First-degree Relatives Group Research Articles

Abstract 5771: Aortic Root Dilatation is a Phenotypic Manifestation of the Bicuspid Aortic Valve Disease Prevalent in Relatives with Normal Aortic Valve.

Background: Bicuspid aortic valve (BAV) and dilated ascending aorta frequently coexist. 10% of first degree relatives (FDRs) of probands with BAV inherit a valvular abnormality, however there is limited data concerning the occurrence of dilated aortic root in families of affected subjects. We evaluated the prevalence of aortic root dilatation among FDRs with a tricuspid aortic valve. Methods: Aortic root dimensions were measured by 2D echocardiography in BAV probands (n=48), their FDRs (n = 49) and controls without structural heart disease matched by age and gender (n=44). Aortic root was measured at: annulus, sinuses of Valsalva, sino-tubular junction and proximal ascending aorta. The dimensions were indexed by body surface area (BSA). Presence of dilatation was determined using published confidence intervals relating normal aortic diameters to BSA and age. Results: Five subjects (10%) in FDR group were found to have BAV, thus they were included in BAV group. Indexed aortic diameter was significantly different in 3 groups namely BAV>FDR>Control at annulus (2.0±0.3, 1.7±0.2, 1.6±0.1, p<0.001) and sinuses of Valsalva (2.8±0.5, 2.4±0.4, 2.2±0.3, p<0.001) Figure . BAV subjects showed significantly larger dimensions in the ascending aorta compared to FDRs and controls (p<0.001). The prevalence of aortic root dilatation at all levels was 51% in BAV subjects, 25% in FDRs and 0% in controls (p<0.001). Conclusions: There is high prevalence of aortic root dilatation in the FDRs of subjects with BAV despite having normal tricuspid aortic valve. This finding suggests that aortic root dilatation is another phenotypic manifestation of BAV disease that is inherited independent of BAV.

Knowledge, health beliefs and health‐related behaviours of first‐degree relatives of women suffering from osteoporosis in Taiwan: a questionnaire survey

No previous study has examined knowledge, health beliefs and health-related behaviours in first-degree relatives (FDRs) of osteoporosis sufferers, especially focusing on Asian women. This study explored osteoporosis knowledge, beliefs and behaviours of women with a family history of osteoporosis, and drew a comparison with women with no such history. This study recruited women at a large public health centre in northern Taiwan. A questionnaire was applied on FDRs and non-FDRs women with a focus on osteoporosis knowledge, health beliefs and behaviours. Descriptive analysis was initially conducted. Differences between FDRs and non-FDRs were rated via Student's t-tests for continuous variables and the chi-squared test for categorical variables. Overall, most of the participants were aware of some osteoporosis-related information but the proportions of correct responses to the questions that tested knowledge between FDRs and non-FDRs were only 44.0% and 42%, respectively. Meanwhile, participants in the FDRs group not only reported higher concern in developing the disease, but also perceived higher barriers compared with the non-FDRs group. As the study demonstrates, for health-related behaviours, the FDRs group did not undertake actual preventive behaviours, and only bone mineral density screening behaviour differed significantly from the non-FDRs group. This study highlights the inadequate information on osteoporosis and constraining beliefs of FDRs women. Additionally, as preventative behaviours for osteoporosis were not noted in FDRs group, community health nurses and researchers should make efforts to assist and encourage women to take practical preventative behaviours. This investigation reviews the knowledge, beliefs and behaviours of the FDRs group for Taiwanese women with osteoporosis. The results of this work can be used to provide effective implementation guidelines for preventing osteoporosis especially for women with a family history of the disease.

S1022 Prevalence of Colorectal Premalignant Lesions Detected By Colonoscopy in Different Risk Groups for Colorectar Cancer

