Stress signalling and STAT1 activation characterize the keratinocytic gene expression pattern in Hidradenitis suppurativa.

BACKGROUND: The pathogenetic factors generating the innate immune signal necessary for T-cell activation, initiation and chronification of Hidradenitis suppurativa (HS, also known as Acne inversa) are still poorly understood. Emerging evidence suggests that a defective keratinocyte function critically contributes to HS disease development and progression. OBJECTIVES: To elucidate the role of keratinocytes in HS lesion formation, we compared the transcriptomes of lesional and perilesional epidermis isolated from HS patients by RNA sequencing (RNA Seq). METHODS: Pairwise-matched lesional and perilesional HS skin samples of five different donors were obtained and epidermal keratinocytes freshly isolated and processed for RNA extraction and RNA seq. Lesionally regulated genes were analysed by large-scale promoter analysis and functional annotation clustering to identify epidermally overrepresented transcription factor binding sites and functionally related gene groups. Results were experimentally validated with independent epidermal isolates of patient-matched lesional and perilesional HS skin employing qRT-PCR, cell culture, immunoblot and immunostaining. RESULTS: We show that HS is characterized by a strong epidermal stress state evident by a significant overrepresentation of an AP-1-driven gene signature and a substantial activation of the stress-activated cJun N-terminal kinase (JNK) pathway in lesional epidermis. Additionally, our data reveal a strong induction of STAT1 activation in lesional HS epidermis that likely results from IFNγ production and triggered expression of key inflammatory genes coordinating innate immune activation and the adaptive T-cell response in HS. CONCLUSIONS: Our data implicate a key role of stress signalling and JAK/STAT1 activation in disease progression of HS and suggest interference with JAK/STAT1 signalling as a potentially promising therapeutic approach for HS.

[Epidemiology, patient quality of life, and treatment costs of hidradenitis suppurativa/acne inversa]. / Epidemiologie, Patientenlebensqualität und Behandlungskosten der Hidradenitis suppurativa/Acne inversa.

Hidradenitis suppurativa/acne inversa (HS) is associated with numerous and relevant restrictions on the quality of life for those affected and their relatives. The exact prevalence of HS varies significantly across studies, but it is likely to be higher than suggested in previous publications. HS care is associated with high costs for the healthcare system and for those affected. The introduction of biologic therapy has led to additional costs, but also to considerable additional benefits in terms of care. In view of the complexity of diagnostics and therapy, there is a particular need for optimized care concepts in order to reduce the burden on those affected, their relatives and the healthcare system.

Advanced cutaneous squamous cell carcinoma: real world data of patient profiles and treatment patterns.

BACKGROUND: Cutaneous squamous cell carcinoma (cSCC) is one of the most common types of cancer in the Caucasian population, with an increasing incidence. cSCC is mostly a local invasive disease that can be treated surgically in the majority of the cases. However, in the case of advanced cSCC (acSCC), a multimodality approach also involving systemic therapies needs to be considered. METHODS: One hundred and ninety-five patients diagnosed with acSCC (stages III and IV) treated in our centre between 2011 and 2018 were included. Patient and tumour characteristics along with treatment patterns were documented and analyzed. Descriptive analysis was performed and survival rates were estimated according to Kaplan-Meier and compared with the Log-rank test. Follow-up was defined as the time between diagnosis of advanced disease and last contact or death. All causes of death were considered as events. RESULTS: The median follow-up was 21 months [IQR = (10.0; 21.0)]. The median age at time of advanced disease diagnosis was 78 years [IQR = (72; 84)], with 40.5% of the patients in stage III and 59.5% in stage IV. One hundred and forty-five patients had resectable tumours. In this group the median overall survival (mOS) was 59 months (95% CI: 28.2-89.8), significantly higher than the mOS in patients with inoperable tumour [n = 50; mOS: 19 months (96% CI: 7-31, P <0.0001)]. Patients receiving immunotherapy (n = 20) showed a statistically significant better survival compared to those treated with other systemic therapies (n = 37; mOS not reached vs. mOS: 22 months (95% CI: 6.5-43.5), P = 0.034). For patients without systemic therapy, a combination of surgery and radiotherapy provided better outcomes compared to radiotherapy alone or best supportive care (P <0.001). CONCLUSION: Surgical complete resection should be the first therapeutic option for patients with acSCC. For patients with inoperable tumour, first-line immunotherapy should be preferably considered.

