Dermoscopy and reflectance confocal microscopy of solitary flat pink lesions: A new combined score to diagnose amelanotic melanoma.

BACKGROUND: Differential diagnosis of amelanotic/hypomelanotic melanoma among solitary flat pink lesions is challenging, due to limited clinical and dermoscopic clues. Dermoscopy and reflectance confocal microscopy assessments improve diagnostic accuracy, but their combined capacity among solitary flat pink lesions is yet to be defined. OBJECTIVES: To determine (i) whether diagnostic accuracy is improved with combined dermoscopy and reflectance confocal microscopy, (ii) a model to estimate probability of flat amelanotic/hypomelanotic melanoma among solitary flat pink lesions. METHODS: A retrospective single-centre study of solitary flat pink lesions, excised for suspected malignancy between 2011 and 2022 was performed. Images were independently evaluated by two dermatologists, blinded to histopathological diagnosis. Diagnostic performance was evaluated on the receiver operating characteristic curve and the area under the curve. Predictive features were identified by univariate and multivariate logistic regression analyses. A final predictive nomogram of independent risk factors was calculated by backward likelihood ratio. Hypothesis being tested was formulated before data collection. RESULTS: A total of 184 patients (87 females, 47.3%) were included; mean age was 57.6 years (19-95). Combined dermoscopy and reflectance confocal microscopy was more sensitive (83%, CI 69.2-92.4 and 91.5%, CI 79.6-97.6) than dermoscopy alone (76.6%, CI 62.0-87.7 and 85.1%, CI 71.7-93.8). Predictive features defined the new model, including linear irregular vessels (4.26-folds, CI 1.5-12.1), peripheral pigment network (6.07-folds, CI 1.83-20.15), remnants of pigmentation (4.3-folds, CI 1.27-14.55) at dermoscopy and atypical honeycomb (9.98-folds, CI 1.91-51.96), disarranged epidermal pattern (15.22-folds, CI 2.18-106.23), dendritic pagetoid cells in the epidermis (3.77-folds, CI 1.25-11.26), hypopigmented pagetoid cells (27.05-folds, CI 1.57-465.5), and dense and sparse nests (3.68-folds, CI 1.24-10.96) in reflectance confocal microscopy. Diagnostic accuracy of the model was high (AUC 0.91). CONCLUSIONS: Adjunctive reflectance confocal microscopy increases diagnostic sensitivity of flat amelanotic/hypomelanotic melanoma differential diagnosis. The proposed model requires validation.

Inhibition of inducible nitric oxide synthase in the human intestinal epithelial cell line, DLD-1, by the inducers of heme oxygenase 1, bismuth salts, heme, and nitric oxide donors.

BACKGROUND: The inducible isoform of nitric oxide synthase (iNOS) may be involved in the mucosal injury associated with inflammatory bowel disease (IBD). In contrast with iNOS, the inducible heme oxygenase 1 (HO-1) is considered to act as a protective antioxidant system. AIMS: To evaluate the effects of the known HO-1 inducers, cadmium and bismuth salts, heme, and nitric oxide (NO) donors, on iNOS activity, and expression in the human intestinal epithelial cell line DLD-1. METHODS: iNOS activity was assessed by the Griess reaction and the radiochemical L-arginine conversion assay. iNOS mRNA and iNOS protein expression were determined by northern and western blotting, respectively. RESULTS: Cytokine exposure led to induction of iNOS activity, iNOS mRNA, and iNOS protein expression. Preincubation of DLD-1 cells with heme (1-50 microM) inhibited cytokine induced iNOS activity in a concentration dependent manner. This inhibitory effect was abolished by the HO-1 specific inhibitor tin protoporphyrin. Preincubation with NO donors sodium nitroprusside (SNP 1-1000 microM) or S-nitroso-acetyl-penicillamine (SNAP 1-1000 microM), or with the heavy metals cadmium chloride (10-40 microM), bismuth citrate, or ranitidine bismuth citrate (10-3000 microM) inhibited iNOS activity in a concentration dependent manner. Moreover, SNP and heme abolished cytokine induced iNOS protein as well as iNOS mRNA expression, whereas cadmium chloride did not modify iNOS protein expression. CONCLUSIONS: Heme, the heavy metals cadmium and bismuth, as well as NO donors, are potent inhibitors of cytokine induced iNOS activity. Heme and NO donors act at the transcriptional level inhibiting iNOS mRNA expression. Such findings suggest the potential for interplay between the iNOS and HO-1 systems, which may modulate the progress of IBD.

