Steroid hormones in systemic sclerosis: associations with disease characteristics and modifications during scleroderma renal crisis.

OBJECTIVE: The renin-angiotensin-aldosterone system (RAAS) and glucocorticoids (GCs) are involved in vascular remodeling and fibrosis, but have not been extensively studied in systemic sclerosis (SSc). Our aim was to investigate the RAAS and GC hormones in SSc patients. METHODS: Serum levels of renin (dosage and activity), aldosterone and its precursors (DOC, B, 18-OH-DOC, 18-OH-B), and GCs (cortisol, cortisone, 11-deoxycortisol, 18-OH-F) were assessed in 122 SSc patients and 52 healthy controls. After applying stringent inclusion criteria aimed at ensuring accurate hormone assessments (exclusion of interfering drugs, strict sampling conditions), we analyzed RAAS hormones in 61 patients, and GCs in 96 patients. Hormone levels were compared between patients and controls; and associations with disease characteristics were assessed in patients. RESULTS: Regarding RAAS hormones, SSc patients displayed significantly lower aldosterone levels (although within normal range), similar renin levels, and higher B levels than controls. Abnormal RAAS hormone levels were associated with a more severe SSc phenotype (lung and skin fibrosis, heart and pulmonary vascular involvements, inflammation). Regarding GC hormones, SSc patients had higher levels of cortisol, 11-desoxycortisol (precursor) and 18-OH-F (metabolite) but lower levels of cortisone (inactive counterpart) than controls.RAAS hormone levels were assessed in 5 SSc patients before and during scleroderma renal crisis (SRC): concentrations varied considerably between patients, but consistently included normal/increased aldosterone levels and elevated renin levels. CONCLUSION: RAAS and GC hormones are abnormally produced in SSc patients, especially in patients with severe SSc and during SRC. This could suggest a participation of these hormonal systems in SSc pathogenesis.

A reactive transport model designed to predict the environmental footprint of an 'in-situ recovery' uranium exploitation.

Worldwide, most uranium production relies on the 'in situ recovery' (ISR) extraction technique. This consists of dissolving the ore using a leaching solution (acid or alkaline) directly within the deposit through a series of injection and extraction wells. Due to the nature of the injected ISR solutions, the water quality of the aquifer could be affected. Reactive transport modeling is a powerful tool for predicting fluid flow and geochemical reactions in ISR reservoirs. In this study we present a coupled 3D environmental geochemical model (EGM) (based on the HYTEC reactive transport software), capable of predicting the physico-chemical conditions in an acid-leaching ISR uranium mine and its environmental footprint on the aquifer in the years following the closure of the production block. The model was validated at the KATCO mine (Kazakhstan) on two different and independent production blocks, over 10 years after their closure. The model shows that incorporating two main geochemical processes, (1) cationic sorption on clay surfaces (smectite-beidellite) and (2) precipitation of gypsum (CaSO4.2H2O), successfully reproduces the measured well data (pH, acidity and SO4) over short- and long-term time scales. Clay surface sites remain mostly saturated in protons during the production phase. Simulations show that sorbed protons on the clay surfaces maintains the acid conditions for a longer period of time. The environmental impact model was also compared to a pre-existing model specifically developed for production simulation purposes: differences are observed as expected for the uranium production, but also for the impact distances, due to differences in the considered reactive mineralogical paragenesis. Thus, the choice of geochemical model should be made with due regard for the desired objectives. This work will assist the mine operator by providing a tool capable of assessing both the short- and long-term environmental footprints of the ISR production operation conditions and of identifying the best remediation strategy.

Temperature, geometry, and bifurcations in the numerical modeling of the cardiac mechano-electric feedback.

