Population Pharmacokinetics of Bepirovirsen in Healthy Participants and Participants with Chronic Hepatitis B Virus Infection: Results from Phase 1, 2a, and 2b Studies.

INTRODUCTION: Bepirovirsen is a novel antisense oligonucleotide in development for chronic hepatitis B virus (HBV) infection therapy. Understanding the impact that clinical characteristics may have on bepirovirsen exposure is important for determining efficacious and well-tolerated dosing regimens. This analysis evaluated demographics and clinical characteristics associated with bepirovirsen exposure using a population pharmacokinetic (PK) analysis. METHODS: Population PK analyses were conducted using pooled data from three phase 1/2 clinical studies (NCT03020745/NCT02981602/NCT04449029) to construct a structural PK model for bepirovirsen that adequately described plasma concentration-time profiles and identify covariates that affect systemic exposure. The final population PK model was used to simulate bepirovirsen exposure measures to inform exposures at different dose levels and within different subpopulations. RESULTS: Bepirovirsen PK data were well-described by a linear, three-compartment model with first-order absorption and absorption delay. Chronic HBV infection status, body weight, and Asian versus non-Asian race were key covariates included in the final model. Visual inspection of correlation scatter plots confirmed general agreement between observed and predicted data from the studies. In simulations, bepirovirsen systemic exposure was dosed proportionally and predicted to be almost completely washed out by 12 weeks following the final 300-mg dose. Differences in body weight, Asian race, or disease status did not result in clinically relevant differences in exposure. CONCLUSIONS: This analysis demonstrated that the linear three-compartmental model accurately described bepirovirsen PK data. The lack of clinically relevant differences seen in exposure indicate that dose adjustments are not recommended for bepirovirsen based on demographics or clinical characteristics.

Evaluation of the on-off fluorescence method for facile measurement of vilazodone in pharmaceutical dosage form; Application to content uniformity testing and greenness evaluation.

Vilazodone is a recently approved antidepressant medicine used for treating major depressive disorder. A simple, extremely sensitive, accurate and green spectrofluorimetric method was constructed for its determination through formation of ion-pair complex with erythrosine B. The formation of ion-pair complex lowers the dye's native fluorescence emission measured at 552 nm (λ ex = 530 nm). In terms of analysis, the system's parameters for producing the vilazodone-erythrosine B complex have been optimized. The reaction was carried out in Teorell-Stenhagen buffering solution (pH 4.6). The fluorescence emission intensity of the dye decreased linearly in the range of 20 - 600 ng mL-1 and the correlation coefficient was 0.9999. The quantitation and detection limit values were 18.5 and 6.1 ng mL-1, respectively. The proposed strategy has been validated according to the ICH criteria. The proposed technique was thoroughly employed for evaluating vilazodone in raw material and pharmaceutical tablet dosage form. Furthermore, it was also successfully used for content uniformity testing. Lastly, using four advanced tools namely the Eco-Scale, the National Environmental Method Index (NEMI), the Green Analytical Procedure Index (GAPI), and the Analytical Greenness metric approach (AGREE), the greenness of the established technique was evaluated.

Classification of Free-Living Body Posture with ECG Patch Accelerometers: Application to the Multicenter AIDS Cohort Study.

