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Lichen planus (LP) is a frequent, chronic inflammatory disease involving the skin, mucous membranes and/or skin appendages. Esophageal involvement in lichen planus (ELP) is a clinically important albeit underdiagnosed inflammatory condition. This narrative review aims to give an overview of the current knowledge on ELP, its prevalence, pathogenesis, clinical manifestation, diagnostic criteria, and therapeutic options in order to provide support in clinical management. Studies on ELP were collected using PubMed/Medline. Relevant clinical and therapeutical characteristics from published patient cohorts including our own cohort were extracted and summarized. ELP mainly affects middle-aged women. The principal symptom is dysphagia. However, asymptomatic cases despite progressed macroscopic esophageal lesions may occur. The pathogenesis is unknown, however an immune-mediated mechanism is probable. Endoscopically, ELP is characterized by mucosal denudation and tearing, trachealization, and hyperkeratosis. Scarring esophageal stenosis may occur in chronic courses. Histologic findings include mucosal detachment, T-lymphocytic infiltrations, epithelial apoptosis (Civatte bodies), dyskeratosis, and hyperkeratosis. Direct immuno-fluorescence shows fibrinogen deposits along the basement membrane zone. To date, there is no established therapy. However, treatment with topical steroids induces symptomatic and histologic improvement in two thirds of ELP patients in general. More severe cases may require therapy with immunosuppressors. In symptomatic esophageal stenosis, endoscopic dilation may be necessary. ELP may be regarded as a precancerous condition as transition to squamous cell carcinoma has been documented in literature. ELP is an underdiagnosed yet clinically important differential diagnosis for patients with unclear dysphagia or esophagitis. Timely diagnosis and therapy might prevent potential sequelae such as esophageal stenosis or development of invasive squamous cell carcinoma. Further studies are needed to gain more knowledge about the pathogenesis and treatment options.

It is unclear to what extent systemic arterial blood pressure influences portal pressure. This relationship is clinically important as drugs, which are conventionally used for therapy of portal hypertension, may also influence systemic arterial blood pressure. This study investigated the potential correlation between mean arterial (MAP) and portal venous pressure (PVP) in rats with healthy livers. In a rat model with healthy livers, we investigated the effect of manipulation of MAP on PVP. Interventions consisted of 0.9% NaCl (group 1), 0.1 mg/kg body weight (bw) Sildenafil (low dose), an inhibitor of phosphodiesterase-5 (group 2), and 1.0 mg/kg bw Sildenafil (high dose, group 3) in 600 µL saline injected intravenously. Norepinephrine was used to increase MAP in animals with circulatory failure while PVP was monitored. Injection of the fluids induced a transient drop in MAP and PVP, probably due to a reversible cardiac decompensation. The drop in MAP and drop in PVP are significantly correlated. The time lag between change in MAP and change in PVP by 24 s in all groups suggests a cause-and-effect relationship. Ten minutes after the injection of the fluid, cardiac function was normalized. Thereafter, MAP gradually decreased. In the NaCl group, PVP decreases by 0.485% for a 1% drop of MAP, by 0.550% in the low-dose sildenafil group, and by 0.651% in the high-dose sildenafil group (p < 0.05 for difference group two vs. group one, group three vs. group one, and group three vs. group two). These data suggest that Sildenafil has an inherent effect on portal pressure that exceeds the effect of MAP. Injection of norepinephrine led to a sudden increase in MAP followed by an increase in PVP after a time lag. These data show a close relationship between portal venous pressure and systemic arterial pressure in this animal model with healthy livers. A change in MAP is consequently followed by a change in PVP after a distinct time lag. This study, furthermore, suggests that Sildenafil influences portal pressure. Further studies should be performed in a model with cirrhotic livers, as these may be important in the evaluation of vasoactive drugs (e.g., PDE-5-inhibitors) for therapy of portal hypertension.

