Bilateral tympanic myxoma: A CARE case report.

INTRODUCTION: Ear myxoma is a rare benign tumor sometimes located on the pinna and the external auditory meatus, associated with Carney Complex (CNC). However, tympanic membrane myxoma has never been described. We present here a case of bilateral tympanic membrane myxoma, following CARE guidelines. OBSERVATION: A 35-year-old woman presented to our department with right otalgia. Otoscopy showed non-specific bilateral tissular masses in the posterior quadrant of the tympanic membranes, with normal hearing thresholds. CT-scan showed a tissular mass without osteolysis. Right-side resection confirmed the lesion as being a myxoma, ruling out differential diagnoses. The patient was then screened for extra-otologic lesions typically associated with ear myxoma in CNC. Only perilabial lesions similar to lentigos suggested CNC. Cardiac, endocrine and thyroid assessment were normal. Genetic testing for a PKRAR1A gene mutation was negative. DISCUSSION: This is to our knowledge the first reported case of tympanic membrane myxoma. It is of particular interest, being bilateral and showing spontaneous involution of the left lesion over the years. Genetic screening was negative; nevertheless, thorough evaluation is essential due to the life-threatening nature of cardiac myxoma and the frequently associated malignant tumors. Potential new mutations associated with CNC should be considered in the future.

Pharyngolaryngeal semiology and prognostic factors in multiple system atrophy.

INTRODUCTION: Multiple system atrophy (MSA) is a rare degenerative neurological disorder in adults. It induces parkinsonian and/or cerebellar syndrome associated with dysautonomia. Pharyngolaryngeal symptoms are common. Our aim is to describe the Pharyngolaryngeal semiology on one hand, and to ascertain whether the presence of these symptoms represents a prognostic factor for MSA on the other. METHODS: Thus, we carried out a retrospective, single-centre study, on a cohort receiving care at the centre of reference for MSA. The patients were referred for otorhinolaryngology assessment. The data was collected over the year 2020 with the help of computer software from the university hospital centre (UHC). Firstly, we described the Pharyngolaryngeal semiology specific to MSA by questioning patients, and by the results of nasofibroscopic examinations and swallowing tests. We then used multivariate analysis of variance to describe the prognostic factors of MSA progression (in UMSARS I and II points per month of progression) and survival (number of years between the first symptoms and death). RESULTS: This study included a hundred and one patients and made it possible to define a Pharyngolaryngeal semiology profile of MSA, which is: a reduction in laryngeal mobility (primarily vocal cord abduction defects), abnormal movements (particularly at rest or when initiating a movement) and a defect in the protection mechanisms of the upper airways. The swallowing difficulties are moderate and the main mechanisms are delayed pharyngeal swallow and/or an oro-pharyngeal transport defect. In the multivariate analyses, the contributing factors are laryngeal anomalies, modification of solid food to fluid food and nutritional complication. CONCLUSION: ENT specialists should pay close attention to problems in the Pharyngolaryngeal dynamic and then consider a neurological cause. They can also itemize the clinical factors that could have a negative effect on the prognosis of the patient with MSA. Indeed, early detection makes it possible to provide care for respiratory and nutritional complications.

Clinical management of Menière's disease: Clinician perspective in 2020.

Menière's disease (MD) still presents both diagnostic and therapeutic difficulties. Today, this pathology is diagnosed only on clinical criteria. The development of high resolution magnetic resonance imaging of the inner is very promising to improve diagnostic criteria in MD. MD treatment depending on the practitioner and the clinical center, is mainly based on conservative therapies, and if this fails, non-ablative or ablative therapies. MD therefore always exposes clinicians to diagnostic uncertainties, but also to therapeutic difficulties which still lead to destructive treatments, in the absence of targeted, curative treatments, acting on the cause and not on the consequence of the pathology.

Vestibular disorders: clinician ENT perspective on the need for research and innovation.

