First-degree Relatives Of People Research Articles

Normalization of glucose intolerance in first-degree relatives of patients with type 2 diabetes

Aims The aim of this study was to estimate the conversion rate to normal glucose tolerance (NGT) from a state of abnormal glucose metabolism and to identify characteristics predicting the conversion rate in first-degree relatives (FDRs) of patients with type 2 diabetes with glucose intolerance. Methods A total of 2368 (614 men and 1754 women) FDRs of consecutive patients with type 2 diabetes aged 20–70 years in 2003–2005 were followed through 2007. Glucose tolerance classification was based on the criteria of the American Diabetes Association base on standard 75 g 2-h oral glucose tolerance test. The study group consisted of 370 participants with glucose intolerance at baseline. Results The conversion rates to normal glucose tolerance from impaired glucose tolerance (IGT) and impaired fasting glucose (IFG) were 16.2% (95% confidence interval (CI) 13.30, 19.10) and 10.9% (95% CI: 5.7, 16.1) per year after an average of 2 years, respectively. Lower baseline fasting plasma glucose (HR 1.02, 95% CI: 1.01, 1.04) and 2-h (HR 1.02, 95% CI: 1.01, 1.04) glucose predicted conversion to NGT, as did changes in body mass index (BMI), waist circumference (WC), and lipids. Conclusions This is the first estimate of conversion rate and predictors from IFG and IGT to NGT in FDRs of people with type 2 diabetes in Iran. Lower baseline fasting, 2-h plasma glucose and changes in BMI, WC, and lipids predicted reversal to NGT at 24 months follow-up.

Breast Magnetic Resonance Imaging: An Overview for Nonradiologists

Magnetic resonance imaging is a major component of breast imaging. Many studies have shown that magnetic resonance imaging is the most sensitive imaging method for detecting invasive breast cancer in comparison with mammography, ultrasound, and clinical breast examinations. Evidence-based clinical indications for breast magnetic resonance imaging include screening patients at high risk for breast cancer, including those with breast/ovarian cancer genes (BRCA1 and BRCA2), those who are untested first-degree relatives of carriers of these genes, those whose lifetime risk of developing breast cancer is 20% to 25% or greater, those who had chest radiation when they were 10 to 30 years old, and those who have or are first-degree relatives of people with Li-Fraumeni syndrome, Cowden syndrome, or Bannayan-Riley-Ruvalcaba syndrome. Breast magnetic resonance imaging is performed in conjunction with mammography and does not replace mammography. Outside of the screening population, utilization of breast magnetic resonance imaging for newly diagnosed breast cancer patients and its use as a problem-solving technique for equivocal mammographic or clinical findings remain controversial. An understanding of the current evidence facilitates appropriate utilization of this important medical resource. This article discusses indications for ordering breast magnetic resonance imaging and how to read the breast magnetic resonance imaging report and understand the lexicon used.

Gene expression in skeletal muscle biopsies from people with type 2 diabetes and relatives: differential regulation of insulin signaling pathways.

BackgroundGene expression alterations have previously been associated with type 2 diabetes, however whether these changes are primary causes or secondary effects of type 2 diabetes is not known. As healthy first degree relatives of people with type 2 diabetes have an increased risk of developing type 2 diabetes, they provide a good model in the search for primary causes of the disease.Methods/Principal FindingsWe determined gene expression profiles in skeletal muscle biopsies from Caucasian males with type 2 diabetes, healthy first degree relatives, and healthy controls. Gene expression was measured using Affymetrix Human Genome U133 Plus 2.0 Arrays covering the entire human genome. These arrays have not previously been used for this type of study. We show for the first time that genes involved in insulin signaling are significantly upregulated in first degree relatives and significantly downregulated in people with type 2 diabetes. On the individual gene level, 11 genes showed altered expression levels in first degree relatives compared to controls, among others KIF1B and GDF8 (myostatin). LDHB was found to have a decreased expression in both groups compared to controls.Conclusions/SignificanceWe hypothesize that increased expression of insulin signaling molecules in first degree relatives of people with type 2 diabetes, work in concert with increased levels of insulin as a compensatory mechanism, counter-acting otherwise reduced insulin signaling activity, protecting these individuals from severe insulin resistance. This compensation is lost in people with type 2 diabetes where expression of insulin signaling molecules is reduced.