Development and validation of the International Hidradenitis Suppurativa Severity Score System (IHS4), a novel dynamic scoring system to assess HS severity.

BACKGROUND: A validated tool for the dynamic severity assessment of hidradenitis suppurativa/acne inversa (HS) is lacking. OBJECTIVES: To develop and validate a novel dynamic scoring system to assess the severity of HS. METHODS: A Delphi voting procedure was conducted among the members of the European Hidradenitis Suppurativa Foundation (EHSF) to achieve consensus towards an initial HS Severity Score System (HS4). Strengths and weaknesses of HS4 were examined by a multicentre prospective study. Multivariate logistic regression, discriminant analysis and receiver operating characteristic curves, as well as examination for correlation (Spearman's rho) and agreement (Cohen's kappa) with existing scores, were engaged to recognize the variables for a new International HS4 (IHS4) that was established by a second Delphi round. RESULTS: Consensus HS4 was based on number of skin lesions, number of skin areas involved and Dermatology Life Quality Index (DLQI), and was evaluated by a sample of 236 patients from 11 centres. Subsequently, a multivariate regression model calculated adjusted odds ratios for several clinical signs. Nodules, abscesses and draining tunnels resulted as the scoring variables. Three candidate scores were presented to the second Delphi round. The resulting IHS4 score is arrived at by the number of nodules (multiplied by 1) plus the number of abscesses (multiplied by 2) plus the number of draining tunnels (multiplied by 4). A total score of 3 or less signifies mild, 4-10 signifies moderate and 11 or higher signifies severe disease. Cohen's kappa was fair (κ = 0·32) compared with Hurley classification, and moderate (κ = 0·49) compared with Expert Opinion. Correlation was good (ρ > 0·6) with Hurley classification, Expert Opinion, Physician's Global Assessment and Modified Sartorius score, and moderate for DLQI (ρ = 0·36). CONCLUSIONS: The novel IHS4 is a validated tool to dynamically assess HS severity and can be used both in real-life and the clinical trials setting.

Keratinocytes and neutrophils are important sources of proinflammatory molecules in hidradenitis suppurativa.

BACKGROUND: The pathogenesis of the chronic inflammatory skin disease hidradenitis suppurativa (HS, also known as acne inversa) involves epidermal alterations such as psoriasiform epidermal hyperplasia and keratin plugging. Keratinocytes are an important source of proinflammatory molecules in inflammatory skin diseases and can be stimulated by interleukin (IL)-17(+) cells. OBJECTIVES: To explore the possible role of the epithelium in the pathogenesis of HS. METHODS: We performed immunohistochemical stainings and Western blot experiments to investigate the localization and expression of inflammation-associated molecules, including the cytokine IL-17, components of the inflammasome including caspase-1, and the endogenous danger-associated molecular pattern molecules S100A8 and S100A9 (calprotectin). To examine a possible effect of upregulated proinflammatory cytokines on the inflammatory infiltrate, differences in the cellular composition of perifollicular and deep dermal infiltrates were analysed. RESULTS: The number of IL-17(+) cells is increased in lesional and perilesional HS skin. The epidermis produces proinflammatory molecules and shows an upregulated expression of components of the NLRP3 inflammasome, activated caspase-1 and expression of S100A8/S100A9. Additionally, the course of the inflammatory process in HS involves influx of innate immune cells, particularly IL-17-expressing neutrophils. CONCLUSIONS: IL-17-producing cells are present in lesional and perilesional HS skin and may contribute to the initiation of inflammatory processes. Furthermore, the epidermis is a source of proinflammatory cytokines, shows inflammasome activation and expresses S100A8/S100A9, thereby possibly contributing to the propagation of inflammation. A massive influx of IL-17-expressing neutrophils is observed in the deep infiltrate.

PD-1 expression and IL-2 loss of cytomegalovirus- specific T cells correlates with viremia and reversible functional anergy.

