The use of digital dermoscopy in the surveillance of melanocytic skin lesions: A real-life retrospective study comparing university hospital and private practices.

BACKGROUND: Few studies have evaluated the role of digital dermoscopy (DD) in the surveillance of pigmented lesions in real-life practice. PATIENTS AND METHODS: Patients followed with DD by 4 hospital dermatologists (group 1) and 4 private dermatologists (group 2) were retrospectively included if they had had at least 2 DD examinations for a minimum of 4 pigmented lesions. Their characteristics, risk factors, history of excision of benign nevi and melanomas prior to and during the DD follow-up, and characteristics of detected melanomas, were recorded. RESULTS: One hundred and ninety-six patients were included in group 1 and 205 in groups 2. A family history of melanoma (25% vs. 12%, p<0.01), a personal history of melanoma before DD follow-up (47% vs. 15%, p<0.01), and a family (3% vs. 0%, p=0.01) and personal (8% vs. 1%, p<0.01) germline CDKN2a mutation were more frequent in group 1 than in group 2. In both groups, the number of excisions of benign lesions was higher before DD follow-up (380 and 347, respectively) than during DD follow-up (194 and 132). During follow-up, 29 melanomas were detected in group 1, with a median Breslow thickness of 0.4mm, versus 1.3mm for melanomas diagnosed before DD follow-up (p<0.02). In group 2, 4 melanoma and 5 superficial atypical melanocytic proliferations of unknown significance were detected. The median Breslow thickness of newly diagnosed melanomas was 0.35mm vs. 0.6mm before DD follow-up (p=0.1). CONCLUSION: In both populations in real-life practice, DD seemed to allow the detection of thin melanomas and to decrease the rate of "futile" resections.

[Clinical patterns and treatment of pyoderma gangrenosum in a French department]. / Caractéristiques cliniques et traitement du pyoderma gangrenosum dans la Marne.

BACKGROUND: Pyoderma gangrenosum (PG) is a rare inflammatory neutrophilic dermatosis for which accurate epidemiological data are limited and therapy remains a challenge. The primary study aim was to examine all cases of PG observed in our regional department over a 15-year period in order to describe the relevant characteristics and outcome under therapy. PATIENTS AND METHODS: The medical records of all patients with PG from 1997 to 2012 in the Marne department of France were studied retrospectively. Clinical and histological characteristics, comorbidities, therapeutic modalities and outcome were analysed. RESULTS: Forty-two patients were included (30 women, 12 men). A classical, ulcerative form was found in 39 cases and PG was multifocal in 28 cases. The number of lesions did not differ according to age or the presence of comorbidities. The most frequent first-line treatments were doxycycline (23 cases) and oral corticosteroids (15 cases), regardless of age, number of lesions or existence of comorbidities. Complete remission of PG was obtained in 38 cases (median time to remission: 3 months), with relapse occurring in 17 patients (median time to relapse: 12 months after treatment withdrawal). After a median follow-up of 46 months, 8 patients had died (median time to death: 26 months after treatment initiation). CONCLUSION: This is the first large French series of patients presenting PG and enabling determination of the annual incidence within the Marne department at around 4.6 cases/1000,000 inhabitants. Our study illustrates the value of first-line treatment with tetracycline, which merits confirmation by further prospective, controlled studies.

Real-time mobile teledermoscopy for skin cancer screening targeting an agricultural population: an experiment on 289 patients in France.

