Dunnigan lipodystrophy syndrome: French National Diagnosis and Care Protocol (PNDS; Protocole National de Diagnostic et de Soins).

Dunnigan syndrome, or Familial Partial Lipodystrophy type 2 (FPLD2; ORPHA 2348), is a rare autosomal dominant disorder due to pathogenic variants of the LMNA gene. The objective of the French National Diagnosis and Care Protocol (PNDS; Protocole National de Diagnostic et de Soins), is to provide health professionals with a guide to optimal management and care of patients with FPLD2, based on a critical literature review and multidisciplinary expert consensus. The PNDS, written by members of the French National Reference Center for Rare Diseases of Insulin Secretion and Insulin Sensitivity (PRISIS), is available on the French Health Authority website (in French). Dunnigan syndrome is characterized by a partial atrophy of the subcutaneous adipose tissue and by an insulin resistance syndrome, associated with a risk of metabolic, cardiovascular and muscular complications. Its prevalence, assessed at 1/100.000 in Europe, is probably considerably underestimated. Thorough clinical examination is key to diagnosis. Biochemical testing frequently shows hyperinsulinemia, abnormal glucose tolerance and hypertriglyceridemia. Elevated hepatic transaminases (hepatic steatosis) and creatine phosphokinase, and hyperandrogenism in women, are common. Molecular analysis of the LMNA gene confirms diagnosis and allows for family investigations. Regular screening and multidisciplinary monitoring of the associated complications are necessary. Diabetes frequently develops from puberty onwards. Hypertriglyceridemia may lead to acute pancreatitis. Early atherosclerosis and cardiomyopathy should be monitored. In women, polycystic ovary syndrome is common. Overall, the management of patients with Dunnigan syndrome requires the collaboration of several health care providers. The attending physician, in conjunction with the national care network, will ensure that the patient receives optimal care through regular follow-up and screening. The various elements of this PNDS are described to provide such a support.

Spontaneous rupture of Achilles tendon and Cushing's disease. Case report.

Spontaneous rupture of Achilles tendon is observed in patients with tumors, metabolic disorders, infections and systemic diseases. Fluoroquinolones may cause tendinopathies. In addition, spontaneous rupture uncommonly occurs in Cushing's syndrome. We report a case of Cushing's disease revealed by recurrent rupture of Achilles tendon. Tendon tears are described in patients receiving long-term steroid treatment, probably via a mechanism similar to that one occurring in Cushing's syndrome. Although exceptional, this diagnosis should be discussed in patients with spontaneous rupture of Achilles tendon.

[Management of gestational hypertriglyceridemia by plasmapheresis]. / Prise en charge d'une hypertriglycéridémie gravidique par plasmaphérèse.

We report a case of unexpected severe hypertriglyceridemia (140N) diagnosed at 33 weeks during a second gestation. The risk of acute pancreatitis indicated plasmapheresis (three procedures) with reduction of hypertriglyceridemia (6N) and no impact on fetal well-being. Immediate recurrence led to induction of labour at 34 weeks. Spontaneous regression occurred after delivery. We demonstrated reduced lipoprotein lipase activity with no mutation for apolipoprotein E, nor lipoprotein lipase in favour of a potential pregnancy-induced inhibitor of lipoprotein degradation.

Glycated haemoglobin (HbA1c): today and tomorrow.

The assay of glycated haemoglobin (HbA1c) is a gold standard in bioanalysis, and is essential to ensure the optimal care of diabetic patients. Accordingly, the principal scientific societies in diabetology and clinical chemistry have made efforts to standardize this assay in order to select and validate certain analytical methods and achieve consistency in the results obtained therewith. However, clinicians have to be aware of the caution required when interpreting HbA1c assay results owing to modified lifetime and (or) abnormal synthesis of haemoglobin. Although this biological examination has now become an essential part of diabetes monitoring, its status as a screening tool is still controversial, even after 30 years of debate. Other uses of HbA1c assay are currently being assessed in cardiology (coronary syndromes), vascular diseases (arteriopathy), nephrology (renal insufficiency), haematology (anaemia) and oncology (factors of predisposition).