Cytomegalovirus (CMV) represents a major cause of infectious complications after transplantation. Recently, chronic infections with lymphocyte choriomeningitis virus (LCMV), HIV or HCV were shown to be associated with functionally exhausted T cells characterized by high expression of the programmed death (PD)-1 molecule and altered cytokine expression patterns. We therefore hypothesized that functional exhaustion of CMV-specific CD4 T cells may determine impaired CMV control in patients after renal transplantation. In viremic transplant recipients, a significantly higher proportion of CMV-specific CD4 T cells was PD-1 positive (median 40.9%, 17.0-88.7%) as compared to nonviremic transplant patients (8.8%, 0.8-80.5%), dialysis patients (8.8%, 0-36.7%) or controls (3.2%, 0.3-15.4%, p < 0.0001). In line with functional impairment, PD-1-positive T cells produced significantly less IFNgamma as compared to PD-1-negative T cells (p < 0.0001). Moreover, unlike controls or nonviremic patients, CMV-specific T cells from viremic patients showed a significant loss of IL-2 production (p < 0.0001). Interestingly, functional anergy of CMV-specific CD4 T cells was reversible in that antibody-mediated blockade of PD-1 signaling with its ligands PD-L1/-L2 led to an up to 10-fold increase in CMV-specific proliferation. In conclusion, expression of PD-1 defines a reversible defect of CMV-specific CD4 T cells that is associated with viremia, and blocking PD-1 signaling may provide a potential target for enhancing the function of exhausted T cells in chronic CMV infection.

Reconstruction of large defects on the scalp and forehead as an interdisciplinary challenge: experience in the management of 39 cases.

AIMS: To describe options and indications for different surgical reconstruction techniques after resection of large skin tumours on the scalp taking into account an interdisciplinary approach of cranio-maxillofacial surgeon, dermatologist, and neurosurgeon, and to evaluate complications and postoperative outcome. PATIENTS AND METHODS: From a total of 39 patients with large skin tumour resections on the scalp and/or the forehead, treated between January 01, 1995 and June 30, 2005, a number of 42 surgical reconstructions were performed. The medical histories, the surgical treatment, postoperative complications, follow-up and outcome were evaluated. RESULTS: The excision defects measured 146 cm(2) (range: 80.6-546 cm(2)) on average. The most common methods for defect closure were multiple rotation-advancement flaps (n=19). Six patients were treated with split-thickness skin grafts after bone drilling for inducing granulation tissue to grow. Free latissimus dorsi muscle flaps were used in 8 patients and radial forearm flaps in 4 cases. Postoperative complications were rare. An algorithm for the surgical approach to large scalp defects was developed. CONCLUSION: For reconstruction of large defects on the scalp and forehead, various reliable methods may be used with regard to individual patient-specific parameters in cooperation with different medical specialties involved.

Pomegranate juice consumption reduces oxidative stress, atherogenic modifications to LDL, and platelet aggregation: studies in humans and in atherosclerotic apolipoprotein E-deficient mice.

BACKGROUND: Dietary supplementation with nutrients rich in antioxidants is associated with inhibition of atherogenic modifications to LDL, macrophage foam cell formation, and atherosclerosis. Pomegranates are a source of polyphenols and other antioxidants. OBJECTIVE: We analyzed, in healthy male volunteers and in atherosclerotic apolipoprotein E-deficient (E(0)) mice, the effect of pomegranate juice consumption on lipoprotein oxidation, aggregation, and retention; macrophage atherogenicity; platelet aggregation; and atherosclerosis. DESIGN: Potent antioxidative effects of pomegranate juice against lipid peroxidation in whole plasma and in isolated lipoproteins (HDL and LDL) were assessed in humans and in E(0) mice after pomegranate juice consumption for

Pomegranate juice flavonoids inhibit low-density lipoprotein oxidation and cardiovascular diseases: studies in atherosclerotic mice and in humans.