BACKGROUND Non-alcoholic steatohepatitis (NASH) has become one of the leading causes of liver disease in the western world. In obese patients weight reduction is recommended. Up to now there are no specific guidelines for weight loss in order to reduce hepatic fat content. AIM To investigate the effects of a 24-wk guided lifestyle intervention program compared to a meal replacement regimen based on soy protein. METHODS Twenty-six subjects with NASH participated in a randomized single-center study. They were randomly assigned to either meal replacement group (MR-G) with soy-yogurt-honey preparation or to guided lifestyle change group (LC-G) with endurance activity and nutrition counselling. Serum alanine transaminase (ALT), aspartate transaminase (AST), lipid parameters, and adipokines were measured. Liver fat content and lipid composition were determined by magnetic resonance imaging and magnetic resonance spectroscopy. Body fat mass and lean body mass were assessed using Bod Pod® device. Pre- and post-intervention monitoring of parameters was performed. Statistical analyses were conducted with SPSS software, results were expressed as median (interquartile range). RESULTS Twenty-two subjects (MR-G, n = 11 and LC-G, n = 11) completed the study (9 women, 13 men; age 52.1 (15.0) years, body mass index (BMI) 32.3 (3.3) kg/m²). In both groups a significant weight loss was achieved (MR-G: -6.4 (3.6) kg, P < 0.01; LC-G: -9.1 (10.4) kg, P < 0.01). BMI dropped in both groups (MR-G: -2.3 (1.5) kg/m2, P = 0.003; LC-G: -3.0 (3.4) kg/m2, P = 0.006). Internal fat and hepatic lipid content were markedly reduced in both groups in comparable amount. There was a strong correlation between reduction in liver fat and decrease in ALT. Likewise, both groups showed an improvement in glycemic control and lipid profile. Changes in adipokines, particularly in adiponectin and leptin were closely related to intrahepatic lipid changes. CONCLUSION Comprehensive lifestyle intervention and meal replacement regimen have comparable effects on body and liver fat, as well as decrease in markers of hepatic inflammation among NASH patients.

Liver cirrhosis is a frequent condition with high impact on patients’ life expectancy and health care systems. Cirrhotic portal hypertension (PH) gradually develops with deteriorating liver function and can lead to life-threatening complications. Other than an increase in intrahepatic flow resistance due to morphological remodeling of the organ, a functional dysregulation of the sinusoids, the smallest functional units of liver vasculature, plays a pivotal role. Vascular tone is primarily regulated by the nitric oxide-cyclic guanosine monophosphate (NO-cGMP) pathway, wherein soluble guanylate cyclase (sGC) and phosphodiesterase-5 (PDE-5) are key enzymes. Recent data showed characteristic alterations in the expression of these regulatory enzymes or metabolite levels in liver cirrhosis. Additionally, a disturbed zonation of the components of this pathway along the sinusoids was detected. This review describes current knowledge of the pathophysiology of PH with focus on the enzymes regulating cGMP availability, i.e., sGC and PDE-5. The results have primarily been obtained in animal models of liver cirrhosis. However, clinical and histochemical data suggest that the new biochemical model we propose can be applied to human liver cirrhosis. The role of PDE-5 as potential target for medical therapy of PH is discussed.