Purpose: As health studies increasingly monitor free-living heart performance via ECG patches with accelerometers, researchers will seek to investigate cardio-electrical responses to physical activity and sedentary behavior, increasing demand for fast, scalable methods to process accelerometer data. We extend a posture classification algorithm for accelerometers in ECG patches when researchers do not have ground-truth labels or other reference measurements (i.e., upright measurement). Methods: Men living with and without HIV in the Multicenter AIDS Cohort study wore the Zio XT® for up to two weeks (n = 1,250). Our novel extensions for posture classification include (1) estimation of an upright posture for each individual without a reference upright measurement; (2) correction of the upright estimate for device removal and re-positioning using novel spherical change-point detection; and (3) classification of upright and recumbent periods using a clustering and voting process rather than a simple inclination threshold used in other algorithms. As no posture labels exist in the free-living environment, we perform numerous sensitivity analyses and evaluate the algorithm against labelled data from the Towson Accelerometer Study, where participants wore accelerometers at the waist. Results: On average, 87.1% of participants were recumbent at 4am and 15.5% were recumbent at 1pm. Participants were recumbent 54 minutes longer on weekends compared to weekdays. Performance was good in comparison to labelled data in a separate, controlled setting (accuracy = 96.0%, sensitivity = 97.5%, specificity = 95.9%). Conclusions: Posture may be classified in the free-living environment from accelerometers in ECG patches even without measuring a standard upright position. Furthermore, algorithms that fail to account for individuals who rotate and re-attach the accelerometer may fail in the free-living environment.

A facile on-off fluorescence approach for fluvoxamine determination in pharmaceutical tablets; application to content uniformity testing.

A green-complied spectrofluorimetric approach for quantification of the antidepressant, fluvoxamine, has been established. The method that has been suggested relies on the development of an association complex between fluvoxamine and erythrosine B in an acetate buffer solution. After being excited at 530 nm, the quenching in erythrosine B's native fluorescence caused by complex formation with fluvoxamine was detected at a wavelength of 552 nm. The values of fluorescence quenching at the most optimal reaction conditions were rectilinear at the concentration range of 0.2-2.0 µg mL-1, with a good correlation coefficient (r = 0.9998). The detection limit for the method was 0.03 µg mL-1 while the quantitation limit was 0.09 µg mL-1. The suggested approach has been validated according to the ICH. The established approach was effectively used to determine the drug under study in its dosage form with an average percent recovery of 98.92 ± 0.87 (n = 5), with no effect caused by the existing excipients. The proposed approach was also successfully used for the content uniformity test.

Type 2 T-Cell Responses against Distinct Epitopes of the Desmoglein 3 Ectodomain in Pemphigus Vulgaris.

Pemphigus vulgaris (PV) is an autoimmune blistering disorder of the skin and/or mucous membranes caused by IgG autoantibodies that predominantly target two transmembrane desmosomal cadherins: desmoglein (DSG)1 and DSG3. DSG-specific T cells play a central role in PV pathogenesis because they provide help to autoreactive B cells for autoantibody production. In this study, we characterized DSG3-specific peripheral T cells in a cohort of 52 patients with PV and 41 healthy controls with regard to cytokine profile and epitope specificity. By ELISpot analysis, type 2 T cells reactive with the DSG3 ectodomain were significantly increased in patients with PV compared with those in healthy controls. By dextramer analysis, CD4+ T cells specific for an epitope within the extracellular domain of DSG3, DSG3(206-220), were found at significantly higher frequencies in patients with PV than in HLA-matched healthy controls. T-cell recognition of two distinct DSG3 epitopes, that is, DSG3(206-220) and DSG3(378-392), correlated significantly, suggesting a synergistic effect in B-cell help. Immunization of HLA-DRB1∗04:02-transgenic mice with PV with the same set of DSG3 peptides induced pathogenic DSG3-specific IgG antibodies, which induced loss of keratinocyte adhesion in vitro. Thus, DSG3 peptide-specific T cells are of particular interest as surrogate markers of disease activity and potential therapeutic targets in PV.

Histopathologic regression in patients with primary cutaneous melanoma undergoing sentinel lymph node biopsy is associated with favorable survival and, after metastasis, with improved progression-free survival on immune checkpoint inhibitor therapy: A single-institutional cohort study.