This article characterizes the cardiac autonomous electrical activity induced by the mechanical deformations in the cardiac tissue through the mechano-electric feedback. A simplified and qualitative model is used to describe the system and we also account for temperature effects. The analysis emphasizes a very rich dynamics for the system, with periodic solutions, alternans, chaotic behaviors, etc. The possibility of self-sustained oscillations is analyzed in detail, particularly in terms of the values of important parameters such as the dimension of the system and the importance of the stretch-activated currents. It is also shown that high temperatures notably increase the parameter ranges for which self-sustained oscillations are observed and that several attractors can appear, depending on the location of the initial excitation of the system. Finally, the instability mechanisms by which the periodic solutions are destabilized have been studied by a Floquet analysis, which has revealed period-doubling phenomena and transient intermittencies.

Breast and ovarian cancer predisposition due to de novo BRCA1 and BRCA2 mutations.

BRCA1 and BRCA2 are the two major genes predisposing to breast and ovarian cancer. Whereas high de novo mutation rates have been demonstrated for several genes, only 11 cases of de novo BRCA1/2 mutations have been reported to date and the BRCA1/2 de novo mutation rate remains unknown. The present study was designed to fill this gap based on a series of 12 805 consecutive unrelated patients diagnosed with breast and/or ovarian cancer who met the inclusion criteria for BRCA1/2 gene analysis according to French guidelines. BRCA1/2 mutations were detected in 1527 (12%) patients, and three BRCA1 mutations and one BRCA2 mutation were de novo. The BRCA1/2 de novo mutation rate was estimated to be 0.3% (0.1%; 0.7%). Although rare, it may be useful to take the possibility of de novo BRCA1/2 mutation into account in genetic counseling of relatives and to improve the understanding of complex family histories of breast and ovarian cancers.

Development of specific dengue virus 2'-O- and N7-methyltransferase assays for antiviral drug screening.

Dengue virus (DENV) protein NS5 carries two mRNA cap methyltransferase (MTase) activities involved in the synthesis of a cap structure, (7Me)GpppA(2'OMe)-RNA, at the 5'-end of the viral mRNA. The methylation of the cap guanine at its N7-position (N7-MTase, (7Me)GpppA-RNA) is essential for viral replication. The development of high throughput methods to identify specific inhibitors of N7-MTase is hampered by technical limitations in the large scale synthesis of long capped RNAs. In this work, we describe an efficient method to generate such capped RNA, GpppA(2'OMe)-RNA74, by ligation of two RNA fragments. Then, we use GpppA(2'OMe)-RNA74 as a substrate to assess DENV N7-MTase activity and to develop a robust and specific activity assay. We applied the same ligation procedure to generate (7Me)GpppA-RNA74 in order to characterize the DENV 2'-O-MTase activity specifically on long capped RNA. We next compared the N7- and 2'-O-MTase inhibition effect of 18 molecules, previously proposed to affect MTase activities. These experiments allow the validation of a rapid and sensitive method easily adaptable for high-throughput inhibitor screening in anti-flaviviral drug development.

[One-dimensional time-dependent model of the cardiac pacemaker activity induced by the mechanoelectric feedback in a thermo-electro-mechanical background]. / Modèle unidimensionnel instationnaire de l'activité pacemaker cardiaque induite par le feedback mécano-électrique dans un environnement thermo-électromécanique.

AIM OF THE STUDY: In a healthy heart, the mechanoelectric feedback (MEF) process acts as an intrinsic regulatory mechanism of the myocardium which allows the normal cardiac contraction by damping mechanical perturbations in order to generate a new healthy electromechanical situation. However, under certain conditions, the MEF can be a generator of dramatic arrhythmias by inducing local electrical depolarizations as a result of abnormal cardiac tissue deformations, via stretch-activated channels (SACs). Then, these perturbations can propagate in the whole heart and lead to global cardiac dysfunctions. In the present study, we qualitatively investigate the influence of temperature on autonomous electrical activity generated by the MEF. METHOD: We introduce a one-dimensional time-dependent model containing all the key ingredients that allow accounting for the excitation-contraction coupling, the MEF and the thermoelectric coupling. RESULTS: Our simulations show that an autonomous electrical activity can be induced by cardiac deformations, but only inside a certain temperature interval. In addition, in some cases, the autonomous electrical activity takes place in a periodic way like a pacemaker. We also highlight that some properties of action potentials, generated by the mechanoelectric feedback, are significantly influenced by temperature. Moreover, in the situation where a pacemaker activity occurs, we also show that the period is heavily temperature-dependent. CONCLUSIONS: Our qualitative model shows that the temperature is a significant factor with regards to the electromechanical behavior of the heart and more specifically, with regards to the autonomous electrical activity induced by the cardiac tissue deformations.