BACKGROUND: Colorectal cancer (CRC) is the second most frequent cancer and the second cause of mortality related to cancer in Argentina. The detection of premalignant lesions (PML) through colonoscopy has been demonstrated to be effective in the prevention of CRC. It is important to be aware of the prevalence of these lesions to estimate their impact on the prevention of CRC in our population. The aim of this study was to assess the prevalence of PML in asymptomatic subjects with different levels of risk of CRC. METHODS: A cross-sectional analysis was performed based on the colonoscopy records of asymptomatic subjects screened for CRC in a General Hospital of Buenos Aires City, Argentina, between July 2004 and March 2007. The prevalence of PML was assessed in 2 groups: 1) average risk and 2) first-degree relatives with CRC. Patients with incomplete colonoscopy, poor preparation or second-degree relatives with CRCwere excluded. PMLwas defined as polyps or flat adenomaswith low or high-grade dysplasia.Multivariate logistic analysis was performed to establish the association between individual characteristics and PML. RESULTS: Data from 1233 subjects was collected (female= 733, mean age= 67.6 years SD= ±11.2). We found a global prevalence of 24.1% for PML and 1.1% for CRC. Average risk group (n=476; female= 246; mean age=61.8 years SD= ±9,06) showed a prevalence of 22.1% for PML (CI 95%= 18.3-25.8), in which 19.2% had low-grade and 2.5% high-grade dysplasia. The prevalence of CRC was 1.05%. First-degree relatives group (n=757; female =487; mean age= 54.9 years SD= ±11.53) showed a prevalence of 25.2% (CI 95%=22.1-28.3), in which 20% had lowgrade and 4.8% high-grade dysplasia. The prevalence of CRC in this group was 1.2%. In the validation set a logistic regressionmodel showed that family history of CRCwas independently associated with increased risk of PML (odds ratio=1.54; CI 95%= 1.15-2.05; P=0.004). This difference was greater in younger subjects (table 1). Male sex was also independently associated with an increased risk of PML (odds ratio=1.50; IC 95%= 1.15-1.97; P=0.003). CONCLUSION: Approximately a quarter of this population presented at least one PML and a significantly increased risk in first-degree relatives with CRC and male sex was observed. These results may contribute to issue local guidelines for CRC prevention. Table 1. Prevalence in different age groups

Prevalence of celiac disease among first degree relatives of Brazilian celiac patients

Several studies have shown that celiac disease, an autoimmune disorder that occurs in genetically susceptible individuals, is highly prevalent among relatives of celiac patients. To determine the prevalence of celiac disease in a group of first degree relatives of Brazilian celiac patients. First degree relatives of celiac patients attending the Brasilia University Hospital Pediatric Gastroenterology Outpatient Clinic or the Celiac Disease Investigation Center, Brasília, DF, Brazil, between March 2001 and November 2004 were invited to undergo serological screening for celiac disease applying the IgA anti-endomysium antibody test (IgA-EMA). All positive IgA-EMA sera underwent a second screening using the IgA anti-tissue transglutaminase antibodies test. Duodenal or small intestinal biopsies were performed in all subjects positive to serological testing. Biopsy samples were classified as type (O) normal, (I) infiltrative, (II) infiltrative hyperplastic, (III) flat destructive, and (IV) atrophic hypoplastic. The final diagnosis was ascertained in subjects showing positive serological tests and a grade I to III small intestinal lesion. Nine new cases of celiac disease were found among the 188 first degree relatives tested (4.8%). The present study confirms the high prevalence of celiac disease among first degree celiac patients relatives and reinforces the need of extensive diagnostic screening in this specific group.

Striatal Dopamine Synthesis in First-degree Relatives of Patients with Schizophrenia

First degree relatives (FDR) of patients with schizophrenia have higher risk of developing schizophrenia than the general population. Previous positron emission tomography (PET) studies have shown that striatal presynaptic dopamine synthesis capacity is increased in schizophrenia. We investigated whether this same phenomenon is shared by individuals with increased genetic risk for schizophrenia. We used 6-[18F]-fluorodopa (FDOPA) PET imaging to measure striatal dopamine synthesis capacity. We studied 17 nonpsychotic subjects with an FDR with schizophrenia. This group was compared to 17 healthy subjects with no FDRs with schizophrenia. A conventional region of interest (ROI)-analysis indicated that FDOPA uptake (K(i)) in the caudate-putamen was statistically significantly higher in the FDR group than in the control group. A voxel-level analysis confirmed these results. These results suggest that the changes of striatal presynaptic dopamine synthesis seen previously in neuroleptic-naive schizophrenic patients is also present in FDRs of patients with schizophrenia. These findings have implications for the early detection of psychosis as well as for pharmacological interventions in individuals at risk for psychosis.

