High prevalence of familial defective apolipoprotein B-100 in Switzerland

Familial defective apolipoprotein B-100 (FDB) is caused by a single G-to-A substitution at nucleotide 10,708 leading to an arginine to glutamine change at amino acid 3,500 of the apolipoprotein B-100 and thus, a reduced binding of the apolipoprotein B to the low density lipoprotein (LDL) receptor. In the present study, the prevalence of FDB in Switzerland was estimated, on the one hand, from a sample of 728 healthy volunteers whose origin was spread out over the entire German, French, and Romansh speaking parts of the country, and, on the other hand, from 142 unrelated Swiss families with primary hypercholesterolemia comprising 520 individuals. Using polymerase chain reaction (PCR)-based methods, three individuals were identified with the point mutation in the sample of volunteers, equivalent to a prevalence of approximately 1/240 (90% confidence interval: 1.51 x 10(-3)-1.03 x 10(-2)). The frequency of FDB in the sample of hypercholesterolemic subjects was 7/142, yielding a prevalence of approximately 1/190 extrapolated to the general population (90% confidence interval: 2.63 x 10(-3)-9.17 x 10(-2)). The combined prevalence based on both samples was 1/209. Thus, the investigated point mutation was highly prevalent in Switzerland and appeared to be more frequent than in other populations studied hitherto. Furthermore, the presence of the mutation was not necessarily associated with an elevation of serum cholesterol levels, particularly in young individuals. While in the non-affected volunteers cholesterol levels increased between the age of 19 and 23 years by 0.22 mmol/l or by 5.6% (P = 0.001), this phenomenon was even more pronounced in individuals with FDB. The three volunteers with the point mutation demonstrated an increase in total cholesterol concentrations by 1.30 mmol/l or by 25% within 2 years, suggesting that, in the early twenties, cholesterol concentrations increase markedly from normal to elevated levels. Considering the estimated high prevalence the relative ease of PCR-based tests, screening for FDB may become a standard procedure in patients with suggested familial forms of hypercholesterolemia

Immune monitoring-guided vs fixed duration of antiviral prophylaxis against cytomegalovirus in solid-organ transplant recipients. A Multicenter, Randomized Clinical Trial

BACKGROUND: The use of assays detecting cytomegalovirus (CMV)-specific T-cell-mediated immunity may individualize the duration of antiviral prophylaxis in transplant recipients. METHODS: In this open-label randomized trial, adult kidney and liver transplant recipients from six centers in Switzerland were enrolled if they were CMV-seronegative with seropositive donors or CMV-seropositive receiving anti-thymocyte globulins. Patients were randomized to a duration of antiviral prophylaxis based on immune-monitoring (intervention) or a fixed duration (control). Patients in the control group were planned to receive 180 days (CMV-seronegative) or 90 days (CMV-seropositive) of valganciclovir. Patients were assessed monthly with a CMV-specific interferon gamma release assay (T-Track® CMV); prophylaxis in the intervention group was stopped if the assay was positive. The primary outcomes were the proportion of patients with clinically significant CMV infection and reduction in days of prophylaxis. Between-group differences were adjusted for CMV serostatus. RESULTS: Overall, 193 patients were randomized (92 in the immune-monitoring and 101 in the control group) of which 185 had evaluation of the primary endpoint (87 and 98 patients, respectively). Clinically significant CMV infection occurred in 26/87 (adjusted percentage, 30.9%) in the immune-monitoring group and in 32/98 (adjusted percentage, 31.1%) in the control group (adjusted risk difference -0.1, 95%CI -13.0%, 12.7%; p = 0.064). The duration of antiviral prophylaxis was shorter in the immune-monitoring group (adjusted difference -26.0 days, 95%-CI -41.1 to -10.8 days, p < 0.001). CONCLUSIONS: Immune monitoring resulted in a significant reduction of antiviral prophylaxis, but we were unable to establish noninferiority of this approach on the co-primary endpoint of CMV infection

Immune monitoring-guided vs fixed duration of antiviral prophylaxis against cytomegalovirus in solid-organ transplant recipients. A Multicenter, Randomized Clinical Trial.