The clinical variability of maternally inherited diabetes and deafness is associated with the degree of heteroplasmy in blood leukocytes.

CONTEXT: Maternally inherited diabetes and deafness (MIDD) is a rare form of diabetes with a matrilineal transmission, sensorineural hearing loss, and macular pattern dystrophy due to an A to G transition at position 3243 of mitochondrial DNA (mtDNA) (m.3243A>G). The phenotypic heterogeneity of MIDD may be the consequence of different levels of mutated mtDNA among mitochondria in a given tissue. OBJECTIVE: The aim of the present study was thus to ascertain the correlation between the severity of the phenotype in patients with MIDD and the level of heteroplasmy in the blood leukocytes. PARTICIPANTS: The GEDIAM prospective multicenter register was initiated in 1995. Eighty-nine Europid patients from this register, with MIDD and the mtDNA 3243A>G mutation, were included. Patients with MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) or with mitochondrial diabetes related to other mutations or to deletions of mtDNA were excluded. RESULTS: A significant negative correlation was found between levels of heteroplasmy and age of the patients at the time of sampling for molecular analysis, age at the diagnosis of diabetes, and body mass index. After adjustment for age at sampling for molecular study and gender, the correlation between heteroplasmy levels and age at the diagnosis of diabetes was no more significant. The two other correlations remained significant. A significant positive correlation between levels of heteroplasmy and HbA(1c) was also found and remained significant after adjustment for age at molecular sampling and gender. CONCLUSIONS: These results support the hypothesis that heteroplasmy levels are at least one of the determinants of the severity of the phenotype in MIDD.

Macular pattern dystrophy in MIDD: long-term follow-up.

A case of maternally inherited diabetes and deafness (MIDD)-associated macular pattern dystrophy with a 15-year follow-up is reported. On initial examination at age 37, visual acuity was normal, but chorioretinal atrophy at the posterior pole was already present in both eyes. At age 52, visual acuity remained normal in the right eye and was only slightly decreased in the left eye despite notable extension of the areas of chorioretinal atrophy in that eye. No evidence of diabetic retinopathy was present at any time. This case shows that visual acuity can remain stable in the long term despite extensive lesions of macular pattern dystrophy.

Retinal and renal complications in patients with a mutation of mitochondrial DNA at position 3,243 (maternally inherited diabetes and deafness). A case-control study.

AIMS/HYPOTHESIS: We assessed the prevalence and determinants of retinal and renal complications in patients with maternally inherited diabetes and deafness (MIDD). METHODS: This was a multicentre prospective study comparing the prevalence of retinopathy and renal disease in 74 patients with MIDD and 134 control patients matched for sex, age and clinical presentation at onset of diabetes, duration of diabetes and current treatment. Comparisons were adjusted for HbA(1c) and hypertension. RESULTS: In MIDD patients, HbA(1c) (7.6 +/- 1.6 vs 8.5 +/- 2.0%, p < 0.002), systolic blood pressure (126.6 +/- 16.2 vs 133.1 +/- 17.3 mmHg, p < 0.007) and prevalence of hypertension (33.8 vs 64.2%, p < 0.0001) were lower than in control patients. Prevalence of diabetic retinopathy was 3.7-fold lower in MIDD patients (6/74, 8 vs 40/134, 29.6%, p < 0.0001). Differences between groups remained significant after adjustment for hypertension, systolic blood pressure and HbA(1c). In MIDD, urinary albumin excretion (314.8 vs 80.1 mg/24 h, p = 0.035) and creatinine plasma levels (103.5 vs 82.2 micromol/l, p = 0.0178) were higher and GFR was lower. Impaired renal function (GFR <60 ml/min) was four- to sixfold more frequent in MIDD. Differences between MIDD and control diabetic patients further increased when adjusted for HbA(1c) and systolic blood pressure (p < 0.0001). Adjustment for treatment with an ACE inhibitor or angiotensin II receptor antagonist did not modify the results. CONCLUSIONS/INTERPRETATION: This study indicates that diabetic retinopathy is less prevalent in MIDD than in control diabetes. This suggests that retinal alterations due to mitochondrial disease may have a protective role. By contrast, nephropathy is far more frequent in MIDD, suggesting the presence of a specific renal disease independent of diabetic nephropathy.

