Survival patterns and cancer determinants in families with myotonic dystrophy type 1.

BACKGROUND AND PURPOSE: Research indicates that patients with myotonic dystrophy type 1 (DM1) are at increased risk of cancer and early death. Family data may provide insights given DM1 phenotypic heterogeneity, the broad range of non-muscular manifestations and the usual delays in the diagnosis of DM1. METHOD: Family history data were collected from 397 genetically and/or clinically confirmed DM1 patients (respondents) enrolled in the US or UK myotonic dystrophy registries. Standardized mortality ratios were calculated for DM1 first-degree relatives (parents, siblings and offspring) by their reported DM1 status (affected, unaffected or unknown). For cancer-related analyses, mixed effects logistic regression models were used to evaluate factors associated with cancer development in DM1 families, including familial clustering. RESULTS: A total of 467 deaths and 337 cancers were reported amongst 1737 first-degree DM1 relatives. Mortality risk amongst relatives reported as DM1-unaffected was comparable to that of the general population [standardized mortality ratio (SMR) 0.82, P = 0.06], whilst significantly higher mortality risks were noted in DM1-affected relatives (SMR = 2.47, P < 0.0001) and in those whose DM1 status was unknown (SMR = 1.60, P < 0.0001). In cancer risk analyses, risk was higher amongst families in which the DM1 respondent had cancer (odds ratio 1.95, P = 0.0001). Unknown DM1 status in the siblings (odds ratio 2.59, P = 0.004) was associated with higher cancer risk. CONCLUSION: There is an increased risk of death, and probably cancer, in relatives with DM1 and in those whose DM1 status is unknown. This suggests a need to perform a careful history and physical examination, supplemented by genetic testing, to identify family members at risk for DM1 and who might benefit from disease-specific clinical care and surveillance.

Pigmentation phenotype, photosensitivity and skin neoplasms in patients with myotonic dystrophy.

BACKGROUND AND PURPOSE: Recent studies have suggested a possible excess risk of skin neoplasms in patients with myotonic dystrophy (DM). Risk factors related to this observation have not been defined. METHOD: Information regarding personal history of skin tumors, pigmentation phenotype, and skin reaction to sun exposure were collected from 266 DM patients who were enrolled in the US National Institutes of Health National Registry of Myotonic Dystrophy and Facioscapulohumeral Muscular Dystrophy Patients and Family Members. RESULTS: Seventy-seven subjects reported having skin tumors that were either benign (n = 31), malignant (n = 32) or both (n = 14). Female gender [odds ratio (OR) = 2.27, 95% confidence interval (CI) 1.02-5.05, P = 0.04], older age (OR = 1.10, 95% CI 1.05-1.16, P < 0.001) and DM1 subtype (OR = 3.42, 95% CI 1.27-9.26, P = 0.02) were associated with a malignant skin tumor. The associations between malignant skin tumors and known risk factors [light eye color (OR = 1.62, 95% CI 0.78-3.39, P = 0.20), light skin complexion (OR = 1.31, 95% CI 0.63-2.73, P = 0.48) and moderate/extensive face freckles (OR = 1.47, 95% CI 0.50-4.34, P = 0.49)] were modest. Strong, but not statistically significant, associations were noted with sunburn reactions when exposed to sunlight (OR = 4.28, 95% CI 0.91-19.95, P = 0.06, and OR = 2.19, 95% CI 0.67-7.09, P = 0.19, for sunburn with and without blistering, respectively). CONCLUSIONS: Although our study was limited by small sample size, the risk factors for malignant skin tumors in DM strongly resemble the general population. It is recommended that DM patients adhere to sun exposure protective behavior.

Expansion of the myotonic dystrophy CTG repeat reduces expression of the flanking DMAHP gene.

