Relationship between smoking and serum levels of eye muscle and orbital connective tissue antibodies in patients with Graves ophthalmopathy.

Over the past three decades, several studies have quantified the risk of smoking in the development of ophthalmopathy in patients with Graves' hyperthyroidism, with an overall odds ratio of approximately 3.0. Smokers also have a greater risk of more advanced ophthalmopathy than non-smokers. We studied 30 patients with Graves' ophthalmopathy (GO) and 10 patients with upper eyelid signs as the only manifestation of ophthalmopathy, whose eye signs were assessed using the clinical activity score (CAS), NOSPECS classes and upper eyelid retraction (UER) score, half of whom were smokers and half of whom were non-smokers. Serum levels of eye muscle (CSQ, Fp2, G2s) and orbital connective tissue type XIII collagen (Coll XIII) antibodies are valuable markers of ophthalmopathy in patients with Graves' disease. Still, their relationship to smoking has not been investigated. These antibodies were measured by enzyme-linked immunosorbent assay (ELISA) in all patients as a component of their clinical management. Mean serum antibody levels of all four antibodies were significantly greater in smokers than in non-smokers in patients with ophthalmopathy but not in those with upper eyelid signs only. As determined using one-way ANOVA and Spearman's correlation test, there was a significant correlation between smoking severity, assessed as pack-years, with mean Coll XIII antibody level, but not with levels of the 3 eye muscle antibodies. These results suggest that in patients with Graves' hyperthyroidism who smoke, the orbital inflammatory reactions are more advanced than in those with Graves' hyperthyroidism who do not smoke. The mechanism of this enhanced Autoimmunity against orbital antigens in smokers is unclear and worthy of further study.

Thyrotropinoma with silent somatotroph and lactotroph adenoma during pregnancy.

Summary: Thyrotropinomas are an uncommon cause of hyperthyroidism and are exceedingly rarely identified during pregnancy, with limited evidence to guide management. Most commonly they present as macroadenomas and may cause symptoms of mass effect including headache, visual field defects and hypopituitarism. We present a case of a 35-year-old woman investigated for headaches in whom a 13 mm thyrotropinoma was found. In the lead-up to planned trans-sphenoidal surgery (TSS), she spontaneously conceived and surgery was deferred, as was pharmacotherapy, at her request. The patient was closely monitored through her pregnancy by a multi-disciplinary team and delivered without complication. Pituitary surgery was performed 6 months post-partum. Isolated secondary hypothyroidism was diagnosed postoperatively and replacement thyroxine was commenced. Histopathology showed a double lesion with predominant pituitary transcription factor-1 positive, steroidogenic factor negative plurihormonal adenoma and co-existent mixed thyroid-stimulating hormone, growth hormone, lactotroph and follicle-stimulating hormone staining with a Ki-67 of 1%. This case demonstrates a conservative approach to thyrotropinoma in pregnancy with a successful outcome. This highlights the need to consider the timing of intervention with careful consideration of risks to mother and fetus. Learning points: Thyrotropinomas are a rare cause of secondary hyperthyroidism. Patients may present with hyperthyroidism or symptoms of mass effect, including headaches or visual disturbance. Thyrotropinoma in pregnancy presents a number of pituitary-related risks including pituitary apoplexy and compression of local structures. Hyperthyroidism in pregnancy raises the risk of complications including spontaneous abortion, preeclampsia, low birthweight and premature labour. Timing of medical and surgical therapies must be carefully considered. A conservative approach requires careful monitoring in case emergent intervention is required.

Macrogonadotropinoma, a venous thromboembolic event and asymptomatic extensive periventricular white matter changes in a patient with Klinefelter syndrome.

Gonadotropinoma in Klinefelter syndrome (KS) is uncommon and may be a result of protracted stimulation of gonadotrophs from lack of androgen feedback. Associations of white matter changes and increased venous thromboembolic risk have been reported and need to be considered in patients with KS.

A safety and pharmacodynamics study of temelimab, an antipathogenic human endogenous retrovirus type W envelope monoclonal antibody, in patients with type 1 diabetes.