Functional magnetic resonance imaging (fMRI) of attention processes in presumed obligate carriers of schizophrenia: preliminary findings

BackgroundPresumed obligate carriers (POCs) are the first-degree relatives of people with schizophrenia who, although do not exhibit the disorder, are in direct lineage of it. Thus, this subpopulation of first-degree relatives could provide very important information with regard to the investigation of endophenotypes for schizophrenia that could clarify the often contradictory findings in schizophrenia high-risk populations. To date, despite the extant literature on schizophrenia endophenotypes, we are only aware of one other study that examined the neural mechanisms that underlie cognitive abnormalities in this group. The aim of this study was to investigate whether a more homogeneous group of relatives, such as POCs, have neural abnormalities that may be related to schizophrenia.MethodsWe used functional magnetic resonance imaging (fMRI) to collect blood oxygenated level dependent (BOLD) response data in six POCs and eight unrelated healthy controls while performing under conditions of sustained, selective and divided attention.ResultsThe POCs indicated alterations in a widely distributed network of regions involved in attention processes, such as the prefrontal and temporal (including the parahippocampal gyrus) cortices, in addition to the anterior cingulate gyrus. More specifically, a general reduction in BOLD response was found in these areas compared to the healthy participants during attention processes.ConclusionThese preliminary findings of decreased activity in POCs indicate that this more homogeneous population of unaffected relatives share similar neural abnormalities with people with schizophrenia, suggesting that reduced BOLD activity in the attention network may be an intermediate marker for schizophrenia.

Factors mediating cognitive deficits and psychopathology among siblings of individuals with schizophrenia.

Schizotypal traits and cognitive disturbances are known to be present in first-degree relatives of people with schizophrenia. However, there is little understanding of how these endophenotypes are related to each other. We explored the nature of this relationship in individuals with schizophrenia, their full siblings, community controls, and their siblings. All participants were assessed in the domains of working memory, attention, episodic memory, and executive function, as well as in their level of positive, negative, and disorganization symptoms. Schizophrenia probands were significantly impaired on all cognitive domains, as compared with the other 3 groups, and displayed the highest levels of positive, negative, and disorganization symptoms. Proband siblings performed significantly worse than controls on tasks of working memory, episodic memory, and executive function, and they displayed significantly more positive and negative symptoms as compared with controls. Poorer task performance across all 4 cognitive domains was most strongly correlated with increased negative symptoms. Mediation analyses revealed that working memory, episodic memory, and executive function deficits partially mediated increases in negative symptoms among proband siblings. Negative symptoms fully mediated deficits in working memory and episodic memory but only partially mediated deficits in executive function. Results suggest that there is a complex relationship between cognitive and clinical factors in this high-risk population.

Is postprandial hypertriglyceridaemia in relatives of type 2 diabetic subjects a consequence of insulin resistance?