BACKGROUND: Histopathologic regression of cutaneous melanoma is considered a favorable prognostic factor, but its significance in clinical practice remains controversial. OBJECTIVE: To investigate the prognostic importance of regression in patients with primary cutaneous melanoma undergoing sentinel lymph node (SLN) biopsy and to assess its significance in patients progressing to an unresectable stage requiring systemic therapy. METHODS: We retrospectively reviewed patients with newly diagnosed melanoma undergoing SLN biopsy between 2010 and 2015 and available information on histopathologic regression (n = 1179). Survival data and associations of clinical variables with SLN status were assessed. RESULTS: Patients with regressive melanoma showed favorable relapse-free (hazard ratio [HR], 0.52; P = .00013), distant metastasis-free (HR, 0.56; P = .0020), and melanoma-specific survival (HR, 0.35; P = .00053). Regression was associated with negative SLN (odds ratio, 0.48; P = .0077). In patients who progressed to an unresectable stage, regression was associated with favorable progression-free survival under immune checkpoint inhibition (HR, 0.43; P = .031) but not under targeted therapy (HR, 1.14; P = .73) or chemotherapy (HR, 3.65; P = .0095). LIMITATIONS: Retrospective, single-institutional design. CONCLUSIONS: Regression of cutaneous melanoma is associated with improved prognosis in patients eligible for SLN biopsy as well as in patients with unresectable disease receiving systemic therapy with immune checkpoint inhibitors.

[Inpatient care for psoriasis: quo vadis?-A retrospective study at the University Hospitals of Aachen, Bonn, and Essen from 2010 to 2019]. / Stationäre Psoriasistherapie: Quo vadis? ­ Eine retrospektive Studie an den Universitätskliniken Aachen, Bonn und Essen im Zeitraum von 2010 bis 2019.

INTRODUCTION: A number of new, highly effective biologic drugs for psoriasis have been approved over the past few decades, which raises the question whether psoriasis is still a disease that requires inpatient treatment. METHODS: We conducted a retrospective analysis of inpatient data between 2010 and 2019 (the last 10 years prior to the coronavirus disease 2019 [COVID-19] pandemic) from three German dermatology departments at university hospitals (Aachen, Bonn, and Essen). The data collected included age, gender, the primary admission diagnosis, length of stay (LOS), and number of all comorbidities recorded during hospitalization. RESULTS: A total of 59,500 patients were admitted to the three dermatological departments in the defined 10-year period. Of these patients, psoriasis (L40.-) was the main diagnosis for 4322 (7.3%). An almost continuous increase was observed in all inpatient dermatological cases, which was as high as 27% in 2016 compared to 2010. For psoriasis patients, the most substantial increase in the number of admissions was reached in 2016 compared to 2010 and was as high as 45%. While there was a statistically significant reduction of the mean LOS for all dermatological inpatient cases from 6.4 ± 6.6 days in 2010 to 5.1 ± 4.6 days in 2019 (p < 0.001), the decrease in 2019 compared to 2010 (from 12.2 ± 5.5 to 8.9 ± 3.3 days) was significantly greater for the inpatient psoriasis patients compared to the inpatient population overall (p < 0.001). CONCLUSIONS: Our data show a stable need for inpatient psoriasis facilities in Germany. Further analysis of hospital admissions after the end of the COVID-19 pandemic is needed to understand the ongoing influence of modern systemic treatment options on inpatient psoriasis care in Germany.

Comprehensive Risk Assessment of Infection Induced by SARS-CoV-2.

The pandemic COVID-19 (coronavirus disease 2019) is caused by the severe acute respiratory syndrome corona virus 2 (SARS-CoV-2), which devastated the global economy and healthcare system. The infection caused an unforeseen rise in COVID-19 patients and increased the mortality rate globally. This study gives an overall idea about host-pathogen interaction, immune responses to COVID-19, recovery status of infection, targeted organs and complications associated, and comparison of post-infection immunity in convalescent subjects and non-infected individuals. The emergence of the variants and episodes of COVID-19 infections made the situation worsen. The timely introduction of vaccines and precautionary measures helped control the infection's severity. Later, the population that recovered from COVID-19 grew significantly. However, understanding the impact of healthcare issues resulting after infection is paramount for improving an individual's health status. It is now recognised that COVID-19 infection affects multiple organs and exhibits a broad range of clinical manifestations. So, post COVID-19 infection creates a high risk in individuals with already prevailing health complications. The identification of post-COVID-19-related health issues and their appropriate management is of greater importance to improving patient's quality of life. The persistence, sequelae and other medical complications that normally last from weeks to months after the recovery of the initial infection are involved with COVID-19. A multi-disciplinary approach is necessary for the development of preventive measures, techniques for rehabilitation and strategies for clinical management when it comes to long-term care.

