Whole-exome sequencing identifies the first French MODY 6 family with a new mutation in the NEUROD1 gene.

AIM: The aim of the present study was to identify the affected gene in a French family with maturity-onset diabetes of the young (MODY) using whole-exome sequencing (WES). METHODS: WES was performed in one patient with MODY, and candidate variants were confirmed in members of the immediate family by Sanger sequencing. RESULTS: In the proband, a new heterozygous missense mutation (c.340A>C) was identified in the NEUROD1 gene by WES analysis and confirmed by Sanger sequencing. Additional Sanger sequencing of the proband's sister and mother revealed the same heterozygous mutation. The proband and his sister displayed typical clinical characteristics of MODY, while their mother had the same typical MODY features except for later onset. When clinical and biological profiles were established for all three patients, the severity of diabetes-related complications varied substantially from one family member to another. CONCLUSION: A novel missense mutation found in NEUROD1 was associated with MODY 6 features in a single French family.

Practical implementation, education and interpretation guidelines for continuous glucose monitoring: A French position statement.

The use by diabetes patients of real-time continuous interstitial glucose monitoring (CGM) or the FreeStyle Libre® (FSL) flash glucose monitoring (FGM) system is becoming widespread and has changed diabetic practice. The working group bringing together a number of French experts has proposed the present practical consensus. Training of professionals and patient education are crucial for the success of CGM. Also, institutional recommendations must pay particular attention to the indications for and reimbursement of CGM devices in populations at risk of hypoglycaemia. The rules of good practice for CGM are the precursors of those that need to be enacted, given the oncoming emergence of artificial pancreas devices. It is necessary to have software combining user-friendliness, multiplatform usage and average glucose profile (AGP) presentation, while integrating glucose and insulin data as well as events. Expression of CGM data must strive for standardization that facilitates patient phenotyping and their follow-up, while integrating indicators of variability. The introduction of CGM involves a transformation of treatment support, rendering it longer and more complex as it also includes specific educational and technical dimensions. This complexity must be taken into account in discussions of organization of diabetes care.

Indication, organization, practical implementation and interpretation guidelines for retrospective CGM recording: A French position statement.

AIM: The benefits of retrospective continuous glucose monitoring (retroCGM) recording have been widely explored in clinical studies, and many diabetes physicians routinely use this examination. However, the method of interpretation of CGM recordings has never been precisely described. METHOD: An expert French panel of physicians met for two days to discuss several aspects of retroCGM use and to produce a position statement. RESULTS: The guidelines cover the indications for retroCGM, the general organization and practical implementation of CGM recordings, a description of the different devices available and guidelines for the interpretation of retroCGM recordings. CONCLUSION: This consensus document should help clinicians in the proper use of retroCGM.

Non-ultrasound-guided ethanol sclerotherapy for the treatment of thyroid cysts.

OBJECTIVE: Ethanol injection under ultrasound (US) guidance has been proposed as an alternative to surgery in the treatment of recurrent benign thyroid cysts following aspiration. We aimed to set up a new procedure of ethanol sclerotherapy without US guidance for the treatment of pure thyroid cysts in order to make this useful treatment, available to more patients, more particularly when access to centers specialized in thyroid ultrasonography is limited. PATIENTS AND METHODS: Nine patients with recurrent large thyroid cysts following aspiration, and showing symptoms of compression and/or cosmetic complaints were treated by ethanol injection without US guidance and followed for up to 11 years. RESULTS: After ethanol injection, mean cyst volume was significantly reduced (9.9 ± 13.6 vs. 31.3 ± 34.1 ml, P=0.007) and the mean percentage volume reduction was 72.7%. A size reduction of the thyroid lesion more than 50% was achieved in eight of the nine patients (89%). Compressive symptoms and cosmetic complaints totally disappeared after sclerotherapy in all patients. During a mean follow-up of 48 months (ranging from 12 to 135 months), no recurrences were observed. The treatment was well tolerated with no major side effects. CONCLUSION: Non-US-guided ethanol sclerotherapy is a safe and "easy-to-use" procedure to treat benign thyroid cysts effectively. Because this new treatment does not need US-guidance, it can be performed by endocrinologists during outpatient visits. This new procedure may be useful in some areas, such as developing countries, where access to US examination is limited.

Effects of 20 mg rosuvastatin on VLDL1-, VLDL2-, IDL- and LDL-ApoB kinetics in type 2 diabetes.

