Familial risk of multiple sclerosis: a nationwide cohort study

Multiple sclerosis (MS) is known to accumulate within families. The magnitude of the familial risk, however, remains uncertain. Using a nationwide MS register and other national registers, the authors estimated relative and absolute risks of MS in a population-based cohort that included 19,615 first-degree relatives of 8,205 Danish MS patients followed from 1968 to 1997. The ratio of observed to expected numbers of MS cases served as the measure of the relative risk of MS. Lifetime risks of MS in first-degree relatives were estimated as the product of the relative risk and the national lifetime risk of MS. Overall, first-degree relatives had a sevenfold increased risk of MS (relative risk=7.1, 95% confidence interval: 5.8, 8.8) (n=90) compared with the background population. By modeling the individual incidence rate of MS as the sum of a familial component and a sporadic risk component, the familial excess lifetime risk was found to be 2.5% (95% confidence interval: 2.0, 3.2) among first-degree relatives of MS patients, irrespective of the gender of the proband and the relative. This percentage should be added to a sporadic absolute risk in the general population of 0.5% in women and 0.3% for men. Spouses of MS patients did not experience an increased risk of MS, suggesting no major role for environmental factors acting in adulthood.     

Carbon and nitrogen stable isotopic composition of hair protein and amino acids can be used as biomarkers for animal-derived dietary protein intake in humans

The stable nitrogen (15N) and carbon (13C) isotopic composition of tissues reflects the isotopic pattern of food sources. We investigated whether the isotopic composition of human hair can be used as a biomarker to predict the dietary intake of animal-derived food. Hair samples were collected from subjects during a 1987-1988 German nutrition survey (VERA) in which dietary information was collected using a 7-d dietary record. Samples of 50 men and 50 women were randomly selected, in addition to 27 samples of subjects with a reported low meat intake. Isotope ratio MS was used to analyze hair bulk and amino acid-specific isotopic composition. Its relation with and feasibility for predicting animal protein intake were tested using regression analysis and cross-tabulation of observed and predicted dietary data and comparison of the individual values for the binary categories of high and low intake. 15N and 13C abundances strongly predicted relative animal protein and meat intake (R2= 0.31, P < 0.01 and R2= 0.20, P <0.01, respectively). Distinct patterns of individual hair amino acid 15N and 13C abundances were observed. In contrast to bulk values, the isotopic abundances in individual amino acids did not show discriminating ability across sex and isotope-specific categories. We conclude that hair 13C values are as predictive for animal protein consumption as hair 15N values. Bulk isotopic abundance of hair can be used as a biomarker for animal protein intake to validate dietary assessment methods provided that the correlation between isotopic abundances and dietary protein intake is verified in dietary intervention studies.     

Novel lycopene metabolites are detectable in plasma of preruminant calves after lycopene supplementation

Appropriate animal models such as preruminant calves are necessary to study the complex physiological functions of carotenoids and to relate them to possible health effects in humans. In this study, the bioavailability and metabolism of lycopene from 2 dietary supplements were compared. LycoVit containing synthetic lycopene and Lyc-O-Mato containing natural tomato oleoresin were administered to 2 groups of preruminant calves (each n = 8) for 14 d in daily doses of 15 mg of lycopene. Plasma was analyzed for carotenoids before the intervention period, directly after, and each day for 5 d after the end of the intervention. All-trans and 5-cis lycopene, and 3 lycopene metabolites not previously found in calf plasma were detected. These metabolites contributed 52% of the total lycopene content measured at the end of the intervention period. Based on spectroscopic data, they might be hydrogenation products, which are formed from all-trans and/or 5-cis lycopene. In the LycoVit group, total lycopene concentrations were approximately 300% higher (286 +/- 89 nmol/L) than in the Lyc-O-Mato group (72 +/- 33 nmol/L) (P < 0.001). This indicates that, unlike in humans, lycopene from LycoVit and Lyc-O-Mato does not have equal bioavailabilities in preruminant calves. Therefore, the preruminant calf may not be a suitable animal model with which to study the biological and physiological effects of lycopene.     

