Cell-cell fusion induced by measles virus amplifies the type I interferon response.

Measles virus (MeV) infection is characterized by the formation of multinuclear giant cells (MGC). We report that beta interferon (IFN-beta) production is amplified in vitro by the formation of virus-induced MGC derived from human epithelial cells or mature conventional dendritic cells. Both fusion and IFN-beta response amplification were inhibited in a dose-dependent way by a fusion-inhibitory peptide after MeV infection of epithelial cells. This effect was observed at both low and high multiplicities of infection. While in the absence of virus replication, the cell-cell fusion mediated by MeV H/F glycoproteins did not activate any IFN-alpha/beta production, an amplified IFN-beta response was observed when H/F-induced MGC were infected with a nonfusogenic recombinant chimerical virus. Time lapse microscopy studies revealed that MeV-infected MGC from epithelial cells have a highly dynamic behavior and an unexpected long life span. Following cell-cell fusion, both of the RIG-I and IFN-beta gene deficiencies were trans complemented to induce IFN-beta production. Production of IFN-beta and IFN-alpha was also observed in MeV-infected immature dendritic cells (iDC) and mature dendritic cells (mDC). In contrast to iDC, MeV infection of mDC induced MGC, which produced enhanced amounts of IFN-alpha/beta. The amplification of IFN-beta production was associated with a sustained nuclear localization of IFN regulatory factor 3 (IRF-3) in MeV-induced MGC derived from both epithelial cells and mDC, while the IRF-7 up-regulation was poorly sensitive to the fusion process. Therefore, MeV-induced cell-cell fusion amplifies IFN-alpha/beta production in infected cells, and this indicates that MGC contribute to the antiviral immune response.

Measles virus nucleoprotein induces cell-proliferation arrest and apoptosis through NTAIL-NR and NCORE-FcgammaRIIB1 interactions, respectively.

Measles virus (MV) nucleoprotein (N) is a cytosolic protein that is released into the extracellular compartment after apoptosis and/or secondary necrosis of MV-infected cells in vitro. Thus, MV-N becomes accessible to inhibitory cell-surface receptors: FcgammaRIIB and an uncharacterized nucleoprotein receptor (NR). MV-N is composed of two domains: NCORE (aa 1-400) and NTAIL (aa 401-525). To assess the contribution of MV-N domains and of these two receptors in suppression of cell proliferation, a human melanoma HT144 cell line expressing (HT144IIB1) or lacking FcgammaRIIB1 was used as a model. Specific and exclusive NCORE-FcgammaRIIB1 and NTAIL-NR interactions were shown. Moreover, NTAIL binding to human NR predominantly led to suppression of cell proliferation by arresting cells in the G0/G1 phases of the cell cycle, rather than to apoptosis. NCORE binding to HT144IIB1 cells primarily triggered caspase-3 activation, in contrast to HT144IIB1/IC- cells lacking the FcgammaRIIB1 intra-cytoplasmic tail, thus demonstrating the specific inhibitory effect of the NCORE-FcgammaRIIB1 interaction. MV-N- and NCORE-mediated apoptosis through FcgammaRIIB1 was inhibited by the pan-caspase inhibitor zVAD-FMK, indicating that apoptosis was dependent on caspase activation. By using NTAIL deletion proteins, it was also shown that the region of NTAIL responsible for binding to human NR and for cell growth arrest maps to one of the three conserved boxes (Box1, aa 401-420) found in N of Morbilliviruses. This work unveils novel mechanisms by which distinct domains of MV-N may display different immunosuppressive activities, thus contributing to our comprehension of the immunosuppressive state associated with MV infection. Finally, MV-N domains may be good tools to target tumour cell proliferation and/or apoptosis.

Bovine immunoglobulin concentrate-clostridium difficile retains C difficile toxin neutralising activity after passage through the human stomach and small intestine.