AIM: To report the first study of temelimab, a monoclonal antibody neutralizing the pathogenic human endogenous retrovirus type W envelope, in patients with type 1 diabetes (T1D). MATERIALS AND METHODS: This double-blind, placebo-controlled, randomized clinical trial recruited adult patients with T1D within 4 years postdiagnosis and remaining C-peptide secretion. Sixty-four patients were randomized (2:1) to monthly temelimab 6 mg/kg or placebo during 24 weeks followed by a 24-week, open-label extension, during which all patients received temelimab. The primary objective was the safety and tolerability of temelimab. The secondary objective was to assess the pharmacodynamics response such as C-peptide levels, insulin use, HbA1c, hypoglycaemia and autoantibodies. RESULTS: Temelimab was well tolerated without any group difference in the frequency or severity of adverse events. Concerning exploratory endpoints, there was no difference in the levels of C-peptide, insulin use or HbA1c between treatment groups at weeks 24 and 48. The frequency of hypoglycaemia events was reduced with temelimab (P = 0.0004) at week 24 and the level of anti-insulin antibodies was lower with temelimab (P < 0.01); the other autoantibodies did not differ between groups. CONCLUSIONS: Temelimab appeared safe in patients with T1D. Pharmacodynamics signals (hypoglycaemia and anti-insulin antibodies) under temelimab were observed. Markers of ß-cell functions were not modified by treatment. These results need to be further explored in younger patients with T1D with earlier disease onset.

Routine glucose assessment in the emergency department for detecting unrecognised diabetes: a cluster randomised trial.

OBJECTIVE: To determine whether routine blood glucose assessment of patients admitted to hospital from emergency departments (EDs) results in higher rates of new diagnoses of diabetes and documentation of follow-up plans. DESIGN, SETTING: Cluster randomised trial in 18 New South Wales public district and tertiary hospitals, 31 May 2011 - 31 December 2012; outcomes follow-up to 31 March 2016. PARTICIPANTS: Patients aged 18 years or more admitted to hospital from EDs. INTERVENTION: Routine blood glucose assessment at control and intervention hospitals; automatic requests for glycated haemoglobin (HbA1c ) assessment and notification of diabetes services about patients at intervention hospitals with blood glucose levels of 14 mmol/L or more. MAIN OUTCOME MEASURE: New diagnoses of diabetes and documented follow-up plans for patients with admission blood glucose levels of 14 mmol/L or more. RESULTS: Blood glucose was measured in 133 837 patients admitted to hospital from an ED. The numbers of new diabetes diagnoses with documented follow-up plans for patients with blood glucose levels of 14 mmol/L or more were similar in intervention (83/506 patients, 16%) and control hospitals (73/278, 26%; adjusted odds ratio [aOR], 0.83; 95% CI 0.42-1.7; P = 0.61), as were new diabetes diagnoses with or without plans (intervention, 157/506, 31%; control, 86/278, 31%; aOR, 1.51; 95% CI, 0.83-2.80; P = 0.18). 30-day re-admission (31% v 22%; aOR, 1.34; 95% CI, 0.86-2.09; P = 0.21) and post-hospital mortality rates (24% v 22%; aOR, 1.07; 95% CI, 0.74-1.55; P = 0.72) were also similar for patients in intervention and control hospitals. CONCLUSION: Glucose and HbA1c screening of patients admitted to hospital from EDs does not alone increase detection of previously unidentified diabetes. Adequate resourcing and effective management pathways for patients with newly detected hyperglycaemia and diabetes are needed. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, ACTRN12611001007921.

Clinical challenges of a co-secreting TSH/GH pituitary adenoma.

