To identify early metabolic abnormalities in type 2 diabetes mellitus, we measured insulin secretion, sensitivity to insulin, and hepatic insulin extraction in 48 healthy normal glucose-tolerant Brazilians, first-degreerelatives of type 2 diabetic patients (FH+). Each indi- vidual was matched for sex, age, weight, and body fat distribution with a person without history of type 2 diabetes (FH-). Both groups were submitted to a hyperglycemic clamp procedure (180 mg/dl). Insulin release was evaluated in its two phases. The first was calculated as the sum of plasma insulin at 2.5, 5.0, 7.5, and 10.0 min after the beginning of glucose infusion, and the second as the mean plasma insulin level in the third hour of the clamp procedure. Insulin sensitivity index (ISI) was the mean glucose infusion rate in the third hour of the clamp experiment divided by the mean plasma insulin concentration during the same period of time. Hepatic insulin extraction was determined under fasting conditions and in the third hour of the clamp procedure as the ratio between C-peptide and plasma insulin levels. FH+ indi- viduals did not differ from FH- individuals in terms of the following parameters [median (range)]: a) first-phase insulin secretion, 174 (116-221) vs 207 (108-277) µU/ml, b) second-phase insulin secretion, 64 (41-86) vs 53 (37-83) µU/ml, and c) ISI, 14.8 (9.0-20.8) vs 16.8 (9.0-27.0) mg kg -1 min -1 /µU ml -1 . Hepatic insulin extraction in FH+
This study has implications for clinicians and research- ers. For clinicians, our results underscore the high prevalence of OCS in children and siblings of individuals with OCD. It also extends the previously detected asso- ciation between coercive behaviors (or rage attacks), OCD and OCS. It indicates the importance and functional relevance of actively evaluating the presence of these symptoms in first-degreerelatives of patients with OCD. For researchers, our results suggest the importance of assessing the predictive value of OCS and coercive behaviors on the later development of OCD. These symptoms may be additional risk markers for developing the disorder in children already at higher risk. Whether they are mediators or moderators of risk and genetically or environmentally mediated are also subjects for future longitudinal studies.
[61,62], most previous work concentrated on the functional correlates of white matter lesions and little work has been done to examine how changes in gray matter may be associated with changes in RSFC. To our knowledge, only one previous study by Lui et al.  has addressed this issue. Even though they did not observe an altered functional network, they found that functional networks that involved areas with focal anatomical lesions were associated with clinical symptom severity in schizophrenia. Other researchers have suggested that using neuroimaging measures which are functionally related to each other would be more useful in understanding the pathophysiological pathways . In response to this, previous task-dependent MRI studies have revealed an association between focal gray matter abnormalities and altered functional connectivity in schizophrenia [63,64]. In our RSFC analysis, we obtained empirical evidence that supports findings obtained by modeling the impact of lesions in the human brain , which showed that anatomical lesions may produce altered RSFCs between distant brain regions. Additionally, the striking finding of our study was the similarly changed structural and functional patterns of the amygdala in schizophrenia families. A key point is that co-occurrences of abnormalities in the structure and function of brain regions in schizophrenic patients and their first-degreerelatives may suggest a functionally linked set of biological markers associated with genetic disposition toward schizophrenia. We, therefore, speculate that gray matter changes may lead to a systems-level alteration in RSFC and that a genetic basis may underlie the relationship between brain structural and functional features in schizophrenia. Although more studies with increased numbers of subjects are needed, this present work may well provide a basis for further research that will lead to improved comprehension of schizophrenia pathophysiology.
searching homologs in published genomes (see S3 Table). All protein sequences were aligned using Expresso (3D Coffee) and a Neighbor-Joining tree was performed using MEGA 5.5. Groups are proposed for clusters within high identity percentages (>42% within each group). Sequence names are referred to as: query used/ microbiome sequence name (Metahit and ID 28117 projects). Black and white symbols are used to distinguish CD-related subjects (patients and asymptomatic first-degreerelatives; CDR) and CD-unrelated healthy subjects, respectively. The queries used (H11G11 and C7D2 transporters) are underlined. Squares and circles correspond to results using respectively H11G11 and C7D2 transporters as query. This in silico exploration of CDR and CDU microbiomes reveals that H11G11 transporter is mostly present in healthy subjects, whereas C7D2 transporter is recovered in CDR subjects, including unaffected relatives. The C7D2 transporter is plasmid-encoded or present on specific Clostridiale chromosomes.