BACKGROUND: The incidence of skin cancer has reached epidemic proportions in the white population and is significantly elevated in agricultural populations, who are exposed to ultraviolet radiation during their professional activities. In 2014, the Agricultural Social Insurance Mutual Benefit Fund (MSA) offered its customers who work in agriculture and live in rural areas with reduced access to dermatologists the ability to participate in a 1-day teledermoscopic (TDS) screening event. OBJECTIVE: This study's aim was to assess the feasibility of real-time mobile TDS triage of a large number of agricultural workers by trained medical officers and occupational physicians. METHODS: Fifteen TDS screening centres were located in different areas of France. Individuals older than 18 years who worked in agriculture and lived in rural area near a TDS screening centre were invited to participate in a 1-day screening event and were examined by an MSA physician. In cases of suspicious skin lesions, clinical and dermoscopic images were obtained and transferred immediately to four dermatologists who were simultaneously present at the tele-platform for diagnosis and decision-making. Low-quality images were retaken. RESULTS: Two-hundred eighty-nine patients underwent skin cancer screening. Among 199 patients (69%), 390 suspicious lesions were identified and generated 412 pictures. All lesions were analysed by dermatologists. For 105 patients (53%), no follow-up was required. Seventeen patients were referred to local dermatologists for rapid examination, including 12 cases of suspected malignant melanocytic lesions. Among the 12 patients with suspected melanoma, face-to-face visits were conducted within 10 days for 11 of them, and 1 case of melanoma was confirmed by histopathology. CONCLUSIONS: Our study suggests that teledermoscopy performed in the context of occupational medicine and targeted to agricultural populations is feasible and could be useful for improving skin cancer screening in at-risk populations while avoiding face-to-face examinations by a dermatologist in 53% of cases.

Efficacy of a general practitioner training campaign for early detection of melanoma in France.

BACKGROUND: To date, no strategy for improving early diagnosis of melanoma has been evaluated on a population basis in France. OBJECTIVE: To evaluate the efficacy of a general practitioner (GP) awareness and training campaign in a pilot French geographical region (Champagne-Ardenne), including 1.34 million inhabitants, 1241 GPs, 56 dermatologists and a population-based melanoma registry. METHODS: All GPs received repeated awareness postal mailings in 2008 and 398 (32.1%) attended training sessions organized by 27 dermatologists. The pre- (2005-7) and post-campaign (2009-11) periods were compared for the following: primary endpoint - the world-standardized incidence of very thick melanomas (VTM) (Breslow thickness ≥ 3 mm); secondary endpoints--the mean Breslow thickness; the proportions of VTM and of thin (< 1 mm) melanomas among invasive cases; and the ratio of in situ/all melanoma cases. Similar measures were performed in the control area of Doubs/Belfort territory (655,000 ha), where no similar campaign was carried out. RESULTS: The incidence of VTM decreased from 1.07 to 0.71 per 100 000 habitants per year (P = 0.01), the mean Breslow thickness from 1.95 to 1.68 mm (P = 0.06) and the proportion of VTM from 19.2% to 12.8% (P = 0.01). The proportion of thin and in situ melanomas increased from 50.9% to 57.4% (P = 0.05) and from 20.1% to 28.2% (P = 0.001), respectively. No significant variation was observed in Doubs/Belfort territory. CONCLUSION: These results strongly support the efficacy of such a campaign targeting GPs and provide a rationale for a larger public health campaign in France, including training of GPs by dermatologists and encouraging patients to ask their GP for a systematic skin examination.

[Diagnostic modalities of visceral metastases during follow-up of patients with stage I-II melanoma]. / Malades suivis pour mélanome de stade I-II: modalités diagnostiques des métastases viscérales.

INTRODUCTION: Although not recommended in France at the consensus conference of 1994, routine monitoring of patients with stage I melanoma using imaging techniques is commonly carried out. The aim of this retrospective regional study was to define methods for diagnosing transition to the metastatic stage of melanoma. PATIENTS AND METHODS: This was a retrospective study based on questionnaires among dermatologists in the Champagne-Ardenne and southern Aisne regions of France. For each patient with stage IV melanoma between 1987 and 2002, data were collected concerning the primary melanoma (date of diagnosis, clinical picture, histopathologic features), stage of melanoma prior to diagnosis of metastatic melanoma and characteristics of the metastases (date, number, type, site and modern discovery: clinical signs or routine imaging). RESULTS: One hundred and eight patients (63 men and 45 women; mean age: 59 years) were included in the study. The predominant site of the primary melanoma was the trunk for men (n=31) and the lower limbs for women (n=16) and the mean Breslow index was 4.31 mm (SD=4.22), with histologic ulceration being present in 40% of cases. The mean time to transition to stage IV after discovery of the primary tumour was 2.8 years (SD=2.95). The modes of discovery of metastases comprised clinical examination (functional signs or physical examination) in 58 cases and routine imaging in 50 cases, with no significant differences based on whether patients were initially in stage I-II or in stage III. DISCUSSION: This study shows that over half of patients progressing to stage IV melanoma had a suspicious sign or clinical symptom, once again highlighting the importance of clinical monitoring. In contrast, many organ metastases, particularly pulmonary, were discovered by routine imaging examinations carried out as part of patient follow-up, although this is not currently recommended practice in France. CONCLUSION: The role of powerful imaging examinations such as scans, with constantly improving resolution, still remains to be defined in the follow-up of patients with stage I-II melanoma, and further prospective studies are thus required.