SUMMARY: Co-secreting thyrotropin/growth hormone (GH) pituitary adenomas are rare; their clinical presentation and long-term management are challenging. There is also a paucity of long-term data. Due to the cell of origin, these can behave as aggressive tumours. We report a case of a pituitary plurihormonal pit-1-derived macroadenoma, with overt clinical hyperthyroidism and minimal GH excess symptoms. The diagnosis was confirmed by pathology showing elevated thyroid and GH axes with failure of physiological GH suppression, elevated pituitary glycoprotein hormone alpha subunit (αGSU) and macroadenoma on imaging. Pre-operatively the patient was rendered euthyroid with carbimazole and underwent successful transphenoidal adenomectomy (TSA) with surgical cure. Histopathology displayed an elevated Ki-67 of 5.2%, necessitating long-term follow-up. LEARNING POINTS: Thyrotropinomas are rare and likely under-diagnosed due to under-recognition of secondary hyperthyroidism. Thyrotropinomas and other plurihormonal pit-1-derived adenomas are more aggressive adenomas according to WHO guidelines. Co-secretion occurs in 30% of thyrotropinomas, requiring diligent investigation and long-term follow-up of complications.

A novel CASR mutation (p.Glu757Lys) causing autosomal dominant hypocalcaemia type 1

Autosomal dominant hypocalcaemia type 1 (ADH1) is a rare familial disorder characterised by low serum calcium and low or inappropriately normal serum PTH. It is caused by activating CASR mutations, which produces a left-shift in the set point for extracellular calcium. We describe an Australian family with a novel heterozygous missense mutation in CASR causing ADH1. Mild neuromuscular symptoms (paraesthesia, carpopedal spasm) were present in most affected individuals and required treatment with calcium and calcitriol. Basal ganglia calcification was present in three out of four affected family members. This case highlights the importance of correctly identifying genetic causes of hypocalcaemia to allow for proper management and screening of family members. Learning points: •• ADH1 is a rare cause of hypoparathyroidism due to activating CASR mutations and is the mirror image of familial hypocalciuric hypercalcaemia. •• In patients with ADH1, symptoms of hypocalcaemia may be mild or absent. Basal ganglia calcification may be present in over a third of patients. •• CASR mutation analysis is required for diagnostic confirmation and to facilitate proper management, screening and genetic counselling of affected family members. •• Treatment with calcium and activated vitamin D analogues should be reserved for symptomatic individuals due to the risk of exacerbating hypercalciuria and its associated complications.

The Effect of Cigarette Smoking during Pregnancy on Endocrine Pancreatic Function and Fetal Growth: A Pilot Study.

INTRODUCTION: Cigarette smoking in pregnancy is a common cause of fetal growth restriction. We aimed to investigate endocrine pancreatic function of mother-infant dyads in relation to cigarette smoking, as a possible mechanism for the poor fetal growth. METHODS: Prospective study of smoking mothers (10 cigarettes or more per day, self-reported to the midwife) and non-smoker control mothers during their first pregnancy. Insulin, glucose, C-peptide, HbA1C, fructosamine, prolactin, serotonin, and cortisol were measured in maternal blood at 24-26 weeks and in umbilical cord blood at birth. Cotinine was also measured in cord blood. RESULTS: Of 37 smokers and 36 non-smokers recruited, cord blood was obtainable from 38 babies (19 in each group). In utero cigarette exposure was associated with lower birthweight (3,035 ± 490 versus 3,405 ± 598 g, p = 0.005), with linear modeling of the smoking cohort showing a 41 g reduction for every increase of one cigarette smoked per day (95% CI -71 to -11 g, p = 0.010). There were no differences between groups in indices of maternal or perinatal endocrine pancreatic dysfunction. Heavier smoking independently correlated with higher maternal fasting levels of glucose (p = 0.044) and C-peptide (p = 0.011). We did not observe any significant associations between the daily number of cigarettes and any of the cord blood parameters. We also looked for differences between cohorts based on infant gender. Serotonin levels were higher in smoking mothers with male fetuses (p = 0.01 to p = 0.004). CONCLUSION: Endocrine pancreatic dysfunction does not appear to be a major contributing factor to nicotine-associated fetal growth restriction. The higher serotonin levels in smoking mothers carrying male infants is of uncertain significance but could be a manifestation of gender differences in susceptibility to the long-term effects of cigarette smoking.

Stimulants for the Control of Hedonic Appetite.