Higher postprandial triglyceride responses reported in first degree relatives of people with type 2 diabetes (REL) were postulated to be the result of an early, possibly intrinsic, defect in oral lipid handling. The postprandial triglyceride response to high fat meals (HFM) in normal subjects is reduced by the insulin response to dietary carbohydrate (CHO) in the meal. The aims of this study were to examine whether (1) insulin resistance is associated with an intrinsic defect in triglyceride handling in insulin-resistant REL and (2) insulin resistance is associated with altered triglyceride handling after HFM with high CHO content. Postprandial responses to a HFM in normolipidaemic, normoglycaemic REL were compared with subjects without a family history of diabetes mellitus (CON). Over 6 h, the insulin, glucose, triglyceride and nonesterified fatty acid (NEFA) responses after a high fat (80 g fat), low CHO (HFM-LC; 20 g CHO, 4250 kJ) meal and a high fat, high CHO (HFM-HC; 100 g CHO, 5450 kJ) meal were examined. The 10 (7F/3M) REL were significantly more insulin-resistant, determined by glucose infusion during a hyperinsulinaemic euglycaemic clamp than the 10 (5F/5M) CON (glucose infusion rate 44.6 +/- 4.9 vs. 60.0 +/- 4.8 micromol min(-1) kg FFM(-1), P = 0.037). Subjects were similar for age and body mass index (BMI). The triglyceride increments after the HFM-LC were similar in both, peaking at 180-240 min (Delta0.77 +/- 0.11 mmol L(-1)), demonstrating no postprandial defect in REL, despite insulin resistance. There was a significantly lower postprandial triglyceride response in CON following the HFM-HC compared with the HFM-LC, but not in REL. In contrast, the higher insulin level during the HFM-HC was associated with significantly greater NEFA level suppression than in the HFM-LC (2.13 +/- 0.51 vs. 0.70 +/- 0.35 mmol L(-1), P = 0.03), only in the REL. These results are inconsistent with a primary aetiological role for postprandial hypertriglyceridaemia in already insulin resistant type 2 diabetic REL, but raise the possibility that this potentially atherogenic manifestation is secondary to insulin resistance lessening VLDL production and/or release from the liver.

Elevated risk for first-degree relatives of people with colorectal neoplasia can be quantified to develop targeted screening

Elevated risk for first-degree relatives of people with colorectal neoplasia can be quantified to develop targeted screening

Risk assessment for developing type 1 diabetes: intentions of behavioural changes prior to risk notification.

Recent progress in predictive techniques allows people at risk of developing type 1 diabetes to be identified in a pre-symptomatic stage and prevention trials to be implemented. The present study examined prospectively whether participants in a screening programme anticipated behavioural changes in the event of having a high risk. Four hundred and three first-degree relatives of people with type 1 diabetes completed a self-administered questionnaire about their views on screening and diabetes, and questionnaires on well-being and locus of control. Prior to risk notification, 73% reported that they intended to introduce lifestyle changes if at high risk. The vast majority of the respondents (87%) reported that eating habits would be the main changes made. Those anticipating changes believed they could take actions to reduce their risk of type 1 diabetes (p<0.001) and to have personal control over diabetes onset (p<0.001). They were also more worried about developing diabetes (p<0.01) and preoccupied with diabetes-related symptoms (p<0.01). Prior to risk notification, the process of being screened raised concerns and expectations about future changes. Despite the lack of any evidence, people believed lifestyle changes would be effective in reducing their risk. Since the impact of lifestyle in the development of type 1 diabetes is not yet established, accurate information about the role of health behaviour in the progression to overt diabetes is needed to avoid unrealistic expectations on the benefit of these changes and unnecessary impairment to quality of life. Personally initiated changes should be monitored since they could importantly influence the progress and outcome of prevention trials.

A general practice-based recruitment strategy for colorectal cancer screening

ObjectiveTo determine whether a screening recruitment strategy for first degree relatives of people with colorectal cancer is effective in enabling eligible relatives to request screening from their general practitioner (GP) and to assess acceptability to GPs and patients. MethodsThirty GPs, from 26 practices, and 303 of their patients aged over 50 who were first degree relatives of a person with colorectal cancer, participated in a randomised controlled trial of a GP-based recruitment strategy, in the Newcastle Area of New South Wales, Australia. ResultsThe proportion of relatives requesting screening was statistically significantly higher in the intervention group than in the control group (18% compared to 4%, respectively; p=0.01). ConclusionsInterest in the study by GPs was low, however for GPs who were involved, the recruitment strategy did prompt first degree relatives to discuss screening. The strategy may be even more effective when combined with other interventions such as a media campaign. The results may be generalisable to feasibility studies of general population screening for colorectal cancer in Australia. ImplicationsThe results of this work are potentially informative to public health practice in Australia given the ensuing pilot programs of colorectal cancer screening.