Evidence of subclinical intestinal inflammation by 99m technetium leukocyte scintigraphy in patients with HLA-B27 positive juvenile onset active spondyloarthropathy.

OBJECTIVE: The concept that gut inflammation is implicated in the pathogenesis of spondyloarthropathies (SpA) has long been considered. Subclinical intestinal inflammation has been reported in adult patients with SpA by histological examination of intestinal biopsies. We assessed the presence of gut inflammation by abdominal 99mTc-hexamethyl propylene amine oxime (99mTc-HMPAO) labeled leukocyte scintigraphy in a group of children and adolescents with HLA-B27 positive SpA without gastrointestinal (GI) symptoms, and correlated the scintigraphic results to disease activity. METHODS: Abdominal scintigraphy with 99mTc-HMPAO labeled leukocytes was performed in 27 HLA-B27 positive children and adolescents with SpA without GI symptoms. Patients were divided into 2 groups according to the presence of active or inactive joint disease: Group A, 17 patients with active disease, and Group B, 10 patients with inactive disease. Patients with positive abdominal scintigraphy underwent complete bowel investigation by means of small bowel barium follow-through, abdominal ultrasound scan, and ileocolonoscopy with mucosal biopsies. RESULTS: Thirteen of 27 patients (48%) had scintigraphy indicating the presence of bowel inflammation. All patients with abnormal scan had active joint disease, whereas no patient with inactive disease had a positive intestinal uptake of labeled leukocytes. Bowel investigation revealed the presence of aspecific mucosal inflammatory changes in the majority of patients with positive scintigraphy. CONCLUSION: The presence of intestinal leukocyte uptake only in patients with active joint disease, even if intestinal inflammatory changes were minimal and clinical gut manifestations were absent, supports the role of gut inflammation in the pathogenesis of joint disease in HLA-B27 positive patients with SpA.

[Small bowel pseudo-obstruction revealing an early scleroderma. Long-term efficacy of octreotide and erythromycin]. / Pseudo-obstruction du grêle, révélatrice d'une sclérodermie débutante. Efficacité à long terme de l'association octréotide et érythromycine.

Skin abnormalities are the most common manifestations in patients with systemic sclerosis but many other organs can be involved. We report here the case of a 61 year-old-man in whom small bowel involvement was the initial presentation of limited systemic sclerosis. The clinical features consisted of recurrent small bowel obstruction without any organic lesion. The patient responded well to erythromycin (125 mg thrice a day before meals) and octreotide (50 microg subcutaneously at bedtime) with complete symptom relief. This permitted recovery of nutritional autonomy for two years. This observation shows that, in patients with intestinal pseudo-obstruction, systemic sclerosis should be considered. The long-term administration of octreotide and erythromycin can be effective in treating small bowel dysmotility in such patients.

Prevalence of liver disease and contributing factors in patients receiving home parenteral nutrition for permanent intestinal failure.