The dual face of microglia (M1/M2) as a potential target in the protective effect of nutraceuticals against neurodegenerative diseases.

The pathophysiology of different neurodegenerative illnesses is significantly influenced by the polarization regulation of microglia and macrophages. Traditional classifications of macrophage phenotypes include the pro-inflammatory M1 and the anti-inflammatory M2 phenotypes. Numerous studies demonstrated dynamic non-coding RNA modifications, which are catalyzed by microglia-induced neuroinflammation. Different nutraceuticals focus on the polarization of M1/M2 phenotypes of microglia and macrophages, offering a potent defense against neurodegeneration. Caeminaxin A, curcumin, aromatic-turmerone, myricetin, aurantiamide, 3,6'-disinapoylsucrose, and resveratrol reduced M1 microglial inflammatory markers while increased M2 indicators in Alzheimer's disease. Amyloid beta-induced microglial M1 activation was suppressed by andrographolide, sulforaphane, triptolide, xanthoceraside, piperlongumine, and novel plant extracts which also prevented microglia-mediated necroptosis and apoptosis. Asarone, galangin, baicalein, and a-mangostin reduced oxidative stress and pro-inflammatory cytokines, such as interleukin (IL)-1, IL-6, and tumor necrosis factor-alpha in M1-activated microglia in Parkinson's disease. Additionally, myrcene, icariin, and tenuigenin prevented the nod-like receptor family pyrin domain-containing 3 inflammasome and microglial neurotoxicity, while a-cyperone, citronellol, nobiletin, and taurine prevented NADPH oxidase 2 and nuclear factor kappa B activation. Furthermore, other nutraceuticals like plantamajoside, swertiamarin, urolithin A, kurarinone, Daphne genkwa flower, and Boswellia serrata extracts showed promising neuroprotection in treating Parkinson's disease. In Huntington's disease, elderberry, curcumin, iresine celosia, Schisandra chinensis, gintonin, and pomiferin showed promising results against microglial activation and improved patient symptoms. Meanwhile, linolenic acid, resveratrol, Huperzia serrata, icariin, and baicalein protected against activated macrophages and microglia in experimental autoimmune encephalomyelitis and multiple sclerosis. Additionally, emodin, esters of gallic and rosmarinic acids, Agathisflavone, and sinomenine offered promising multiple sclerosis treatments. This review highlights the therapeutic potential of using nutraceuticals to treat neurodegenerative diseases involving microglial-related pathways.

Clinical, Gender, Socioeconomic Characteristics and Outcomes of Individuals Receiving Hepatitis B Treatment in Ethiopia: 18-Month Follow-Up.

There is a lack of real-world data on hepatitis B (HBV) treatment in Africa. We conducted a single-center 18-month prospective cohort study in Ethiopia to understand clinical, laboratory, and demographic variables associated with HBV treatment. One hundred fifty HBV-positive patients were included: 51 on treatment, 99 with no treatment. Median age was similar between groups. Those on treatment were more likely to be male (86%), report higher coffee intake (90% versus 70%, P < 0.05), lower khat intake (0% versus 9%, P = 0.08), lower alcohol consumption (0% versus 5%, P = 0.1), and had attained higher levels of education (56% versus 42%, P = 0.19). Individuals on treatment had higher median aspartate aminotransferase (AST), alanine aminotransferase (ALT), HBV DNA, and median Aminotransferase-to-Platelet Ratio Index and Fibrosis-4 scores. At 6 and 12 months, those on treatment showed a decrease in median AST, ALT, and fibrosis scores and had less hepatocellular carcinoma development at 6 months (2% versus 4%). Our study highlights potential demographic disparities in HBV treatment as well as benefits in a real-life setting in Africa.