OBJECTIVE: Vertigo and dizziness are a frequent reason for medical consultation. However, diagnostic and therapeutic management is sometimes limited, and clinicians are faced with many unmet needs. The purpose of this study was to identify and prioritize these needs. METHODS: A questionnaire methodology was used to determine the need for innovation in vestibular disorder management. The questionnaire was sent to 19 teams in French-speaking ENT centers. We measured the concordance of the panel of experts on 56 questions related to the different vestibular pathologies encountered and the desired modalities of innovations. RESULTS: Thirteen questions were identified as priorities. The needs expressed by the experts had better knowledge of the pathophysiological mechanisms of the main diseases encountered and the development of new treatment modalities. Particular attention was paid to inner ear imaging techniques and the development of specific electrophysiology techniques. DISCUSSION: Some of the anticipated innovations are already under development, such as new inner ear fluid imaging techniques (hydrops visualization using MRI) or in situ treatments (transtympanic dexamethasone or gentamicin injections). Others, such as new electrophysiological techniques, are still not fully developed CONCLUSION: This study provides a snapshot of the needs of the medical profession in vestibular disorder management. It highlights a real concern of the attending personnel, as well as a critical need to optimize the means of diagnosing and treating patients with vestibular disorders.

Transnasal Endoscopic Sphenopalatine Artery Ligation Compared With Embolization for Intractable Epistaxis: A Long-term Analysis.

Background Transnasal endoscopic sphenopalatine artery ligation (TESPAL) and selective embolization both provide excellent treatment success rate in the management of intractable epistaxis. Few long-term studies comparing these approaches have been previously published. Recommendations often present these techniques as alternatives, but there is no clear consensus. Objective The purpose of this study was to evaluate and compare the clinical efficacy of sphenopalatine artery ligation versus embolization to control intractable epistaxis. Methods We performed a retrospective study including all patients referred to our tertiary medical center for severe epistaxis and treated by surgical ligation and/or embolization. The patients were classified into 2 groups: those who underwent TESPAL only and those who underwent endovascular embolization only. We evaluate and compare long-term clinical outcomes after surgical ligation or embolization for the control of intractable epistaxis in terms of effectiveness (recurrence rate) and safety (complication rate). Results Forty-one procedures of supraselective embolization and 39 procedures of surgical ligation for intractable epistaxis are reported and analyzed. No significant difference was observed between the groups in terms of demographic factors, comorbidities, or average length of hospital stay. The 1-year success rate was similar (75%) in both groups. Complications (minor and/or major) occurred in 34% cases in the embolization group and in 18% in the surgical group ( P = .09, ns). Bilateral embolization including facial artery was the only treatment method associated with a significant risk of complications ( P = .015). Conclusion TESPAL seems to provide a similar control rate with a decrease in the number of complications compared to selective embolization in the context of intractable epistaxis. Further studies are required.

Intractable epistaxis: which arteries are responsible? An angiographic study.

PURPOSE: Epistaxis constitutes a significant proportion of the Otolaryngologist's emergency workload. Optimal management differs in relation to the anatomic origin of the bleeding. The outcome of our study was to determine which artery(ies) could be considered as the cause of severe bleeding in the context of severe epistaxis. METHODS: Fifty-five procedures of embolization preceded by angiography were reviewed. Medical records of interventionally treated patients were analysed for demographics, medical history, risk factors and clinical data. Angiographic findings were also assessed for active contrast extravasation (blush), vascular abnormality and embolised artery. RESULTS: Previous angiography showed an active contrast extravasation in only 20 procedures. The most common bleeding source was the sphenopalatine artery (SPA) followed by anterior ethmoïdal artery (AEA) and facial artery. Majority of multiple or bilateral extravasations occured in patients with systemic factors. CONCLUSIONS: A better understanding of the potential bleeding source might help and limit the risk of treatment failures. Our study confirms that the SPA is the most common cause of severe bleeding. We also emphasise the role of the AEA not only in traumatic context. Others arteries are rarely involved except in patients with comorbidities or frequent recurrences.

Combination of blood tests for significant fibrosis and cirrhosis improves the assessment of liver-prognosis in chronic hepatitis C.