Suppression of glucagon secretion is lower after oral glucose administration than during intravenous glucose administration in human subjects

The incretin effect describes the augmentation of postprandial insulin secretion by gut hormones. It is not known whether glucagon secretion is also influenced by an incretin effect. A glucagon suppression deficiency has been reported in some patients with type 2 diabetes, but it is unclear whether this abnormality is present prior to diabetes onset. We therefore addressed the questions: (1) Is glucagon secretion different after oral and during intravenous glucose administration? (2) If so, is this related to the secretion of incretin hormones? (3) Is glucagon secretion abnormal in first-degree relatives of patients with type 2 diabetes? We examined 16 first-degree relatives of patients with type 2 diabetes and ten matched control subjects with an oral glucose load (75 g) and with an 'isoglycaemic' intravenous glucose infusion. Glucagon levels were significantly suppressed by both oral and intravenous glucose (p < 0.0001), but glucagon suppression was more pronounced during intravenous glucose administration (76 +/- 2%) than after oral glucose administration (48 +/- 4%; p < 0.001). The differences in the glucagon responses to oral and i.v. glucose were correlated with the increments in gastric inhibitory polypeptide (GIP) (r = 0.60, p = 0.001) and glucagon-like peptide (GLP)-1 (r = 0.46, p < 0.05). There were no differences in glucagon levels between first-degree relatives and control subjects. Despite the glucagonostatic actions of GLP-1, the suppression of glucagon secretion by glucose is diminished after oral glucose ingestion, possibly due to the glucagonotropic actions of GIP and GLP-2. Furthermore, in this group of first-degree relatives, abnormalities in glucagon secretion did not precede the development of other defects, such as impaired insulin secretion.

Complications obstétricales dans la schizophrénie : étude comparative en population tunisienne

The neurodevelopmental hypothesis in schizophrenia argues that this disorder may be a result of abnormal brain development due to genetic risk and or to environmental injury such as those due to obstetric complications. Very few studies from emerging countries have been published concerning obstetric complications in schizophrenia. However, meteorological, demographic and health factors in most of these countries are different from those in Western countries, and studies in this field may bring more findings. Our objectives were to compare the frequency of obstetric complications in a group of schizophrenic patients compared to two other groups: a group of first-degree relatives and a healthy control group, and to search for the relationships between these complications and the epidemiological and clinical features of schizophrenic patients. The study is a retrospective case-controlled one: a schizophrenic patient group ( N = 55, 43 males and 12 females, median age = 30 years) was compared to a group of non-affected first degree relatives ( N = 40, 31 males and 9 females, median age = 29 years) and to healthy controls without familial psychiatric history ( N = 38, 25 males and 13 females, median age = 29 years), all matched according to age and sex. Obstetric complications were collected at home from the biological mothers at the time of a visit using the McNeil-Sjostrom questionnaire. Schizophrenic patients were clinically assessed using the Positive and Negative Symptoms (PANSS), the General Assessment of Functioning (GAF) and the Clinical Global Impressions (CGI). Obstetric complications frequency was significantly higher in schizophrenic patients: 67,3 versus 20,0% in their non affected relatives and 28,9% in the healthy controls ( P < 0,001). The mean total score of obstetric complications was significantly higher in the schizophrenic group: 1,52 ± 1,47 versus 0,8 ± 1,77 in the non affected relatives and 0,5 ± 0,97 in the healthy controls ( P < 0,001). In the schizophrenic patients, obstetric complications were more frequent during delivery period (50,9%) and neonatal period (45,5 %). More particularly in pre-term births (21,8%), low birth weight and fetal distress (18,2%) and premature rupture of the membranes (16,4%). A statistical relationship was established between obstetric complications frequency, autumn-wintry birth season, low school level and negative symptoms in the PANSS. However, no significant correlation was found between obstetric complications frequency, family psychiatric history and age of onset of schizophrenia. Through an investigation involving mental recall, our results proved a higher frequency of obstetric complications in schizophrenic patients. Our results support the role of obstetric complications in the etio-pathology of schizophrenia, in interaction with other environmental or genetic factors. This association favors the neuro-developmental hypothesis in schizophrenia. Further studies assessing influence of weather, specific infectious agents, and demographic factors could also be relevant.