OPHDIAT: a telemedical network screening system for diabetic retinopathy in the Ile-de-France.

OBJECTIVE: International and national guidelines recommend an annual funduscopic examination for all diabetic patients, but such annual fundus examinations are not sufficiently performed in France. Non-mydriatic fundus photography is a valid method of evaluation for diabetic retinopathy (DR) and a viable alternative to ophthalmoscopy. After two pilot studies demonstrated the feasibility of telemedical screening for diabetic retinopathy in both hospital and primary-care settings, we developed a regional telemedical network, OPHDIAT, designed to facilitate access to regular annual evaluations of patients with diabetes while saving medical time. MATERIALS AND METHODS: OPHDIAT comprises peripheral screening centres equipped with non-mydriatic cameras, where fundus photographs are taken by technicians linked by telemedicine to a reference centre, where ophthalmologists grade the images. Currently in the Ile-de-France region, 16 screening centres are linked through a central server to an ophthalmologic reading centre and includes 11 centres located in the diabetes departments of 11 hospitals, one diabetic retinopathy screening centre located in northern Paris, three in healthcare centres and one in a prison. RESULTS: During the 28-month evaluation period, 15,307 DR screening examinations were performed. Retinal photographs of at least one eye could not be graded in 1332 patients (9.7%) and diabetic retinopathy was detected in 3350 patients (23.4%). After the screening examination, 3478 patients (25.2%) were referred to an ophthalmologist for either DR, cataract and/or non-gradable photographs. CONCLUSION: Fundus photography combined with telemedicine has the potential to improve the regular annual evaluation for diabetic retinopathy. The organization of the network around a central reading centre serves to guarantee quality control.

OPHDIAT: quality-assurance programme plan and performance of the network.

AIMS: There is a need for evaluation of screening and grading services for diabetic retinopathy (DR) in compliance with quality-assurance (QA) standards. We describe the screening/grading QA programme set up for OPHDIAT over the 2005-2006 period. METHODS: Screening and grading objectives, evaluation criteria and minimum acceptable QA standards were set. To ensure the quality of DR photos, the proportion of nongradable photos in at least one eye had to be less than 10%. To ensure grading accuracy, intergrading agreement had to be greater than 90%. Grader-generated reports had to be available in less than 48 h for more than 80% photos. Readers had to grade 500 to 3000 photos per year. RESULTS: Sixteen screening centres were opened between June 2004 and December 2006, and 14,769 patients were screened. Percentages of nongradable photos were consistently below the QA requirement (less than 10%). Overall, 800 photos were graded a second time by a reader blinded to original grading; agreement between graders ranged from 92 to 99%. More than 90% of grader-generated reports were produced within 48 h. The number of readings by each grader nearly achieved the QA standard. CONCLUSION: QA for DR telescreening should be a continuous process to provide performance feedback, thus guaranteeing a high standard for delivered results. Almost all of the predetermined QA standards in OPHDIAT for screening and grading were met. Besides the quality/sensitivity of the screening/grading modalities, it is important to evaluate at-risk patients so that they can be treated efficiently; this should be addressed in a global QA programme.

[A new grading system from color fundus photographs for screening for diabetic retinopathy]. / Classification simplifiée de la rétinopathie diabétique adaptée au dépistage par photographies du fond d'oeil.