The focus of this paper is treatment of obesity in relation to the management of hedonic appetite. Obesity is a complex condition which may be potentiated by excessive reward seeking in combination with executive functioning deficits that impair cognitive control of behavior. Stimulant medications address both reward deficiency and enhance motivation, as well as suppressing appetite. They have long been recognized to be effective for treating obesity. However, stimulants can be abused for their euphoric effect. They induce euphoria via the same neural pathway that underlies their therapeutic effect in obesity. For this reason they have generally not been endorsed for use in obesity. Among the stimulants, only phentermine (either alone or in combination with topiramate) and bupropion (which has stimulant-like properties and is used in combination with naltrexone), are approved by the United States Food and Drug Administration (FDA) for obesity, although dexamphetamine and methylpenidate are approved and widely used for treating attention deficit hyperactivity disorder (ADHD) in adults and children. Experience gained over many years in the treatment of ADHD demonstrates that with careful dose titration, stimulants can be used safely. In obesity, improvement in mood and executive functioning could assist with the lifestyle changes necessary for weight control, acting synergistically with appetite suppression. The obesity crisis has reached the stage that strong consideration should be given to adequate utilization of this effective and inexpensive class of drug.

Does autoimmunity against thyroglobulin play a role in the pathogenesis of Graves' ophthalmopathy: a review.

While most authors believe that autoimmunity against the TSH receptor expressed in the orbital connective tissue cells is the main reaction that leads to the development of ophthalmopathy in patients with Graves' hyperthyroidism, an older hypothesis that deserves fresh consideration is based on the notion that thyroglobulin (Tg) in the thyroid gland passes in a retrograde fashion to the orbit where it is recognized by Tg autoantibodies, leading to inflammation. Here, we review new evidence that supports a role of Tg and propose a new hypothesis based on the notion that Tg is targeted in the orbit leading to a complex cascade of reactions that leads to Graves' ophthalmopathy.

Novel single-nucleotide polymorphisms in the calsequestrin-1 gene are associated with Graves' ophthalmopathy and Hashimoto's thyroiditis.

BACKGROUND: The eye disorder associated with Graves' disease, called Graves' ophthalmopathy (GO), greatly reduces the quality of life in affected patients. Expression of the calsequestrin (CASQ1) protein in thyroid tissue may be the trigger for the development of eye muscle damage in patients with GO. We determined the prevalence of rs74123279, rs3747673, and rs2275703 single-nucleotide polymorphism (SNPs) in patients with autoimmune thyroid disorders, GO, Graves' hyperthyroidism (GH), or Hashimoto's thyroiditis (HT) and control subjects with no personal or family history of autoimmune thyroid disorders. Furthermore, we measured the concentration of the CASQ1 protein in normal and Graves' thyroid tissue, correlating levels with parameters of the eye signs, CASQ1 antibody levels, and the CASQ1 gene polymorphism rs74123279 and rs2275703. METHODS: High-quality genomic DNA was isolated from fresh blood samples, assayed for identification of rs74123279, rs3747673, and rs2275703 SNPs in CASQ1 gene by MassARRAY SNP analysis using iPLEX technology of SEQUENOM. RESULTS: DNA samples from 300 patients and 106 control subjects (100 males, 306 females) with GO (n=74), GH (n=130), HT (n=96) and control subjects (n=106) were genotyped for the SNPs rs74123279, rs3747673 (n=405), and rs2275703 (n=407). The SNP rs74123279, rs3747673, and rs2275703 were identified as 1) common homozygous or wild type, 2) heterozygote, and 3) rare homozygous. Minor allele frequency for rs74123279, rs3747763, and rs2275703 were 21%, 40%, and 44%, respectively. Multiple comparisons of genotype frequency for rs74123279, rs3747763, and rs2275703 in the GO, GH, HT, and control groups showed P=0.06, 0.641, and 0.189, respectively. These results were substantiated by multiple comparison of alleles frequency for rs74123279, rs3838216, rs3747763, and rs2275703 in the GO, GH, HT, and control groups showed, P=0.36, 0.008, 0.66, and 0.05, respectively. Pairwise analysis of alleles frequency distribution in patients with GO showed significant probability for rs2275703, P=0.008. CONCLUSION: Based on their evolutionary conservation and their significant prevalence, we suggest that CASQ1 gene SNPs rs74123279, rs3838216, and rs2275703 may be considered as genetic markers for GO.