Serum Antibodies in First-Degree Relatives of Patients with IBD: A Marker of Disease Susceptibility? A Follow-Up Pilot-Study after 7 Years

Introduction: Various disease-specific serum antibodies were described in patients with inflammatory bowel disease and their yet healthy first-degree relatives. In the latter, serum antibodies are commonly regarded as potential markers of disease susceptibility. The present long-term follow-up study evaluated the fate of antibody-positive first-degree relatives. Patients and Methods: 25 patients with Crohn’s disease, 19 patients with ulcerative colitis and 102 first-degree relatives in whom presence of ASCA, pANCA, pancreatic- and goblet-cell antibodies had been assessed were enrolled. The number of incident cases with inflammatory bowel disease was compared between antibody-positive and antibody-negative first-degree relatives 7 years after storage of serum samples. Results: 34 of 102 (33%) first-degree relatives were positive for at least one of the studied serum antibodies. In the group of first-degree relatives, one case of Crohn’s disease and one case of ulcerative colitis were diagnosed during the follow-up period. However, both relatives did not display any of the investigated serum antibodies (p = 1). Discussion: The findings of our pilot study argue against a role of serum antibodies as a marker of disease susceptibility in first-degree relatives of patients with inflammatory bowel disease. However, these data have to await confirmation in larger ideally prospective multicenter studies before definite conclusions can be drawn.

Increased adiposity and reduced adipose tissue mRNA expression of uncoupling protein‐2 in first‐degree relatives of type 2 diabetic patients: evidence for insulin stimulation of UCP‐2 and UCP‐3 gene expression in adipose tissue

The mitochondrial uncoupling proteins (UCP-2 and UCP-3), which have been suggested to be involved in the development of obesity by controlling the energy expenditure (EE), were studied in 22 healthy first-degree relatives (FDRs) of patients with type 2 diabetes and 13 body mass index (BMI)- and age-matched healthy control subjects. Abdominal subcutaneous adipose tissue biopsies were obtained before and after 150-min hyperinsulinaemic clamp (average serum insulin 250 pM). Basal adipose tissue UCP-2 mRNA levels in the FDR group were significantly lower than that in the control group. After the hyperinsulinaemic clamp, adipose tissue UCP-2 mRNA levels were increased by 32% in the control group (p < 0.05) and 32% in the FDR group (p < 0.05). The basal adipose tissue UCP-3 mRNA level was similar in the two groups and increased in both the groups during hyperinsulinaemia (p < 0.001). Dual energy X-ray absorptiometry showed that despite similar BMI the FDR group had significantly higher fat mass (FM) per cent compared to that of the control group (p < 0.01). The UCP-2 mRNA expression was inversely correlated with the amount of adipose tissue (r = -0.53, p < 0.001), and multiple regression analysis revealed that only the amount of FM was independently correlated with basal UCP-2 mRNA levels, whereas age, gender nor family history of type 2 diabetes contributed independently to the variation in UCP-2 mRNA levels. No differences in EE were observed between the two groups, and no association between EE and UCP mRNA expression was found. In conclusion, we have demonstrated that adipose tissue UCP-2 and UCP-3 mRNA levels are significantly increased during a 150-min hyperinsulinaemic clamp. The UCP-2 mRNA levels were expressed at a significantly lower level FDR to type 2 diabetes compared to control subjects. However, in multiple regression analysis controlling for amount of adipose tissue, the difference between the two groups disappeared. Thus, only the amount of adipose tissue contributed independently to the variation in UCP-2 mRNA expression.

Mutation analysis of suppressor of cytokine signalling 3, a candidate gene in Type 1 diabetes and insulin sensitivity.

Beta cell loss in Type 1 and Type 2 diabetes mellitus may result from apoptosis and necrosis induced by inflammatory mediators. The suppressor of cytokine signalling (SOCS)-3 is a natural inhibitor of cytokine signalling and also influences insulin signalling. SOCS3 could therefore be a candidate gene in the development of Type 1 and Type 2 diabetes mellitus. Mutation analysis of the SOCS3 gene was performed in 21 patients with Type 1 diabetes mellitus and in seven healthy subjects. An identified promoter variant was examined in (i) 250 families with Type 1 diabetic family members (1097 individuals); (ii) 212 glucose-tolerant first-degree relatives of Type 2 diabetic patients; and (iii) 370 population-based young, healthy subjects who were unrelated. Three mutations were identified in the promoter region, but none in the coding region or the 3'UTR. Two of the three mutations had allele frequencies below 1% whereas the C -920-->A substitution had a minor allele frequency of 8%. In the group of young healthy subjects the insulin sensitivity index was higher among homozygous carriers of the A-allele than among heterozygous and wild-type subjects ( p=0.027, uncorrected). The same trend was found in the group of first-degree relatives of Type 2 diabetic patients. No association or linkage was found to Type 1 diabetes mellitus. Homozygosity for the A-allele of the C -920-->A promoter polymorphism of the SOCS3 gene may be associated with increased whole-body insulin sensitivity, but deserves further investigation.