BACKGROUND: Recent longitudinal studies have emphasised the prognostic value of noninvasive tests of liver fibrosis and cross-sectional studies have shown their combination significantly improves diagnostic accuracy. AIM: To compare the prognostic accuracy of six blood fibrosis tests and liver biopsy, and evaluate if test combination improves the liver-prognosis assessment in chronic hepatitis C (CHC). METHODS: A total of 373 patients with compensated CHC, liver biopsy (Metavir F) and blood tests targeting fibrosis (APRI, FIB4, Fibrotest, Hepascore, FibroMeter) or cirrhosis (CirrhoMeter) were included. Significant liver-related events (SLRE) and liver-related deaths were recorded during follow-up (started the day of biopsy). RESULTS: During the median follow-up of 9.5 years (3508 person-years), 47 patients had a SLRE and 23 patients died from liver-related causes. For the prediction of first SLRE, most blood tests allowed higher prognostication than Metavir F [Harrell C-index: 0.811 (95% CI: 0.751-0.868)] with a significant increase for FIB4: 0.879 [0.832-0.919] (P = 0.002), FibroMeter: 0.870 [0.812-0.922] (P = 0.005) and APRI: 0.861 [0.813-0.902] (P = 0.039). Multivariate analysis identified FibroMeter, CirrhoMeter and sustained viral response as independent predictors of first SLRE. CirrhoMeter was the only independent predictor of liver-related death. The combination of FibroMeter and CirrhoMeter classifications into a new FM/CM classification improved the liver-prognosis assessment compared to Metavir F staging or single tests by identifying five subgroups of patients with significantly different prognoses. CONCLUSIONS: Some blood fibrosis tests are more accurate than liver biopsy for determining liver prognosis in CHC. A new combination of two complementary blood tests, one targeted for fibrosis and the other for cirrhosis, optimises assessment of liver-prognosis.

Bone status in a mouse model of genetic hemochromatosis.

UNLABELLED: Genetic hemochromatosis is a cause of osteoporosis; mechanisms leading to iron-related bone loss are not fully characterized. We assessed the bone phenotype of HFE (-/-) male mice, a mouse model of hemochromatosis. They had a phenotype of osteoporosis with low bone mass and alteration of the bone microarchitecture. INTRODUCTION: Genetic hemochromatosis is a cause of osteoporosis. However, the mechanisms leading to iron-related bone loss are not fully characterized. Recent human data have not supported the hypothesis of hypogonadism involvement. The direct role of iron on bone metabolism has been suggested. METHODS: Our aim was to assess the bone phenotype of HFE (-/-) male mice, a mouse model of human hemochromatosis, by using microcomputed tomography and histomorphometry. HFE (-/-) animals were sacrificed at 6 and 12 months and compared to controls. RESULTS: There was a significant increase in hepatic iron concentration and bone iron content in HFE (-/-) mice. No detectable Perls' staining was found in the controls' trabeculae. Trabecular bone volume (BV/TV) was significantly lower in HFE (-/-) mice at 6 and 12 months compared to the corresponding wild-type mice: 9.88 ± 0.82% vs 12.82 ± 0.61% (p = 0.009) and 7.18 ± 0.68% vs 10.4 ± 0.86% (p = 0.015), respectively. In addition, there was an impairment of the bone microarchitecture in HFE (-/-) mice. Finally, we found a significant increase in the osteoclast number in HFE (-/-) mice: 382.5 ± 36.75 vs 273.4 ± 20.95 ¢/mm(2) (p = 0.004) at 6 months and 363.6 ± 22.35 vs 230.8 ± 18.7 ¢/mm(2) (p = 0.001) at 12 months in HFE (-/-) mice vs controls. CONCLUSION: Our data show that HFE (-/-) male mice develop a phenotype of osteoporosis with low bone mass and alteration of the microarchitecture. They suggest that there is a relationship between bone iron overload and the increase of the osteoclast number in these mice. These findings are in accordance with clinical observations in humans exhibiting genetic hemochromatosis and support a role of excess iron in relation to genetic hemochromatosis in the development of osteoporosis in humans.

FibroMeters: a family of blood tests for liver fibrosis.