Myotonic dystrophy, or dystrophia myotonica (DM), is a highly variable multisystem disease in which the classic adult-onset form displays progressive muscle wasting, cataracts, heart block, gonadal atrophy, insulin resistance and neuropsychiatric impairment. Its genetic basis is an expansion of CTG trinucleotide repeats in the DMPK protein kinase gene. Among the triplet repeat expansion disorders, DM is distinguished by the extended length of the repeat tract (5-13 kb in postmortem tissue) and its location in the 3' untranslated region of the gene that contains it. The pathophysiological mechanism for multisystem degeneration in DM is not understood. In contrast to the profound muscle wasting that characterizes advanced DM, only minor histopathological abnormalities have occurred in DMPK knockout mice or in mice that overexpress a human DMPK transgene, making it unlikely that changes in DMPK activity provide a unitary explanation for the disease. A DNAse hypersensitive site that maps 0.7 kb downstream (centromeric) from the CTG repeats is eliminated on DM chromosomes. This finding indicates that the repeat expansion may alter the adjacent chromatin structure and raises the possibility that it may also affect the expression of flanking genes. An interesting candidate flanking gene is DMAHP, a recently discovered homeodomain-encoding gene. We show here that DMAHP expression in myoblasts, muscle and myocardium is reduced by the DM mutation is cis, and the magnitude of this effect depends on the extent of CTG repeat expansion. These observations support the hypothesis that DMAHP participates in the pathophysiology of DM.

A four-season longitudinal study of enterohaemorrhagic Escherichia coli in beef cow-calf herds in Mississippi and Nebraska.

Our objective was to describe the probability of detecting seven serogroups of enterohaemorrhagic Escherichia coli (EHEC-7) of public health importance in faecal samples from beef cow-calf herds and to test for factors associated with their detection. Fresh faecal samples (n = 85) from two Mississippi and two Nebraska herds were collected in each of four seasons. Samples were tested for each EHEC-7 serogroup by a molecular screening assay. Separate management groups within herds were sampled, and group-level factors were recorded. To measure the effects of factors on faecal shedding of EHEC-7, separate multivariable logistic regression models were used, accounting for the random effect of clustering by group within farm. Statistical significance was set α = 0.05. Fifty-nine samples (4.3%) were positive for EHEC O26, and Nebraska samples were more likely to be positive than Mississippi samples (OR = 12.4, 95% CI: 1.1, 139.2). Forty-four samples (3.2%) were positive for EHEC O45. Odds for detection were greater in the summer than all other seasons combined (OR = 4.2, 95% CI: 1.3, 14.0), and odds decreased if a precipitation event occurred (OR = 0.07, 95% CI: 0.006, 0.8). EHEC O103 was detected in 66 samples (4.9%) with increased probability to be detected at increased temperature. EHEC O111 was detected in 71 samples (5.2%), and 43 samples (3.2%) were positive for EHEC O145. Both EHEC O111 and O145 were associated separately with season, with greater probability for detection in the summer. Eighteen (1.3%) and 68 (5.0%) samples were positive for EHEC O121 and EHEC O157, respectively. We failed to detect significant explanatory factors associated with probability to detect EHEC O121 or O157. Factors that vary by time and place, such as precipitation, ambient temperature, region and season, are uniquely associated with the probability to detect EHEC-7 in fresh faeces collected from cow-calf herds.

Cross-sectional study to estimate the prevalence of enterohaemorrhagic Escherichia coli on hides of market beef cows at harvest.

Cattle hides are an important source of enterohaemorrhagic Escherichia coli (EHEC) carcass contamination at slaughter. Seven EHEC serogroups are adulterants in raw, non-intact beef: EHEC O26, O45, O103, O111, O121, O145 and O157. The objective of this study was to estimate the probability for hide contamination with EHEC among US market beef cows at slaughter and to test the effects of season and geographic region on prevalence of hide contamination. Hides (n = 800) of market cows were swabbed at slaughter immediately after exsanguination, prior to hide removal. Cows were sampled from two geographically distinct beef packing plants during four seasons of 2015. Cattle source was categorized by northern or southern region. Samples were tested for EHEC by a molecular screening assay. The effects of region, season and their interaction on the probability of hide contamination by each EHEC serogroup were tested in separate multilevel multivariable logistic regression models, accounting for the random effect of clustering by plant. Statistical significance was set α = .05. Of 800 total samples, at least one EHEC was detected on 630 (79%) hides. Enterohaemorrhagic E. coli O26 was detected on 129 (16%) of all hides sampled, EHEC O45 on 437 (55%), EHEC O103 on 289 (36%), EHEC O111 on 189 (24%), EHEC O121 on 140 (18%), EHEC O145 on 171 (21%) and EHEC O157 on 89 (11%). Detection of EHEC O26 and EHEC O121 was associated with season. Season and region were associated with detecting EHEC O45 and EHEC O157. Season-by-region interactions were associated with the outcome of detecting EHEC O103, EHEC O111 and EHEC O145. Season, region of origin and the interaction of these factors affect hide contamination of market beef cattle at slaughter by EHEC, and each serogroup responds to these factors uniquely.