Evoked gamma band synchronization and the liability for schizophrenia

Objective: Electroencephalographic (EEG) synchronization in the gamma band is thought to represent a neuronal mechanism by which the brain integrates information processed in different cortical areas to build a coherent internal representation. Previous studies have reported abnormal gamma range (∼40 Hz) synchronization in schizophrenic patients. We tested a group of first-degree relatives of schizophrenic probands who have schizophrenia spectrum personality symptoms, and a group of schizophrenic patients, to examine whether individuals with increased liability for schizophrenia have reduced gamma synchronization. Method: A steady-state auditory evoked potential paradigm was used to evaluate the brain's capacity to sustain 20, 30, and 40 Hz EEG synchronization in 11 relatives, 24 schizophrenic patients (11 on conventional, 13 on new generation antipsychotic medications), and 17 normal controls. Results: Relatives with schizophrenic spectrum personality symptoms had reduced power at 40 Hz synchronization compared to normal controls ( p=0.022). Previous findings of reduced steady-state gamma band synchronization in schizophrenic patients were not directly replicated in this study. Patients as a group did not significantly differ from controls, but patients taking new generation antipsychotics had significantly enhanced 40 Hz synchronization compared to patients taking conventional antipsychotics ( p<0.001). There were no group differences in 20 or 30 Hz synchronization. Conclusions: Gamma band synchronization was found to be reduced in first-degree relatives with schizophrenia spectrum personality symptoms. Patients on new generation antipsychotic medications may exhibit enhanced gamma band synchronization.

First-degree relatives of persons suffering from osteoporosis: beliefs, knowledge, and health-related behavior.

The aim of the present study was to compare the beliefs, knowledge, and health-related behaviors of first-degree relatives (FDRs) of osteoporotic women with a comparison group of women not having a FDR with osteoporosis. Telephone interviews. Participants were 172 women (48 FDRs and 124 comparisons), recruited by a systematic sampling from the list of all women aged 40+ attending an outpatient screening program at a large tertiary medical center in Israel. Information was collected regarding participants' perceived susceptibility to develop osteoporosis, perceived concerns, and perceived prevention optimism. Additionally, information was collected regarding knowledge about osteoporosis, and participation in screening and preventive behavior. Participants in the FDR group reported higher perceived susceptibility and higher concerns about developing the disease than participants in the comparison group. A higher proportion of FDRs reported engaging in screening behavior, but no differences were found in preventive behaviors. Screening behavior was associated with perceived concerns and age for members of the comparison group, and with age for FDRs. FDRs are characterized by greater perceived vulnerability and concerns. However, they are no more likely to engage in preventive behaviors or have more knowledge about the disease. These findings stress the importance of expanding efforts to increase the knowledge and awareness of at-risk persons.

Family history of gastric cancer: should we test and treat for Helicobacter pylori?

A close link has been established between infection and gastric cancer. In this article, we suggest that using a risk stratification technique (like that for colorectal cancer), the high-risk group of first-degree relatives of patients with gastric cancer can be separated out for testing and treatment. This would be more manageable and more cost-effective than screening the whole population, in which the mortality from distal gastric cancer has declined concomitant with the eradication of infection. Support for the feasibility of this approach is derived from studies showing that the family is the core unit of transmission and that childhood colonization, especially with a virulent strain, is apparently a major risk factor for disease progression to the neoplastic stage. When there is a case of gastric cancer in the family, first-degree relatives, who might be infected by a bacterium with an identical genetic fingerprint, are at higher risk than normal for developing gastric cancer. Furthermore, genetic and epidemiologic studies based on the Correa model have shown that both primary and secondary prevention of gastric cancer is possible. Calculations done in high-risk populations, such as Japanese-Americans, confirm the savings in cost and the safety of the test-and-treat strategy. Considering that eradication should be done as early as possible, at a point in the cascade when the changes are still reversible, and that gastric cancer is associated with a high mortality rate, we suggest that this strategy be applied to this high-risk population.