FibroMeters are blood tests for liver fibrosis with several specificities: two main diagnostic targets (fibrosis stage and area of fibrosis); adaptation to specific causes; and results confirmed by an expert system. Thus, FibroMeters comprise six different tests: one for staging and one for quantitation of liver fibrosis in each of the three main causes of chronic liver disease-chronic viral hepatitis, alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD). FibroMeters display a high overall diagnostic accuracy and are the only tests to correctly classify 100% of HCV patients without fibrosis or with cirrhosis. They have 90% predictive values in a higher proportion of patients than with other usual blood tests. A 90% correct classification is available in 100% of HCV patients with the following reliable diagnostic intervals: F0/1, F1/2, F2+/-1, F3+/-1. In real-life conditions, the reproducibility of FibroMeters is higher than that of liver biopsy or ultrasonographic elastometry. FibroMeters are robust tests with the most stable diagnostic performance across different centers. Optional tests are also available, such as a specific one for cirrhosis, which has a diagnostic accuracy of 93.0% (AUROC: 0.92) and a 100% positive predictive value for diagnosis of HCV cirrhosis. Determination by FibroMeters of the area of fibrosis - the only direct, non-invasive, quantitative measurement of liver fibrosis - are especially useful for following-up cirrhosis as it correlates well with clinical events. FibroMeters are also very accurate in HVB or HIV-HCV co-infected patients. The tests specific for ALD and NAFLD also have a high diagnostic accuracy (AUROCs: 0.96 and 0.94, respectively, for significant fibrosis).

Distribution of adipose tissue: quantification and relationship with hepatic steatosis and vascular profiles of type 2 diabetic patients with metabolic syndrome.

AIM: As the distribution of fat is increasingly related to cardiovascular events, we examined whether or not abdominal-fat quantification using magnetic resonance imaging (MRI) software is reliable, and whether or not it is related to clinical markers of fat distribution as well as to metabolic and vascular status. METHODS: We recorded the anthropometric measurements of 34 obese type 2 diabetic patients with metabolic syndrome. The patients were enrolled to evaluate their abdominal (visceral and subcutaneous) adipose tissue by single-slice L3-L4 MRI. Manual and automated analyses were compared. The relationships between anthropometric measurements, biological markers and intima-media thickness of the common carotid artery were also assessed. RESULTS: We validated the automated software to quantify abdominal-fat deposition with MRI compared with manual measurements (r2=0.95). The waist-to-hip-circumference ratio (WHR) was the only clinical parameter that correlated with the proportion and quantity of visceral and subcutaneous abdominal-adipose tissue evaluated by MRI (r=0.60). In addition, fat repartition as evaluated by WHR was related to hepatic steatosis parameters (ferritin and ALAT) and to intima-media thickness, whereas simple waist circumference was not a determinant in these obese patients. We also showed that the adiponectin-to-leptin ratio was related to adipose tissue distribution. CONCLUSION: Distribution of abdominal fat, as evaluated by MRI, can be reflected by clinical determination of the WHR. Differences in regional accumulations of abdominal fat may be specifically related to variations in the risks of steatosis and vascular rigidity among obese type 2 diabetic patients.

Osteopontin is histochemically detected by the AgNOR acid-silver staining.

Silver nitrate staining of decalcified bone sections is known to reveal osteocyte canaliculi and cement lines. Nucleolar Organising Regions (NOR) are part of the nucleolus, containing argyrophilic proteins (nucleoclin/C23, nucleophosmin/B23) that can be identified by silver staining at low pH. The aim of this study was to clarify the mechanism explaining why AgNOR staining also reveals osteocyte canaliculi. Human bone and kidney sections were processed for silver staining at light and electron microscopy with a modified method used to identify AgNOR. Sections were processed in parallel for immunohistochemistry with an antibody direct against osteopontin. Protein extraction was done in the renal cortex and decalcified bone and the proteins were separated by western blotting. Purified hOPN was also used as a control. Proteins were electro-transferred on polyvinylidene difluoride membranes and stained for AgNOR proteins. In bone, Ag staining identified AgNOR in cell nuclei, as well as in osteocyte canaliculi, cement and resting lines. In the distal convoluted tubules of the kidney, silver deposits were also observed in cytoplasmic granules on the apical side of the cells. Immunolocalization of osteopontin closely matched with all these locations in bone and kidney. Ag staining of membranes at low pH revealed bands for NOR proteins and 56 KDa (kidney), 60KDa (purified hOPN) and 75 KDa (bone) bands that corresponded to osteopontin. NOR proteins and osteopontin are proteins containing aspartic acid rich regions that can bind Ag. Staining protocols using silver nitrate at low pH can identify these proteins on histological sections or membranes.