Analysis of low molecular weight intracellular associations of a human mannan binding lectin (MBL).

Human mannan binding lectin (MBL) is a member of the collectins, a group of proteins that contain a dual structure with a lectin and a collagenous moieties. The collectins are considered as major actors of innate immunity. We report the presence of low molecular weight intracellular MBL forms in human hepatocytic cell lysates, with binding capacities associated to its lectin and/or its collagen moiety. Competition with D-mannose and with antibodies directed against the lectin binding site of MBL indicate that the 60 kDa form represents an intracellular association of MBL through its lectin moiety. The effects of collagenase or MBL associated serine proteases (MASPs) from a MBL deficient plasma, gave evidence that the 60 KDa form contains also collagen and suggested the binding of a ligand to this collagen part. These results show that this intracellular form of MBL shares binding properties with circulating MBL. The binding potential of the lectin and the collagenous parts of precursor forms of intracellular MBL may suggest that they behave as molecular chaperone. The complexity of MBL structure and functions deserves further investigation on other intracellular forms of MBL.

[Non infectious skin conditions associated with diabetes mellitus: a prospective study of 308 cases]. / Dermatoses non infectieuses au cours du diabète sucré: étude prospective de 308 malades.

INTRODUCTION: Non-infectious dermatoses during diabetes appear frequent if one refers to some of the studies in the literature that have attempted to assess its prevalence. PATIENTS AND METHODS: From November 2000 to November 2001, 308 randomly selected, hospitalized, diabetic patients were examined. The data were collected prospectively and systematically in a pre-established questionnaire. Statistical analysis included a descriptive and univariate analysis. RESULTS: 206/308 diabetics (67 p. 100) exhibited at least one non-infectious dermatitis, the most frequent of which was cutaneous xerosis (39 p. 100), diabetic dermopathy (24 p. 100), facial erythrosis (24 p. 100), purpural and pigmented capillaritis of the legs (20 p. 100), xanthochromia (12 p. 100) pseudo-scleroderma (8 p. 100) and acanthosis nigricans (7 p. 100). The non-infectious dermatoses were globally more frequent in type II diabetic patients exhibiting at least one microvascular complication. DISCUSSION: This study is the first French prospective work on the subject. We found a prevalence of non-infectious dermatoses during diabetes close to that of the major studies in the literature. Some of these dermatoses are markers of macrovascular (acanthosis nigricans, purpural and pigmented capillarity) or microvascular (xerosis, acanthosis nigricans, purpural and pigmented capillarity, Dupuytren's disease) complications for type II diabetes or are markers of auto-immunity (alopecia areata, vitiligo) for type I.

Evaluation and clinical interest of mannan binding lectin function in human plasma.

The mannan binding lectin (MBL) plays a major role in innate immunity through its ability to activate complement upon binding to carbohydrate arrays on the surface of various microorganisms. The question of a possible association of the MBL structural gene polymorphism and the oligomeric state of MBL was poorly documented. For these reasons, it appears difficult to evaluate MBL in blood patients on the only basis of protein contents, even in combination with MBL genotyping. This study reports a method to calculate a specific activity for circulating MBL, that relies on: (i) the availability of purified MBL; and (ii) a simplified MBL activity assay based on complement activation. The three-step MBL purification from human plasma reported here is characterized by a highly purified MBL, that occurs in two different oligomeric forms. The results on the specific activity of these forms show that the higher oligomeric forms of MBL have the ability to induce C4 cleavage more efficiently than the corresponding lower oligomers. The usefulness of this approach is illustrated by its potential interest in the biological exploration of certain pathology, for example in the follow-up of chronic hepatitis C. Further investigation is needed to establish whether MBL specific activity (MBLsa) is correlated to the polymorphic state of the molecule. The relative simplicity of the test described here allows better investigation on the relationship between MBL biological activity and its genotype.