A randomized controlled trial to evaluate the effects of dietary fibre from distillers grains on enterohemorrhagic Escherichia coli detection from the rectoanal mucosa and hides of feedlot steers.

Feeding high levels (≥40% dry matter) of distillers grains may increase the risk for cattle to carry enterohemorrhagic Escherichia coli (EHEC) O157. The mechanism for the increased risk is not known nor whether non-O157 EHEC are similarly affected. Our objective was to test whether the fibre content or other components of modified distillers grains plus solubles (MDGS) affects the probability for cattle to carry EHEC serogroups of public health importance. A 2 × 2 plus 1 factorial treatment arrangement within a randomized block design was utilized. Within each of four blocks, 25 feedlot pens (n = 8 steers/pen) were assigned randomly to (i) corn-based control diet; (ii) 20% dry matter (DM) MDGS; (iii) 40% DM MDGS; (iv) corn bran added to corn-based diet to match fibre of 20% MDGS or (v) 40% MDGS. Rectoanal mucosa swabs (RAMS) were collected on day (d)0, d35, d70 and d105; hide swabs were collected on the last feeding day. Samples were tested for EHEC by a molecular screening assay. The effects of fibre source and fibre level on EHEC carriage were tested using multilevel logistic regression (generalized linear mixed models; α = 0.05). EHEC O45 RAMS detection was associated with fibre level, source and sampling day. EHEC O103 RAMS detection increased by feeding 40% MDGS but not the corresponding corn bran diet. Hide contamination by EHEC O45 or O103 was less likely in cattle fed MDGS compared to corn bran diets. EHEC O111 RAMS detection decreased by feeding 40% MDGS but not by feeding the corresponding corn bran diet. Detection of EHEC O157 or O145 was not associated with dietary factors. Feeding 40% MDGS increased the probability for carriage of some EHEC serogroups but decreased probability of others, which indicated that EHEC serogroups have different risk factors associated with feeding MDGS and little association with dietary fibre.

Enhancement of insulin action after oral glucose ingestion.

Previous investigations in normal humans and rats have shown an increase in insulin sensitivity and binding affinity of adipocytes isolated 1-3 h after glucose ingestion. To determine whether a rapid enhancement of the action of insulin follows glucose ingestion in vivo, the present studies have utilized 120-min 20 mU/m2 X min euglycemic insulin infusions before and after 7.5-, 15-, 25-, and 100-g oral glucose loads. Euglycemic insulin infusions after the carbohydrate challenge were begun after arterialized blood glucose and insulin values had returned to baseline. After 15- and 25-g oral glucose loads during the 20-120-min interval of insulin infusion, glucose infusion rates increased by 44 +/- 6% (P less than 0.0001) and 47 +/- 9% (P less than 0.0002), respectively. No significant differences in arterialized glucose or insulin values existed between basal and post-glucose insulin infusions. In addition, no significant differences in hepatic glucose production or counter-regulatory hormone levels were found between basal and post-glucose insulin infusions. Control infusion studies including subjects who ingested saline or mannitol failed to show an increase in insulin action. Studies were carried out to mimic the insulin curve seen after 15- and 25-g oral glucose loads. Euglycemic insulin infusions after these insulin simulation studies show a 34 +/- 7% enhancement compared to baseline euglycemic insulin infusions. These results demonstrate a rapid enhancement of insulin action after oral glucose challenge in normal humans. The insulin simulation studies suggest that insulin itself either directly or through release of another factor acts on muscle to increase insulin sensitivity. The increase in insulin action demonstrated in these investigations may represent an important regulatory mechanism to modulate tissue insulin sensitivity.

Effects of brief starvation on muscle amino acid metabolism in nonobese man.

A reduction in the release of substrate amino acids from skeletal muscle largely explains the decrease in gluconeogenesis characterizing prolonged starvation. Brief starvation is associated with an increase in gluconeogenesis, suggesting increased release of amino acids from muscle. In the present studies, accelerated amino acid release from skeletal muscle induced by brief starvation was sought to account for the accompanying augmentation of gluconeogenesis. To do this amino acid balance across forearm muscles was quantified in 15 postabsorptive (overnight fasted) subjects and in 7 subjects fasted for 60 h. Fasting significantly reduced basal insulin (11.3-7.5 muU/ml) and increased glucagon (116-134 pg/ml). Muscle release of the principal glycogenic amino acids increased. Alanine release increased 59.4%. The increase in release for all amino acids averaged 69.4% and was statistically significant for threonine, serine, glycine, alanine, alpha-aminobutyrate, methionine, tyrosine, and lysine. Thus, with brief starvation, muscle release of glycogenic amino acids increases strikingly. This contrasts with the reduction of amino acid release characterizing prolonged starvation. The adaptation of peripheral tissue metabolism to brief starvation is best explained by the decrease in insulin.