Sensitivity and specificity of select biological indices in characterizing psychotic patients and their relatives

Background: Although studies have detailed biological abnormalities in schizophrenia patients and their first-degree biological relatives, few studies have directly compared the utility of biological indices in these individuals. Methods: Measures of global smooth-pursuit ocular motor (OM) function, low frequency and alpha band electroencephalogram (EEG) power, and nonspecific fluctuations (NSF) in electrodermal activity and visibility of the plexus in the nailfold were collected from 136 schizophrenia patients and 67 of their first-degree biological relatives, 71 affective disorder psychotic patients and 68 of their first-degree biological relatives, and 169 nonpsychiatric comparison subjects. We conducted receiver operator characteristic (ROC) analyses to determine how well each index differentiated the patient groups and the groups of first-degree relatives. Results: Smooth-pursuit ocular motor function, low frequency and alpha band EEG power, and nailfold plexus visibility differentiated schizophrenia patients from nonpsychiatric comparison subjects. Nailfold plexus visibility was the only measure that significantly differentiated schizophrenia patients from both nonpsychiatric controls and affective patients. Smooth-pursuit ocular motor function and the number of electrodermal nonspecific fluctuations differentiated relatives of schizophrenia patients from nonpsychiatric comparison subjects. Conclusion: Increased nailfold plexus visibility may mark a process associated with abnormal brain development leading to schizophrenia. Smooth-pursuit dysfunction may mark genetic vulnerability that is relatively specific to schizophrenia.

Adiponectin expression in adipose tissue is reduced in first-degree relatives of type 2 diabetic patients.

Adiponectin is suggested to be an important mediator of insulin resistance. Therefore, we investigated the association between adiponectin and insulin sensitivity in 22 healthy first-degree relatives (FDR) to type 2 diabetic patients and 13 matched control subjects. Subcutaneous adipose tissue biopsies were taken before and after a hyperinsulinemic euglycemic clamp. FDR subjects were insulin resistant, as indicated by a reduced M value (4.44 vs. 6.09 mg x kg(-1) x min(-1), P < 0.05). Adiponectin mRNA expression was 45% lower in adipose tissue from FDR compared with controls (P < 0.01), whereas serum adiponectin was similar in the two groups (6.4 vs. 6.6 microg/ml, not significant). Insulin infusion reduced circulating levels of adiponectin moderately (11-13%) but significantly in both groups (P < 0.05). In the control group, adiponectin mRNA levels were negatively correlated with fasting insulin (P < 0.05) and positively correlated with insulin sensitivity (P < 0.05). In contrast, these associations were not found in the FDR group. In conclusion, FDR have reduced adiponectin mRNA in subcutaneous adipose tissue but normal levels of circulating adiponectin. Adiponectin mRNA levels are positively correlated with insulin sensitivity in control subjects but not in FDR. These findings indicate dysregulation of adiponectin gene expression in FDR.

Hematopoietic and lymphatic cancers in relatives of patients with infectious mononucleosis.

Young adults with a history of Epstein-Barr virus (EBV)-related infectious mononucleosis have an increased risk for Hodgkin's lymphoma. EBV is detected in Hodgkin's lymphoma Reed-Sternberg cells from some patients, but in young adult patients, it is detected at a relatively low frequency in these cells. Hodgkin's lymphoma and infectious mononucleosis are both associated with high social class, and unknown confounding factors that are also associated with socioeconomic status might explain or contribute to the apparent association between these diseases. To indirectly assess the importance of socioeconomic status on the association between these diseases, we determined the risk for hematopoietic and lymphatic cancers in first-degree relatives of patients with confirmed EBV-related infectious mononucleosis. We identified parents, siblings, and offspring of 17,045 persons with serologically confirmed EBV-related infectious mononucleosis. Subjects in these cohorts were linked with the population-based Danish Cancer Register to identify those developing hematopoietic/lymphatic cancers after the index patient was diagnosed with infectious mononucleosis. The relative risk for cancer in the infectious mononucleosis family members was expressed as standardized incidence ratios (SIRs; i.e., the ratio between the number of cancers observed and the number of cancers expected, obtained from age-specific, sex-specific, and period-specific incidence rates). We identified 8052 parents, 5264 siblings, and 28,605 offspring of patients with EBV-related infectious mononucleosis who were followed for a total of 892,213 person-years at risk. The risk for Hodgkin's lymphoma was unaltered in the combined group of first-degree relatives of these patients (SIR = 0.99; 95% confidence interval [95% CI] = 0.62 to 1.59; number of cases [n] = 17), in the group of parents (SIR = 0.83; 95% CI = 0.31 to 2.22; n = 4), in the group of siblings (SIR = 0.96; 95% CI = 0.31 to 2.97; n = 3), and in the group of offspring (SIR = 1.08; 95% CI = 0.58 to 2.02; n = 10). The unremarkable risk for Hodgkin's lymphoma in family members of patients with EBV-related infectious mononucleosis indicates that socioeconomic confounding is an unlikely explanation for the association between EBV-related infectious mononucleosis and Hodgkin's lymphoma.