["Vein School." A program of education for chronic venous insufficiency patients at the La Léchère Hotspring]. / "L'Ecole de la Veine". Un programme d'éducation pour les patients atteints d'insuffisance veineuse chronique à la station thermale de La léchère.

Chronic venous insufficiency is a frequent and invalidating condition, which also represents an important socio-economical burden. As it is a chronic disease with no effective curative therapy, the preventive and educational means are of particular interest. The present health policy insists on the education given to patients suffering from chronic disease, but contrasting with other chronic conditions (diabetes, asthma, chronic back pain), to our knowledge, there is no published structured educational training programme dedicated to people suffering from CVI. Such an educational programme was developed at the spa resort of La Léchère (Savoie, France), which is specialized in the treatment of CVI. Proposed to voluntary patients taking the waters and driven by a multidisciplinary team (doctors, nurses, pharmacists), the objective was to promote a better knowledge in venous disease by the patients and to make them adopt a more active behaviour in their treatment. Three topics were approached in interactive work-groups using a problem solving teaching technique: "anatomy and physiology of the circulatory system", "venous diseases", "practical aspects life with compression stockings". Comparison of pre and post-teaching evaluations was performed in 149 unselected patients, allowing a short-term appraisal of the knowledge improvement. It showed a 25 to 40% increase in right answers according to the tested topic. Further evaluation of long term beneficial effects is needed. However, the high interest of patients regarding this teaching method and the content of the programme provides good expectations regarding a real beneficial effect on health and quality of life.

Complement C4 monitoring in the follow-up of chronic hepatitis C treatment.

The overall role of complement in the host--pathogen relationship is now well understood. However, its involvement at a chronic stage of infection, such as chronic hepatitis C, is less well documented. Here, results are reported which point to the use of specific C4 monitoring in the follow-up of HCV patients. This study concerns 66 patients with chronic HCV infection, treated with interferon alpha 2b alone or with interferon alpha 2b + ribavirin, and 50 healthy adults as controls. Complement blood tests were performed to measure C1q, C3, C4, mannan binding lectin (MBL), C1s-C1 inhibitor complexes, total (CH50) and C4 (C4H) haemolytic activity; specific C4 activity was taken as the C4H/C4 protein ratio. Rheumatoid factor (RF) levels were also measured. A significant reduction in CH50 and specific C4 activity in HCV patients, compared with the healthy controls, was observed before the onset of treatment; the other parameters were not affected and no C1s-C1 inhibitor complexes were detected. At the same time, a significant reduction in specific C4 activity was observed in relapsers compared with sustained responders. These results point to a potential predictive function of C4 specific activity to monitor the response to therapy. Restoration of specific C4 activity at 6 months was better in responders than in non-responders. Complement activation in chronic hepatitis C does not seem to involve the C1 stage of the classical pathway. A negative correlation between specific C4 activity and RF titres suggests a possible involvement of RF in C4 activation, via the lectin pathway. Specific C4 monitoring appears to be a valuable tool for the follow-up of chronic hepatitis C treatment, together with the other conventional investigations.

[Incidence of erysipelas of the lower limbs in a spa resort. Efficacy of a strategy of sanitation education (La Lechere: 1992-1997)]. / Incidence de l'érysipèle des membres inférieurs en milieu thermal phlébologique. Efficacité d'une stratégie d'éducation sanitaire (La Léchère: 1992-1997).

OBJECTIVE: Erysipela is a common skin infection readily found in patients with venous insufficiency or lymphedema. The aim of this work was to measure the incidence of erysipela in a spa resort specialized in the treatment of venous and lymphatic diseases and to evaluate the influence of a preventive strategy principally based on education of patients at risk. PATIENTS AND METHODS: The measurement of incidence was based on the detection of the reasons for which the patients did not attend their thermal care sessions. Quality control was obtained from the reports of cases diagnosed by local private and public health care centers. RESULTS: The incidence of erysipela in this high risk population was 40.2 and 48.5 cases for 1000 persons per exposure-year in 1993 and 1994 respectively. The preventive strategy carried out was able to induce a reduction of 65% during the next years (p<0.01). CONCLUSION: This study confirms the high incidence of erysipela in subjects with severe venous insufficiency or lymphedema and the efficacy of an active educational preventive strategy.