Decreased insulin sensitivity of forearm muscle in myotonic dystrophy.

Previous studies of patients with myotonic dystrophy have demonstrated hyperinsulinism after glucose loading. This hyperinsulinism has been attributed by some investigators to tissue insulin resistance. We have directly studied insulin sensitivity of forearm muscle in patients having such hyperinsulinism. The effect of an intrabrachial arterial insulin infusion (100 mu U/kg per min) on glucose uptake was determined in six cases of myotonic dystrophy, six normal subjects, and in seven disease control subjects with myotonia or wasting from other disorders. There was no significant difference in insulin tolerance comparing myotonic dystrophy patients to the normal and disease control groups. Glucose tolerance and basal insulin levels were normal in the myotonic dystrophy patients, but hyperinsulinism occurred after glucose ingestion. After 25 min of intra-arterial insulin, the mean peak muscle glucose uptake in myotonic dystrophy was 2.54 +/- 0.54 mu mol/min per 100 ml forearm compared to 5.24 +/- 0.86 mu mol/min per 100 ml for disease controls (P is less than 0.05). Myotonic dystrophy patients showed a peak glucose uptake increment of only 2.6 +/- 0.2-fold over basal contrasted with the disease control value of 6.5 +/- 1.0-fold (P is less than 0.02) and the normal control value of 8.8 +/- 1.1-fold (P is less than 0.01). Thus, there was an absolute as well as a relative decrease in muscle insulin sensitivity in myotonic dystrophy patients compared to both control groups. The peak increments in arterio-superficial venous glucose concentration differences after insulin infusion were not significantly different comparing myotonic dystrophy and control groups. These data suggest that in myotonic dystrophy, there is insulin insensitivity of skeletal muscle.

Isotype-specific antibody responses against Escherichia coli O157:H7 locus of enterocyte effacement proteins in adult beef cattle following experimental infection.

Escherichia coli O157:H7 is an important food-borne pathogen and cause of hemorrhagic colitis and hemolytic uremic syndrome in humans. Cattle are an important reservoir of E. coli O157:H7, in which the organism colonizes the intestinal tract and is shed in the feces. Vaccination of cattle has significant potential as a pre-harvest intervention strategy for E. coli O157:H7; however, basic information about the bovine immune responses to important bacterial colonization factors resulting from infection has not been reported. The serum and fecal IgG and IgA antibody responses of adult cattle to E. coli O157:H7 intimin, translocated intimin receptor (Tir), E. coli-secreted proteins (Esp)A, EspB and O157 lipopolysaccharide (LPS) in response to infection were determined. All animals were seropositive for all five antigens prior to inoculation, with antibody titers to EspB and O157 LPS significantly higher (P<0.05) than those to Tir, intimin and EspA. After inoculation, the cattle became colonized and developed significant increases in their serum antibody titers to intimin, Tir, EspB, EspA and O157 LPS (P<0.05); however, by 42 days post-inoculation the titers to all except EspB were on the decline. In contrast, pre- and post-inoculation fecal IgG and IgA antibodies to these same antigens were not detected (<1:5). These results indicate that cattle respond serologically to E. coli O157:H7 type III secreted proteins, intimin and O157 LPS during the course of infection and the response is correlated with the extent of fecal shedding.

Efficacy of dose regimen and observation of herd immunity from a vaccine against Escherichia coli O157:H7 for feedlot cattle.