Osteopontin is an argentophilic protein in the bone matrix and in cells of kidney convoluted tubules.

Nucleolar organising regions (NOR) are part of the nucleolus, containing argyrophilic proteins (nucleoclin/C23, nucleophosmin/B23). They are identified by silver staining at low pH. The method also reveals osteocyte canaliculi and cement lines and granules in the cytoplasm of kidney cells in locations that mimic osteopontin distribution. Human bone and kidney sections, benign and lymphomatous pleural effusions were processed for silver staining to identify AgNOR. Sections were processed in parallel for immunohistochemistry with an antibody direct against osteopontin. In pleural effusions, AgNORs were found increased in the nuclei of lymphoma cells. In bone, Ag staining identified AgNOR in cell nuclei, as well as in osteocyte canaliculi, cement and resting lines. In the distal convoluted tubules of the kidney, silver deposits were also observed in cytoplasmic granules on the apical side of the cells. Immunolocalization of osteopontin closely matched with all these locations in bone and kidney. NOR proteins and osteopontin are proteins containing aspartic acid rich repeats that can bind Ag. Staining protocols using silver nitrate at low pH can identify these proteins on histological sections. AgNOR is a useful histochemical method to identify osteopontin in bone sections.

Disuse and orchidectomy have additional effects on bone loss in the aged male rat.

INTRODUCTION: A severely osteopenic rat model was obtained by combining orchidectomy (ORX) and disuse (due to local paralysis induced by botulinum toxin [BTX] in the quadriceps muscle). METHODS: Forty-two aged male rats (5-6 months old) were randomized into three groups: 18 were SHAM operated; 6 were ORX; and 18 were ORX and BTX injected in the right hindlimb. One, two, and three months after surgery, bone mass (BV/TV) and microarchitectural parameters (Tb.Th, Tb.N, Tb.Sp, Tb.Pf, and structure model index [SMI]) were measured by microcomputed tomography (microCT) on the primary and secondary spongiosa of the femur. Osteoid parameters (OS/BS, O.Th), the number of osteoclasts (Nb.Oc), and the mineral apposition rate (Ct.MAR, Cn.MAR) were measured by histology. The serum tartrate-resistant acid phosphatase (TRAcP) 5b activity was measured by immunoassay. RESULTS: ORX induced a decrease of BV/TV, Tb.N and an increase of Tb.Sp, Tb.Pf, and SMI on both primary and secondary spongiosa. ORX and BTX had cumulative effects on bone loss, since differences were maximized on the right femur. The decrease in BV/TV reached -65%. Osteoid parameters and mineral apposition rate increased during the time course of the study. A peak of serum TRAcP was found at 7 days post-ORX. TRAcP levels reached the highest values in the ORX-BTX groups and the effect lasted longer than in the group with ORX alone. The association of ORX-BTX induced a greater bone resorption, due to the removal of complete trabeculae, compared to ORX alone. CONCLUSION: This model induced a severe and rapid bone loss and can be used to explore pharmacological- and biomaterial-based countermeasures.

Ex vivo bone mineral density of the wrist: influence of medullar fat.

The cone beam technology was recently proposed in a third generation of densitometers (dual photon X-ray absorptiometry, DXA such as the Lexxos densitometer). Because fat is a well-known problem with DXA, we have designed a cadaver study to compare the influence of medullary lipids on the measures performed with the Hologic QDR4500 and the Lexxos. Twenty-three human distal radii were obtained and analyzed in parallel on both densitometers; bone mineral density (BMD) was measured at the distal radius with standard softwares and on a standardized square regions of interest (ROI). Bones were then defatted and a new series of measurement was performed. Bones were then thoroughly dried and a cube was prepared at the distal radius with a banding saw. Trabecular and total bone volumes were measured by microcomputerized tomography. Ash eight was obtained after calcination of the blocks. BMD could be measured on the Lexxos before and after delipidation but this was not possible with the QDR4500. The X-ray image quality was better with the Lexxos. Delipidation had a very significant effect on measurements: after defatting, BMD values were considerably reduced (-49.8 +/- 19.4%). BMD before/after defatting were significantly correlated (r = 0.81, P < 0.0001) but bone mass appeared to reflect 66% of the variance. BMD was significantly correlated with BV/TV after defatting (r = 0.44, P < 0.03) but the correlation improved when cortices were taken into account (r = 0.70, P < 0.0001). Ash weight was significantly correlated with BMD and total bone volume (respectively, r = 0.84, P < 0.0001; r = 0.53, P < 0.03), but not with BV/TV. BMD at the distal radius is influenced by marrow fat and cortical density.