Radiotherapy of pituitary adenomas: state of the art.

Pituitary adenomas represent approximately 12% of intracranial tumors. They are defined as tumors that are functional or nonfunctional and invasive or noninvasive. Therapeutic strategies rely on surgery, medical treatment, and radiotherapy depending on histology. Neither the role of external radiotherapy nor the technique to be used are firmly established. Nonfunctioning adenomas must be operated on to relieve the compression. Prolactin-secreting adenomas are first treated with dopamine agonists, and GH-secreting adenomas are first treated by surgery if excising the complete tumor is possible; otherwise medical treatment is started. The first-line treatment of ACTH-secreting adenomas is surgery; however, in many cases, insufficient control of either secretion or tumoral volume leads to consideration of irradiation. Complications of conventional radiotherapy are well known and fractionated stereotactic radiotherapy appears to be as safe as radiosurgery. The volume to irradiate is still difficult to define, and this parameter can influence the technique chosen for treatment. Because the indications of radiotherapy are still debated, irradiation of pituitary adenomas must be decided by the complete team of endocrinologists, neurosurgeons, radiologists and radiotherapists.

P53/Rb inhibition induces metastatic adrenocortical carcinomas in a preclinical transgenic model.

Adrenocortical carcinoma (ACC) is a rare cancer with poor prognosis. Pan-genomic analyses identified p53/Rb and WNT/ß-catenin signaling pathways as main contributors to the disease. However, isolated ß-catenin constitutive activation failed to induce malignant progression in mouse adrenocortical tumors. Therefore, there still was a need for a relevant animal model to study ACC pathogenesis and to test new therapeutic approaches. Here, we have developed a transgenic mice model with adrenocortical specific expression of SV40 large T-antigen (AdTAg mice), to test the oncogenic potential of p53/Rb inhibition in the adrenal gland. All AdTAg mice develop large adrenal carcinomas that eventually metastasize to the liver and lungs, resulting in decreased overall survival. Consistent with ACC in patients, adrenal tumors in AdTAg mice autonomously produce large amounts of glucocorticoids and spontaneously activate WNT/ß-catenin signaling pathway during malignant progression. We show that this activation is associated with downregulation of secreted frizzled related proteins (Sfrp) and Znrf3 that act as inhibitors of the WNT signaling. We also show that mTORC1 pathway activation is an early event during neoplasia expansion and further demonstrate that mTORC1 pathway is activated in ACC patients. Preclinical inhibition of mTORC1 activity induces a marked reduction in tumor size, associated with induction of apoptosis and inhibition of proliferation that results in normalization of corticosterone plasma levels in AdTAg mice. Altogether, these data establish AdTAg mice as the first preclinical model for metastatic ACC.

Happy@feet application for the management of diabetic foot osteomyelitis.

OBJECTIVE: We aimed to develop and implement an application that could improve the management of patients presenting with diabetic foot osteomyelitis. PATIENTS AND METHODS: Physicians from the multidisciplinary diabetic foot infection team and a software engineer first assessed the needs required for the infection management and application. An experimental version was then designed and progressively improved. A final version was implemented in clinical practice in 2013 by the multidisciplinary diabetic foot infection team of our university hospital. RESULTS: The application, known as Happy@feet, helps gather and allows access to all required data for patient management, dispenses prescriptions (antibiotics, nursing care, blood tests), and helps follow the evolution of the wound. At the end of the consultation, a customizable letter is generated and may be directly sent to the persons concerned. This application also facilitates clinical and economic research. In 2014, Happy@feet was used to follow 83 patients during 271 consultations, 88 of which were day care hospitalizations. CONCLUSION: The Happy@feet application is useful to manage these complex patients. Once the learning period is over, the time required for data collection is compensated by the rapid dispense of prescriptions and letters. Happy@feet can be used for research projects and will be used in a remote patient management project.

Glucocorticoids do not regulate the expression of proteolytic genes in skeletal muscle from Cushing's syndrome patients.