BACKGROUND: Bovine immunoglobulin concentrate (BIC)-Clostridium difficile is prepared from the colostrum of cows immunised against C difficile toxins and contains high concentrations of neutralising IgG antitoxin. AIMS: To determine the proportion of BIC-C difficile which survives passage through the human stomach and small intestine. METHODS: Six volunteers with an end ileostomy took 5 g of BIC-C difficile containing 2.1 g of bovine IgG on four occasions: alone, with an antacid, during treatment with omeprazole, and within enteric coated capsules. RESULTS: When BIC-C difficile was taken alone, a mean (SEM) of 1033 (232) mg of bovine IgG was recovered in the ileal fluid representing 49% of the total ingested dose. Bovine IgG recovery was not significantly increased by antacid (636 (129) mg) or omeprazole (1052 (268) mg). The enteric capsules frequently remained intact or only partially opened in the ileal effluent and free bovine IgG levels were low in this treatment group (89 (101) mg). Bovine IgG recovery was higher in volunteers with shorter (less than two hours) mouth to ileum transit times (68% versus 36%, p<0. 05). Specific bovine IgG against C difficile toxin A was detected in ileal fluid following oral BIC. Toxin neutralising activity was also present and correlated closely with bovine IgG levels (r=0.95, p<0. 001). CONCLUSION: BIC-C difficile resists digestion in the human upper gastrointestinal tract and specific anti-C difficile toxin A binding and neutralising activity was retained. Passive oral immunotherapy with anti-C difficile BIC may be a useful non-antibiotic approach to the prevention and treatment of C difficile antibiotic associated diarrhoea and colitis.

Effects of tobacco abstinence on food intake among cigarette smokers.

The total caloric and specific nutrient intakes of smokers who became abstinent were compared with those of a control group. Both groups were composed of volunteer inpatients housed in a research ward for 7 days. After smoking ad libitum for 3 days, the experimental group was required to abstain from tobacco for the next 4 days while the control group continued to smoke. Significant increases in total caloric intake and in grams of carbohydrates, protein, fat, and sucrose were observed in the experimental relative to the control group, whereas no significant differences were found in fructose intake. The increase in caloric intake was not specific to increases in snacking. Preliminary analyses showed gender differences in food intake as a result of tobacco abstinence.

Metabolic effects of dietary sucrose in type II diabetic subjects.

OBJECTIVE: To assess in diabetic subjects the effects of dietary sucrose on glycemia and lipemia. RESEARCH DESIGN AND METHODS: Twelve type II diabetic subjects consumed, in random order, two isocaloric, 55% carbohydrate study diets for 28 days. In one diet, 19% of energy was derived from sucrose. In the other diet, < 3% of energy was derived from sucrose, and carbohydrate energy came primarily from starch. Both study diets were composed of common foods. All meals were prepared in a metabolic kitchen where foods were weighed during meal preparation. RESULTS: No significant differences were noted between the study diets at any time point in mean plasma glucose. At day 28, mean plasma glucose values for the sucrose diet were 9.6 +/- 0.5 mM and for the starch diet were 9.4 +/- 0.6 mM (P = 0.63). Also, no significant differences were observed between the study diets in urine glucose, fasting serum total, HDL, or LDL cholesterol; fasting serum TG; or peak postprandial serum TG. CONCLUSIONS: A high sucrose diet did not adversely affect glycemia or lipemia in type II diabetic subjects.

Metabolic effects of dietary fructose in diabetic subjects.

