Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024523 (malabsorption)
 7,319 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Raised plasma triglycerides (TGs) and nonesterified fatty acid (NEFA) concentrations are thought to play a role in the pathogenesis of insulin-resistant diabetes. We report on two sisters with extreme hypertriglyceridemia and overt diabetes, in whom surgical normalization of TGs cured the diabetes. In all of the family members (parents, two affected sisters, ages 18 and 15 years, and an 11-year-old unaffected sister), we measured oral glucose tolerance, insulin sensitivity (by the euglycemic-hyperinsulinemic clamp technique), substrate oxidation (indirect calorimetry), endogenous glucose production (by the [6,6-2H2]glucose technique), and postheparin plasma lipoprotein lipase (LPL) activity. In addition, GC-clamped polymerase chain reaction-amplified DNA from the promoter region and the 10 coding LPL gene exons were screened for nucleotide substitution. Two silent mutations were found in the father's exon 4 (Glu118 Glu) and in the mother's exon 8 (Thr361 Thr), while a nonsense mutation (Ser447 Ter) was detected in the mother's exon 9. Mutations in exons 4 and 8 were inherited by the two affected girls. At 1-2 years after the appearance of hyperchylomicronemia, both sisters developed hyperglycemia with severe insulin resistance. Because medical therapy (including high-dose insulin) failed to reduce plasma TGs or control glycemia, lipid malabsorption was surgically induced by a modified biliopancreatic diversion. Within 3 weeks of surgery, plasma TGs and NEFA and cholesterol levels were drastically lowered. Concurrently, fasting plasma glucose levels fell from 17 to 5 mmol/l (with no therapy), while insulin-stimulated glucose uptake, oxidation, and storage were all markedly improved. Throughout the observation period, plasma TG levels were closely correlated with both plasma glucose and insulin concentrations, as measured during the oral glucose tolerance test. These cases provide evidence that insulin-resistant diabetes can be caused by extremely high levels of TGs.
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PMID:Triglyceride-induced diabetes associated with familial lipoprotein lipase deficiency. 1034 13

We studied two siblings with a mitochondrial myopathy, familial thiamine deficiency, and an A3243G mutation of the mitochondrial DNA (mtDNA). The elder brother (patient 1, now 36 years old) developed myopathy and beriberi heart at 20 years of age. Thiamine therapy resolved the cardiac symptoms and hyperpyruvicemia and improved the myopathy. The younger brother presented aged 19 years with a myopathy (patient 2, now 35 years old). Thiamine deficiency was present in the siblings and parents, and ragged-red fibers (RRFs) were noted in muscle biopsies from the siblings. Analysis 17 years later demonstrated thiamine malabsorption and an A3243G mutation of the mtDNA in both siblings and their mother, progressive myopathy, and an increased number of RRFs and elevated serum CKMB activity in patient 1. Thiamine treatment decreased the serum concentrations of lactate and pyruvate in patient 2, but not patient 1. The role of thiamine in mitochondrial dysfunction caused by an electron transfer disorder in the setting of A3243G mtDNA mutation is discussed.
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PMID:Mitochondrial myopathy and familial thiamine deficiency. 1088 1

The aim of the present study was to evaluate the influence of severe protein-energy malnutrition on the antioxidant defense system in the small and large intestine in rats at weaning. Chronic diarrhea and the subsequent malnutrition were induced by oral intake of a lactose-enriched diet. Twenty rats were weaned at 21 days of age, and the control group was fed a semipurified synthetic diet for two weeks. The malnourished group was fed the same diet but carbohydrates were replaced by lactose, and they developed diarrhea one day after. Rats were killed, and macroscopic and histological features were analyzed, DNA content was measured, and alkaline phosphatase, myeloperoxidase, and gamma-glutamyltranspeptidase activities were determined to assess the degree of intestinal injury. Glutathione levels as well as the activities of intestinal glutathione transferase, glutathione reductase, total glutathione peroxidase, selenium-dependent glutathione peroxidase, superoxide dismutase, and catalase were measured to study the antioxidant defense system. Malnourished rats showed loss of body weight and an increase in length and weight in jejunum and ileum, while no significant changes were observed in colon. Epithelial cells showed fewer and shorter microvilli, larger mitochondria with low inner density and loss of cristae, dilated endoplasmic reticulum, and Golgi apparatus. The protein-to-DNA ratio was higher in the jejunum, ileum, and colon of malnourished rats. Glutathione levels decreased 40% in jejunum and 50% in colon of malnourished rats. A 40-50% decrease in the activity of all the enzymes of the antioxidant defense system was observed in the jejunum and ileum of malnourished rats, while only catalase and glutathione transferase activities decreased 50% in colon. These results suggest that early chronic diarrhea and severe protein-energy malnutrition impair the antioxidant defense system in both the small and large intestine, which may have a role in the pathogenesis and maintenance of the vicious circle of malabsorption-diarrhea-malnutrition in infancy.
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PMID:Chronic diarrhea impairs intestinal antioxidant defense system in rats at weaning. 1111 81