Glucocorticoids signal enhanced proteolysis in various instances of muscle atrophy and increased gene expression of components of the lysosomal, Ca(2+)-dependent, and/or ubiquitin-proteasome proteolytic pathways in both rat skeletal muscle and myotubes. Cushing's syndrome is characterized by chronic excessive glucocorticoid production, which results in muscle wasting. We report here no change in messenger RNA levels for cathepsin D (a lysosomal proteinase), m-calpain (a Ca(2+)-activated proteinase), ubiquitin, 14-kDa ubiquitin-activating enzyme E2, and 20S proteasome subunits (i.e. critical components of the ubiquitin-proteasome proteolytic process) in skeletal muscle from such patients. Thus, in striking contrast with animal studies, glucocorticoids did not regulate the expression of muscle proteolytic genes in Cushing's syndrome. In humans, messenger RNA levels, for at least ubiquitin and proteasome subunits, are elevated in acute situations of muscle wasting, such as head trauma or sepsis. Because Cushing's syndrome is a chronic catabolic condition, we suggest that the lack of regulation of proteolytic genes in such patients may represent an adaptive regulatory mechanisms, preventing sustained increased protein breakdown and avoiding rapid muscle wasting.

Response of leucine metabolism to hyperinsulinemia in hypothyroid patients before and after thyroxine replacement.

We have investigated the effect of hypothyroidism and insulin on protein metabolism in humans. Six hypothyroid patients were studied in a postabsorptive state before and after 5 months of regular treatment for hypothyroidism (153 +/- 17 microg/day of L-T4). The effect of insulin was assessed under hyperinsulinemic euglycemic and eukalemic conditions. Insulin was infused for 140 min at 0.0063 +/- 0.0002 nmol/kg x min. An amino acid infusion was used to blunt insulin-induced hypoaminoacidemia. Whole body protein turnover was measured using L-[1-13C] leucine. When compared to L-T4-induced subclinical thyrotoxic state, hypothyroidism induced a significant decrease (P < 0.05) in leucine endogenous appearance rate (a reflection of proteolysis; 0.89 +/- 0.09 vs. 1.33 +/- 0.05 micromol/kg x min), oxidation (0.19 +/- 0.02 vs. 0.25 +/- 0.03 micromol/kg x min), and nonoxidative disposal (a reflection of protein synthesis; 0.87 +/- 0.11 vs. 1.30 +/- 0.05 micromol/ kg x min). Insulin lowered proteolysis during both the subclinical thyrotoxic and hypothyroid states. Hypothyroidism impaired the antiproteolytic effects of insulin. Thyroid hormones are, therefore, essential for the normal antiproteolytic action of insulin.

Plasma levels of 8-epiPGF2alpha, an in vivo marker of oxidative stress, are not affected by aging or Alzheimer's disease.

Free radicals are likely involved in the aging process and there is a growing body of evidence that free radical damage to cellular function is associated with a number of age-related diseases such as atherosclerosis, cancer, and neurologic disorders. The present study was designed to evaluate in a healthy population the evolution with age of 8-epiPGF2alpha plasma levels, a recently proposed marker of in vivo lipid peroxidation. Moreover we investigated this marker of oxidative stress in patients with Alzheimer's disease (AD), an age-related neurodegenerative disorder in the development of which free radicals have been involved. Our results show that in the healthy population studied, despite decreased antioxidant defenses with increasing age as monitored by antioxidant capacity measurement, plasma 8-epiPGF2alpha levels were not correlated with age. Moreover, we have demonstrated that AD patients presented no modification of plasma 8-epiPGF2alpha level and no major alteration of the antioxidant status. In conclusion, the measurement of plasma 8-epiPGF2alpha did not allow us to detect alterations in oxidative stress with aging or in AD.

Divergence in plasmatic and urinary isoprostane levels in type 2 diabetes.

