The effect of vildagliptin relative to sulphonylureas in Muslim patients with type 2 diabetes fasting during Ramadan: the VIRTUE study.

AIMS: To assess, in a real-world setting, the effect of vildagliptin compared with sulphonylurea (SU) treatment on hypoglycaemia in Muslim patients with type 2 diabetes mellitus (T2DM) fasting during Ramadan. METHODS: This multinational, non-interventional study, conducted in Asia and the Middle East, included Muslim adult patients with T2DM who received treatment with vildagliptin or SU as add-on to metformin or monotherapy. During a ~16-week observation period, data were collected up to 6 weeks before and 6 weeks after Ramadan fasting. The primary study objective was to compare the proportion of patients with ≥ 1 hypoglycaemic event (HE) during fasting. RESULTS: Of > 1300 patients enrolled in the study, 684 were treated with vildagliptin and 631 with SUs. Significantly fewer patients experienced ≥ 1 HE with vildagliptin compared with those receiving SUs (5.4% vs. 19.8%, respectively; p < 0.001); no vildagliptin-treated patients reported a grade 2 HE, vs. 4 SU-treated patients (p = 0.053). Mean HbA1c changes from baseline were vildagliptin: -0.24%, SUs: +0.02% (p < 0.001). Mean body weight reductions from baseline were vildagliptin: -0.76 kg, SUs: -0.13 kg (p < 0.001). A higher proportion of SU-treated patients experienced adverse events (AEs) compared with vildagliptin (22.8% vs. 10.2%). This difference was driven by hypoglycaemia as the most common AE. CONCLUSIONS: In this real-world study of fasting Muslim patients with T2DM, vildagliptin was associated with significantly fewer hypoglycaemic episodes compared with SU therapy. This outcome is particularly meaningful when viewed in the context of good glycaemic and weight control observed in vildagliptin-treated patients. Vildagliptin was well tolerated in this patient population.

Genetics of autoimmune thyroid disease in the Lebanese population.

This study aims to investigate the association of human leukocyte antigen (HLA) class II genes and cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) with autoimmune thyroid diseases in the Lebanese population. A total of 128 patients with autoimmune thyroid disease (55 with Graves' disease (GD) and 73 with Hashimoto's thyroiditis (HT)) were typed for HLA DQA1 (0301 and 0501) and DQB1 (0201, 0302, and 0303) and for 49A/G CTLA-4 using PCR-based sequence-specific priming methods. A total of 186 matched controls were typed for the same alleles and compared to the diseased population. Results showed no significant differences in HLA DQB1*0201 or DQB1*0301 allelic frequencies or CTLA-4 polymorphisms between patients and controls. For GD, there was a weak association with HLA DQB1*0302 [34.6% (19 of 55) vs. 21.5% (40 of 186), P = 0.048, odds ratio (OR) = 1.926, confidence interval (CI) = 0.999-3.715] and HLA DQB1*0302-DQA1*0501 haplotype [56.36% (31 of 55) vs. 40.8% (76 of 186), P = 0.042, OR = 1.870, CI = 1.018-3.433]. For HT, the frequencies of DQB1*0302-DQA1*0501 haplotype [28.8% (21of 73) vs. 14.5% (27 of 186), P = 0.008, OR = 2.378, CI = 1.241-4.558] and DQB1*0302-DQA1*0301 haplotype [60.2% (44 of 73) vs. 38.7% (72 of 186), P = 0.002, OR = 2.402, CI = 1.381-4.180] were significantly higher in patients. On the other hand, weak association was found between HT and DQA1*0301 allele [32.9% (24 of 73) vs. 20.9% (39 of 186), P = 0.044, OR = 1.846, CI = 1.011-3.373]. Findings show that DQB1*0302-DQA1*0501 and DQB1*0302-DQA1*0301 haplotypes may play a role in the pathogenesis of HT in the Lebanese population. For the 49A/G CTLA-4 polymorphism, no significant difference was found between patients and controls.

Predictors of intra-operative parathyroid hormone decline in subjects operated for primary hyperparathyroidism by minimally invasive parathyroidectomy.