Distance perception of vehicle rear lights in fog.

Perceptual difficulty is one of the main explanations given for the behavioral modifications and high accident rate associated with driving in fog. The present study investigates how fog and the characteristics of vehicle rear lights affect distance perception. Two experiments in a fog chamber (meteorological visibility range of 5-15 m) were run under conditions simulating nighttime fog. The participants gave verbal estimates of the distance (8-28 m) of vehicles simulated by rear-light arrangements. The results revealed an average increase of 60% in the perceived distance of vehicles in fog as compared with normal visibility conditions. Distance overestimation was particularly pronounced when the vehicle had only 1 fog light instead of 2 and when the lights were close together. No effect of light height was observed. These results suggest that the perception of vehicle distance in nighttime fog could be significantly improved by the presence of 2 lights with maximal spacing. Actual or potential applications of this research include vehicle rear light design.

[Acquired angioneurotic edema. Clinical and biological characteristics in 9 patients]. / L'oedème angioneurotique acquis. Caractéristiques cliniques et biologiques chez 9 patients.

OBJECTIVE: Angioneurotic edema (AE) is a rare but severe disease. Hereditary AE is the more well-known form. The acquired form is exceptional: the symptoms are the same but there are some biologic and treatment differences. We investigated the clinical and biochemical features in nine patients with acquired angioneurotic edema (AAE). PATIENTS AND METHODS: Four of the patients with type I AAE presented an accelerated metabolism of C1Inh, associated with a hematology disease. Their C4, C1q and C1Inh plasma levels were low. Four patients had type II AAE associated with an autoantibody to C1Inh. Their C1Inh plasma levels were normal or low but the functional levels were low in all four. One patient had AAE induced by oral contraceptives. The C1Inh plasma level was normal but the functional level was very low; there were no autoantibodies. Symptoms resolved when oral contraceptives were withdrawn and the C1Inh level returned to normal. DISCUSSION: Treatment of AAE is a difficult matter. For type I AAE, it consists in treating the associated disease. For type II AAE, the treatment goal is to lower the autoantibody level. Management of these diseases requires close collaboration between clinicians and biologists.

Hepatitis C virus NS3 serine protease interacts with the serpin C1 inhibitor.

Both NS3 protein (1007-1657) and its protease moiety (NS3p, 1027-1207) were able to interact in vitro with C1 Inhibitor (C1Inh) to give a 95-kDa Mr C1Inh cleavage product similar to that obtained upon proteolysis by complement protease C1s. High-Mr reaction products were also detected after incubation of C1Inh with NS3 but not with NS3p; they correspond to ester-bonded complexes from their hydroxylamine lability. Similar reactivity of NS3 was observed upon incubation with alpha2-antiplasmin. Serpin cleavage was prevented by treatment of NS3 with synthetic serine protease inhibitors. This interaction between viral NS3 and host serpins suggests that NS3 is likely to be controlled by infected cell protease inhibitors.

Heat shock increases antigenic peptide generation but decreases antigen presentation.

The heat shock response is a universal and highly conserved cellular response to stress. We describe here the effect of elevated temperature on the capacity of B cells to present antigen. Heat shock markedly affects the ability of these cells to process and present tetanus toxin to class II-restricted T cell clones. Inhibition of antigen presentation is due neither to a modification of antigen capture nor to a variation of major histocompatibility complex (MHC) class II molecule synthesis and cell surface expression. Stressed and nonstressed B cells are able to present peptides loaded at the cell surface with the same efficiency. Nevertheless, heat shock leads to an increase of antigen peptide generation in subcellular compartments; an enhancement of cathepsin B activity is also observed. These data suggest that such a stress induces a failure in the intracellular peptide loading onto MHC class II molecules.

Covalent binding of C3b to tetanus toxin: influence on uptake/internalization of antigen by antigen-specific and non-specific B cells.