AIM To investigate the potential effect of inhibitors of phosphodiesterase-5 (PDE-5) for therapy of portal hypertension in liver cirrhosis. METHODS In the rat model of thioacetamide-induced liver fibrosis/cirrhosis the nitric oxide-cyclic guanosine monophosphate (NO-cGMP) pathway was investigated. Expression and localization of PDE-5, the enzyme that converts vasodilating cGMP into inactive 5’-GMP, was in the focus of the study. Hepatic gene expression of key components of the NO-cGMP pathway was determined by qRT-PCR: Endothelial NO synthase (eNOS), inducible NO synthase (iNOS), soluble guanylate cyclase subunits α1 and β1 (sGCa1, sGCb1), and PDE-5. Hepatic PDE-5 protein expression and localization were detected by immunohistochemistry. Serum cGMP concentrations were measured using ELISA. Acute effects of the PDE-5 inhibitor Sildenafil (0.1 mg/kg or 1.0 mg/kg) on portal and systemic hemodynamics were investigated using pressure transducers. RESULTS Hepatic gene expression of eNOS (2.2-fold; P = 0.003), sGCa1 (1.7-fold; P = 0.003), sGCb1 (3.0-fold; P = 0.003), and PDE-5 (11-fold; P = 0.003) was increased in cirrhotic livers compared to healthy livers. Overexpression of PDE-5 (7.7-fold; P = 0.006) was less pronounced in fibrotic livers. iNOS expression was only detected in fibrotic and cirrhotic livers. In healthy liver, PDE-5 protein was localized primarily in zone 3 hepatocytes and to a lesser extent in perisinusoidal cells. This zonation was disturbed in cirrhosis: PDE-5 protein expression in perisinusoidal cells was induced approximately 8-fold. In addition, PDE-5-expressing cells were also found in fibrous septa. Serum cGMP concentrations were reduced in rats with cirrhotic livers by approximately 40%. Inhibition of PDE-5 by Sildenafil caused a significant increase in serum cGMP concentrations [+ 64% in healthy rats (P = 0.024), + 85% in cirrhotic rats (P = 0.018)]. Concomitantly, the portal venous pressure was reduced by 19% in rats with liver cirrhosis. CONCLUSION Overexpression and abrogated zonation of PDE-5 likely contribute to the pathogenesis of cirrhotic portal hypertension. PDE-5 inhibition may therefore be a reasonable therapeutic approach for portal hypertension.

Non-selective beta-blockers are the mainstay of medical therapy for portal hypertension in liver cirrhosis. Inhibitors of phosphodiesterase-5 (PDE-5-inhibitors) reduce portal pressure in the acute setting by > 10% which may suggest a long-term beneficial effect. Currently, there is no available data on long-term treatment of portal hypertension with PDE-5-inhibitors. This case of a patient with liver cirrhosis secondary to autoimmune liver disease with episodes of bleeding from esophageal varices is the first documented case in which a treatment with a PDE-5-inhibitor for eight years was monitored. In the acute setting, the PDE-5-inhibitor Vardenafil lowered portal pressure by 13%. The portal blood flow increased by 28% based on Doppler sonography and by 16% using MRI technique. As maintenance medication the PDE-5-inhibitor Tadalafil was used for eight consecutive years with comparable effects on portal pressure and portal blood flow. There were no recurrence of bleeding and no formation of new varices. Influencing the NO-pathway by the use of PDE-5 inhibitors may have long-term beneficial effects in compensated cirrhosis.

PURPOSE To test a magnetic resonance (MR) scanning protocol as a noninvasive tool to determine hepatic hemodynamics and to assess the degree of liver fibrosis in an animal model of liver fibrosis and cirrhosis. MATERIALS AND METHODS Fifty-four male Wistar rats were studied. Thirty-nine received thioacetamide (TAA) in their drinking water for either 12 or 16 weeks. MR measurements were performed using flow-sensitive 2D phase-contrast MRI and a 9.4T preclinical scanner. The following hemodynamic parameters were investigated: portal cross-sectional area, mean portal flow velocity, and portal and aortic flow volume rate. Therefore, rats (n = 46) were divided into three groups: CON (control, n = 13), FIB (fibrosis, n = 25), and CIR (cirrhosis, n = 8). Furthermore, the degree of liver fibrosis was assessed by a self-established MR score and verified by a standardized histological score (n = 48). RESULTS Portal and aortic flow parameters could be reliably detected. A significant decrease in portal flow velocity was found in FIB (FIB vs. CON: -21%, P = 0.006 and CIR vs. CON: -17%, P = 0.105) and in portal flow volume rate in FIB and CIR (FIB vs. CON: -20%, P = 0.009 and CIR vs. CON: -25%, P = 0.024). If the histological score is taken as standard, the self-established MR score enabled discrimination between healthy and diseased livers (sensitivity to identify diseased livers: 89% and specificity to identify healthy livers: 100%). CONCLUSION This MR scanning protocol presents a noninvasive tool to determine hepatic hemodynamics in healthy and diseased rats. LEVEL OF EVIDENCE 2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2017;46:1526-1534.