A clinical trial was conducted to test the effect of a vaccine product containing type III secreted proteins of Escherichia coli O157:H7 on the probability that feedlot steers shed E. coli O157:H7 in feces. Six hundred eight same-source steers were utilized. Of these, 480 steers were assigned randomly to 60 pens (eight head per pen) and to one of four vaccination treatments (120 cattle per treatment, two head per treatment per pen). The four treatments were (i) no vaccination; (ii) one dose, vaccinated once at reimplant (day 42); (iii) two doses, vaccinated on arrival (day 0) and again at reimplant (day 42); and (iv) three doses, vaccinated on arrival (day 0), on day 21, and again at reimplant (day 42). The remaining 128 steers were assigned randomly to 12 pens within the same feedlot to serve as unvaccinated external controls. The probability of detecting E. coli O157:H7 among cattle receiving different doses of vaccine was compared with that of unvaccinated external control cattle, accounting for clustering by repeated measures, block, and pen and fixed effects of vaccine, corn product, and test period. Vaccine efficacy of receiving one, two, and three doses of vaccine was 68, 66, and 73%, respectively, compared with cattle in pens not receiving vaccine. Cattle receiving three doses of vaccine were significantly less likely to shed E. coli O157:H7 than unvaccinated cattle within the same pen. Unvaccinated cattle housed with vaccinated cattle were 59% less likely to shed E. coli O157:H7 than cattle in pens not receiving vaccine, likely because they benefited from herd immunity. This study supports the hypothesis that vaccination with this vaccine product effectively reduces the probability for cattle to shed E. coli O157:H7. There was no indication that the vaccine affected performance or carcass quality. In addition, we found that vaccinating a majority of cattle within a pen offered a significant protective effect (herd immunity) to unvaccinated cattle within the same pen.

Effect of a vaccine product containing type III secreted proteins on the probability of Escherichia coli O157:H7 fecal shedding and mucosal colonization in feedlot cattle.

Preharvest intervention strategies to reduce Escherichia coli O157:H7 in cattle have been sought as a means to reduce human foodborne illness. A blinded clinical trial was conducted to test the effect of a vaccine product on the probability that feedlot steers, under conditions of natural exposure, shed E. coli O157:H7 in feces, are colonized by this organism in the terminal rectum, or develop a humoral response to the respective antigens. Steers (n = 288) were assigned randomly to 36 pens (eight head per pen), and pens were randomized to vaccination treatment in a balanced fashion within six dietary treatments of an unrelated nutrition study. Treatments included vaccination or placebo (three doses at 3-week intervals). Fecal samples for culture (n = 1,410) were collected from the rectum of each steer on pretreatment day 0 and posttreatment days 14, 28, 42, and 56. Terminal rectum mucosal (TRM) cells were aseptically collected for culture at harvest (day 57 posttreatment) by scraping the mucosa 3.0 to 5.5 cm proximal to the rectoanal junction. E. coli O157:H7 was isolated and identified with selective enrichment, immunomagnetic separation, and PCR confirmation. Vaccinated cattle were 98.3% less likely to be colonized by E. coli O157:H7 in TRM cells (odds ratio = 0.014, P < 0.0001). Diet was also associated with the probability of cattle being colonized (P = 0.04). Vaccinated cattle demonstrated significant humoral responses to Tir and O157 lipopolysaccharide. These results provide evidence that this vaccine product reduces E. coli O157:H7 colonization of the terminal rectum of feedlot beef cattle under conditions of natural exposure, a first step in its evaluation as an effective intervention for food and environmental safety.

Effect of Lactobacillus acidophilus strain NP51 on Escherichia coil O157:H7 fecal shedding and finishing performance in beef feedlot cattle.

A 2-year study was conducted during the summer months (May to September) to test the effectiveness of feeding Lactobacillus acidophilus strain NP51 on the proportion of cattle shedding Escherichia coli O157:H7 in the feces and evaluate the effect of the treatment on finishing performance. Steers (n = 448) were assigned randomly to pens, and pens of cattle were assigned randomly to NP51 supplementation or no supplementation (control). NP51 products were mixed with water and applied as the feed was mixed daily in treatment-designated trucks at the rate of 10(9) CFU per steer. Fecal samples were collected (n = 3,360) from the rectum from each animal every 3 weeks, and E. coli O157:H7 was isolated by standard procedures, using selective enrichment, immunomagnetic separation, and PCR confirmation. The outcome variable was the recovery of E. coli O157:H7 from feces, and was modeled using logistic regression accounting for year, repeated measures of pens of cattle, and block. No significant differences were detected for gain, intakes, or feed efficiency of control or NP51-fed steers. The probability for cattle to shed E. coli O157:H7 varied significantly between 2002 and 2003 (P = 0.004). In 2002 and 2003, the probability for NP51-treated steers to shed E. coli O157:H7 over the test periods was 13 and 21%, respectively, compared with 21 and 28% among controls. Over the 2 years, NP51-treated steers were 35% less likely to shed E. coli O157: H7 than were steers in untreated pens (odds ratio = 0.58, P = 0.008). This study is consistent with previous reports that feeding NP51 is effective in reducing E. coli O157:H7 fecal shedding in feedlot cattle.