Antigen opsonization by the C3b fragment of complement is a significant event in the modulation of cell-mediated immune response, but its mechanism is still largely unknown. The structural characteristics of C3b allow it to act as a bifunctional ligand between antigen and cells via their membrane C3b receptors. It was thus of interest to study the influence of the covalent link between C3b and antigen on the fixation and internalization of this antigen by antigen-presenting cells. Tetanus toxin (TT) was used as antigen, either free or covalently linked to C3b (TT-C3b). The antigen-presenting cells were TT-specific (4.2) or non-specific (BL15) Epstein-Barr virus (EBV)-transformed B cells. C3b was found to play an important role in antigen fixation and internalization by both antigen-specific and antigen non-specific cells. Covalent binding of C3b on TT (1) permitted fixation and internalization of this antigen by non-specific cells via their complement receptors; (2) enhanced antigen fixation and resulted in cross-linking between membrane immunoglobulins and complement receptors on antigen-specific cells. The consequences of covalent C3b binding to TT were analysed using antigen-specific and antigen-nonspecific cells. In both cases, a net increase in antigen fixation was observed. At the intracellular level, covalent C3b binding to TT resulted in a large TT incorporation in endosomes of nonspecific cells, similar to that observed in antigen-specific cells. Thus, C3b covalently linked to antigen enlarges the array of B-cell types capable of presenting antigen, including non-specific cells.

Species specificity of anti-beta 2 glycoprotein I autoantibodies and its relevance to anticardiolipin antibody quantitation.

Some patients suspected of having antiphospholipid antibody syndrome (APS) were found to be positive for anti-beta 2 glycoprotein I (beta 2GPI) antibodies despite negative results for antibodies to cardiolipin (ACA). Since the major source of beta 2GPI in the ACA assay is animal (usually bovine) serum, we studied the influence on ACA quantitation of the species specificity of anti-beta 2GPI antibodies from patients with various autoimmune disorders, mostly systemic lupus erythematosus and primary APS. Ninety-seven sera were selected based on IgG (n = 76) or IgM (n = 64) positivity by ELISA using gamma-irradiated plates coated with human or bovine purified beta 2GPI. A higher proportion of IgM (43.7%) than IgG (7.9%) reacted to human, but not bovine, beta 2GPI. Furthermore, from the samples reactive to both proteins, the ratio of antibody level against bovine to that against human beta 2GPI was 1.08 +/- 0.58 for IgG and 0.58 +/- 0.3 for IgM (p < 10(-5)). IgG and IgM ACA were detected in 78 and 40 sera, respectively; concordance between the two ELISAs for ACA and anti-beta 2GPI antibodies was 94% for IgG and 75% for IgM. Out of 28 IgM showing recognition restricted to human beta 2GPI, 21 were missed by the ACA assay, possibly because of lower concentrations of beta 2GPI in those patients' sera. The antibody reactivity pattern towards human and bovine beta 2GPI of individual sera showed no variation with time and was related to the relative antibody avidity for each protein. A murine anti-human beta 2GPI monoclonal antibody, 9G1, that cross-reacts with bovine beta 2GPI, competed to a large extent with the patients' anti-beta 2GPI antibody binding sites whatever isotype involved or protein recognized. Therefore, anti-beta 2GPI antibodies of IgM isotype display a marked preference for human compared to bovine beta 2GPI responsible for frequent inconsistencies in the ACA assay.

Monoclonal IgG as antigens: reduction is an early intracellular event of their processing by antigen-presenting cells.

Murine mAb injected into patients behave as exogenous antigens and trigger a specific immune response characterized mainly by CD4+ T lymphocytes. They are recognized by T cells under a processed form and in a MHC class II-restricted fashion. IgG degradation which occurs in antigen-presenting cells (APC) has been studied in vitro. We have shown that partial reduction of this antigen is an early event which is significant for the generation of class II-restricted fragments presentable to antigen-specific T cells. Two different murine mAb were used as antigens and human monocytic U937 or antigen non-specific Epstein-Barr virus-transformed B cells as APC. Upon cellular internalization IgG are rapidly cleaved leading to 24-25 kDa fragments. One of the major and early events corresponds to partial reduction of IgG--the light chain is released from the intact molecule, heavy chains remaining bound together. Partial in vitro reduction of IgG followed by presentation by fixed B cells to specific T cells showed that only kappa light chain-specific T cell clones are stimulated, in contrast to heavy chain-specific T cell clones. The response to the kappa chains of specific T cells points to a significant role played by the early IgG partial reduction in the generation of kappa light chain class II binding fragments.