CpG oligonucleotides induce strong humoral but only weak CD4+ T cell responses to protein antigens in rhesus macaques in vivo

Oligonucleotides containing CpG motifs (CpG ODN) are strong adjuvants for humoral immune responses but data on cellular immune responses in primates are scarce. Rhesus macaque blood contained similar numbers of plasmacytoid dendritic cells and B cells, the key sensors of CpG ODN, as human blood, and these cells were activated by CpG-A and CpG-B in vitro. In vivo, both ODNs induced equal plasma levels of interferon-inducible protein 10 and similarly enhanced antibody responses following i.m. injections of the ODNs, protein antigen, and aluminium hydroxide into rhesus macaques, whereas antigen-specific CD4(+) T cell responses were only slightly increased by CpG ODN.     

The evolving role of staging laparoscopy in the treatment of colorectal hepatic metastasis

HYPOTHESIS: Laparoscopy is an increasingly important tool in the staging and treatment of hepatic malignancies. This study evaluates the effect of staging laparoscopy (SL) using intraoperative ultrasonography (IOUS) on the regional treatment of isolated hepatic colorectal metastasis. DESIGN: Analytic cohort study. SETTING: Tertiary care center. PATIENTS: Consecutive patients who have a colorectal metastasis confined to the liver and selected for surgical regional treatment. INTERVENTIONS: All patients underwent preoperative evaluation followed by SL/IOUS. Operative plans were based on preoperative imaging and were either carried out or altered intraoperatively according to SL/IOUS findings. MAIN OUTCOME MEASURE: Effect of SL/IOUS on surgical management. RESULTS: Between September 1996 and May 2004 one hundred fifty-two SL/IOUSs were performed in 136 patients (77 males and 59 females), who had a mean (SD) age of 63 (11) years. Data sets were complete in 138 events. All patients had isolated hepatic disease as defined by preoperative computed tomography in 152 (100%) and positron emission tomography in 107 (70%). Staging laparoscopy/IOUS identified surgically untreatable disease in 34 events (25%) because of peritoneal metastases (n = 15), nodal involvement (n = 11), diffuse hepatic disease (n = 5), no identifiable disease (n = 2), and untreatable disease (n = 1). Laparoscopic treatment events included radiofrequency ablations (n = 78), hepatic artery pump implantations (n = 40), resections (n = 26), and combined procedures (n = 37). Overall, SL/IOUS changed the treatment plan in 66 (48%) of 138 of events. This includes 32 (23%) of 138 events in which SL/IOUS findings significantly altered the actual procedure performed relative to the preoperative plan. Three minor complications occurred in the SL/IOUS-only group with a mean (SD) hospital stay of 1.3 (1) days. CONCLUSION: In the regional management of isolated colorectal hepatic metastasis, SL/IOUS avoids unnecessary laparotomies and influences definitive surgical intervention in a substantial proportion of patients.     

Winged-helix transcription factors and pancreatic development

The forkhead gene family, named after the founding gene member in Drosophila, is characterized by a unique DNA-binding domain. This so-called forkhead box encodes a winged-helix DNA-binding motif, the name of which describes the structure of the domain when bound to DNA. The three Fox (forkhead box) group A genes, Foxa1, Foxa2 and Foxa3, are expressed in embryonic endoderm, the germ layer that gives rise to the digestive system, and contribute to the specification of the pancreas and the regulation of glucose homoeostasis. Deletion of the Foxa2 gene in pancreatic beta-cells in mice results in a phenotype resembling PHHI (persistent hyperinsulinaemic hypoglycaemia of infancy). Molecular analyses have demonstrated that Foxa2 is an important regulator of the genes encoding Sur1, Kir6.2 and Schad (short chain L-3-hydroxyacyl-CoA dehydrogenase), mutation of which causes PHHI in humans. Foxa1 was shown to be an essential activator of glucagon gene expression in vivo. An additional winged-helix protein, Foxo1, contributes to pancreatic beta-cell function by regulating the Pdx1 gene, which is required for pancreatic development in cooperation with Foxa2.