BACKGROUND: The predictors of intra-operative PTH (IOPTH) decline during minimally invasive parathyroidectomy (MIP) for primary hyperparathyroidism have been but poorly studied. MATERIALS AND METHODS: This retrospective study included 108 patients who underwent MIP for a single adenoma. Serum calcium and phosphorus were measured before surgery and 1 day post-operatively. IOPTH was measured before (intra-operative preincision or PTHt0) and 10 min after removal of the adenoma (PTHt10). The Modification of Diet in Renal Disease (MDRD) equation was used to estimate the glomerular filtration rate. The weight of the adenoma was assessed in all the subjects. RESULTS: The sex ratio female/male was 5.37 with a mean age of 57.3 yr. The mean pre- and postoperative values were for calcium 2.80 and 2.19 mmol/l, respectively (p<0.0001) and for phosphorus 0.90 and 1.16 mmol/l, respectively (p<0.0001). The PTH dropped from a mean value of 184.8 to 50.8 pg/ml 10 min after adenoma resection with a mean drop of 69.7%. Thirteen patients (12%) did not achieve a PTH fall of more than 50%. In a bivariate analysis, age, an MDRD<60 ml/min and weight of adenoma were inversely associated with IOPTH fall (p=0.009, p=0.004, and p<0.001, respectively) while gender, body mass index, hypertension, diabetes, pre-operative phosphorus and calcium had no significant effects. In the multivariate analysis, age, weight of adenoma, and MDRD were still independent negative predictors of the IOPTH fall (p=0.01, p=0.018, and p<0.001, respectively). CONCLUSION: Our results suggest that during MIP the presence of a parathyroid adenoma with a high weight, in an elderly subject or in a subject with altered renal function, will result in a lesser degree of IOPTH fall.

Diabetes mellitus and optic atrophy: a study of Wolfram syndrome in the Lebanese population.

Wolfram syndrome (WFS) is a rare hereditary neurodegenerative disorder also known as DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness). WFS seems to be a heterogeneous disease that has not yet been fully characterized in terms of clinical features and pathophysiological mechanisms because the number of patients in most series was small. In this study we describe 31 Lebanese WFS patients belonging to 17 families; this, to our knowledge, is the largest number of patients reported in one series so far. Criteria for diagnosis of WFS were the presence of insulin-dependent diabetes mellitus and optic atrophy unexplained by any other disease. Central diabetes insipidus was found in 87% of the patients, and sensorineural deafness confirmed by audiograms was present in 64.5%. Other less frequent features included neurological and psychiatric abnormalities, urodynamic abnormalities, limited joint motility, cardiovascular and gastrointestinal autonomic neuropathy, hypergonadotropic hypogonadism in males, and diabetic microvascular disease. New features, not reported in previous descriptions, such as heart malformations and anterior pituitary dysfunction, were recognized in some of the patients and participated in the morbidity and mortality of the disease. Genetic analysis revealed WFS1 gene mutations in three families (23.5%), whereas no abnormalities were detected in mitochondrial DNA. In conclusion, WFS is a devastating disease for the patients and their families. More information about WFS will lead to a better understanding of this disease and hopefully to improvement in means of its prevention and treatment.

Malignant struma ovarii: an unusual presentation.

Malignant struma ovarii is a rare disease; only a few cases are well documented in the literature. Thus, the overall prognosis and modalities of treatment are still somewhat controversial. In this article, the authors report a case of malignant struma ovarii discovered 4 years after ovariectomy after metastasis to the lungs and bones. Review of the pathology of the ovarian struma did not reveal the classic criteria of malignancy, there were, however, many features considered to be atypical and thus suspicious. The patient was treated by total thyroidectomy followed by repetitive doses of 131I. However, because of difficulties in increasing the level of endogenous thyrotropin (TSH) because of functional thyroid metastases in such an advanced disease, recombinant human thyrotropin (rhTSH; Thyrogen, thyrotropin alpha, Genzyme Corporation, Cambridge, MA) was used before administration of radioiodine. With this therapeutic protocol, the patient is still clinically stable 2 years after diagnosis.