BACKGROUND: Liver cholestasis can be a life-threatening complication during home parenteral nutrition and may lead to combined liver-intestinal transplantation. OBJECTIVE: To assess the prevalence of home parenteral nutrition-related liver disease and its contributing factors in patients with permanent intestinal failure. DESIGN: Prospective cohort study. SETTING: Two approved home parenteral nutrition centers. PATIENTS: 90 patients with permanent intestinal failure who were receiving home parenteral nutrition were enrolled from 1985 to 1996. INTERVENTION: Clinical, biological, endoscopic, and ultrasonographic follow-up. Histologic examination of the liver was done in 57 patients (112 liver biopsies). MEASUREMENTS: The Kaplan-Meier method was used to determine the actuarial occurrence of chronic cholestasis and complicated home parenteral nutrition-related liver disease (bilirubin level > or =60 micromol/L [3.5 mg/dL], factor V level < or =50%, portal hypertension, encephalopathy, ascites, gastrointestinal bleeding, or histologically proven extensive fibrosis or cirrhosis). Contributing factors were assessed by using univariate and multivariate (Cox model) analysis. RESULTS: 58 patients (65%) developed chronic cholestasis after a median of 6 months (range, 3 to 132 months), and 37 (41.5%) developed complicated home parenteral nutrition-related liver disease after a median of 17 months (range, 2 to 155 months). Of these patients, 17 showed extensive fibrosis after 26 months (range, 2 to 148 months) and 5 had cirrhosis after 37 months (range, 26 to 77 months). The prevalence of complicated home parenteral nutrition-related liver disease was 26%+/-9% at 2 years and 50%+/-13% at 6 years. Six patients died of liver disease (22% of all deaths). In multivariate analysis, chronic cholestasis was significantly associated with a parenteral nutrition-independent risk for liver disease, a bowel remnant shorter than 50 cm in length, and a parenteral lipid intake of 1 g/kg of body weight per day or more (omega-6-rich long-chain triglycerides), whereas complicated home parenteral nutrition-related liver disease was significantly associated with chronic cholestasis and lipid parenteral intake of 1 g/kg per day or more. CONCLUSION: The prevalence of complicated home parenteral nutrition-related liver disease increased with longer duration of parenteral nutrition. This condition was one of the main causes of death in patients with permanent intestinal failure. Parenteral intake of omega-6-rich long-chain triglycerides lipid emulsion consisting of less than 1 g/kg per day is recommended in these patients.

Regulation of induction of nitric oxide synthase and the inhibitory actions of dexamethasone in the human intestinal epithelial cell line, Caco-2: influence of cell differentiation.

1. The inducible isoform of nitric oxide synthase (iNOS) may be involved in the pathogenesis of inflammatory bowel disease. Using the human intestinal epithelial cell line, Caco-2, iNOS expression, regulation and sensitivity to the glucocorticoid, dexamethasone after cytokine exposure and its relationship to the degree of differentiation has been studied. 2. NOS activity, assessed by NO2- and NO3- release, was time-dependently increased after exposure to interferon gamma alone or in combination with interleukin-1beta and tumour necrosis factor alpha. 3. Cytokine-induced iNOS activity was increased with days in culture over 20 days and number of passages, suggesting iNOS up-regulation during enterocyte-like differentiation. This activity was inhibited by the selective iNOS inhibitor 1400 W (0.1 - 100 microM). In addition, iNOS protein induction was confirmed by Western blot. 4. Actinomycin D (5 microg ml(-1) inhibited cytokine-induced iNOS activity, protein expression and mRNA level. Pyrrolidine dithiocarbamate (PDTC: 10 - 200 microM) and 3,4 dichloroisocoumarin (0.1 - 100 microM) reduced cytokine-induced iNOS activity and protein expression at both day 10 and 15 after confluence. PDTC also decreased iNOS mRNA levels, suggesting NF-kappaB involvement in its transcription at these times. 5. The tyrphostins A25 and B42 reduced cytokine-induced iNOS activity at both day 10 and 15 after confluence, indicating the JAK-2 kinase is also involved at these times. The tyrphostins also reduced the iNOS protein expression. 6. Dexamethasone (0.1 - 10 microM, for 24 h) reduced cytokine-induced iNOS activity at day 15 and 20 after cell confluence, but not at day 5 or 10. 7. Dexamethasone (5 microM) decreased cytokine-induced iNOS protein expression at day 10 as well as at day 15 after confluence. 8. These findings indicate that iNOS induction and its inhibition by dexamethasone in this human intestinal epithelial cell line is dependent on the degree of differentiation.