BACKGROUND: Oxidative stress is currently suggested as a mechanism underlying diabetes. The present study was designed to evaluate isoprostane levels in plasma and in urine in type 2 diabetic patients, and to compare them to other currently used biomarkers of oxidative stress. METHODS: The work was performed in a control group (n = 10) and in a type 2 diabetic group (n = 10). Besides the traditional biochemical parameters, we evaluated the plasma and urine levels of isoprostanes and malondialdehyde (MDA) as markers of oxidative stress. RESULTS: We found increased plasma and urine MDA in the diabetic patients and almost significantly decreased plasma vitamin E. Urinary isoprostane levels in diabetic patients were increased but they presented a strong tendency to a decrease in plasma isoprostanes. It is therefore suggested that, in the studied diabetic patients, although the production of isoprostanes in the body was increased (as other plasma oxidative stress biomarkers were altered) it did not lead to an increase in plasma isoprostane levels. It could be hypothesised that this results from an increased elimination of this metabolite and therefore an increased excretion in urine. CONCLUSION: Our results showed that the measurement of same oxidative stress biomarker, isoprostane, in two different biologic fluids, plasma and urine, led to divergent results and emphasised the importance to measure a biomarker both in the circulation fluid (plasma) and in the elimination fluid (urine), to have a general idea of what is occurring in the organism.

[Carbimazole and leukocytoclastic vasculitis: apropos of a case]. / Carbimazole et vascularite leucocytoclasique: à propos d'un cas.

INTRODUCTION: The authors describe the case of biopsy-proven cutaneous leukocytoclastic vasculitis secondary to treatment with carbimazole. EXEGESIS: A 78-year-old white female developed erythematous macules on the lower limbs which cleared after discontinuation of her current treatment and implementation of oral steroid therapy. Causal explorations (lack of systemic disorder or infectious disease) remain negative, except for positive immune complexes. This case clearly differs from the two cases of microvasculitis (myositis and nephritis) secondary to treatment with carbimazole previously mentioned in the literature. CONCLUSION: To our knowledge this is the first report of biopsy-proven cutaneous leukocytoclastic vasculitis associated with this antithyroid agent. Its widespread use makes awareness of the side-effect important.

[Epidemiology of goiter in Auvergne]. / Epidémiologie du goitre en Auvergne.

An epidemiological study about goiter, related to the French national survey concerning school children aged 10-16, was carried out in region Auvergne. The prevalence of goiter was 12.52%, including 2.8% patients with WHO stages I and II, thus being slightly below national average (16.7%). Iodine urinary excretion was 62.9 +/- 34.3 micrograms per gram creatinine (French mean value 85.0), although sometimes major variation was noted in the same area. Later, two studies were performed in adults, in two places of Haute-Loire and Puy-de-Dôme, respectively Arsac-en-Velay and Besse-en-Chandesse. Both places were selected because of high frequency of goiter in children. Prevalence in adults was 16.1% in Arsac-en-Velay including 12.5% stages I and II, and 8.9% in Besse-en-Chandesse including 5.9% stages I and II. Mean iodine urinary excretion was respectively 59.78 micrograms/gram creatinine and 43.45 micrograms/liter. Thus, these surveys confirm a significant prevalence of goiter in Region Auvergne, with endemic places, and a generally low iodine urinary excretion.

[Painful chronic thyroiditis. A rare cause of thyroid pain]. / Thyroïdite chronique douloureuse. Une cause rare de douleur thyroïdienne.

The usual clinical presentation of Hashimoto's chronic lymphocytic thyroiditis is a firm and painless goiter. We report two atypical observations with painful symptoms. Case 1: a 33 year old woman with a two months history of L-thyroxine treated primary hypothyroidism associated with elevated antithyroglobulin and antithyroperoxydase antibodies (respectively 36.000 and 7.000 U/l, normal values < 100 U/l) presents with anterior cervical pain. She is euthyroid, but displays biological inflammatory syndrome. Neck ultrasonography reveals low amplitude echoes of the thyroid gland. Antithyroid antibodies remain at high titers. After failure of NSAI drugs, prednisolone (oral 30 mg/day for 10 days, followed by degression) allows rapid disappearance of both pain inflammatory syndrome. When treatment was stopped pain recurred and required steroids for 3 months. After one year, the patient is painless and only receives L-thyroxine. Case 2: a 36 year old woman is referred for anterior neck pain, fever and hypothyroidism. Biological inflammation is also noted. High levels of antithyroglobulin and antithyroperoxydase antibodies are found. Thyroid uptake was maintained. L-thyroxine and prednisolone (oral 20 mg/day) therapies are associated with rapid pain relief. After two months, steroids are stopped. The patient remains normothyroid under L-thyroxine. Antithyroid antibodies persist at high levels. Other aetiological diagnosis of painful thyroid include acute infectious thyroiditis, cancers, intracystic hemorrhages and mainly subacute De Quervain's thyroiditis. Beyond clinical symptoms (revelation with hypothyroidism), persistent scintiscan uptake and prolonged elevated levels of antithyroglobulin and antithyroperoxydase antibodies remain the strongest arguments in favor of the 33 reported cases of painful Hashimoto's chronic lymphocytic thyroiditis. Eventually, among various therapies used, steroids in conjunction with thyroid hormones, seem the most efficient.