Piloting a new approach to the treatment of obesity using dexamphetamine.

BACKGROUND AND AIMS: There is a clear need for a new approach to the treatment of obesity, which is inexpensive and is effective for establishing lifestyle change. We conducted a pilot study to evaluate whether dexamphetamine can be used safely, combined with diet and exercise, for treating obesity. Our ultimate aim is to develop a 6-month treatment program for establishing the lifestyle changes necessary for weight control, utilizing dexamphetamine for its psychotropic effect on motivation. We viewed the anorexigenic effect as an additional advantage for promoting initial weight loss. METHODS: Obese adults were treated with dexamphetamine for 6 months (maximum of 30 mg twice daily), diet, and exercise. Weight, electrocardiogram, echocardiogram, and blood pressure were monitored. RESULTS: Twelve out of 14 completed 6 months treatment. Weight loss by intention to treat was 10.6 kg (95% CI 5.8-15.5, p < 0.001). The mean weight gain in the 6 months after ceasing dexamphetamine was 4.5 kg (95% CI 1.9-7.2, p = 0.003), leaving a mean weight loss at 12 months from baseline of 7.0 kg (95% CI -13.4 to -0.6, p = 0.03). All reported favorable increases in energy and alertness. Dose-limiting symptoms were mood changes (2) and insomnia (2). None had drug craving on ceasing dexamphetamine, and there were no cardiac complications. Among the seven women, there was a significant correlation for those who lost most weight on treatment to have the least regain in the following 6 months (r = 0.88, p = 0.009). CONCLUSION: Our treatment with dexamphetamine, diet, and exercise was well tolerated and effective for initial weight loss. Future research will focus on identifying baseline predictive variables associated with long-term weight control.

Relationship between Clinical and Immunological Features of Thyroid Autoimmunity and Ophthalmopathy during Pregnancy.

Problem. Clinical features of Graves' hyperthyroidism (GH) generally improve during pregnancy and rebound in the postpartum period. It is unclear whether the ophthalmopathy that is associated with GH and, less often, Hashimoto's thyroiditis (HT) changes in parallel with the thyroid associated antibody reactions and clinical features or runs a different course. Method of Study. We retrospectively studied 19 patients with autoimmune thyroid disease over 22 pregnancies: 9 pregnancies with GH and 13 with HT. Ophthalmopathy was defined by NOSPECS class. Results. Thyroid peroxidase (TPO) and thyroglobulin (Tg) antibody titres decreased during pregnancy and rose in the postpartum period. During pregnancy, 5 patients with GH and 4 patients with HT developed mild ophthalmopathy and two patients with GH and HT developed new upper eyelid retraction (UER). In the postpartum period, eye scores improved in 3 patients with GH and 3 with HT, remained stable in two and 5 patients, respectively, and worsened in 2 patients with GH and one with HT. Conclusions. In patients with mild to moderate eye signs associated with GH and HT, the orbital and thyroid reactions ran different courses during pregnancy. Since no patient had severe ophthalmopathy, we cannot draw definitive conclusions from this preliminary study.

Diabetic ketoacidosis due to fulminant type 1 diabetes: A rare subtype of type 1 diabetes leading to unusual sequelae.

Diabetic ketoacidosis (DKA) is a life-threatening complication of type 1 diabetes (T1D), which without treatment leads to death. Fulminant type 1 diabetes (FT1D) is a subtype characterised by a markedly rapid and almost complete destruction of pancreatic ß-cells, with acute onset leading to severe metabolic derangement and commonly ICU admission. We present a case of an 18-year-old male presenting with FT1D with two rare complications of pneumomediastinum and stress-induced cardiomyopathy (SIC) with significant myocardial necrosis. We also discuss the aetiology of the pneumomediastinum; the latest thoughts on SIC: moving beyond the simple description of 'Takotsubo cardiomyopathy'; the role of troponins in critical illness; and genetic predisposition for DKA due to FT1D.