The DD genotype of the ACE gene polymorphism is associated with diabetic nephropathy in the type-1 diabetics.

Genetic factors are involved in the development of diabetic nephropathy in type-1 diabetes. We are examining the association of the angiotensin-converting enzyme (ACE), insertion/deletion (I/D) polymorphism with the presence of diabetic nephropathy in type-1 diabetic patients. 52 type-1 diabetic patients with diabetic nephropathy (30 with either microalbuminuria or macroalbuminuria and 22 with end stage renal disease on dialysis) were compared with 10 type-1 diabetic patients with normoalbuminuria and duration of disease longer than 15 years and 27 non-diabetic healthy subjects. We found that the D-allele frequency was higher in patients with nephropathy than in the healthy and normoalbuminuric controls. There was an association in the DD polymorphism of the ACE gene with patients with diabetic nephropathy and not with the control subjects. We conclude that the DD genotype of ACE gene polymorphism is associated with diabetic nephropathy in patients with type-1 diabetes mellitus.

[Endocrinologic recovery after treatment of an intrasellar aneurysm]. / Récupération endocrinienne après cure d'un anévrisme intrasellaire.

OBJECTIVE: Cavernous intrasellar aneurysms are rare, but may be clinically mistaken for an hypophyseal tumor, thus the need for a preoperative diagnosis. CLINICAL PRESENTATION: We report on a 60-year-old woman suffering from retroorbital headache, diplopia and decreased visual acuity, along with hyperprolactinemia and both gonadotropic and thyreotropic deficencies. Computed tomography revealed a sellar mass with superior extension, but MR raised the possibility of a cavernous aneurysm, that was confirmed by arteriography, avoiding a disastrous transsphenoidal surgery. DISCUSSION: Intracavernous aneurysms are known having a benign course, but serious meningeal hemorrhage can occur in 1.4% of cases and carotid-cavernous fistulae in 8% of patients, warranting treatment. Medial development is rare and may be responsible for endocrinologic manifestations. Neurosurgical approach remains hazardous, and endovascular occlusion represents the method of choice. CONCLUSION: Intracavernous aneurysm must be taken into consideration in the differential diagnosis of pituitary masses because it has a completely different management.

[A rare manifestation of hypothyroidism: intestinal obstruction. Report of 2 cases and review of the literature]. / Manifestation rare de l'hypothyroïdie: l'occlusion intestinale. Rapport de deux cas et revue de la littérature.

Gastrointestinal manifestations of hypothyroidism are unfrequent. They consist particularly in hypomotility, intestinal atony, and pseudoobstruction. A high index of suspicion must exist, especially in elder subjects, in order to avoid unnecessary and even harmful investigation and intervention. We are reporting two cases of intestinal occlusion due to hypothyroidism with review of the literature.

[Extrapontine myelinolysis: treatment with TRH]. / Myélinolyse extra-pontine: traitement par T.R.H.

Central pontine and extra-pontine myelinolysis are a well known complication of hyponatremia. Other causes may be present. We report a case of head injury in a 13 year-old girl, who recovered well after surgery for extra-dural hematoma, but presented endocrinological disorders with hyperglycemia followed by a severe hyponatremia. Despite the correction of these metabolic disorders, the patient became comatose, and MRI, on T2 weighted image, showed hyperintense signals in the basal ganglia consistent with extra-pontine myelinolysis. The patient's state remained unchanged for six weeks. Since S. Konno and H. Wakui published cases of myelinolysis who dramatically improved after TRH treatment, the patient was given 0.6 mg i.v daily of TRH for six weeks. Improvement began within a few days, and continued until complete recovery.

Heterogeneity in clinical manifestation of autosomal dominant neurohypophyseal diabetes insipidus caused by a mutation encoding Ala-1-->Val in the signal peptide of the arginine vasopressin/neurophysin II/copeptin precursor.