OBJECTIVE: To assess the metabolic effects of chronic dietary fructose consumption in diabetic subjects. RESEARCH DESIGN AND METHODS: Six type I and 12 type II diabetic subjects consumed, in random order, two isocaloric study diets for 28 days. In one diet, 20% of energy was derived from fructose. In the other diet, < 3% of energy came from fructose, and carbohydrate energy was derived primarily from starch. Both study diets were composed of common foods. All meals were prepared in a metabolic kitchen where all foods were weighed during meal preparation. RESULTS: Mean plasma glucose, urine glucose, and serum glycosylated albumin values were lower during the fructose diet than during the starch diet, but the differences achieved only marginal statistical significance. The day-28 value for mean plasma glucose was 12.5% lower (P = 0.03) during the fructose diet than during the starch diet. At days 14, 21, and 28, fasting serum cholesterol and LDL cholesterol were both significantly higher during the fructose diet than during the starch diet. The day-28 values for serum cholesterol and LDL cholesterol during the fructose diet were 6.9% (P = 0.008) and 10.9% (P = 0.002) higher, respectively, than the corresponding values during the starch diet. No differences were observed between the study diets in fasting serum HDL cholesterol, fasting serum triglycerides, peak postprandial serum triglycerides, or fasting serum lactate. Peak postprandial serum lactate was significantly higher during the fructose diet. Type I and type II diabetic subjects responded to the diets in a consistent way, but type I subjects experienced significantly more hypoglycemia during the fructose diet than during the starch diet. CONCLUSIONS: A high-fructose diet may result in reduced glycemia in diabetic subjects but at the expense of increased fasting serum total and LDL cholesterol.

Metabolic effects of dietary fructose in healthy subjects.

To determine if dietary fructose causes adverse metabolic effects, we used a crossover design to compare a diet containing 20% of energy from fructose with an isoenergic high-starch diet that contained less than 3% fructose. Fourteen healthy subjects consumed each diet for 28 d. There were no significant differences between the diets in the mean values of hemoglobin A1C, serum glycosylated albumin, fasting plasma glucose, peak postprandial plasma glucose, integrated plasma glucose, fasting serum lactate, or fasting serum triglycerides. Peak postprandial serum lactate was significantly higher during the fructose diet at days 1, 7, and 14 but not at days 21 or 28. Peak postprandial serum triglycerides were significantly higher only at day 1 of the fructose diet. Day-28 fasting serum total and LDL cholesterol for the fructose diet were 9.0% and 11.0% higher, respectively, than the corresponding values for the starch diet. A high-fructose diet compared with a high-starch diet resulted in significantly higher fasting serum total and LDL cholesterol and also caused transient changes in postprandial serum lactate and triglycerides.

Glucose and insulin response in diabetic subjects: acute effect of carbohydrate level and the addition of soy polysaccharide in defined-formula diets.

This single-meal pilot study compared the plasma glucose and serum insulin response to defined-formula diets with two levels of carbohydrate (CHO) (55% and 30% of the kilocalories) with and without added soy polysaccharide (10 g) in subjects with type 2 diabetes mellitus. Subjects received each of the four liquid-formula test meals in a randomly assigned order: 1) high CHO, low fiber (HC, LF), 2) high CHO, high fiber (HC, HF), 3) low CHO, low fiber (LC, LF), and 4) low CHO, high fiber (LC, HF). On the day of each test meal the formula was consumed, eight blood samples were drawn for plasma glucose and serum insulin measurements, and a 4-h urine collection was obtained for measuring glucose excretion. Our results showed that area increments under glucose and insulin curves were significantly lower with both low-CHO formulas (p less than 0.001). The addition of soy polysaccharide to the liquid formula did not result in statistically different area increments for glucose or insulin.

Day-to-day variation in glycemic control in type I and type II diabetes mellitus.

In an attempt to assess day-to-day variation in glycemic control, 12 type I and 12 type II diabetic subjects were hospitalized and had plasma glucose sampled frequently on two consecutive days, during which medication, diet, and physical activity were all held constant. In type I subjects, there was no significant day-to-day correlation in overall mean plasma glucose, mean preprandial plasma glucose, mean postprandial plasma glucose, or urinary glucose excretion. In contrast, these measures were all highly correlated in type II subjects. The data suggest that individuals with type I diabetes may not be able to achieve good glycemic control simply by taking the same dose or doses of insulin each day while rigorously attempting to control diet and exercise.