This study has compiled relevant data that should make a contribution to the understanding of the psychological factors associated with the course of BD and the observation of first-degreerelatives who do not develop the disease. The study also contributes to a better understanding of coping strategies and their importance in the context of BD. Notwithstanding, there is a need to explore more specific strategies using prospective studies in order to understand coping throughout the course of the disease. Longitudinal studies employing psychological and clinical assessments allow the changes in participants’ psychological patterns to be better mapped, thereby further facilitating understanding of the role played by cognitive processes in bipolar symptoms. Along the same lines, interventions employing psychotherapy to improve patients’ coping strategies to help them control their disease also merit further investigation.
Our aim was to observe the induction of panic attacks by a hyperven- tilation challenge test in panic disorder patients (DSM-IV) and their healthy first-degreerelatives. We randomly selected 25 panic disorder patients, 31 healthy first-degreerelatives of probands with panic disorder and 26 normal volunteers with no family history of panic disorder. All patients had no psychotropic drugs for at least one week. They were induced to hyperventilate (30 breaths/min) for 4 min and anxiety scales were applied before and after the test. A total of 44.0% (N = 11) panic disorder patients, 16.1% (N = 5) of first-degreerelatives and 11.5% (N = 3) of control subjects had a panic attack after hyperventilating ( c² = 8.93, d.f. = 2, P = 0.011). In this challenge test the panic disorder patients were more sensitive to hyperventilation than first-degreerelatives and normal volunteers. Although the hyper- ventilation test has a low sensitivity, our data suggest that there is no association between a family history of panic disorder and hyperreac- tivity to an acute hyperventilation challenge test. Perhaps cognitive variables should be considered to play a specific role in this associa- tion since symptoms of a panic attack and acute hyperventilation overlap.
The present study also encountered higher levels of TSH (even within the normal reference value) in FDR individ- uals compared with controls, a finding not previous de- scribed. Previous studies evaluated the association of TSH (in the upper limit, but within a normal reference value) with components of the metabolic syndrome . The pathophysiological mechanism of this association is still unclear, but it is known that the myocardium and vascular endothelial tissue have receptors for thyroid hormones and are sensitive to changes in their serum concentrations. Even minor variations in such concentrations could lead to a negative impact on the cardiovascular system [17, 18]. Table 2 Clinical and laboratory characteristics of first-degreerelatives (FDR) of patients with premature acute myocardial infarction and individuals with no family history of coronary artery disease (controls)
Twenty-seven non-diabetic first-degreerelatives (FDR) of NIDDM and 21 non- diabetic subjects with no family history of diabetes were studied. All subjects under- went a standard 75-g oral glucose tolerance test (OGTT) and were classified as having NGT, impaired glucose tolerance (IGT) or diabetes mellitus (DM) on the basis of the World Health Organization criteria (4). Only the subjects with NGT were included in the study, while 12 relatives (4 with NIDDM and 8 with IGT) and 1 control with NIDDM were excluded. Therefore, the study popula- tion comprised 35 individuals: 20 subjects with normal glucose tolerance and without diabetes among their FDR (NGT group, 8 men and 12 women) served as normal con- trols, and 15 with normal glucose tolerance and FDR of patients with NIDDM (FDR group, 5 men and 10 women). There were no differences in age, sex distribution and body
Case 1 : 16-year-old male, with asymptomatic periumbilical lesions since his first years of life, pro- gressing in number and size for the last 3 years. He presented right hypoacusia, tingling in hands and feet and burning plantar pain, which worsened with hot weather and physical activity.
What still deserves investigation is whether markers of endothelial imbalance like CRP and fibrinogen may be used as markers of the beneficial effects of metformin in metabolic disorders. Our aim is to investigate if metformin acts on some classical markers of the CV risk profile, like the lipid profile, blood pressure, and fasting plasma glucose (FPG), and whether fibrinogen and CRP may be used as indirect markers of its action in first-degreerelatives of T2DM subjects who have MS and normal glucose tolerance.