Commentary on “Illness Representations Among First-Degree Relatives of People With Alzheimer Disease”

Genetics Program and Alzheimer's Disease Center, Boston, Massachusetts, U.S.A. Address correspondence and reprint requests to Robert C. Green, M.D., M.P.H., Associate Professor of Neurology, Genetics Program and Alzheimer's Disease Center, 715 Albany Street, L-320, Boston, MA 02118, U.S.A. Supported by HG/AG01877, AG09029, and P30-AG13846.

Illness Representations Among First-Degree Relatives of People With Alzheimer Disease

The purpose of this study was to examine attitudes, beliefs, and experiences regarding Alzheimer disease (AD) among patients' first-degree relatives, a group that is at increased AD risk and often involved in health care decision-making for affected family members. Children and siblings (N = 203; age range, 30-92 years; 75% female) of people with AD completed a questionnaire (response rate, 90%) that assessed mental representations of AD, including knowledge, cause and treatment beliefs, distress, and perceived threat. In general, relatives were knowledgeable about AD, had an accurate sense of their disease risk, and endorsed etiologically significant factors as causes. Nonetheless, many participants held misconceptions about AD (e.g., most cases are hereditary) and what may be unrealistic expectations for future treatment developments. Levels of perceived distress and threat were generally high and associated with female gender and younger age. AD represented the foremost health concern of approximately one third of first-degree relatives. Health education efforts are needed to address misconceptions about AD genetics and to disseminate information about the availability of effective treatments. Further research on illness representations is needed to better understand coping and decision-making among those at risk for AD.

Subarachnoid Hemorrhage and Genetics

Several studies have indicated that first-degree relatives of people with subarachnoid hemorrhage (SAH) have an increased risk for suffering SAH

Nicotinamide inhibits enhanced in vitro production of interleukin-12 and tumour necrosis factor-α in peripheral whole blood of people at high risk of developing Type 1 diabetes and people with newly diagnosed Type 1 diabetes

Macrophages and T lymphocytes are the first cells to appear in pancreatic islets in the development of autoimmune diabetes. It has been suggested that cytokines released by monocytes/macrophages, including interleukin-1β (IL-1β), interleukin-12 (IL-12) and tumour necrosis factor-α (TNF-α) could have an initial role in islet B-cell damage. The aim of the present study was to estimate the effect of human insulin and nicotinamide on the levels of monocyte/macrophage derived cytokines in the peripheral blood of humans at risk of Type 1 diabetes, and in patients with newly diagnosed Type 1 diabetes compared to healthy control subjects. The study was carried out on three groups of subjects: 20 first degree relatives of people with Type 1 diabetes (with two or more antibodies against pancreatic B-cell antigens); 22 patients with recent onset of Type 1 diabetes (duration of the disease 3–6 months); and 25 age- and sex-matched healthy subjects. Cytokine levels (IL-1β, IL-12, and TNF-α) in the supernatants of whole blood cultures incubated with PHA alone (10 μg/ml), or PHA+human insulin (50 μg/ml), or PHA+nicotinamide (100 μmol/1) were quantified by ELISA. In the cultures with nicotinamide the concentration of IL-12 and TNF-α was significantly lower in the prediabetic group, diabetic patients, and the healthy controls than in the cultures with PHA only or with PHA+insulin. There were no significant differences in IL-1β production in the cultures after incubation with the different stimuli in the studied groups and healthy controls. No significant influence of human insulin on macrophage/monocyte cytokines secretion in in vitro cultures of the peripheral blood was found. This suggests that nicotinamide could influence monocyte/macrophage function in peripheral blood by inhibiting production of IL-12 and TNF-α.