The major consequence of extensive intestinal resection is loss of absorptive surface area, which results in malabsorption of nutrients; this condition is known as short-bowel syndrome (SBS). Patients with extensive small intestinal resection and colectomy leading to jejunostomy have the most severe SBS. Ornithine decarboxylase (ODC) plays a central role in cell proliferation and in the process of gut adaptation. Polyamine synthesis in crypt cells mediates the action of extracellular growth factors on DNA synthesis and mitotic activity. The aim of this study was to examine ODC expression and activity, diamine oxidase (DAO) activity and polyamine levels in the jejunal mucosa and red blood cells of SBS patients with a jejunostomy. The study group consisted of 6 patients (4 men and 2 women, mean age 55.8+/-9.8 years), who had undergone extensive small bowel resection and colectomy. All patients were maintained on cyclic parenteral nutrition and non-restricted oral nutrition. Two groups of patients operated on for unrelated reasons were included as the jejunum control group (n=6) and the ileum control group (n=13). Non statistical differences were observed in polyamine levels of red blood cells versus the control group (spermidine: 21.0+/-3.6 vs. 17.7+/-1.1 and spermine: 17.1+/-8.6 vs. 13.2+/-1.6 nmol/ml RBC, respectively). No significant decreases in putrescine and spermidine levels were observed between the groups, but spermine levels in SBS jejunum were significantly lower than the controls (P<0.05). In SBS patients a significant decrease in ODC and DAO activity were observed vs jejunum. A significant decrease in ODC-mRNA abundance was found for the SBS patients as compared to the two control groups (P<0.05). These results suggest that in SBS patients with jejunostomy intestinal adaptation may be impaired.
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PMID:Intestinal ornithine decarboxylase in short bowel syndrome patients with oral diet. 1132 46

Menkes disease is an X-linked recessive disorder of the copper metabolism and affected males suffer a systemic copper deficiency due to malabsorption and defective distribution of dietary copper. It is caused by a defect in the Menkes (ATP7A) gene, which encodes a transmembrane copper-transporting P-type ATPase. A variety of mutations were reported; however, only a few mutations were reported in Asian patients. We identified four novel mutations and one known mutation in five Korean patients. Arg646Ter in exon 8, a novel mutation transmitted from his carrier mother, was identified in one patient. Prenatal DNA diagnosis on an unaffected fetus in this carrier mother was successfully accomplished. An additional three novel mutations, Leu706Arg in exon 9, Gly1118Asp in exon 17, and Gly1255Arg in exon 19, were identified. Splicing mutation was not identified. Menkes disease in Korean patients appears to be caused by heterogeneous mutations with different spectrums from Caucasian patients.
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PMID:Identification of four novel mutations in classical Menkes disease and successful prenatal DNA diagnosis. 1135 Jan 87

Whipple's disease is a rare bacterial infection that may involve any organ system in the body. It occurs primarily in Caucasian males older than 40 years. The gastrointestinal tract is the most frequently involved organ, with manifestations such as abdominal pain, malabsorption syndrome with diarrhea, and weight loss. Other signs include low-grade fever, lymphadenopathy, skin hyperpigmentation, endocarditis, pleuritis, seronegative arthritis, uveitis, spondylodiscitis, and neurological manifestations, and these signs may occur in the absence of gastrointestinal manifestations. Due to the wide variability of manifestations, clinical diagnosis is very difficult and is often made only years or even decades after the initial symptoms have appeared. Trimethoprim-sulfamethoxazole for at least 1 year is usually considered adequate to eradicate the infection. The microbiological diagnosis of this insidious disease is rendered difficult by the virtual lack of culture and serodiagnostic methods. It is usually based on the demonstration of periodic acid-Schiff-positive particles in infected tissues and/or the presence of bacteria with an unusual trilaminar cell wall ultrastructure by electron microscopy. Recently, the Whipple bacteria have been characterized at the molecular level by amplification of their 16S rRNA gene(s). Phylogenetic analysis of these sequences revealed a new bacterial species related to the actinomycete branch which was named "Tropheryma whippelli." Based on its unique 16S ribosomal DNA (rDNA) sequence, species-specific primers were selected for the detection of the organism in clinical specimens by PCR. This technique is currently used as one of the standard methods for establishing the diagnosis of Whipple's disease. Specific and broad-spectrum PCR amplifications mainly but not exclusively from extraintestinal specimens have significantly improved diagnosis, being more sensitive than histopathologic analysis. However, "T. whippelii" DNA has also been found in persons without clinical and histological evidence of Whipple's disease. It is unclear whether these patients are true asymptomatic carriers or whether differences in virulence exist among strains of "T. whippelii" that might account for the variable clinical manifestations. So far, six different "T. whippelii" subtypes have been found by analysis of their 16S-23S rDNA spacer region. Further studies of the pathogen "T. whippelii" as well as the host immune response are needed to fully understand this fascinating disease. The recent cultivation of the organisms is a promising major step in this direction.
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PMID:Whipple's disease and "Tropheryma whippelii". 1143 14