AIMS/HYPOTHESIS: In addition to its efficacy in reducing LDL-cholesterol, rosuvastatin has been shown to significantly decrease plasma triacylglycerol. The use of rosuvastatin may be beneficial in patients with type 2 diabetes, who usually have increased triacylglycerol levels. However, its effects on the metabolism of triacylglycerol-rich lipoproteins in type 2 diabetic patients remains unknown. METHODS: We performed a randomised double-blind crossover trial of 6-week treatment with placebo or rosuvastatin 20 mg in eight patients with type 2 diabetes who were being treated with oral glucose-lowering agents. In each patient, an in vivo kinetic study of apolipoprotein B (ApoB)-containing lipoproteins with [13C]leucine was performed at the end of each treatment period. A central randomisation centre used computer-generated tables to allocate treatments. Participants, caregivers and those assessing the outcomes were blinded to group assignment. RESULTS: Rosuvastatin 20 mg significantly reduced plasma LDL-cholesterol, triacylglycerol and total ApoB. It also significantly reduced ApoB pool sizes of larger triacylglycerol-rich VLDL particles (VLDL1; p = 0.011), smaller VLDL particles (VLDL2; p = 0.011), intermediate density lipoprotein (IDL; p = 0.011) and LDL (p = 0.011). This reduction was associated with a significant increase in the total fractional catabolic rate of VLDL1-ApoB (6.70 +/- 3.24 vs 4.52 +/- 2.34 pool/day, p = 0.049), VLDL2-ApoB (8.72 +/- 3.37 vs 5.36 +/- 2.64, p = 0.011), IDL-ApoB (7.06 +/- 1.68 vs 4.21 +/- 1.51, p = 0.011) and LDL-ApoB (1.02 +/- 0.27 vs 0.59 +/- 0.13, p = 0.011). Rosuvastatin did not change the production rates of VLDL2-, IDL- or LDL-, but did reduce VLDL1-ApoB production rate (12.4 +/- 4.5 vs 19.5 +/- 8.4 mg kg(-1) day(-1), p = 0.035). No side effects of rosuvastatin were observed during the study. CONCLUSIONS/INTERPRETATION: In type 2 diabetic patients rosuvastatin 20 mg not only induces a significant increase of LDL-ApoB catabolism (73%), but also has favourable effects on the catabolism of triacylglycerol-rich lipoproteins, e.g. a significant increase in the catabolism of VLDL1-ApoB (48%), VLDL2-ApoB (63%) and IDL-ApoB (68%), and a reduction in the production rate of VLDL1-ApoB (-36%). The effects of rosuvastatin on the metabolism of triacylglycerol-rich lipoproteins may be beneficial for prevention of atherosclerosis in type 2 diabetic patients.

Normal metabolism of apolipoprotein B100-containing lipoproteins despite qualitative abnormalities in type 1 diabetic men.

AIMS/HYPOTHESIS: Type 1 diabetic subjects are at increased risk of cardiovascular disease and exhibit multiple qualitative abnormalities of apolipoprotein (apo) B100-containing lipoproteins. This stable isotope kinetic experiment was designed to study whether these abnormalities are associated with changes in the synthesis and fractional catabolic rates of VLDL-, IDL- and LDL-apoB100. METHODS: Using a bolus followed by a 16-h constant infusion of 13C-leucine, we performed a kinetic study in eight men with type 1 diabetes treated with a continuous subcutaneous insulin infusion administered by an external pump and in seven healthy men, in the fed state. RESULTS: The mean HbA1c level in the type 1 diabetic patients was 8.00+/-1.48%. Plasma triglyceride, and total, LDL and HDL cholesterol levels were similar in patients and control subjects. VLDL were less triglyceride rich in type 1 diabetic patients than in control subjects (VLDL triglyceride : apoB 6.91+/-0.81 vs 8.29+/-1.24 mmol/g, p=0.05). Conversely, the IDL and LDL of the type 1 diabetic patients contained relatively higher levels of triglycerides (IDL triglycerides : apoB 2.16+/-0.36 vs 1.57+/-0.30 mmol/g, p<0.01; LDL triglycerides : apoB 0.27+/-0.06 vs 0.16+/-0.04 mmol/g, p<0.05). The apoB100 pool size, production and fractional catabolic rates in the two groups of subjects were similar for all lipoprotein fractions. CONCLUSIONS/INTERPRETATION: Despite qualitative abnormalities, especially abnormalities of triglyceride content, the metabolism of apoB100-containing lipoproteins is not altered in type 1 diabetic men with fair glycaemic control with continuous subcutaneous insulin infusion. The high risk of atherosclerosis in these patients cannot be explained by kinetic abnormalities of apoB100-containing lipoproteins.

Role of guanine nucleotides in the regulation of the Ras/cAMP pathway in Saccharomyces cerevisiae.