Colorectal cancer screening: discussions with first degree relatives

AbstractScreening by faecal occult blood test and colonoscopy is recommended for first degree relatives of people with colorectal cancer. While it is known that screening participation among relatives is low, relatives' beliefs and attitudes towards screening have not been explored at an indepth level. In this study, four focus group discussions with first degree relatives of people with colorectal cancer were held. Discussions were audio-taped, transcribed verbatim and the data were independently coded and analysed by the authors. Three main themes were identified: risk, understanding, and screening. Perceived risk was determined by family history, age and gender. Of concern, there was limited understanding of the asymptomatic nature of screening with most relatives initially ‘screened’ after consulting a doctor with colorectal symptoms. These findings need to be considered in screening programs.

IgG subclass antibodies to glutamic acid decarboxylase and risk for progression to clinical insulin-dependent diabetes

Pancreatic islet beta cell destruction leading to insulin-dependent diabetes mellitus (IDDM) is believed to be mediated by a T-helper 1 (T H1) lymphocyte response to islet antigens. In the mouse, T H1 (IL-2, IFN-γ) and T H2 (IL-4, -5, -6, -10) responses are associated with the generation of IgG2a and IgG1 subclasses, respectively. The equivalent human subclasses have not been defined. Because the IgG subclass response to an antigen may be a potentially useful marker of T H1/T H2 immune balance we measured IgG subclass antibodies to glutamic acid decarboxylase (GAD), a major islet autoantigen in IDDM, in 34 newly-diagnosed IDDM patients and in 28 at-risk, first-degree relatives of people with IDDM. In the newly-diagnosed patients, total IgG antibodies to GAD were detected in 74% (25/34); IgG1 and/or IgG3 were significantly more frequent than IgG4 or IgG4/IgG2 (14/34 versus 5/34, p = 0.01). GAD antibody-negative patients were significantly younger ( p = 0.01). In 15 at-risk relatives who had not progressed to clinical diabetes after a median of 4.5 years, 10 had IgG2 and/or IgG4 antibodies compared to only 3/13 progressors ( p = 0.02). Total IgG and IgG2 antibodies were higher in non-progressors. Non-progressors were older than progressors ( p = 0.01), and relatives with IgG2 and/or IgG4 responses were also older ( p = 0.01). These results suggest that IgG subclass antibodies to GAD may contribute to diabetes risk assessment in islet antibody relatives.

High T Cell Responses to the Glutamic Acid Decarboxylase (GAD) Isoform 67 Reflect a Hyperimmune State that Precedes the Onset of Insulin-Dependent Diabetes

Pancreatic islet β-cell destruction leading to insulin-dependent diabetes mellitus (IDDM) is an autoimmune T cell-mediated process. Peripheral blood T cells, which proliferate to islet antigens such as glutamic acid decarboxylase (GAD), (pro)insulin or tyrosine phosphatase IA-2, can be detected in at-risk, first degree relatives of people with IDDM. However, cross-sectional studies cannot define the relationship between T cell responses and progression to IDDM. Longitudinal studies were therefore undertaken on 50 at-risk, first degree relatives tested at least yearly for up to 4 years, during which time five developed IDDM. Peripheral blood T cell responses to a GAD67(aa208–404)-glutathione-S-transferase (GST) fusion protein, GST, insulin and tetanus toxoid were measured, together with antibodies to islet cells, GAD, insulin and IA-2. High levels of antibodies to GAD or insulin were generally associated with low T cell responses to these antigens. Relatives who developed IDDM were characterized by high levels of antibodies to insulin and/or islet cells, and high T cell responses to GAD67-GST and tetanus, but not insulin, in the 24 months before clinical diagnosis. Cross-sectionally, T cell responses to GAD67(aa208–404)-GST and to full-length GAD65-GST were highly correlated (r=0.75, P<0.002). In conclusion, increased cellular immunity to the mid region of GAD67 was a marker of late pre-clinical IDDM, but appears to reflect a more general, transient state of cellular immune hyperresponsiveness.