Comparative Analysis of Organ-Specific Autoantibodies and Celiac Disease—Associated Antibodies in Type 1 Diabetic Patients, Their First-Degree Relatives, and Healthy Control Subjects

In type 1 diabetes the coexistence with other endocrine diseases and organ-specific autoantibodies has been frequently reported leading to the concept of autoimmune polyendocrine syndrome (APS). In addition, an association of type 1 diabetes with celiac disease has been described. These disorders share a similar genetic background, and first-degree relatives of type 1 diabetic patients may also be affected significantly. Screening for specific antibodies allows early diagnosis of these disorders. In the present cross-sectional study, we analyzed sera from 197 recent-onset type 1 diabetic patients at the time of diagnosis, 882 first-degree relatives, and sera of 150 healthy control subjects for prevalence and co-occurence of the following antibodies (method): insulin autoantibodies (radioimmunoassay); GAD and IA-2 antibodies (radioligand assay); islet cell antibody, anti-adrenal cortex antibodies, and anti-gastric parietal cell antibodies (indirect immunofluorescence); anti-thyroglobulin and anti-thyroid peroxidase antibodies; and gliadin IgG/A and tissue-transglutaminase IgA (enzyme-linked immunosorbent assay). The overall frequency of gastric patietal cell antibodies and adrenal antibodies did not differ significantly among groups. In contrast, type 1 diabetes-associated antibodies and thyroid antibodies were significantly more frequent both in recent-onset type 1 diabetic patients and in the group of first-degree relatives (P < 0.05). The prevalence of gliadin IgG/IgA and transglutaminase IgA was significantly higher in the group of recent-onset type 1 diabetic patients (P < 0.05), but the difference between first-degree relatives and control subjects did not reach statistical significance. Focusing on the coexistence of antibodies, the group of recentonset type 1 diabetic patients presented with 27.4% of the subjects testing antibody-positive-specific for two or more of the envisaged disorders (i.e., type 1 diabetes, autoimmune thyroiditis, and celiac disease) compared with 3.1% in the group of first-degree relatives and 0 of 150 in the control population (P < 0.05). We conclude that, in an active case-finding strategy, recent-onset type 1 diabetic patients should be routinely screened at least for concomitant autoimmune thyroid disease and additionally for celiac disease. Screening in their first-degree relatives should include at a minimum the search for thyroid autoimmunity in addition to screening for pre-type 1 diabetes.

Gender-Related Differences in Severe, Early-Onset Chronic Obstructive Pulmonary Disease