Anti-capsular antibodies activate killing of Escherichia coli O8:K87 by the alternate complement pathway in porcine serum.

Enterotoxigenic Escherichia coli (ETEC) strains that produce K88 (F4)+ fimbria are important causes of diarrhea and post-diarrheal septicemia in swine. ETEC O8:K87, a serotype represented by a number of these strains, is typically serum resistant. Strain-specific antibodies are known to activate alternative C pathway-mediated killing of other serum-resistant E. coli [Hill, A.W., Shears, A.L., Hibbitt, K.G., 1978. The requirement of specific antibody for the killing of E. coli by the alternate complement pathway in bovine serum. Immunology 34, 131-136], but their antigenic targets have not been determined. We tested the hypothesis that anti-K87 antibodies activate alternative pathway-mediated killing of ETEC O8:K87. Pigs were immunized with ETEC O8:K87 strain 2534-86 cells or purified K87 polysaccharide. Post-, but not pre-immunization sera killed 2534-86 cells, and absorption with 2534-86 cells or by K87 affinity chromatography eliminated bactericidal activity. Complementation of absorbed serum with anti-K87 antibodies restored bactericidal activity, confirming the ability of these antibodies to activate C-mediated serum killing. Serum from age-matched, non-vaccinated control pigs also killed 2534-86. This activity was eliminated by absorption with 2534-86 cells, but not K87 affinity chromatography, indicating that specific non-capsular antibodies are also able to activate C-mediated killing. In all cases, Mg-EGTA-treated serum was as effective as non-treated serum in killing, suggesting that bactericidal activity was mediated predominantly if not exclusively via the alternative C pathway.

Lack of rapid enhancement of insulin action after oral glucose challenge in myotonic dystrophy.

Oral glucose administration to normal humans stimulates insulin release and simultaneously enhances the action of insulin by producing a rapid increase in tissue insulin sensitivity by a mechanism separate from the amount of hormone released. We determined whether insulin-resistant patients with myotonic dystrophy lose the ability to produce the normal rapid increase in tissue insulin action after oral glucose. Nine ambulatory, nonobese men with myotonic dystrophy were studied with 120-min euglycemic insulin infusions (20 mU X m-2 X min-1) given before and after glucose ingestion (4 and 5 patients received 15- and 25-g loads, respectively). Identical studies were performed in nonobese normal volunteers (16 and 13 patients received 15- and 25-g oral glucose loads, respectively). Glucose infusion rates at 20-120 min (GIR20-120) during euglycemic insulin infusions without prior glucose were 2.87 +/- 0.6 mg X kg-1 X min-1 in patients with myotonic dystrophy compared to 4.70 +/- 0.3 mg X kg-1 X min-1 in normal subjects. Euglycemic insulin infusions after glucose ingestion were begun after arterialized blood glucose values had returned to baseline. After glucose ingestion by normal subjects, GIR20-120 increased by 44.4 +/- 7.1% (P less than .0001) and by 46.8 +/- 8.6% (P less than .0002) with 15- and 25-g glucose loads, respectively. GIR20-120 in the nine patients with myotonic dystrophy showed no significant increase after glucose ingestion. These results confirmed the existence of a decrease in whole-body insulin sensitivity in myotonic dystrophy and indicated that the patients lack the normal mechanism that enhances insulin action after oral glucose.(ABSTRACT TRUNCATED AT 250 WORDS)

Loss of insulin response to ingested amino acids after jejunoileal bypass surgery for morbid obesity.

Amino acid tolerance tests were performed before and after jejunoileal bypass surgery for morbid obesity to determine whether an enteric factor(s) originating in the bypassed jejunum and/or ileum potentiates the insulin response to oral nitrogen loading. Preoperatively a 30-gm. mixture of amino acids given orally evoked a larger peak insulin than an intravenous load yielding comparable plasma amino acid elevations (82 +/- 17 muU./ml versus 38 +/- 8 muU./ml., p less than 0.05). Four months after operation, basal insulin concentrations were 46 per cent (p less than 0.001) of preoperative values. After surgery the response to intravenous amino acids was preserved when expressed as percentage increase above basal. In contrast, the peak increment and the percentage increase in insulin secretion after 30-gm. oral amino acid loading was significantly blunted (p less than 0.005). A smaller amino acid load (16.5 gm.) was given preoperatively to duplicate the plasma amino acid elevations seen postoperatively with the 30-gm. mixture given by mouth. The insulin response postoperatively was still significantly lower (167 +/- 33 per cent versus 98 +/- 16 per cent, p less than 0.05). After various explanations for the diminished postoperative insulin release following oral amino acid ingestion are considered, the results are best explained by the loss of an enteric insulinotrophic factor(s) normally released by the bypassed portions of jejunum or ileum in response to ingested protein.