Serum triglycerides are a predictive factor for the development and the progression of renal and retinal complications in patients with type 1 diabetes.

OBJECTIVES: It is controversial that serum lipIds affect the development and progression of microvascular complications in patients with type 1 diabetes. METHODS: We prospectively followed 297 patients with type 1 diabetes without end-stage renal disease for 7 Years (range: 2-10). Serum lipIds were measured at baseline (total and HDL-cholesterol, triglycerIdes and calculated LDL-cholesterol, Lipoprotein (a)). The primary end-point was the occurrence of a renal event and the secondary end-point was the occurrence of a retinal event, defined as the progression to a higher stage of diabetic nephropathy or retinopathy, respectively. RESULTS: Serum triglycerIde (TG) levels were higher in patients who progressed in nephropathy than in those who dId not [median 1.21 (range 0.41-2.96) vs 0.91 (0.31-11.07) mmol/l; p=0.0037] and in those who developed retinal events than in those who dId not [1.05 (0.46-8.27) vs 0.87 mmol/l (0.31-11.07); p=0.0302], both in the whole cohort and in patients with normoalbuminuria at baseline. After adjustment for systolic blood pressure (SBP), diabetes duration, gender, stage of complications at baseline and glycohemoglobin (HbA1c), the relative risk for progression was 2.01 (95% CI: 1.07-3.77) for nephropathy and 2.30 (95% CI: 1.03-5.12) for retinopathy for patients having serum TG in the highest tertile, compared to the others. This result persisted when only patients with normoalbuminuria were consIdered. CONCLUSION: High triglycerIde levels are an independent predictive factor of both renal and retinal complications in patients with type 1 diabetes.

Angiotensin-I-converting enzyme insertion/deletion polymorphism and high urinary albumin concentration in French Type 2 diabetes patients.

AIMS: Family-based studies suggest a genetic basis for nephropathy in Type 2 diabetes. The angiotensin-I-converting enzyme (ACE) gene is a candidate gene for Type 1 diabetes nephropathy. We assessed the association between high urinary albumin concentration and ACE insertion/deletion (I/D) polymorphism, in French Type 2 diabetes patients. METHODS: We studied 3139 micro/macroalbuminuric French patients recruited in the DIABHYCAR Study, an ACE inhibition trial in Type 2 diabetes patients with renal and cardiovascular outcomes. The main inclusion criteria were age >/= 50 years, urinary albumin concentration >/= 20 mg/l assessed centrally during two consecutive screening visits, and plasma creatinine concentration

[Polymorphism of aldose reductase gene and susceptibility to retinopathy and nephropathy in Caucasians with type 1 diabetes]. / Polymorphismes du gène de l'aldose réductase et susceptibilité à la rétinopathie et à la néphropathie chez des caucasiens diabétiques de type 1.