Men have higher prevalence rates of chronic obstructive pulmonary disease (COPD) than women, which has been attributed to the historically higher rates of cigarette smoking in males. However, the increased rates of cigarette smoking in females within the last several decades have been associated with steadily increasing rates of COPD in women. As part of a study of the genetics of severe, early-onset COPD, we assembled a group of 84 probands with severe, early-onset COPD (without severe alpha(1)-antitrypsin deficiency) and 348 of their first-degree relatives. We found a markedly elevated prevalence (71.4%) of females among the early-onset COPD probands. Among the entire group of first-degree relatives of early-onset COPD probands, univariate analysis demonstrated similar spirometric values and bronchodilator responsiveness in males and females; however, among current or ex-smokers, female first-degree relatives had significantly lower FEV(1)/ FVC (81.4 +/- 17.2% in females versus 87.0 +/- 12.9% in males, p = 0.009) and significantly greater bronchodilator responsiveness (expressed as percentage of baseline FEV(1)) (7.7 +/- 9.4% pred in females versus 4.1 +/- 6.4% pred in males, p = 0.002). Female smoking first-degree relatives were significantly more likely to demonstrate profound reductions in FEV(1) (< 40% pred) than male smoking first-degree relatives (p = 0. 03). Multivariate analysis, performed with generalized estimating equations, demonstrated that current or ex-smoking female first-degree relatives had significantly greater risk of FEV(1) < 80% pred (OR 1.91, 95% CI 1.03- 3.54), FEV(1) < 40% pred (OR 3.56, 95% CI 1.08-11.71), and bronchodilator response greater than 10% of baseline FEV(1) (OR 4.74, 95% CI 1.91-11.75). These results suggest that women may be more susceptible to the development of severe COPD.

Endothelial cell autoantibodies are a marker of disease susceptibility in inflammatory bowel disease but apparently not linked to persistent measles virus infection.

Intestinal vasculitis caused by persistent measles virus infection of intestinal endothelial cells was described in Crohn's disease. Furthermore, endothelial cell autoantibodies have been demonstrated in inflammatory bowel disease (IBD). Autoantibodies against intestinal endothelial cells were visualized by indirect immunofluorescence in patients with IBD, in their healthy first-degree relatives, in patients with infectious enterocolitis, and in healthy, unrelated controls. In intestinal tissue specimens of 22 antibody-positive IBD patients a search for the measles virus genome was performed. Endothelial cell autoantibodies were significantly more frequent in patients with IBD, in both groups of first-degree relatives, and in patients with infectious enterocolitis than in the healthy controls (P = 0.0002 or less). The measles virus genome was found in none of the intestinal biopsies. Endothelial cell autoantibodies are not a genetic but rather an epigenetic (infectious) marker of disease susceptibility. The expression of these autoantibodies is unlikely to be triggered by a persistent measles virus infection.

Prevalence of colorectal adenomas in individuals with a family history of colorectal cancer based on initial colonoscopy: Implications for colonoscopic surveillance

Background: Increasing evidence suggests that inherited susceptihility is an important factor in the pathogenesis of colorectal adenomas and colorectal cancer; because of that, screening strategies that consider familial risk could increase their effectiveness. Aims : The aim of this study was to know the risk for colorectal adenomas, colorectal cancer and extracolonic cancers in first degree relatives of patients with colorectal adenomas. Methods and Patients : We evaluated patients referred to our institution for initial colonoscopy between June 1996 and July 1997 who did not have a family or personal history of familial polyposis, inflammatory bowel disease neither previous polypectomies or colorectal cancer (n= 379). Patients were divided in two groups: Group A) patients with complete colonoscopy with removal of one or more adenomas (n= 164) and. Group B) patients with complete colonoscopy without adenomas (n= 215). Mean age in group A and B was 62 and 61 respectively (p= NS).As well, no significant differences in sex between group A (MIF 40%/60%) and group B (MIF 52%/48%). They all were interviewed in order to determine if history of colorectal adenomas, colorectal cancer or extracolonic cancers had been documented in their first degree relatives . Result s:A mong first degree relatives of patients with adenomas (n= 1132). 12 ( J.I %) had personal history of colorectal adenomas. 19 (1.7%) of colorect al cancer and 16 ( 1.4%) antecedents of extracolonic cancer. In the group of first degree relatives of those without adenomas (n= 1478). 3 ( 0.2%) had personal history of colorectal adenomas, 16 ( J.I %) of colorec tal cancer and 17 ( 1.1 %) antecedents of extracolon ic cancer. Odds Ratio for colorectal adenomas, colorectal cancer and extracolonic cancers in the relatives of the patients with adenomas as compared with controls was 5 27 ( 95% CI: 1.38-23.53; p=0.009*), 1.72 (95 % CI: 0.79-3.76; p=0.19) and 1.23 (95% CI: 0.59-2.57; p= 0.67) respectively. Conclusions:First degree relatives of patients with newly diagnosed adenomas are at increased risk for developing colorectal adenomas. It supports a familial predisposition for these premalignant lesions and suggests that total colonoscopy screening could be indicated in these subjects.