Autosomal dominant neurohypophyseal diabetes insipidus (ADNDI) is a familial form of diabetes insipidus due to progressive vasopressin deficiency with onset typically at 1-6 yr of age. Affected individuals demonstrate specific degeneration of the vasopressinergic magnocellular neurons in the hypothalamic supraoptic and paraventricular nuclei and loss of the posterior pituitary bright spot on magnetic resonance imaging. The genetic locus of ADNDI is the arginine vasopressin-neurophysin II (AVP-NPII) gene. Mutations that cause ADNDI have been found to occur both within the signal peptide of the prepro-AVP-NPII precursor and within the coding sequence for neurophysin II, but not within the coding sequence for AVP itself. We evaluated the AVP-NPII genes in two independent families with ADNDI and identified a mutation (C280-->T) in the coding sequence for the signal peptide of the prepro-AVP-NPII precursor in both families. This mutation encodes an Ala-->Val substitution at the C-terminus of the signal peptide (-1 amino acid). This mutation predicts the complete inability of signal peptidase to cleave the signal peptide from the preproprecursor and supports the hypothesis that the progressive neural degeneration that underlies ADNDI is caused by accumulation of malprocessed precursor. However, considerable heterogeneity in the age of onset (1-28 yr of age) and the severity of diabetes insipidus among affected members of these two families suggests that additional factors modulate the rate and extent of progression of the neurodegeneration that results from this one specific ADNDI mutation.

Symptoms, hormones, and glucose fluxes during a gradual hypoglycaemia induced by intraperitoneal vs venous insulin infusion in Type I diabetes.

Intraperitoneal (IP) insulin infusion with programmable implantable pumps is associated with a reduction in hypoglycaemic events when compared to intensive diabetes management with subcutaneous insulin in patients with Type 1 diabetes mellitus. The mechanism may involve more physiological insulin kinetics, lower peripheral insulin levels or a specific hepatic action of portal insulin on hypoglycaemic counter regulation. To investigate the latter two hypotheses, we performed two hypoglycaemic clamps (controlled blood glucose decrement to 2.2 mmol l-1) in random order in 12 Type 1 diabetic patients. Insulin was infused either IP or IV for 150 min, at rates chosen to generate similar peripheral insulin levels (1 mU/kg-1 min-1 IV or 2 mU/kg-1 min-1 IP, n = 6) to evaluate direct hepatic action, or at similar rates (1 mU/kg-1 min-1 IV and IP, n = 6) to evaluate IP indirect effects via lower peripheral insulinaemia. Hepatic glucose production and glucose utilization were measured by [6.6 2H] glucose dilution technique. Glucose production was lower (1.7 +/- 0.4 vs 0.5 +/- 0.4 mg kg-1 min-1, p < 0.05), and utilization was similar at the end of the matched-insulinaemia IV and IP clamps, respectively. By contrast, glucose production was higher (1.7 +/- 0.5 IV vs 2.7 +/- 0.3 IP mg kg-1 min-1, p < 0.01) and glucose utilization lower (4.4 +/- 1.0 IV vs 3.3 +/- 0.2 IP mg kg-1 min-1, p < 0.05) with IP delivery at the end of the matched-dose clamps. Counterregulatory hormones and hypoglycaemic symptoms increased similarly in all clamps. In summary, IP insulin, when compared to IV insulin at similar delivery rates, but not at similar insulinaemia, is associated with a less negative glucose balance (glucose production-glucose utilization) during hypoglycaemia. Such a mechanism may play a role in the reduced hypoglycaemic risk seen with IP implantable pumps.

[Primary hyperparathyroidism. Experiences at the Hôtel Dieu. A study of 28 cases]. / Hyperparathyroïdie primaire. Expérience de l'Hôtel-Dieu. Etude de 28 cas.

Primary hyperparathyroidism is a more frequently recognized entity. The clinical picture historically severe, has changed overtime. We present herein our experience relating 28 cases with emphasis of our results compared to the medical literature.

[Genes of the Y chromosome and Turner syndrome]. / Gènes du chromosome Y et syndrome de Turner.