Background: Although lichen planus (LP) is a common skin disorder, the prevalence of esophageal involvement (ELP) and its clinical manifestations are poorly defined. We aimed to establish diagnostic criteria and characterize disease outcomes of ELP. Methods: Clinical, endoscopic, histological, and immunofluorescence data from consecutive patients with known LP between 2013 and 2018 were analyzed. We established endoscopic (denudation and tearing of the mucosa, hyperkeratosis and trachealization) and histological criteria (mucosal detachment, T-lymphocytic infiltrate, intraepithelial apoptosis, dyskeratosis, and fibrinogen deposits along the basement membrane) to grade disease severity. Endoscopic findings were correlated with clinical symptoms. Response to medical therapy was monitored. Results: Fifty-two consecutive patients (median age 59.5 years) were analyzed. According to our grading system, 16 patients were considered as severe and 18 as mild ELP. Dysphagia was the only symptom which differentiated patients with severe (14/16) or mild ELP (8/18) from patients without ELP (1/18). Concomitant oral and genital involvement of LP was associated with the presence of ELP, while oral involvement alone was not. Follow-up of 14/16 patients with severe EPL for at least one year revealed that most of these patients responded to topical corticosteroids (budesonide: n = 9/10 or fluticasone n = 2/2). Three budesonide patients experienced a resolution of symptomatic esophageal stenosis. Conclusions: Esophageal involvement of LP is frequent, but may be asymptomatic. ELP can be diagnosed using the diagnostic criteria proposed here. Dysphagia and combined oral and genital manifestation are associated with ELP. Therapy with topical corticosteroids appears to be a prudent therapeutic approach for ELP.

Objective To evaluate the efficacy and community effectiveness of larvivorous fish for the control of dengue vectors and dengue transmission, when used as a single agent or in combination with other vector control methods. Method Comprehensive literature search of published and grey literature using PubMed, EMBASE (DMDI), Web of Science, WHOLIS, WILEY, LILACS, GIFT, Cochrane Library, ELDIS, New York Academy of Medicine Grey Literature Report and Google. All results were checked for duplicates and examined for eligibility. Methodological quality of the studies was assessed using RoBANS. Results Thirteen articles were considered eligible for inclusion. Incorporating a wide range of interventions and outcome measures, three were efficacy studies and 10 assessed community effectiveness. None of the studies were randomised or cluster-randomised controlled trials. All three efficacy studies and seven community effectiveness studies investigated fish as a single agent. All efficacy studies reported elimination of Aedes larvae from treated containers, while community effectiveness studies reported reductions in immature vector stages, two of which also detected a continuous decline over 2 years. An impact on adult mosquitoes was shown in only two community effectiveness studies. Reductions in dengue cases following intervention were reported in two studies, but it was not possible to attribute this to the intervention. Conclusion While the use of larvivorous fish as a single agent or in combination with other control measures could lead to reductions in immature vector stages, considerable limitations in all the studies restricted any conclusions with respect to the evaluation of community effectiveness. Evidence for the community effectiveness of larvivorous fish as a single agent remains minimal and cluster-randomised controlled studies that include the assessment of impact on dengue are recommended.