BACKGROUND The use of assays detecting cytomegalovirus (CMV)-specific T-cell-mediated immunity may individualize the duration of antiviral prophylaxis in transplant recipients. METHODS In this open-label randomized trial, adult kidney and liver transplant recipients from six centers in Switzerland were enrolled if they were CMV-seronegative with seropositive donors or CMV-seropositive receiving anti-thymocyte globulins. Patients were randomized to a duration of antiviral prophylaxis based on immune-monitoring (intervention) or a fixed duration (control). Patients in the control group were planned to receive 180 days (CMV-seronegative) or 90 days (CMV-seropositive) of valganciclovir. Patients were assessed monthly with a CMV-specific interferon gamma release assay (T-Track® CMV); prophylaxis in the intervention group was stopped if the assay was positive. The primary outcomes were the proportion of patients with clinically significant CMV infection and reduction in days of prophylaxis. Between-group differences were adjusted for CMV serostatus. RESULTS Overall, 193 patients were randomized (92 in the immune-monitoring and 101 in the control group) of which 185 had evaluation of the primary endpoint (87 and 98 patients, respectively). Clinically significant CMV infection occurred in 26/87 (adjusted percentage, 30.9%) in the immune-monitoring group and in 32/98 (adjusted percentage, 31.1%) in the control group (adjusted risk difference -0.1, 95%CI -13.0%, 12.7%; p = 0.064). The duration of antiviral prophylaxis was shorter in the immune-monitoring group (adjusted difference -26.0 days, 95%-CI -41.1 to -10.8 days, p < 0.001). CONCLUSIONS Immune monitoring resulted in a significant reduction of antiviral prophylaxis, but we were unable to establish noninferiority of this approach on the co-primary endpoint of CMV infection

Effects of recombinant human insulin-like growth factor I and insulin on counterregulation during acute plasma glucose decrements in normal and type 2 (non-insulin-dependent) diabetic subjects

Insulin-like growth factor I (65 micrograms/kg) or insulin (0.1 IU/kg) were injected i.v. on two separate occasions in random order in normal and in Type 2 (non-insulin-dependent) diabetic subjects. Insulin-like growth factor I and insulin injection resulted in identical decrements of plasma glucose concentrations after 30 min but in delayed recovery after insulin-like growth factor I as compared to insulin in both groups (p textless 0.05 insulin-like growth factor I vs insulin). Counterregulatory increases in plasma glucagon, adrenaline, cortisol and growth hormone concentrations after hypoglycaemia (1.9 +/- 0.2 mmol/l) in normal subjects were blunted after insulin-like growth factor I administration compared to insulin (p textless 0.05). Plasma glucose in Type 2 diabetic subjects did not reach hypoglycaemic levels but the acute glucose decrease to 4.5 +/- 0.8 mmol/l was associated with significantly lower responses of plasma glucagon and adrenaline but higher cortisol levels after insulin-like growth factor I compared to insulin (p textless 0.003). Plasma concentrations of non-esterified fatty acids and leucine decreased similarly after insulin-like growth factor I and insulin in both groups. The present results demonstrate that insulin-like growth factor I is capable of mimicking the acute effects of insulin on metabolic substrates (plasma glucose, non-esterified fatty acids, leucine). The decreases of plasma glucose were similar after both peptides in normal and in diabetic subjects who were presumably insulin resistant. Counterregulatory hormone responses to plasma glucose decrements differed, however, between insulin-like growth factor I and insulin and in the diabetic and the control subjects.(ABSTRACT TRUNCATED AT 250 WORDS

Comparison of the effects of recombinant human insulin-like growth factor-I and insulin on glucose and leucine kinetics in humans.