Polymorphisms of the -106 mutation and z - 2 or z + 2 microsatellites (-2.1 kb) of the Aldose Reductase (AR) gene have been associated to microangiopathic complications of the diabetes mellitus. The study aimed to establish a relation between the occurrence and progression of the renal and retinal complications and these polymorphisms. The genotypes were realised in 3 populations: DESIR (n = 369), non-diabetic control subjects from the general French population: GENEDIAB (n = 494), type 1 diabetic patients who are suffering from proliferative retinopathy associated with a variable seriousness nephropathy (absent: n = 157; incipient: n = 104; established: n = 126; advanced: n = 107); SURGENE (n = 310), type 1 diabetic patients whom the renal status is prospectively assessed since 1989 in one single center Angers University Hospital. The genotype of the -106 polymorphism was determined using the Molecular Beacons. For the microsatellites analysis, we used an automatized method (GeneScan Abi Prism 3100). There was a strong linkage disequilibrium between the z - 2 allele and the T allele (chi 2 = 120; p = 0.001). The frequency of the C-106T is similar for the DESIR and GENEDIAB cohorts (chi 2 = 3.32; p = 0.19); the Hardy Weinberg law was verified in this group (chi 2 = 0.001, 0.9; p = 1.5 and 0.5 respectively). The law was not verified for the SURGENE cohort (chi 2 = 4.7; p = 0.03) where the frequency of the TT genotype was significantly more important compared to the DESIR population (chi 2 = 6.4; p = 0.01). The z, z - 2 and z + 2 alleles was more frequent compared with other alleles (n = 909, 830 and 349; 39, 38 and 15%). The frequency of the C-106T and microsatellites genotypes did not parallel the nephropathy staging in the GENEDIAB population (chi 2 = 10.9, 2.7, 2.4; p = NS respectively). In the SURGENE population, the survival without renal events did not differ according C-106T and z - 2 or z + 2 microsatellites genotypes (log-rank: 0.6, 3.9, 0.1; p = NS respectively). At the end of the follow-up, we found an effect of the -106 mutation and of the z - 2 microsatellite on the staging of the retinopathy (chi 2 tendency test = 4.61, 0.12; p = 0.031, 0.02; 6 d.f., respectively). The logistic regression multivariable analysis shows that the retinopathy during the final evaluation is independently explained by several factors: diabetes duration (p < 0.0001; OR 21.756; 95% CI: 7.024-67.389), presence of nephropathy (p < 0.0001; OR: 4.086; 95% CI: 2.094-7.973), and genotype TT (p = 0.011; OR: 0.38; 95% CI: 0.18-0.803). In contrast, age of diabetes onset (p = 0.112; OR: 1.556; 95% CI: 0.9-2.692), median HbA1c (p = 0.164; OR: 1.479; 95% CI: 0.85-2.576) and sex (p = 0.156; OR: 1.495; 95% CI: 0.856-2.612) have no independent effect. In conclusion, the association of these AR genetic variants seems absent about the renal risk and slight about the retinal risk associated to the type 1 diabetes mellitus.

Genetically increased angiotensin I-converting enzyme level and renal complications in the diabetic mouse.

Diabetic nephropathy is a major risk factor for end-stage renal disease and cardiovascular diseases and has a marked genetic component. A common variant (D allele) of the angiotensin I-converting enzyme (ACE) gene, determining higher enzyme levels, has been associated with diabetic nephropathy. To address causality underlying this association, we induced diabetes in mice having one, two, or three copies of the gene, normal blood pressure, and an enzyme level range (65-162% of wild type) comparable to that seen in humans. Twelve weeks later, the three-copy diabetic mice had increased blood pressures and overt proteinuria. Proteinuria was correlated to plasma ACE level in the three-copy diabetic mice. Thus, a modest genetic increase in ACE levels is sufficient to cause nephropathy in diabetic mice.

Physicochemical properties of structured water in human albumin and gammaglobulin solutions.

The physicochemical properties of the different phases of water molecules were studied in concentrated solutions (132 g/L) of human serum albumin and gammaglobulin by (1)H NMR relaxometry. Spin-lattice (T1) relaxation times of total water and structured water (non-freezable water) were measured at 40 MHz above and below the freezing point of bulk water (ordinary, liquid water) at different temperatures. Analysis of the temperature dependence of the T1 demonstrated that total water differed qualitatively while structured water characteristics changed both quantitatively and qualitatively in the two protein solutions. Comparison of the temperature dependence of the structured water's T1 in the two solutions in the presence of an increasing concentration of manganese chloride allowed two main conclusions to be drawn. Firstly, the differences observed in total water and structured water physicochemical properties are directly related to protein structure and three-dimensional arrangement. Secondly, the motion of structured water determines the motion of the total water in the system through the values of the translational diffusion and chemical exchange correlation times tau(D) and tau m.