[Bilateral adrenal tumoral formation. Regressive spontaneous evolution]. / Formation tumorale surrénalienne bilatérale. Evolution spontanée régressive.

A case of bilateral adrenal tumoral formation associated with Addison's disease is reported, and the possible cause of this association is discussed. The short-term deleterious course of metastatic malignancies, hemopathies or severe infections when left without specific treatment, and the long-term course of our patient's tumoral pathology excluded these diagnoses. The spontaneous regression of a bilateral pseudotumoral mass was suggestive of 2 causes: haematoma or tuberculosis. Haematoma was unlikely in the absence of causal factors, and this, combined with the slow regression of the adrenals, made tuberculosis the most probable diagnosis. The few similar cases found in the literature are reviewed.

[Primary hypothyroidism in the adult older than 60 years. Characteristics and follow-up after initiation of replacement treatment in hospital]. / Hypothyroïdie primaire de l'adulte de plus de 60 ans. Caractéristiques et suivi après initiation du traitement substitutif en milieu hospitalier.

OBJECTIVE: Primary hypothyroidism is common in the elderly. Yet its care remains unclear. PATIENTS AND METHODS: Clinical, biological characteristics and outcome of 45 patients aged over 60 years admitted for in-hospital initiation of treatment for primary hypothyroidism were recorded. Causes and tolerance of treatment (clinical and ECG monitoring in hospital) were seek for. RESULTS: Initial symptoms, predominantly fatigue (84.4%), were moderate, contrasting with severe biological hormonal deficiency. The most common routine biological change was hypercholesterolemia (57.6%). Female predominance was obvious (77.8%) and the most usual aetiology autoimmune chronic thyroiditis. Despite variability of symptoms, long term follow-up demonstrates a positive response to treatment, including an improvement in fatigue, eye-lid swelling, bradycardia and overweight. This clinical improvement was achieved on an average dose of 1.22 +/- 0.47 mg/kg/day L-T4 in order to maintain normal TSH (3.76 +/- 2.93 mUI/l). Cardiovascular incidents while starting treatment require experienced care and low dose initial treatment. CONCLUSION: Primary hypothyroidism is still lately discovered in the elderly. Yet, since treatment is efficacious and simple, the disease should be searched for and cared after whenever a related symptom occurs.

A brief psychological intervention to improve adherence in type 2 diabetes.

OBJECTIVE: Diabetes perceptions, acceptance and treatment motivation are changeable factors of adherence. This study aimed to test the effects of brief psychological interventions based on diabetes threat and mastery perceptions in terms of adherence, acceptance and motivation. Physicians may find such interventions useful during a 15-minute consultation with diabetes patients. RESEARCH DESIGN AND METHODS: This randomized controlled study included 80 patients with type 2 diabetes, recruited from the hospital diabetes department, who were randomly assigned to four intervention groups based on autobiographical recall. Those in the two intervention groups were asked to recall diabetic events based on mastery and threat perceptions, respectively, whereas those in the two control groups recalled non-diabetic events based on positive and negative emotions, respectively. Following this, all participants completed validated self-questionnaires assessing diabetes perceptions, acceptance, treatment motivation and adherence. RESULTS: Patients in the threat group reported less adherence (P<0.01) and less avoidance (P<0.05), and perceived diabetes as less threatening (P<0.05) than those in the mastery group. Similar results were obtained when the threat group was compared with its matched negative-emotion control group (P<0.05, P<0.05 and P=0.087, respectively). Patients in the mastery group reported feeling a stronger sense of mastery (P<0.05) than those in their positive-emotion control group and greater treatment acceptance than those in the threat group (P<0.01). CONCLUSION: Contrary to conventional medical belief, discussing threatening personal events with patients can yield positive results. Health professionals should take threat and mastery perceptions of diabetes into account during regular consultations with a view to improving treatment acceptance and adherence. With this brief intervention of type 2 diabetes patients, it was also more effective to alleviate their emotional difficulties than to enhance their perception of mastery.