Objective Vector control remains the only available method for primary prevention of dengue. Several interventions exist for dengue vector control, with limited evidence of their efficacy and community effectiveness. This systematic review compiles and analyses the existing global evidence for community effectiveness of copepods for dengue vector control. Methods The systematic review follows the PRISMA statement, searching six relevant databases. Applying all inclusion and exclusion criteria, 11 articles were included. Results There is evidence that cyclopoid copepods (Mesocyclops spp.) could potentially be an effective vector control option, as shown in five community effectiveness studies in Vietnam. This includes long-term effectiveness for larval and adult control of Ae. aegypti, as well as dengue incidence. However, this success has so far not been replicated elsewhere (six studies, three community effectiveness studies – Costa Rica, Mexico and USA, and three studies analysing both efficacy and community effectiveness – Honduras, Laos and USA), probably due to community participation, environmental and/or biological factors. Judging by the quality of existing studies, there is a lack of good study design, data quality and appropriate statistics. Conclusion There is limited evidence for the use of cyclopoid copepods as a single intervention. There are very few studies, and more are needed in other communities and environments. Clear best practice guidelines for the methodology of entomological studies should be developed. Objectif La lutte antivectorielle reste la seule methode disponible pour la prevention primaire de la dengue. Plusieurs interventions existent pour la lutte contre le vecteur de la dengue, avec peu de donnees sur leur efficacite et sur l'efficacite communautaire. Cette revue systematique compile et analyse les donnees globales existantes sur l'efficacite communautaire des copepodes dans la lutte contre le vecteur de la dengue. Methodes L'examen systematique suit l'instruction de PRISMA, recherchant dans six bases de donnees pertinentes. En appliquant tous les criteres d'inclusion et d'exclusion, 11 articles ont ete retenus. Resultats Il existe des donnees indiquant que les copepodes de cyclopoides (Mesocyclops spp.) pourraient etre une option de lutte antivectorielle efficace, comme indique dans cinq etudes sur l'efficacite communautaire au Vietnam. Cela comprend l'efficacite a long terme pour la lutte contre les larves et les adultes d’Ae. aegypti, ainsi que sur l'incidence de la dengue. Cependant, ce succes n'a jusqu’a present pas ete reproduit ailleurs (six etudes, dont trois etudes sur l'efficacite communautaire - Costa Rica, Mexique et USA, et trois etudes analysant l'efficacite et l'efficacite communautaire - Honduras, Laos et USA), probablement due a des facteurs de la participation communautaire, environnementaux et/ou biologiques. A en juger par la qualite des etudes existantes, il y a le manque d'une bonne conception d’etude, de qualite des donnees et de statistiques appropriees. Conclusion Il y a peu de donnees sur l'utilisation des copepodes de cyclopoides comme intervention unique. Il y a tres peu d’etudes et des etudes supplementaires sont necessaires dans d'autres communautes et environnements. De meilleures directives de pratiques claires pour la methodologie des etudes entomologiques devraient etre developpees. Objetivo El control vectorial continua siendo el unico metodo para la prevencion primaria del dengue. Existen varias intervenciones para el control del vector del dengue, con una evidencia limitada sobre su eficacia y efectividad comunitaria. Esta revision sistematica recoge y analiza la actual evidencia global sobre la efectividad comunitaria de los Copepodos para el control vectorial del dengue. Metodos La revision sistematica siguio la Declaracion PRISMA, realizando la busqueda en seis bases de datos relevantes. Aplicando todos los criterios de inclusion y exclusion, se incluyeron 11 articulos. Resultados Existe evidencia de que los Copepodos Ciclopoides (Mesocyclops spp.) serian una opcion potencialmente efectiva para el control vectorial, tal y como ha sido demostrado en cinco estudios de efectividad comunitaria en Vietnam. Incluyen tanto la efectividad a largo plazo para el control de larvas y adultos de Ae. aegypti, como sobre la incidencia de dengue. Sin embargo, hasta el momento estos resultados no han sido replicados en ningun otro lugar (seis estudios, tres estudios de efectividad comunitaria, - Costa Rica, Mejico y Estados Unidos, y tres estudios que analizaban tanto la eficacia y efectividad comunitaria - Honduras, Laos y Estados Unidos), probablemente debido a la participacion comunitaria y los factores ambientales y/o biologicos. Juzgando la calidad de los estudios actualmente disponibles, hacen falta un buen diseno del estudio, calidad de datos y estadisticas apropiadas. Conclusion Existe una evidencia limitada sobre el uso de los Copepodos Ciclopoides como intervencion unica. Hay muy pocos estudios y se requieren mas en otras comunidades y ambientes. Deberian desarrollarse unas guias practicas sobre la metodologia de estudios entomologicos que fuesen mejores y mas claras.