Relatives of individuals with SLE are at a higher risk of developing not only SLE but also other autoimmune diseases (3,31). A heritable predisposition to increased IFN- a pathway activation in SLE patient families could explain some of the burden of both SLE and non-SLE autoimmu- nity in the population. Single nucleotide polymorphisms (SNPs) in the IFN-a pathway genes IFN regulatory factor 5 (IRF5) and non-receptor tyrosine-protein kinase (TYK2) (42-45) are associated with SLE, suggesting that genetic variability in endogenous IFN-a signaling may be involved in the etiology of this disease, although the impact of these polymorphisms on IFN-a activity in vivo is not known (3,43). We did not observe any differences in serum IFN-a levels between first-degreerelatives of SLE patients and controls. However, the limited sample size may have affected these results.
Another finding from this group is that 79% of the unaffected control families carried genotype DQ2 and/or DQ8, which is one of the highest frequencies so far described among first-degreerelatives. Just like the genotypes DQ2 and DQ8, A1*0201, A1*05, B1*02 and B1*0302 alleles were very frequently found among the first-degreerelatives of the patients. We raise the possibility that these data were overestimated because of characteristics peculiar to this group of controls. We believe that one of the biggest limitations to this study is that, among the family controls, there might be some patients. This would occur both because of the characteristic that celiac disease may be manifested at any time during life, which would put limits on evaluations made at a single time, and because of the possibility of false negative tTG findings. However, most studies on HLA among first-degreerelatives used designs similar to ours, and found that no more than 59.5% of first-degreerelatives in Europe presented HLA DQ2 and DQ8. 7,15
In this study, the results were favoring the increased risk of endometriosis in first-degreerelatives of endometriosis patients was found. Nouri et al. study supported the theory of genetic predisposition is the only a contributing factor for the development the familial incidence of endometriosis. (13)
Firstdegreerelatives of these 39 children were invited to undergo serological screen for CD, from September 2010 to October 2011. All irst degreerelatives were questioned with regards to the presence of CD related diseases (such as autoim- mune thyroiditis, diabetes mellitus, Down syndrome), and pres- ence of gastrointestinal or non-gastrointestinal symptoms of CD. All family members were on gluten-containing diet when serologic tests were performed. In all seropositive relatives, small intestinal biopsy and HLA typing was recommended.
– First-degreerelatives are two to three times more likely to contract colorectal cancer than the general population. If the individual’s parents had colorectal cancer, the chance to present the disease is ive times greater than the general population. Colonoscopy is recommended every three years in all these family members.
We determined the gene expression profiles in skeletal muscle biopsies from healthy individuals, people with type 2 diabetes, and firstdegreerelatives. For simplicity reasons these groups will be termed ‘C’ (controls), ‘D’ (diabetics), and ‘R’ (relatives). Gene expression values were determined using the microarray technology from Affymetrix as described above. All subjects were Danish Caucasian males, and all biopsies were taken after a 2 hour hyperinsulinemic euglycemic clamp as previously described . Clinical characteristics determined for the different experimental groups are listed in Table 1. The ‘C’ and the ‘R’ group consisted of 15 individuals each, whereas the ‘D’ group consisted of 5 individuals. The ‘D’ group was slightly older and significantly more obese as compared to the two other groups. Additionally, they were hyperglycemic, hyperinsulinemic, had increased free fatty acid (FFA) levels and increased blood pressure compared to healthy controls. The firstdegreerelatives were healthy, normoglycemic and mildly insulin resistant as revealed by their M-values. However, they were notably hyperinsulinemic compared to the controls.