The beneficial health effects attributed to the consumption of fruit and vegetables are related, at least in part, to their antioxidant activity. Of special interest is the inverse relationship between the intake of dietary nutrients rich in polyphenols and cardiovascular diseases. This effect is attributed to polyphenols' ability to inhibit low-density lipoprotein (LDL) oxidation, macrophage foam cell formation and atherosclerosis. Pomegranate polyphenols can protect LDL against cell-mediated oxidation via two pathways, including either direct interaction of the polyphenols with the lipoprotein and/or an indirect effect through accumulation of polyphenols in arterial macrophages. Pomegranate polyphenols were shown to reduce the capacity of macrophages to oxidatively modify LDL, due to their interaction with LDL to inhibit its oxidation by scavenging reactive oxygen species and reactive nitrogen species and also due to accumulation of polyphenols in arterial macrophages; hence, the inhibition of macrophage lipid peroxidation and the formation of lipid peroxide-rich macrophages. Furthermore, pomegranate polyphenols increase serum paraoxonase activity, resulting in the hydrolysis of lipid peroxides in oxidized lipoproteins and in atherosclerotic lesions. These antioxidative and antiatherogenic effects of pomegranate polyphenols were demonstrated in vitro, as well as in vivo in humans and in atherosclerotic apolipoprotein E deficient mice. Dietary supplementation of polyphenol-rich pomegranate juice to atherosclerotic mice significantly inhibited the development of atherosclerotic lesions and this may be attributed to the protection of LDL against oxidation.

Surgical reconstruction after subtotal ear resection in malignant melanoma of the ear.

Surgery in malignant melanoma of the external ear often leads to substantial defects where reconstruction poses a difficult challenge. We describe an option of a one-step ear reconstruction after subtotal ear resection in malignant melanoma surgery. In a patient with a high-risk melanoma of the helical rim, a wide local excision was performed. Because of a metastasis-suspect lymph node in the parotid gland, surgery included asservation of the sentinel lymph node, neck dissection and parotidectomy. A complete reconstruction of the ear was achieved using a bilobed flap from the retroauricular and neck region with acceptable cosmetic and functional results by one-step surgery. One micrometastasis was detected in the nuchal region but not in the marked sentinel lymph node. An adequate one-step ear reconstruction as described may also be performed to the benefit of patients with high-risk melanomas, allowing early adjuvant therapy.

Oxidized low-density lipoprotein reduces plasma coagulation in vitro.

Oxidation of low-density lipoprotein (LDL) was shown to occur in vivo and involved lipid peroxidation and apolipoprotein modification. We studied the effect of oxidized-LDL (Ox-LDL) on plasma coagulation by measuring prothrombin time (PT) and partial thromboplastin time (PTT) following the addition of Ox-LDL to normal plasma. Ox-LDL, but not native LDL, caused prolongation of PT and PTT by 30% in a dose- and time-dependent pattern. This effect was also shown to be present following lipoprotein delipidation, suggesting that it was the apolipoprotein fraction of Ox-LDL, but not its lipid fraction, that was responsible for the prolongation of PT and PTT. This was further substantiated since similar effect could be obtained by adding LDL treated with trinitrobenzenesulphonic acid to block the lysine groups, as occurs in oxidized LDL. Ox-LDL, unlike LDL, was found to reduce plasma ionized calcium by 33%. Moreover, adding calcium ions to Ox-LDL negated its effect on PT and PTT, suggesting that Ox-LDL apolipoprotein may influence coagulation by binding calcium ions.

Consumption of eggs with meals increases the susceptibility of human plasma and low-density lipoprotein to lipid peroxidation.

Consumption of eggs for a long period was shown to result in hypercholesterolemia and is generally restricted for this reason. In the present study we analyzed the effect of eggs consumption for 3 weeks on lipoprotein atherogenicity. Consumption of 2 eggs per day with the meals, for 3 weeks resulted in a minor elevation in plasma glucose and urea concentrations. Plasma cholesterol concentration increased by 11% (p < 0.05) as a result of increased plasma low-density lipoprotein (LDL) cholesterol levels. Plasma triglycerides decreased by 13% (p < 0.01), but there were no significant alterations in plasma apolipoproteins A-I or B-100 concentrations. Plasma high-density lipoprotein (HDL) cholesterol decreased by 11% (p < 0.05). There was a 13% reduction, though not significant, in the cholesterol efflux from J-774 A.1 macrophages by HDL that was derived after eggs consumption in comparison to HDL that was obtained at baseline. The susceptibility of plasma [using 100 mM of 2,2' azobis 2-amidinopropane (AAPH)] as well as that of LDL (using 10 microM of copper ions) to lipid peroxidation was increased by 42% and 34%, respectively, as measured by the thiobarbituric acid reactive substance (TBARS) assay (p < 0.01). Kinetic analysis of LDL oxidation by copper ions revealed a 37% reduction in the lag time required for the initiation of LDL oxidation after 3 weeks of eggs consumption. The total plasma fatty acids concentration increased from 2.2 +/- 0.5 to 3.2 +/- 0.6 mg/ml. The plasma antioxidants, vitamin E and carotenoids were not significantly affected by eggs consumption. We conclude that eggs consumption, in addition to its hypercholesterolemic effect, increases plasma and LDL oxidizability, a phenomenon which was shown to enhance the progression of atherosclerosis. The atherogenic properties may contribute to the accelerated atherosclerosis prevalent in populations with high cholesterol intake.