Turner syndrome is a complex human phenotype most commonly seen in association with a 45,X karyotype and it has been proposed that the phenotype is the result of monosomy for genes common to the X and Y chromosomes. Detection of unrecognized Y derived material is now possible by PCR of the SRY gene. Its presence is correlated with the presence of testicular tissue, known to increase the risk of developing gonadal neoplasia. Study of Y chromosome allowed the localisation of a candidate gene for the development of gonadoblastoma, GBY. Moreover, some groups described genes on the Y chromosome whose defects seem to be involved in the development of Turner stigmata: ZFY and RPS4Y. In conclusion; molecular genetics of the Y chromosome develops new pathophysiological and fundamental perspectives of the molecular genetics of the Turner syndrome.

PCR analysis and sequencing of the SRY sex determining gene in four patients with bilateral congenital anorchia.

OBJECTIVE: We explored the possibility of a genetic anomaly in the sex determining region of the Y chromosome, SRY gene, known to be equated to the testis determining region. PATIENTS: Four patients with bilateral congenital anorchia, absence of testicular tissue, elevated FSH and a lack of testosterone response to human chorionic gonadotrophin stimulation tests were studied. MEASUREMENTS: Amplification by polymerase chain reaction of the SRY gene and direct double stranded DNA sequencing were performed with the same primers. RESULTS: The expected 648 basepairs band of SRY was detected in the four DNA samples from patients with bilateral congenital anorchia. Direct sequencing did not show any difference with the previous published sequence. CONCLUSIONS: These data suggest that, in the four patients, bilateral congenital anorchia is not related to an anomaly of the opening reading frame sequence of the SRY gene.

[Incidentally discovered adrenal tumor: myelolipoma]. / Tumeur surrénalienne de découverte fortuite: le myélolipome.

The wider application of increasingly sensitive ultrasonography and CT scanning has created a new problem for clinical management: the incidental discovery of asymptomatic adrenal lesions. These lesions, also called "incidentalomas" may be due to a large variety of etiologies, and although most of them prove to be benign cortical adenomas, diagnostic confirmation is frequently impossible preoperatively. For this reason, a general approach, based on the relative prevalence of benign and malignant, clinically silent adrenal masses, has been defined. This same approach is usually needed in the case of myelolipoma, a rare form of benign and silent adrenal neoplasms, containing hematopoietic and fatty elements. Actually, computed tomographic aspect of such tumors is very evocative but not pathognomonic, so it doesn't eliminate the possibility of malignant lesions, especially in the presence of heterogeneities. Because of these limitations and awaiting the development of more specific diagnostic procedures, it seems cautious to approach these tumors like incidentalomas in general.

Screening for Y-derived sex determining gene SRY in 40 patients with Turner syndrome.

In Turner patients, the presence of a Y chromosome or derivative Y is correlated with the risk of gonadoblastoma induction. "Marker" chromosomes originating from Y, may not show characteristic fluorescence and then be very difficult to identify by conventional cytogenetic techniques, although they still predispose the patients to gonadal tumors. Using polymerase chain reaction of the gene from the sex-determining region of the Y chromosome, we screened 40 Turner patients (thirty seven 45X and three 45X,46XX) for the presence of Y chromosomal DNA. We were able to identify karyotypically unrecognized Y chromosome material in 1 patient out of the 40 studied. In this patient mild clinical and biological hyperandrogenism was observed. Reliability of our technique was ascertained by the detection of the expected 648 base pairs amplified DNA fragment in all normal male controls as well as in 3 Turner patients with confirmed 45X,46XY mosaicism. Despite the low frequency of unrecognized Y chromosome material (1 case over 40 in our experience), our data suggest that polymerase chain reaction of the gene from the sex-determining region of the Y chromosome is worthy of being performed in Turner patients considering the potential risk of the presence of a Y chromosome.

[Virilizing tumor in a woman. Management]. / Tumeur masculinisante chez la femme. Conduite a tenir.

Androgen secreting ovarian or adrenal neoplasms represent a rare cause of hirsutism in women. Because of their small volume and episodic secretion, a number of these tumors may be difficult to diagnose and treat. The authors report a case of lipoid cell tumor of the ovary, which was only detected, because of its small volume, by catheterization of adrenal and ovarian veins. This latter procedure should be performed when strong clinical and biological suspicion is faced by the negativity of other imaging techniques.