The CDC25 gene product is a guanine nucleotide exchange factor for Ras proteins in yeast. Recently it has been suggested that the intracellular levels of guanine nucleotides may influence the exchange reaction. To test this hypothesis we measured the levels of nucleotides in yeast cells under different growth conditions and the relative amount of Ras2-GTP. The intracellular GTP/GDP ratio was found to be very sensitive to growth conditions: the ratio is high, close to that of ATP/ADP during exponential growth, but it decreases rapidly before the beginning of stationary phase, and it drops further under starvation conditions. The addition of glucose to glucose-starved cells causes a fast increase of the GTP/GDP ratio. The relative amount of Ras2-GTP changes in a parallel way suggesting that there is a correlation with the cytosolic GTP/GDP ratio. In addition 'in vitro' mixed-nucleotide exchange experiments done on purified Ras2 protein demonstrated that the GTP and GDP concentrations influence the extent of Ras2-GTP loading giving further support to their possible regulatory role.

Management of diabetes in French prisons: a cross-sectional study.

AIMS: To assess by a survey the management of prisoners with diabetes treated with insulin in French prisons. METHODS: A questionnaire was sent to the head of healthcare services for prisoners of every French prison. Information was obtained on prevalence of insulin-treated diabetes prisoners and diabetes care in prison. The number of episides of ketoacidosis and hypoglycaemia needing hospital admissions were evaluated during the past year. RESULTS: Among the 163 questionnaires sent, 115 were returned, giving an overall response rate of 69%. At the time of the study the prison population was 38 175 people. One hundred and sixty-nine prisoners were treated by insulin (0.4%). Self-monitoring of blood glucose was available only for 94 (55.6%) insulin-treated prisoners. A total of 130 (76.9%) prisoners performed two insulin injections daily or less, 105 (62.1%) prisoners were not allowed to keep their insulin delivery systems with them. Of the prisoners who treated themselves, 14 (12.1%) used syringes and 42 (36.5%) used pen devices. Ninety-two (55.1%) prisoners had had access to a diabetes specialist during the previous year. Diabetic diets were available in only 65 (60.7%) prisons. From June 1998 to June 1999, there were 20 hospital admissions for a diabetic ketoacidosis and 14 for hypoglycaemia. CONCLUSIONS: This study shows that prison decreases the autonomy of diabetic prisoners who often cannot self-inject or test their blood. Access to visiting consultant diabetologists and specialist nurses to educate both prisoners with diabetes and prison staff could improve diabetic care.

The overexpression of the CDC25 gene of Saccharomyces cerevisiae causes a derepression of GAL system and an increase of GAL4 transcription.

The CDC25 gene product is an exchange factor for Ras proteins and it activates the Ras/cAMP pathway in the yeast Saccharomyces cerevisiae. The overexpression of the CDC25 gene in S. cerevisiae cells causes a partial glucose-derepressed phenotype which is particularly evident for expression of invertase. To define domains of Cdc25 protein relevant for this derepression and to test another glucose repressed system, different to invertase, we have overexpressed different regions of the CDC25 gene under the control of a GAL-promoter. We found that a derepression of both GAL regulated promoters and invertase was related to the overexpression of CDC25 regions that contain a functional guanine nucleotide exchange (GEF) domain. The effect on GAL-promoters was particular evident when the CDC25 gene was under the control of a UASgal element and operates at transcriptional level, although a moderate derepression was found also for UASgal/lacZ reporter gene. Finally, the overexpression of the GEF domain of CDC25 also caused an increase in the expression of the GAL4 regulatory gene, while a constitutive activation of the Ras/cAMP pathway did not produce any increase in GAL4 expression. These findings indicate that the overexpression of the catalytic domain of CDC25 gene is necessary and sufficient to give a glucose-derepression of GAL promoters and of invertase. They also suggest that the derepression of GAL promoters occurs through an increase of GAL4 expression in a Ras cAMP independent way.

HCV infection and diabetes mellitus: influence of the use of finger stick devices on nosocomial transmission.

An increased prevalence of hepatitis C virus (HCV) infection in patients with diabetes mellitus has suggested a link between these two conditions and the possibility of patient-to-patient HCV transmission during hospital admissions in diabetes units. We investigated the prevalence of HCV antibodies in 259 patients with diabetes mellitus consecutively admitted to our diabetic unit in 1998. The control group was composed of 14,100 volunteer blood donors. We divided the diabetic patients into two groups according to their HCV antibody status and also analysed patients for the following variables: age, disease duration, diabetes treatment, previous hospital admissions in a diabetes unit and use of finger stick devices. Anti-HCV antibodies were detected in 8 diabetic patients and 6 blood donors (3.09% vs 0.04%, p < 0.001). No differences were observed between anti-HCV-positive and anti-HCV-negative diabetic patients in terms of mode of treatment, previous hospital admissions in a diabetic unit and use of finger stick devices for capillary blood sampling. Our findings indicate that these medical practices play no role in nosocomial transmission of HCV in diabetic patients.