This study included primary CRC tissue, and, when available, distant normal mucosa from carriers of the PPARD variant from 303 patients (group I) diagnosed at the University Hospitals in Linko¨ping and Vrinnevi Hospital in Norrko¨ping. Tissue was collected during primary surgery between 1989 and 2004, and stored 270uC. Blood samples were not available for this cohort. Further, blood samples from unrelated CRC patients: 50 sporadic CRC patients (group II), 50 patients with 2 affected first-degreerelatives (group III), 50 hereditary patients with 3 or more affected first-degreerelatives (group IV), and 360 non-cancer controls, were examined. The blood samples (group II–III) were obtained between 2004 and 2009 from 14 different hospitals in middle Sweden. To estimate population frequency of the PPARD variants, control non-cancer subgroup, comprising blood donors recruited during the year 2010 from Uppsala region of Sweden, were used. Both cases and controls were of European ancestry and from Sweden. Written informed consent from the donor or the next of kin was obtained for use of their samples for research purposes. Characteristics of the patients and controls are shown in Table 1. The tumors with better differentiation included well and moderately differentiated tumors, and worse differentiation included poorly differentiated, mucinous or signet-ring cells carcinoma. Tumor differentiation data could not be obtained for groups II to IV.
ABSTRACT – Context - Celiac disease susceptibility has been shown to be associated with the HLA alleles DQA1*0501 and DQB1*0201 (together encoding the DQ2 heterodimer) that are present in practically all celiac disease patients. The DQ8 heterodimer (coded by DQA1*03-DQB1*0302), which is carried on a DRB1*04 (DR4) haplotype, is commonly encoded for by the few celiacs who do not carry the DQ2 heterodimer. Only a few celiac disease patients have been reported without these known risk alleles. Objective - To assess the prevalence of celiac disease in a group of firstdegreerelatives of celiac patients, and the frequency of HLA predisposing alleles both in the group of celiac patients and in their firstdegreerelatives, identifying those firstdegreerelatives who would need further screening for celiac disease. Methods - Ninety celiac disease patients and 207 firstdegreerelatives underwent serologic screening for celiac disease (endomysial and transglutaminase antibodies) followed by intestinal biopsy in positive patients. The HLA-DQA1*0501, DQB1*0201 and DRB1*04 frequencies of celiac patients and their firstdegreerelatives were determined utilizing the PCR method. Results - All the celiac disease patients (n = 90) with the exception of one (1.1%) carried at least one of the alleles investigated. Altogether 11 (5.3%) of the investigated firstdegreerelatives did not carry any of the alleles studied. Fourteen (6.7%) new cases of celiac disease were found among the 207 celiac disease patients firstdegreerelatives. Conclusions - Considering the cost-benefit of the HLA typing of all the firstdegreerelatives of celiac patients, their HLA status should be decided on an individual basis, taking account of their profile and preferences, and the existence of other medical conditions.
ABSTRACT – Background – Familial aggregation of gastric cancer has pointed out to a possible hereditary and genetic factor involved in the carcinogenesis of this disease. The diffuse type gastric cancer patients are frequently younger and the tumor has locally infiltrative growth pattern early in its development. Observation of families with frequent early onset gastric cancer has led to the identification of a novel gene implicated in gastric cancer susceptibility: CDH1/E-cadherin. Diffuse familiar gastric cancer is defined as any family presenting: two first-degreerelatives with diffuse gastric cancer, one of them with age under 50 years or at least 3 first-degreerelatives irrespective age of onset. Case report – The family reported by us does not fit in any of the classification proposed. The precise identification of these families by clinical and molecular tools is of great importance. The case reported is an example of a family that probably is a form of hereditary gastric cancer not yet fully understood. Conclusion – Soon there will be new criteria, possibly including genetic and molecular characteristics.
The present study was performed according to the Declaration of Helsinki and approved by the School of Health Sciences Ethics Committee. All subjects were informed about the objectives of the study and the eventual necessity of small intestinal biopsy. Informed consent was obtained from adults and from the parents for their children. Firstdegreerelatives of CD patients attending the Brasilia University Hospital Pediatric Gastroenterology out-patient clinic or the Celiac Disease Investigation Center, Brasília, DF, Brazil, between March 2001 and November 2004 were invited to undergo serological screen for CD. The Celiac Disease Center is a weekly walking-in clinic open for diagnosis and follow-up of CD patients, attending both children and adults. The diagnosis of CD patients had been based on the modified European Society of Paediatric Gastroenterology and Nutrition (ESPGAN) criteria (32) . All family members