To test a magnetic resonance (MR) scanning protocol as a noninvasive tool to determine hepatic hemodynamics and to assess the degree of liver fibrosis in an animal model of liver fibrosis and cirrhosis.Fifty-four male Wistar rats were studied. Thirty-nine received thioacetamide (TAA) in their drinking water for either 12 or 16 weeks. MR measurements were performed using flow-sensitive 2D phase-contrast MRI and a 9.4T preclinical scanner. The following hemodynamic parameters were investigated: portal cross-sectional area, mean portal flow velocity, and portal and aortic flow volume rate. Therefore, rats (n = 46) were divided into three groups: CON (control, n = 13), FIB (fibrosis, n = 25), and CIR (cirrhosis, n = 8). Furthermore, the degree of liver fibrosis was assessed by a self-established MR score and verified by a standardized histological score (n = 48).Portal and aortic flow parameters could be reliably detected. A significant decrease in portal flow velocity was found in FIB (FIB vs. CON: -21%, P = 0.006 and CIR vs. CON: -17%, P = 0.105) and in portal flow volume rate in FIB and CIR (FIB vs. CON: -20%, P = 0.009 and CIR vs. CON: -25%, P = 0.024). If the histological score is taken as standard, the self-established MR score enabled discrimination between healthy and diseased livers (sensitivity to identify diseased livers: 89% and specificity to identify healthy livers: 100%).This MR scanning protocol presents a noninvasive tool to determine hepatic hemodynamics in healthy and diseased rats.2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2017;46:1526-1534.

Patients with dengue fever and comorbidities seem to be at higher risk of developing complications and/or severe dengue compared to healthier individuals. This study systematically reviews the evidence related to comorbidities and dengue. A systematic literature review was performed in five databases (EMBASE, PUBMED, Global Health, SciELO, Cochrane) and grey literature for full-text articles since its inceptions until October 10, 2015. A total of 230 articles were retrieved. Sixteen studies were analysed after applying all inclusion and exclusion criteria. Seven case control studies and nine retrospective cohort studies showed that comorbidities may contribute to severe dengue, especially 1) cardiovascular disease, 2) stroke, 3) diabetes, 4) respiratory disease and 5) renal disease, as well as old age. However, due to heterogeneity in studies, the real estimate effect of comorbidities as modifiers of dengue severity could not be established. Further research in regions with high prevalence of dengue infection would contribute to a better understanding of the relevance of comorbidities in severe dengue, especially with a standardised protocol, for outcomes, specific comorbidities, study design—best using prospective designs—and sample sizes., Author Summary Dengue fever is a viral disease, transmitted by Aedes mosquitoes. Although for most cases of dengue fever the illness is self-limiting or asymptomatic, severe dengue can occur. Severe dengue is now classified by 1) plasma leakage, and/or 2) severe haemorrhage and/or 3) organ failure. Complications and deaths occur in this group of cases with severe dengue. Patients with dengue fever and comorbidities seem to be at higher risk of developing complications and/or severe dengue compared to healthier individuals. This study systematically reviews the evidence related to comorbidities and the severe forms of dengue fever. Sixteen studies were analysed after applying all inclusion and exclusion criteria. Seven case control studies and nine retrospective cohort studies assessed comorbidities and development of severe forms of dengue. The results showed that comorbidities are relevant to severe dengue, especially 1) cardiovascular disease, 2) stroke, 3) diabetes, 4) respiratory disease and 5) renal disease, as well as old age. The study of comorbidities in dengue fever is fundamental for improved patient outcome by differential case management of patients, reducing the burden of the disease. Further research in regions with high prevalence of dengue infection would contribute to a better understanding of the relevance of comorbidities with severe forms of dengue fever. An agreed protocol for such studies is urgently needed.

Protein-losing enteropathy (PLE) is characterized by loss of serum proteins into the gastrointestinal tract. It may lead to hypoproteinemia and clinically present as protein deficiency edema, ascites, pleural or pericardial effusion and/or malnutrition. In most cases the site of protein loss is the small intestine. Here we present an unusual case of severe PLE in a 55-year old female with a one-year history of recurrent diarrhea, crampy abdominal pain, and peripheral edema. Endoscopy and MRI showed a diffuse inflammatory thickening of the sigmoid colon and the rectum. Surgical resection of the involved colon was performed and the symptoms were significantly resolved. The final histologic evaluation confirmed a diagnosis of a pseudomembranous colitis with cap polyposis-like features. Such a cause of PLE has never been described before.