A survey of screening compliance among first degree relatives of people with colon cancer in New South Wales.

To survey screening practices, knowledge, and attitudes towards screening among first degree relatives of people with colon cancer. A random sample of people with colon cancer listed on the New South Wales (NSW) Cancer Registry were mailed a questionnaire to be passed on to an appropriate first degree relative. Two hundred and twenty five first degree relatives completed a self administered questionnaire. Although there were high levels of awareness about colorectal cancer, and attitudes towards colorectal cancer were generally positive, screening rates were low, and only three relatives had been screened in accordance with current Australian recommendations. Factors associated with previous participation in any type of screening test (usually once) included receiving a medical recommendation to screen, having more than one relative with colorectal cancer, being a sibling of the relative with colon cancer, the relative with cancer being female, and perceiving screening as messy, but not painful. Strategies to enhance screening awareness and participation among relatives need to be considered. This study provides some insight into factors to be considered in developing awareness programmes. Further research is required to explore these factors, and to identify ways to overcome barriers.

Similar Peptides from Two β Cell Autoantigens, Proinsulin and Glutamic Acid Decarboxylase, Stimulate T Cells of Individuals at Risk for Insulin-Dependent Diabetes

Insulin (1) and glutamic acid decarboxylase (GAD) (2) are both autoantigens in insulin-dependent diabetes mellitus (IDDM), but no molecular mechanism has been proposed for their association. We have identified a 13 amino acid peptide of proinsulin (amino acids 24-36) that bears marked similarity to a peptide of GAD65 (amino acids 506-518) (G. Rudy, unpublished). In order to test the hypothesis that this region of similarity is implicated in the pathogenesis of IDDM, we assayed T cell reactivity to these two peptides in subjects at risk for IDDM. Subjects at risk for IDDM were islet cell antibody (ICA)-positive, first degree relatives of people with insulin-dependent diabetes. Peripheral blood mononuclear cells from 10 pairs of at-risk and HLA-DR matched control subjects were tested in an in vitro proliferation assay. Reactivity to both proinsulin and GAD peptides was significantly greater among at-risk subjects than controls (proinsulin; p < 0.008; GAD; p < 0.018). In contrast to reactivity to the GAD peptide, reactivity to the proinsulin peptide was almost entirely confined to the at-risk subjects. This is the first demonstration of T cell reactivity to a proinsulin-specific peptide. In addition, it is the first example of reactivity to a minimal peptide region shared between two human autoimmune disease-associated self antigens. Mimicry between these similar peptides may provide a molecular basis for the conjoint autoantigenicity of proinsulin and GAD in IDDM.

Epidemiological Survey of Coeliac Disease and Inflammatory Bowel Disease in First-Degree Relatives of Coeliac Patients

One hundred and sixty-two of 182 patients with coeliac disease provided satisfactory details of family size and the prevalence of coeliac disease and inflammatory bowel disease among their first-degree relatives. Patients ranged in age from 11 months to 79 years with a mean age of 41 (+/- 23) years. Twenty patients had at least one first-degree relative with coeliac disease: a total of 25 of 861 relatives were affected (prevalence = 2904/100,000) compared with an expected 0.9 cases (prevalence = 100/100,000; p less than 0.001). Six relatives had inflammatory bowel disease (prevalence = 697/100,000) compared with an expected 1.3 cases (prevalence = 150/100,000; p less than 0.001). Five of these had ulcerative colitis, and one had Crohn's disease. The relative risk of ulcerative colitis is, therefore, five times greater for first-degree relatives of people with coeliac disease than for the general population (95 per cent confidence interval, 4.7-7.2). There is a clear association between coeliac disease and ulcerative colitis, which may point to factors involved in the aetiology of colitis.