Comparison of predictive capabilities of diabetic exchange lists and glycemic index of foods.

To determine whether the diabetic exchange lists or the glycemic index of foods better predicts postprandial responses to carbohydrate-containing foods eaten as part of a mixed meal, three test meals were developed and fed to 12 subjects with non-insulin-dependent diabetes mellitus (NIDDM) and 13 healthy subjects. Each test meal contained exactly the same exchanges (1 milk, 4 starch, 2 fruit, 2 meat, 3 fat, 1 vegetable). In one meal, foods of high glycemic index (GI) were used, in a second meal, foods of intermediate GI were used, and in a third meal foods of low GI were used. The total GIs of the meals were: high, 184; intermediate, 131; and low, 107, thus predicting responses to intermediate and low GI, which were 71 and 58%, respectively, of the responses to high GI. Although some of the observed differences in the glycemic responses to the test meals were statistically significant, primarily in healthy subjects, the differences were usually much less than predicted by the GIs of the meals. In NIDDM subjects, peak postprandial plasma glucose, plasma glucose area, plasma glucose area increment, and mean plasma glucose responses after intermediate and low GI were greater than 90% of the corresponding responses to high GI. In healthy subjects, only the plasma glucose area increment after the low-GI meal was close to the predicted response. High GI produced significantly greater insulin responses than low GI in healthy subjects. We conclude that the diabetic exchange lists more accurately predict postprandial responses to carbohydrate-containing foods eaten as part of a mixed meal than does the GI of foods.(ABSTRACT TRUNCATED AT 250 WORDS)

Naloxone but not CCK-8 may attenuate binge-eating behavior in patients with the bulimia syndrome.

We undertook a study to see if putative anorectic agents could attenuate binge eating episodes in bulimic patients. Bolus intravenous administration, followed by continuous intravenous infusion of naloxone, resulted in a significant decrease in the amount of food consumed during binge-eating episodes, whereas bolus followed by continuous intravenous infusion of CCK-8 failed to significantly suppress binge eating behavior. These results suggest that the endogenous opioid system is involved in the maintenance of binge eating behavior in patients with bulimia.

Metabolic effects of dietary fructose and sucrose in types I and II diabetic subjects.

To learn more about the metabolic effects of dietary fructose and sucrose, 12 type I and 12 type II diabetic subjects were fed three isocaloric (or isoenergic) diets for eight days each according to a randomized, crossover design. The three diets provided, respectively, 21% of the energy as fructose, 23% of the energy as sucrose, and almost all carbohydrate energy as starch. The fructose diet resulted in significantly lower one- and two-hour postprandial plasma glucose levels, overall mean plasma glucose levels, and urinary glucose excretion in both type I and type II subjects than did the starch diet. There were no significant differences between the sucrose and starch diets in any of the measures of glycemic control in either subject group. The fructose and sucrose diets did not significantly increase serum triglyceride values when compared with the starch diet, but both increased postprandial serum lactate levels. We conclude that short-term replacement of other carbohydrate sources in the diabetic diet with fructose will improve glycemic control, whereas replacement with sucrose will not aggravate glycemic control.

Urine C-peptide and creatinine (Jaffe method) excretion in healthy young adults on varied diets: sustained effects of varied carbohydrate, protein, and meat content.