[Embolia cutis medicamentosa (Nicolau syndrome) after intra-articular injection]. / Embolia cutis medicamentosa (Nicolau-Syndrom) nach intraartikulärer Injektion.

Embolia cutis medicamentosa (Nicolau Syndrome) is a very rare complication of intramuscular injections which presents with extensive necrosis of the injected skin area. Intra-arteria and/or para-arterial injections after prior perforation of certain vessels are discussed as possible pathogenetic mechanisms. We describe the occurrence of embolia cutis medicamentosa after intra-articular injections into the knee.

Fulminant hepatitis. A presentation of Wilson's disease.

A boy, 10 years of age, was admitted to the hospital with rapid onset of hepatic failure and died within three weeks. Laboratory and pathological data were consistent with Wilson's disease. We discuss the importance of Wilson's disease in the differential diagnosis of acute liver failure.

Effect of dietary supplementation of red or white wine on human blood chemistry, hematology and coagulation: favorable effect of red wine on plasma high-density lipoprotein.

Twenty healthy males were divided into two groups: 10 subjects were supplemented for 2 weeks with 400 ml of red wine (11% alcohol) per day and the other 10 subjects were given 400 ml of white wine (11% alcohol) per day for a similar period. Blood samples were drawn prior to wine supplementation, after 1 week and at the end of the study. No significant effects were found on plasma concentrations of urea, creatinine, bilirubin, creatine kinase, amylase, blood cell counts, platelet counts and platelet aggregation. Both red- and white-wine supplementation resulted in a transient minor reduction in plasma glucose concentration and in a minor elevation in blood coagulation properties such as prothrombin time and partial thromboplastin time. Red (but not white) wine resulted in an 11 and 26% increment in plasma triglyceride concentrations after 1 and 2 weeks of supplementation, respectively. Plasma cholesterol, as well as very-low- and low-density-lipoprotein levels did not change during the 2 weeks of red- or white-wine supplementation. The most impressive effect of red-wine intake was a significant (p < 0.01) increase in plasma high-density lipoprotein (HDL) cholesterol and in plasma apolipoprotein A-I concentrations by up to 26 and 12%, respectively. These effects were not observed after the intake of white wine. We conclude that the major effect of red-wine supplementation (about 40 g of alcohol per day for a period of 2 weeks) was a significant increase in plasma HDL concentration which may contribute to the reduced risk for cardiovascular diseases observed in red-wine drinkers.

Managed care does not lower costs but may result in poorer outcomes for patients with gestational diabetes.

OBJECTIVE: Our purpose was to compare the costs of prenatal care and subsequent maternal and neonatal outcomes in patients with gestational diabetes cared for in an inner-city university hospital house staff clinic versus an inner-city managed care organization. STUDY DESIGN: A retrospective cohort study was conducted. The groups consisted of 115 patients with gestational diabetes who were cared for in a house staff clinic and a demographically similar group of 85 patients cared for in a neighborhood managed care organization. The groups were examined regarding baseline demographics, intensity of prenatal care, maternal and neonatal outcomes, and total cost of the provision of care. RESULTS: There was no difference between groups in the total cost of maternal-infant care. A larger percentage of patients in the house staff group saw the physician frequently. In contrast, patients cared for in the managed care organization underwent more tests of fetal well-being. There was a greater rate of neonatal macrosomia in the managed care organization group compared with the house staff group. CONCLUSIONS: Managed care does not decrease the cost of caring for patients with gestational diabetes but does lead to a greater rate of neonatal macrosomia, which may reflect poorer glucose control.