Metabolism of forearm tissues in man. Studies with glucagon.

The role of glucagon in regulating peripheral tissue metabolism in man was assessed in the present studies. To do this, glucagon was infused for two hours into the brachial artery to produce a high but physiologic increment in the glucagon content of arterial blood supplying ipsilateral tissues. Metabolic effects on muscle and on subcutaneous adipose tissue plus skin were sought in seven overnight-fasting subjects and seven subjects starved briefly (60 hours). In the overnight-fasted group the infusion increased bassl glucagon concentration by 1,216 pg./ml. but was without effect on forearm tissue metabolism of glucose, lactate,glycerol, or amino acids. Starvation significantly reduced basal insulin (11.0 to 7.4 muU./ml.) and increased endogenous glucagon (116 to 134 pg./ml.). Basally, there was substantial ketone utilization and a decrease in glucose consumption by both muscle and subcutaneous adipose tissue plus skin. The glucagon infusion increased basal glucagon by 784 pg./ml. Muscle balances of glucose, lactate, acetoacetate, amino acids, and glycerol were unaffected. The metabolism of glucose, lactate, acetoacetate, glycerol, and free fatty acids by subcutaneous adipose tissue plus skin was also unchanged. It is concluded that physiologic increments of glucagon lasting two hours are without effect on forearm tissues in overnight-fasted and briefly starved man.

Rapid increase in the insulin sensitivity of rat adipocytes after intravenous glucose administration.

To study the mechanism underlying the enhancement of insulin action after carbohydrate challenge, rats were given an iv infusion of 100 mg glucose or saline. Adipocytes were isolated 1, 2, and 3 h after the infusions, and their ability to respond to insulin was examined. Two and 3 h postglucose, the cells showed a 50% increase in insulin sensitivity, as measured by glucose incorporation into total lipid and 2-deoxyglucose uptake. The effect was characterized by a leftward shift in the insulin dose-response curve. There was no change in maximum insulin stimulation. Insulin binding by the fat cells and by liver plasma membranes was not altered by glucose administration. These results demonstrate the presence of a physiological process that acutely enhances the insulin sensitivity of rat adipocytes after iv glucose infusion.

Effect of oral amino acid supplementation on liver disease after jejunoileal bypass for morbid obesity.

Previous work in our laboratory and others suggests that protein malnutrition plays an important role in the pathogenesis of hepatic steatosis and dysfunction which characteristically appears after jejunoileal bypass for morbid obesity. Postoperative protein-calorie malnutrition is at least in part a consequence of diminished intestinal absorption of free amino acids. In an attempt to prevent liver disease, six morbidly obese patients were orally supplemented with essential amino acids for 4 months after surgery. Oral amino acid supplementation only partially influenced protein malnutrition and had no effect on deterioration of hepatic morphology and dysfunction. Although this mode of therapy appears to be ineffective in preventing postoperative liver abnormalities, other studies suggest that oral oligopeptide supplementation and parenteral administration of amino acids are beneficial. In addition to protein deificiency, other factors which may contribute to the development of liver disease are reviewed.

Early predictors of poor outcome in congenital fiber-type disproportion myopathy.

We report the cases of eight children with histologic findings in the muscle of congenital fiber-type disproportion myopathy. Five had severe muscle weakness at birth; three of them died at 6 months, 18 months, and 6.5 years of age, respectively, and the other two are ventilator dependent and need total care at 2.5 and 4 years of age. The five children with severe weakness at birth had profound respiratory muscle weakness and needed assisted ventilation since early infancy. They also had severe facial and bulbar muscle weakness that required tube feeding, and four had gastrostomy. Ptosis and marked external ophthalmoparesis were also noted. Our study shows that the presence of the above constellation of signs at birth or in early infancy is a predictor of a high rate of mortality in infancy and poor developmental outcome in the survivors.