[Dermoid cyst of the ovary. False positive diagnosis in iodine 131 scintigraphy of differentiated thyroid cancers]. / Kyste dermoïde de l'ovaire. Faux positif à reconnaître lors de la surveillance scintigraphique à l'iode 131 des cancers différenciés thyroïdiens.

BACKGROUND: Total body 131-iodine labeled scintiscan is used to screen for residual tumoral tissue after ablation of differentiated thyroid carcinoma. At therapeutic doses, radioactive iodine can also be used for treatment. Thyroglobulin level, usually undetectable a few months after total thyroidectomy and metabolic irradiation with 131-iodine in patients without initial metastases, is absolutely necessary for interpreting the scintiscans. Iodine uptake occur in dermoid cysts which usually contain thyroid tissue. CASE REPORT: A 44-year old woman underwent total thyroidectomy with node dissection for papillary carcinoma of the thyroid with a vesicular architecture. Four months later, the total body 131-iodine scintiscan demonstrated a round zone of uptake in the pelvic area. The lesion was found to be a typical dermoid cyst. No thyroid or tumoral tissue could be demonstrated. DISCUSSION: Dermoid cysts can be the cause of false positive 131-scintiscans in patients followed after resection of differentiated thyroid carcinoma. Unlike previously reported cases, the dermoid cyst in this patient was totally devoid of thyroid tissue.

Intravenous methylprednisolone pulse therapy in the treatment of Graves' ophthalmopathy.

Graves' ophthalmopathy (GO) is a specific immune-mediated disorder, whose treatment is sometimes difficult. In order to investigate the efficacy of intravenous methylprednisolone (MP) pulse therapy in GO, we studied eight patients with GO, followed up for at least 6 months by clinical patient self-assessment, ophthalmological examination and orbital computed tomography (OCT). A 12.5 mg/kg dose of MP was administered intravenously over a 10 hour period, once every month. Three to six MP pulse administrations were performed in each patient. All patients were outpatients. A 0.5 mg/kg/day oral prednisone dose was given to each patient as interpulse therapy. Clinical assessment of MP pulse therapy showed a good response in 87.5% and no response in 12.5% of patients. The treatment was rapidly efficient, mostly on patient self-assessment, soft tissue inflammation, ophthalmoplegia, corneal involvement, visual acuity and extraocular muscle enlargement on OCT. Post-treatment ophthalmic index was significantly improved (6.75 +/- 3.06 vs. 2.5 +/- 1.41: p < 0.05). MP pulse therapy had less effect on proptosis (22.94 +/- 2.32 mm vs. 21.56 +/- 2.22 mm: p < 0.05). No adverse effects were noted with MP pulse therapy. Patients showed no relapse of eye involvement during a mean follow up of 31.8 months (2-77 months). In conclusion, our results suggest that intravenous MP pulse therapy is a good immunosuppressive therapy for GO. Moreover, in comparison with the previous studies, the MP dose used in our present study appears to be optimal with high efficacy. MP pulse therapy represents a safe and efficient treatment in GO, which can easily be performed in outpatients.

Identification of gene encoding a putative RNA-helicase, homologous to SKI2, in chromosome VII of Saccharomyces cerevisiae.

We have determined the nucleotide sequence of a segment of VII of the yeast Saccharomyces cerevisiae contained in the cosmid clone pEGH101 for a total of 7 kbp. This sequence contains a large open reading frame (ORF) called G9365, coding for a protein of 1967 amino acids that shows a significant homology with the product of the SKI2 gene of S. cerevisiae and contains domains characteristics of RNA-helicases. The ORF is transcribed in vegetative cells but it is not essential for viability as demonstrated by gene disruption.

[False positive scintigraphic images in the surveillance of differentiated thyroid cancers]. / Faux positifs scintigraphiques à l'iode 131 dans la surveillance des cancers thyroïdiens différenciés.

Iodine-131 whole body imaging and serum thyroglobulin are used in the follow-up evaluation of differentiated thyroid carcinomas. Iodine 131 is used to detect and treat functioning lesions. Iodine 131 activity detected outside the normal thyroid bed is usually attributed to metastatic disease. False-positive localization of radioiodine has been described, and may be a potential pitfall. We report here six personal cases of false-positive localisations of radioiodine du to body secretions, pathologic exudate, activity in nonlactating breast, salivary gland inflammation, ovarian teratoma. Some of these false-positive can be ruled out easily by removing of clothes, removing of nozzle in patients with tracheostomy, or by ingestion of water in subjects with abnormal mediastinal hyperfixation. Recognition of false-positive radioiodine images is very important to prevent costly additional investigation and possibly inappropriate therapy.