To compare the metabolic effects of elevated plasma concentrations of IGF-I and insulin, overnight-fasted normal subjects were studied twice, once receiving IGF-I and once insulin at doses that resulted in identical increases in glucose uptake during 8-h euglycemic clamping. Recombinant human IGF-I or insulin were infused in one group at high doses (30 micrograms/kg per h IGF-I or 0.23 nmol/kg per h insulin) and in another group at low doses (5 micrograms/kg per h IGF-I or 0.04 nmol/kg per h insulin). Glucose rate of disappearance (measured by [6,6-D2]-glucose infusions) increased from baseline by 239 +/- 16% during high dose IGF-I vs 197 +/- 18% during insulin (P = 0.021 vs IGF-I). Hepatic glucose production decreased by 37 +/- 6% during high dose IGF-I vs 89 +/- 13% during insulin (P = 0.0028 vs IGF-I). IGF-I suppressed whole body leucine flux ([1-13C]-leucine infusion technique) more than insulin (42 +/- 4 vs 32 +/- 3% during high doses, P = 0.0082). Leucine oxidation rate decreased during high dose IGF-I more than during insulin (55 +/- 4 vs 32 +/- 6%, P = 0.0001). The decreases of plasma concentrations of free fatty acids, acetoacetate, and beta-hydroxybutyrate after 8 h of IGF-I and insulin administration were similar. Plasma C-peptide levels decreased by 57 +/- 4% during high doses of IGF-I vs 36 +/- 6% during insulin (P = 0.005 vs IGF-I). The present data demonstrate that, compared to insulin, an acute increase in plasma IGF-I levels results in preferential enhancement of peripheral glucose utilization, diminished suppression of hepatic glucose production, augmented decrease of whole body protein breakdown (leucine flux), and of irreversible leucine catabolism but in similar antilipolytic effects. The data suggest that insulin-like effects of IGF-I in humans are mediated in part via IGF-I receptors and in part via insulin receptors

Protein content of the evening meal and nocturnal plasma glucose regulation in type-I diabetic subjects

The effect of two isocaloric evening meals (low protein-high fat vs. high protein-low fat content) on plasma glucose regulation during the night were compared. Eight C-peptide-deficient type-I diabetic subjects without autonomic neuropathy were treated with fixed doses of continuous infusions of insulin during 2 nights. At 7 p.m. they received in random order either a low protein-high fat (5% of total energy protein, 60% fat, 35% carbohydrate) or a high protein-low fat (35% protein, 30% fat, 35% carbohydrate) evening meal. Venous plasma samples were drawn hourly thereafter. Plasma glucose concentrations were similar postprandially during the 2 nights between 7 p.m. and 11 p.m., but they were higher in the early morning hours after the high protein meal (p textless 0.02 vs. the low protein meal). Two subjects developed symptomatic hypoglycemia after the low protein meal. Plasma glucagon concentrations were higher (p = 0.023) and serum free insulin lower (p textless 0.05) after the high protein-low fat meal. Plasma cortisol and growth hormone were not significantly different between the two diets. Therefore, an increase in the protein content of the evening meal (fat content diminished) increases plasma glucose concentrations several hours later in the night, possibly due to protein-induced glucagon secretion and to lower plasma free insulin levels. Patients with type-I diabetes with a tendency to develop hypoglycemia during the night may avoid this problem by increasing the protein content of the evening meal

A metapopulation model of dog rabies transmission in N'Djamena, Chad.

Rabies transmission was interrupted for several months in N'Djamena, the capital city of Chad, after two mass vaccination campaigns of dogs. However, there was a resurgence in cases, which was not predicted by previous models of rabies transmission. We developed a deterministic metapopulation model with importation of latent dogs, calibrated to four years of weekly incidence data from passive surveillance, to investigate possible causes for the early resurgence. Our results indicate that importation of latently infective dogs better explains the data than heterogeneity or underreporting. Stochastic implementations of the model suggest that the two vaccination campaigns averted approximately 67 cases of dog rabies (out of an estimated 74 cases without vaccination) and 124 human exposures (out of an estimated 148 human exposures without vaccination) over two years. Dog rabies vaccination is therefore an effective way of preventing rabies in the dog population and to subsequently reduce human exposure. However, vaccination campaigns have to be repeated to maintain the effect or reintroduction through importation has to be prevented