We studied effects of isocaloric diets of varied composition (each diet offered for 5 to 7 days) on urine C-peptide and creatinine excretion in eight healthy subjects. C-peptide excretion was higher on the high carbohydrate (60% CHO, 20% PRO) and high protein (45% CHO, 30% PRO) diets than on the low carbohydrate (30% CHO, 20% PRO) and low protein diets (45% CHO, 10% PRO). C-peptide excretion correlated with total kilocalories ingested (r = 0.594, p less than 0.001), and also with CHO (r = 0.469, p = 0.003) and PRO intake (r = 0.453, p = 0.004). Multiple regression analysis is given by the formula: Urine C-peptide (nmol/24 h) = 17.3 + 0.01 (kcal/24 h) + 0.021 (gm CHO/24 h) + 0.049 (gm PRO/24 h) Creatinine excretion was related to body weight (r = 0.959, p less than 0.001) and also to total PRO intake (r = 0.569, p less than 0.001) and meat intake (r = 0.367, p less than 0.05). We conclude that diet composition, especially protein intake, is an important stimulus to sustained insulin production as measured by C-peptide in healthy subjects. Diet composition has a significant impact on creatinine excretion. Urine creatinine cannot be assumed to reflect only lean body weight when it is used as a measure of the adequacy of timed urine collections.

[Does the ferritin level have a practical value in chronically hemodialized patients?]. / Le dosage de la ferritine a-t-il un intérêt pratique chez les malades en hémodialyse chronique?

In order to determine whether serum ferritin assay has any advantages compared with usual hematologic parameters, serum ferritin was assessed in 70 hemodialysed patients. It was positively correlated with the number of blood units infused, but there was no correlation with iron treatment, serum iron or the degree of anemia. However, the interpretation of the results is difficult, because of the large dispersion of serum ferritin levels. Therefore, the determination of serum ferritin concentration cannot be recommended as a current method to follow-up and manage anemic chronic hemodialysed patients, especially when the cost of the test is taken into account.

Urinary C-peptide as a measure of beta-cell function after a mixed meal in healthy subjects: comparison of four-hour urine C-peptide with serum insulin and plasma C-peptide.

Urinary C-peptide (UCP) is a noninvasive measure of integrated insulin production, and the usefulness of 24-h collections has been previously reported. Only small numbers of subjects have been studied using shorter urine collections. To see how well 4-h urine collections for C-peptide (UCP) correlate with serum immunoreactive insulin (SI) and plasma C-peptide (PCP), we studied 41 healthy subjects (19 men, 22 women) using as a stimulus a 600-kcal mixed meal and the same mixed meal after oral prednisone. UCP values correlated best with the area under the curves for SI (r = 0.457, P less than 0.001) and PCP (r = 0.557, P less than 0.001). UCP was also significantly correlated with peak SI (r = 0.382, P less than 0.001), peak PCP (r = 0.496, P less than 0.001), fasting SI (r = 0.297, P = 0.007), and fasting PCP (r = 0.341, P = 0.007) values. Urinary C-peptide was significantly correlated with SI and PCP concentrations in a broad range of physiologic values for SI and PCP supporting the usefulness of UCP as a simple, noninvasive measure of beta-cell function. Four-hour collections for UCP may be useful in further studies of beta-cell function.

Postprandial glucose and insulin responses to meals containing different carbohydrates in normal and diabetic subjects.

To examine whether the form of dietary carbohydrate influences glucose and insulin responses, we studied the glucose and insulin responses to five meals--each containing a different form of carbohydrate but all with nearly identical amounts of total carbohydrate, protein, and fat--in 10 healthy subjects, 12 patients with Type I diabetes, and 10 patients with Type II diabetes. The test carbohydrates were glucose, fructose, sucrose, potato starch, and wheat starch. In all three groups, the meal containing sucrose as the test carbohydrate did not produce significantly greater peak increments in the plasma concentration of glucose or greater increments in the area under the plasma glucose-response curves than did meals containing potato, wheat, or glucose as test carbohydrates. Urinary excretion of glucose in patients with diabetes was not significantly greater after the sucrose meal. The meal containing fructose as the test carbohydrate produced the smallest increments in plasma glucose levels, but the differences were not always statistically significant. In healthy subjects and patients with Type II diabetes, peak serum concentrations of insulin were not significantly different in response to the five test carbohydrates. Our data do not support the view that dietary sucrose, when consumed as part of a meal, aggravates postprandial hyperglycemia.