Potentiation of cytokine induced iNOS expression in the human intestinal epithelial cell line, DLD-1, by cyclic AMP.

BACKGROUND: Nitric oxide production by the inducible isoform of nitric oxide synthase (iNOS) is thought to play a role in the pathogenesis of inflammatory bowel disease along with other proinflammatory mediators. AIMS: To examine the effects of cAMP, an intracellular mediator of several proinflammatory mediators, on iNOS expression in the human intestinal epithelial cell line, DLD-1. METHODS: iNOS activity was assessed by measuring the NO stable oxidative product NO(2)(-). iNOS protein expression and iNOS mRNA levels were determined by western blotting and northern blotting, respectively. RESULTS: iNOS activity, protein, and mRNA were induced by a combination of interleukin 1beta (0.5-5 ng/ml), interferon gamma (20-200 u/ml), and tumour necrosis factor alpha (10-100 ng/ml). The cytokine induced NOS activity was potentiated by N(6), 2'-O-dibutyryladenosine 3':5'-cyclic monophosphate and 8-bromoadenosine 3':5'-cyclic monophosphate (0.1-1 mM), and the adenylate cyclase activator, forskolin (1-100 microM). This activity was inhibited by the selective iNOS inhibitor, 1400W (0.1-100 microM). These agents increased iNOS protein. The cAMP analogues potentiated iNOS at the transcriptional level as shown by effects of actinomycin D (5 microgram/ml) and northern blot analyses; the nuclear factor (NF) kappaB inhibitor, pyrrolidine dithiocarbamate (10-200 microM), significantly reduced this potentiation. The cAMP potentiated iNOS activity was inhibited by the tyrosine kinase inhibitor, A25 (10-200 microM) and the Janus activated kinase 2 inhibitor, B42 (10-200 microM). CONCLUSIONS: Increased intracellular cAMP is a potent stimulus of iNOS expression in combination with cytokines in DLD-1 cells, acting at the transcriptional level and involving NF-kappaB and the JAK-STAT pathways. Thus, proinflammatory mediators that increase cAMP levels may augment iNOS expression and NO production.

[Dysphagia revealing Crohn's disease]. / Dysphagie révélant une maladie de Crohn.

Esophageal involvement in Crohn's disease is uncommon. We report here a case with pre-eminent esophageal symptoms and numerous tuberculoid granulomas at histopathological examination. This is an opportunity to review the differential diagnoses and to describe the clinical, endoscopic and histopathological features of this localisation.

Value of liver biopsy for the rapid diagnosis of infection in human immunodeficiency virus-infected patients who have unexplained fever and elevated serum levels of alkaline phosphatase or gamma-glutamyl transferase.

We prospectively determined the value of liver biopsy for microbiological diagnosis of infection in patients infected with the human immunodeficiency virus (HIV) who had unexplained fever and whose serum levels of alkaline phosphatase or gamma-glutamyl transferase were at least 1.5 times the upper limit of normal. From December 1989 to December 1991, 108 HIV-infected patients were referred to the Liver Unit at Hôpital Laënnec (Paris) with liver abnormalities related to viral hepatitis (generally chronic), AIDS-related sclerosing cholangitis, or nonspecific lesions (detected on histologic examination). Twenty-four patients had unexplained fever and increased levels of alkaline phosphatase or gamma-glutamyl transferase, and none had evidence of hepatobiliary disease. All 24 patients had undergone routine microbiological tests to determine the cause of their chronic fever. The results of all microbiological tests were negative. We performed liver biopsies for these 24 patients and examined the specimens by means of standard direct microbiological techniques; in addition, the specimens were cultured, the specimens were analyzed by standard histopathologic methods, and specific histologic studies for fungi, mycobacteria, and viruses were performed. A microbiological diagnosis was made in 13 (54%) of the 24 cases within 12 hours to 3 days of the liver biopsy. In conclusion, liver biopsy is a powerful diagnostic tool for rapid diagnosis of infection in HIV-infected patients who have unexplained fever and abnormal liver function test results.