection. The extent and duration of the pathological features in the serum protein concentrations varied with the plane of nutrition. More severe effects were noted in sheep which had been maintained on a low protein ration and which exhibited severe protein depletion of the liver, spleen, and thymus, than in animals on a high protein ration. Within the low protein group the most severe depressions in serum protein concentrations resulted from infection with small multiple doses of larvae compared with the same total number given in a single dose.

Thyroid Function in Female Rats Severely Depleted of Body Protein

The effect of protein depletion on thyroid function was studied in growing female rats fed low iodine diets. Severe protein depletion caused a marked reduction in thyroid growth; this reduction was accompanied by an apparent suppression of thyroidal activity as indicated by thyroid to serum radioiodide concentration ratios (T/S). Upon repletion of protein-starved animals, thyroid size and function returned to normal. Treatment of iodine-deficient, proteindepleted animals with thyroid-stimulating hormone (TSH) failed to increase thyroidal activity over that observed in iodine-deficient controls. In protein-depleted animals, there was no relative impairment of thyroxine synthesis as indicated by the distribution of radioiodide among the iodinated amino acids of thyroid digests. (Endocrinology 79:1023,1966)

“Kwashiorkor-like” syndrome, associated with burning feet syndrome, in an adult male

A kwashiorkor-like syndrome, associated with “burning feet,” is described in a forty-five year old Negro man, in whom, ten years after a gastrectomy for intractable duodenal ulcer, progressively severe diarrhea developed which resulted in pronounced protein depletion, affecting particularly the endocrine glands, with apparent decline in the trophic hormones. After all possible etiologies were considered, the patient was explored surgically and no abnormality was found. In the process of preparing for surgery the patient was given a large quantity of plasma protein, including 20 units of plasma, and apparently as a result of this therapy his severe protein depletion was corrected. Subsequently, the patient rapidly recovered.The clinical picture was not unlike that described in the syndrome of kwashiorkor, even to the red hair. Eight months after admission to the hospital, and five months after the institution of protein therapy, the patient appears and acts perfectly healthy.

Distribution in renal cell fractions of sulfhydryl groups in rats on normal and sucrose diets and its relation to renal mercury distribution after mercuric chloride injection.

Most rats fed a diet of sucrose and vitamins for 3 or more weeks survive intravenous injection of mercuric chloride, 3 mg/kg, a dose uniformly lethal to rats on a normal diet. It is found that the sulfhydryl content of the ‘soluble’ fraction obtained from kidney by means of the centrifuge is greater in sucrose-fed than in chow-fed rats. Three hours after injection of mercuric chloride the sucrose-fed as compared with the chow-fed rat shows the same total mercury content in kidney, but a much higher content in the ‘soluble’ fraction and much lower contents in the ‘nuclear’ and ‘granular’ fractions. The increase in resistance to the toxicity of mercuric chloride seen in sucrose-fed rats may be related to a decrease in the binding of mercury by sulfhydryl groups of the renal nuclei and mitochondria. Severe protein depletion may be causally involved in producing the state of increased resistance.