AIM: Fundus photographs using a nonmydriatic digital camera are the reference method for diabetic retinopathy screening today. The aim of this study was to validate a simplified diabetic retinopathy classification, adapted for diabetic retinopathy screening, including all diabetic retinopathy severity scales. PATIENTS AND METHODS: One hundred and twenty-one diabetic patients had three digital color fundus photographs taken, which were graded by four independent ophthalmologists according to the proposed screening classification, and a reference examination (nine field fundus photographs and optical coherence tomography examination of the macula). RESULTS: The proposed diabetic retinopathy screening classification was easy to use, as it was based on a visual comparison between the three digital color fundus photographs and standard retinal photographs. This classification provided the diagnosis of severe levels of diabetic retinopathy with high sensitivity and accurate specificity (100% and 50%-58%,respectively, for a moderate nonproliferative diabetic retinopathy level or higher on the screening examination) and the diagnosis of macular edema with a high sensitivity and specificity (96%-97% and 89%-91%, respectively). The results of the screening examination using this classification were highly reproducible (weighted k for interobserver agreement: 0.78-0.93). CONCLUSION: These results suggest that this new simplified classification is accurate. The screening method should not be used above the threshold level of mild nonproliferative diabetic retinopathy. Thus, from the moderate nonproliferative level (inclusive), a complete fundus examination should be undertaken. Severe levels of diabetic retinopathy will be referred to an ophthalmologist without delay for laser treatment.

Evaluation of the effect of JPEG and JPEG2000 image compression on the detection of diabetic retinopathy.

AIMS: To compare the effect of classic Joint Photographic Experts Group (JPEG) and JPEG2000 compression algorithms on detection of diabetic retinopathy (DR) lesions. METHODS: In total, 45 colour fundus photographs obtained with a digital nonmydriatic fundus camera were saved in uncompressed Tagged Interchanged Files Format (TIFF) format (1.26 MB). They were graded jointly by two retinal specialists at a 1 month interval for soft exudates, hard exudates, macular oedema, newvessels, intraretinal microvascular abnormalities (IRMA), and retinal haemorrhages and/or microaneurysms. They were compressed to 118, 58, 41, and 27 KB by both algorithms and 24 KB by classic JPEG, placed in random order and graded again jointly by the two retina specialists. Subjective image quality was graded, and sensitivity, specificity, positive and negative predictive values, and kappa statistic were calculated for all lesions at all compression ratios. RESULTS: Compression to 118 KB showed no effect on image quality and kappa values were high (0.94-1). Image degradation became important at 27 KB for both algorithms. At high compression levels, IRMA and HMA detection were most affected with JPEG2000 performing slightly better than classic JPEG. CONCLUSION: Performance of classic JPEG and JPEG2000 algorithms is equivalent when compressing digital images of DR lesions from 1.26 MB to 118 KB and 58 KB. Higher compression ratios show slightly better results with JPEG2000 compression, but may be insufficient for screening purposes.

A prospective, randomised, single-blinded, controlled trial comparing two topical anaesthetic modalities for the application of a tenaculum to the cervix.

The aim of this study was to compare the efficacy of equivalent doses of lignocaine spray vs lignocaine jelly in reducing pain during the application of a tenaculum to the cervix. A total of 58 women undergoing hysterosalpingography were prospectively randomised to receive either two doses of 10% lignocaine spray or 1 ml of 2% lignocaine jelly (both doses equivalent to 20 mg of lignocaine base) topically onto the cervix before tenaculum attachment. There was no difference in pain scores (measured by visual analogue scale and 4-point verbal descriptor scale) between lignocaine spray and lignocaine jelly during the attachment of the tenaculum to the cervix. In conclusion, there was no difference in pain during tenaculum attachment to the cervix following topical application of equivalent doses of either lignocaine jelly or spray.

Advanced glycation end products can induce glial reaction and neuronal degeneration in retinal explants.