Whipple disease is a rare infectious disorder with multiorgan manifestations and a widely varied clinical presentation. Involvement of the small intestine with resultant malabsorption is a classic finding, although extraintestinal manifestations such as fever and arthralgias may precede gastrointestinal symptoms by many years. We describe a 63-year-old man in whom Whipple disease was diagnosed 22 years after his initial presentation (36 years after symptom onset) with lymphadenopathy, when a biopsy yielded nonnecrotizing granulomas. His recent symptoms included persistent fatigue, weight loss, fever, and arthralgias. Endoscopic biopsy specimens from the distal duodenum showed features consistent with Whipple disease, and Tropheryma whippelii DNA was detected in both the small bowel biopsy specimen and the blood specimen by polymerase chain reaction and DNA probe hybridization. His symptoms resolved with long-term co-trimoxazole therapy. We discuss the protean manifestations of Whipple disease, the difficulties in clinical diagnosis, and the recent advances in the molecular diagnosis of this disorder.
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PMID:Successful treatment of Whipple disease diagnosed 36 years after symptom onset. 1160 93

The objective of this study was to investigate whether folinic acid supplementation would protect young mice against suppression of growth by methotrexate (MTX). Four equal groups of Balb/c young male mice (5 animals in each group; mean+/-SD body weight 9.64+/-0.85 g, in their rapid growth phase) were subjected to the following drug treatment: One group was given MTX (3.5 mg/kg body weight) intraperitoneally on every 2nd day, another received folinic acid (7.0 mg/kg body weight) intraperitoneally every 2nd day. The third group was given both of these drugs (MTX on every 2nd day and folinic acid 8 h post-MTX injection). The fourth group was injected with physiological saline every other day to serve as a control group. Total body weight, food and water consumption by animals in each group were monitored every second day for a period of 3 weeks. After this period mice were sacrificed and liver, spleen and kidneys were excised, weighed and analyzed for MTX and dihydrofolate reductase activity. A small segment of the proximal part of small intestine and small pieces of liver and kidney were also removed to study morphological changes. Compared to the groups, which received folinic acid alone, folinic acid plus MTX or physiological saline, mean increase in body weight (6.8+/-0.8 g) of mice over a period of 3 weeks was minimal in the group receiving MTX alone (one-way ANOVA p=0.0001). The mean weights of liver and kidney in this group receiving MTX alone were also found to be significantly less than the mean weights of these organs in the 3 groups (p<0.001). The negative effect on growth of animals appears not only due to malabsorption but inhibition of pathway of de novo DNA synthesis may also be involved. This is supported by loss of villous pattern in small intestine of mice treated with MTX alone and increased accumulation of free MTX and decreased dihydrofolate reductase in the liver of the group receiving MTX alone as compared with the group receiving MTX plus folinic acid. The data indicate that the administration of folinic acid protects mice against suppression of growth by MTX. On the basis of these observations it can be deduced that patients suffering from juvenile rheumatoid arthritis or acute lymphoblastic leukaemia receiving MTX over a long period of time might be at a risk of experiencing short-term suppression of growth, however they could benefit from supplementation with folinic acid.
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PMID:Folinic acid protects against suppression of growth by methotrexate in mice. 1174 19

The case of a 61-year-old woman with Whipple's disease-associated sicca complex is reported. Tropheryma whipplei infection was diagnosed by histological and ultrastructural examination of the jejunal mucosa and sequence analysis of the bacterial 16S ribosomal DNA. The role of vitamin A malabsorption in sicca complex secondary to Whipple's disease is discussed.
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PMID:Sicca syndrome associated with Tropheryma whipplei intestinal infection. 1214 93

The goals and objectives of these studies, conducted over the past 30 y, were to determine: a) how chronic alcoholism leads to folate deficiency and b) how folate deficiency contributes to the pathogenesis of alcoholic liver disease (ALD). The intestinal absorption of folic acid was decreased in binge drinking alcoholics and, prospectively, in volunteers fed alcohol with low folate diets. Monkeys fed alcohol for 2 y developed decreased hepatic folate stores, folic acid malabsorption and decreased hepatic uptake but increased urinary excretion of labeled folic acid. Micropigs fed alcohol for 1 y developed features of ALD in association with decreased translation and activity of intestinal reduced folate carrier. Another study in ethanol-fed micropigs demonstrated abnormal hepatic methionine and DNA nucleotide imbalance and increased hepatocellular apoptosis. When alcohol feeding was combined with folate deficiency, micropigs developed typical histological features of ALD in 14 wk, together with elevated plasma homocysteine levels, reduced liver S-adenosylmethionine and glutathione and increased markers for DNA and lipid oxidation. In summary, chronic alcohol exposure impairs folate absorption by inhibiting expression of the reduced folate carrier and decreasing the hepatic uptake and renal conservation of circulating folate. At the same time, folate deficiency accelerates alcohol-induced changes in hepatic methionine metabolism while promoting enhanced oxidative liver injury and the histopathology of ALD.
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PMID:Metabolic interactions of alcohol and folate. 1216 94


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