Screening for deprivation using the EPICES score: a tool for detecting patients at high risk of diabetic complications and poor quality of life.

AIM: Deprivation has been linked to more complicated and uncontrolled diabetes. The validated Évaluation de la précarité et des inégalités de santé dans les centres d'examens de santé (EPICES; Evaluation of the Deprivation and Inequalities of Health in Healthcare Centres) score could help to identify such deprived patients. The present study evaluated the relationships between deprivation and prevalence of complications, uncontrolled diabetes and quality of life. METHODS: This prospective study was conducted in the diabetology department of a tertiary university hospital from November 2006 to July 2007. Patients with diabetes were divided into two groups, according to their deprivation status [non-deprived: EPICES score<30.17; deprived: EPICES score≥30.17 (56.5%)]. Diabetes control, complications and quality of life [Short Form Health Survey (SF-36)] were compared in the two groups. RESULTS: Of a total of 102 patients, 97 completed all of the questionnaires: 18 had type 1 diabetes and 79 had type 2 diabetes, in a geographical area moderately affected by deprivation. No statistical relationship could be demonstrated between deprivation and HbA(1c). Deprived patients with diabetes presented with higher levels of fasting blood glucose, lower levels of LDL cholesterol and a significantly higher risk of obesity (P=0.0020). As for complications, microalbuminuria was linked to deprivation (P=0.03), but no associations with other complications were found. Quality of life was poorer for all physical, mental and social dimensions in deprived patients. CONCLUSION: In this diabetic population, deprivation and glycaemic control were not associated. However, more deprived subjects with diabetes were at higher risk of renal disease. A deprived state was related to an altered quality of life as assessed by the SF-36 score.

Culture of per-wound bone specimens: a simplified approach for the medical management of diabetic foot osteomyelitis.

Surgical percutaneous bone biopsy specimen after a 14-day antibiotic-free period represents the gold standard of care for diabetic foot osteomyelitis but may be difficult to implement in many institutions. We evaluate a simplified strategy based on the results of per-wound bone specimen culture. For that purpose, we retrospectively reviewed the charts of 80 consecutive patients with diabetic osteomyelitis and bone sample obtained via the wound after a careful debridement. The outcome was defined as favourable if there was a complete healing of the wound with no sign of infection and stable or improved bone X-ray 6 months after antibiotic therapy completion. Culture of bone specimens was positive in 96% of patients, although half of the patients did receive a course of antimicrobials within 14 days of the bone specimen being obtained. A total of 129 bacterial isolates were obtained from bone cultures with a mean of 1.6 ± 1 isolates per patient (Staphylococcus aureus: 33%; central nervous system: 14%; streptococci: 9%; enterococci: 12%; corynebacteria: 4%; Gram-negative bacilli: 20%; anaerobes: 4%). Forty-six percent of cultures were monomicrobial. The mean duration of follow-up from diagnosis was 17 ± 1 months. Six months after discontinuation of antibiotic, six patients (7.5%) had died, nine were considered as therapeutic failures and 65 were considered as cured. Fifty-four of these 65 patients had follow-up data available at 1 year and remained in remission. In conclusion, a simplified procedure based on the culture of bone sample obtained via the ulcer after a careful debridement of the wound is effective in the medical management of diabetic foot osteomyelitis.