BACKGROUND/AIMS: Neuronal degeneration has been reported to occur in diabetic retinopathy before the onset of detectable microvascular abnormalities. To investigate whether advanced glycation end products (AGE) could be directly responsible for retinal neurodegeneration, retinal explants were incubated with glycated bovine serum albumin (BSA). METHODS: Retinal explants obtained from non-diabetic adult rats were incubated 4 days with or without 200 mug/ml glycated BSA. Neural apoptosis was quantified by terminal dUTP nick end labelling (TUNEL) binding and immunostaining with anti-cleaved caspase-3 antibody. Expression of glial fibrillary acidic protein (GFAP) was localised by immunofluorescence. RESULTS: TUNEL and cleaved caspase-3 positive cells increased significantly by 2.2-fold and 2.5-fold in retinal explants incubated in glycated BSA (p<0.05), respectively. The ganglion cell layer was the most sensitive retinal layer to the glycated BSA. Neuronal degeneration was confirmed by the increased GFAP labelling in Müller glial cells from retinal explants treated with glycated BSA. CONCLUSION: These results suggest that AGE could induce retinal neurodegeneration in the absence of blood perfusion. Cells in the ganglion cell layer appeared to be the most sensitive as in diabetic retinopathy and its animal models. AGE toxicity could therefore contribute to the early pathological mechanisms of diabetic retinopathy.

[Optic neuropathy associated with primary antiphospholipid syndrome]. / Neuropathie optique associée à un syndrome primaire des anti-phospholipides.

We describe a 45-year-old male patient with an atypical unilateral optic neuropathy who was diagnosed with primary antiphospholipid syndrome. The initially poor vision lasting several months completely recovered and long-term oral anticoagulation therapy prevented potential further systemic thrombotic complications.

Spontaneous resolution of vitreomacular traction associated with diabetic macular edema.

PURPOSE: Little information is available about the natural history of vitreomacular traction (VMT) associated with diabetic macular edema. A few cases of spontaneous resolution of VMT associated with diabetic macular edema have been described, but have not been documented by optical coherence tomography (OCT). The authors report the spontaneous resolution of VMT associated with diabetic macular edema 1 month after the end of panretinal photocoagulation therapy (PRP). CASE REPORT: A 66-year-old woman presented with complicated proliferative diabetic retinopathy and diabetic macular edema associated with VMT, documented by OCT, in the right eye. Left eye examination showed complete PRP and ischemic maculopathy. PRP was immediately realized in the right eye in regard to the presence of complicated proliferative diabetic retinopathy. RESULTS: One month after the end of PRP, right eye visual acuity improved. OCT examination showed complete release of foveal posterior hyaloid traction, and significant reduction in foveal thickness. The follow-up was 1 year. At the end of follow-up, visual acuity slightly improved again; only a small residual foveal retinal thickening remained. CONCLUSIONS: The authors report spontaneous resolution of VMT associated with diabetic macular edema, probably facilitated by PRP, with concurrent reduction of macular thickness and visual improvement. As spontaneous resolution may occur in some eyes with diabetic macular edema associated with VMT, a period of observation after the end of the PRP may be considered prior to vitrectomy.

Tubulointerstitial nephritis and uveitis syndrome (TINU syndrome) with unilateral neuroretinitis: a case report.

PURPOSE: To report a case of tubulointerstitial nephritis and uveitis syndrome (TINU syndrome) with unusual unilateral neuroretinitis. METHODS: An 11-year-old girl who developed anterior uveitis 3 months after acute tubulointerstitial nephritis, without any etiologic factors for either nephritis or uveitis, is presented. RESULTS: Several days after the anterior uveitis, the patient presented with unilateral optic disk edema associated with a serous retinal detachment of the posterior pole, never previously described in TINU syndrome, leading to the formation of perifoveal intraretinal exudates. CONCLUSIONS: In spite of these posterior lesions, clinical course confirmed the previously reported favorable visual outcome of TINU syndrome treated with corticosteroids. It appeared that ocular impairment in TINU syndrome could be more diffuse and more extensive than previously described. As well as the whole uveal tract, the retina and the optic nerve may also be the ocular targets of the idiopathic inflammatory response in TINU syndrome.