Spaced scenario demonstrations improve knowledge and confidence in pediatric acute illness management.

OBJECTIVES: Nationally accredited simulation courses such as advance pediatric life support and pediatric advance life support are recommended for health care professionals (HCPs) at two yearly intervals as a minimum requirement, despite literature evidence suggesting rapid decline in knowledge shortly after course completion. The objective of this study was to evaluate an observation-based, educational intervention program aimed at improving previously acquired knowledge and confidence in managing critical illnesses. METHODS: A prospective cohort longitudinal study was conducted over a 6-month period. Participants were assessed with a knowledge based questionnaire immediately prior to and after observing 12 fortnightly critical illness scenario demonstrations (CISDs). The outcome measure was performance on questionnaires. Regression analysis was used to adjust for potential confounders. Questionnaire practice effect was evaluated on 30 independent HCPs not exposed to the CISDs. RESULTS: Fifty-four HCPs (40 doctors and 14 nurses) participated in the study. All participants had previously attended nationally accredited simulation courses with a mean time since last attendance of 1.8 ± 0.4 years. The median number of attendances at CISD was 6 (2-12). The mean questionnaire scores at baseline (17.2/25) were significantly lower than the mean post intervention questionnaire scores (20.3/25), p = 0.003. The HCPs self-rated confidence in managing CISD was 6.5 times higher at the end of the program in the intervention group (p = 0.002) than at baseline. There was no practice effect for questionnaires demonstrated in the independent sample. CONCLUSION: The educational intervention program significantly improved the knowledge and confidence of the participants in managing pediatric critical illnesses. The CISD program provides an inexpensive, practical, and time effective method of facilitating knowledge acquisition and retention. Despite the distinctively different approach, this study has shown the effectiveness of the participant being an observer to enhance pediatric resuscitation skills.

Gestational Diabetes Independently Increases Birth Length and Augments the Effects of Maternal BMI on Birth Weight: A Retrospective Cohort Study.

OBJECTIVE: To investigate the effect of the interaction between gestational diabetes mellitus (GDM) and maternal body mass index (BMI) on the individual neonatal growth parameters. DESIGN: Retrospective cohort study. SETTING: A tertiary maternity service in Sydney, Australia, between 2005 and 2009. POPULATION: A cohort of 8859 women. METHODS: Generalized linear models. MAIN OUTCOME MEASURES: Neonatal growth parameters, represented by z-scores for infant birth weight (BW), birth length (BL), and head circumference (HC) in GDM and non-GDM groups. RESULTS: Only GDM alone had an independent and positive effect on BL (p = 0.02) but not on BW or HC. In addition, in pregnancies complicated with GDM, the association between maternal weight and BW was significantly stronger (p < 0.001). In combination, GDM and maternal BMI significantly affected z-score differences between BW and BL (p < 0.001), in that underweight mothers had babies that were lighter relative to their length and inversely obese mothers had babies that were heavier relative to their length. CONCLUSION: GDM independently influences BL and increases the association between maternal BMI and BW. In accordance with the hypothesis of the fetal origins of health and disease, the pronounced effects of GDM on fetal growth patterns demonstrated in this study are likely to influence long-term health outcomes in children.

Thyroid-stimulating immunoglobulins as measured in a reporter bioassay are not detected in patients with Hashimoto's thyroiditis and ophthalmopathy or isolated upper eyelid retraction.

Although ophthalmopathy is mainly associated with Graves' hyperthyroidism, milder eye changes are also found in about 25% of patients with Hashimoto's thyroiditis (HT). The recent finding of negative thyrotropin receptor (TSHR) antibodies, as measured in the Thyretain™ thyroid-stimulating immunoglobulin (TSI) reporter bioassay, in patients with euthyroid Graves' disease raises the possibility that TSHR antibodies are not the cause of ophthalmopathy in all situations. Here, we have tested serum from patients with HT with and without ophthalmopathy or isolated upper eyelid retraction (UER) for TSHR antibodies, using the TSI reporter bioassay and collagen XIII as a marker of autoimmunity against the orbital fibroblast. Study groups were 23 patients with HT with ophthalmopathy, isolated UER, or both eye features and 17 patients without eye signs. Thyretain™ TSI results were expressed as a percentage of the sample-to-reference ratio, with a positive test being taken as a sample-to-reference ratio of more than 140%. Serum collagen XIII antibodies were measured in standard enzyme-linked immunosorbent assay. TSI tests were positive in 22% of patients with HT with no eye signs but in no patient with eye signs. In contrast, TSI tests were positive in 94% of patients with Graves' ophthalmopathy. Tests were negative in all normal subjects tested. Collagen XIII antibodies were detected in 83% of patients with ophthalmopathy, UER, or both eye features, but in only 30% of patients with no eye signs. Our findings suggest that TSHR antibodies do not play a major role in the pathogenesis of ophthalmopathy or isolated UER in patients with HT. Moreover, the role of TSHR antibodies in the development of ophthalmopathy in patients with Graves' disease remains to be proven. In contrast, collagen XIII antibodies appear to be a good marker of eye disease in patients with HT.

Tracing Arab-Islamic inheritance in Madagascar: study of the Y-chromosome and mitochondrial DNA in the Antemoro.

Madagascar is located at the crossroads of the Asian and African worlds and is therefore of particular interest for studies on human population migration. Within the large human diversity of the Great Island, we focused our study on a particular ethnic group, the Antemoro. Their culture presents an important Arab-Islamic influence, but the question of an Arab biological inheritance remains unresolved. We analyzed paternal (n=129) and maternal (n=135) lineages of this ethnic group. Although the majority of Antemoro genetic ancestry comes from sub-Saharan African and Southeast Asian gene pools, we observed in their paternal lineages two specific haplogroups (J1 and T1) linked to Middle Eastern origins. This inheritance was restricted to some Antemoro sub-groups. Statistical analyses tended to confirm significant Middle Eastern genetic contribution. This study gives a new perspective to the large human genetic diversity in Madagascar.

Eye findings and immunological markers in probands and their euthyroid relatives from a single family with multiple cases of thyroid autoimmunity.

BACKGROUND: Ophthalmopathy is a common manifestation of Graves' disease (GD) occurring in up to 50% of patients. Mild eye signs are also common in patients with Hashimoto's thyroiditis. Whilst a genetic predisposition to GD has been demonstrated this is not the case for the ophthalmopathy which often runs a separate course. OBJECTIVE: We determined the prevalences of eye and eyelid signs and positive thyroid and orbital antibody tests in first and second degree relatives from a single family with multiple cases of Graves' disease, ophthalmopathy and Hashimoto's thyroiditis. DESIGN: The study cohort comprised 16 subjects from the same family, 4 probands namely, 3 with GD and one with Hashimoto's thyroiditis and hypothyroidism and 12 of their euthyroid first or second degree relatives. We measured antibodies against calsequestrin (CASQ1) and collagen XIII in an enzyme-linked-immunosorbent assays and TSH-Receptor (TSH-R) antibodies as i) TSH-R binding inhibiting immunoglobulin (TBII) and ii) thyroid stimulating immunoglobulin (TSI). Eye signs were classified and quantified using the clinical activity score (CAS), NOSPECS classes, Nunery types 1 and 2 and the margin-reflex-distance (MRD) as a measure of upper eyelid retraction (UER). MAIN OUTCOMES: Whilst significant ophthalmopathy was uncommon in the relatives, mild eye signs, in particular UER, were demonstrated in about a third of them. The presence of eye signs was moderately, but not significantly, associated with the detection of CASQ1 and collagen XIII antibodies, but not TSH-R antibodies. CONCLUSION: Our study demonstrates a significant prevalence of positive orbital antibody tests and ophthalmopathy in probands with thyroid autoimmunity and their euthyroid relatives, favouring a role of genetic factors in the development of ophthalmopathy in patients with thyroid autoimmunity.