The potential role of miRNAs in the pathogenesis of gallbladder cancer - A focus on signaling pathways interplay.

microRNAs (also known as miRNAs or miRs) are a class of small non-coding RNAs that play a critical role in post-transcriptional gene regulation as negative gene regulators by binding complementary sequences in the 3'-UTR of target messenger RNAs (mRNAs) leading to translational repression and/or target degradation a wide range of genes and biological processes, including cell proliferation, invasion, migration, and apoptosis. The development and progression of cancer have been linked to the anomalous expression of miRNAs. According to recent studies, miRNAs have been found to regulate the expression of cancer-related genes through multiple signaling pathways in gallbladder cancer (GBC). Besides, miRNAs are implicated in several modulatory signaling pathways of GBC, including the Notch signaling pathway, JAK/STAT signaling pathway, protein kinase B (AKT), and Hedgehog signaling pathway. This review summarizes our current knowledge of the functions of miRNAs in the mechanisms underlying the pathogenic symptoms of GBC and illustrates their potential significance as treatment targets.

Macrophage migration inhibitory factor (MIF) and its homolog D-dopachrome tautomerase (D-DT) are significant promotors of UVB- but not chemically induced non-melanoma skin cancer.

Non-melanoma skin cancer (NMSC) is the most common cancer in Caucasians worldwide. We investigated the pathophysiological role of MIF and its homolog D-DT in UVB- and chemically induced NMSC using Mif-/-, D-dt-/- and Mif-/-/D-dt-/- mice on a hairless SKH1 background. Knockout of both cytokines showed similar attenuating effects on inflammation after acute UVB irradiation and tumor formation during chronic UVB irradiation, without additive protective effects noted in double knockout mice, indicating that both cytokines activate a similar signaling threshold. In contrast, genetic deletion of Mif and D-dt had no major effects on chemically induced skin tumors. To get insight into the contributing mechanisms, we used an in vitro 3D skin model with incorporated macrophages. Application of recombinant MIF and D-DT led to an accumulation of macrophages within the epidermal part that could be reversed by selective inhibitors of MIF and D-DT pathways. In summary, our data indicate that MIF and D-DT contribute to the development and progression of UVB- but not chemically induced NMSC, a role at least partially accounted by effects of both cytokines on epidermal macrophage accumulation. These data highlight that MIF and D-DT are both potential therapeutic targets for the prevention of photocarcinogenesis but not chemical carcinogenesis.

Augmentation of Brexpiprazole fluorescence through photoinduced electron transfer inhibition for the sensitive spectrofluorimetric assay of pharmaceutical dosage forms and spiked human plasma: Application to content uniformity testing.

Brexpiprazole (BRX) is a new antipsychotic drug that recently was used in the treatment of schizophrenia and other psychosis. The presence of benzothiophene ring in its chemical structure makes BRX naturally fluoresces. However, the native fluorescence of the drug was low in neutral or alkaline medium owing to the occurrence of photoinduced electron transfer (PET) from the nitrogen of the piperazine ring to the benzothiophene ring. Protonation of this nitrogen atom using sulfuric acid could efficiently block PET process and thus retaining the strong fluorescence of the compound. Accordingly, a straightforward, highly sensitive, fast and green spectrofluorimetric approach was established for BRX determination. In 1.0 M sulfuric acid solution, BRX exhibited significant native fluorescence measured at emission wavelength of 390 nm after excitation at 333 nm. ICH requirements were used to evaluate the method. The fluorescence intensity and BRX concentration were found to be correlated linearly within the range of 5-220 ng mL-1 with a coefficient of correlation 0.9999. The limit of quantitation was 2.38 ng mL-1 while limit of detection was 0.78 ng mL-1. The developed approach was successfully used to analyze BRX in biological fluids and pharmaceutical dosage form. The suggested approach worked well when applied for testing the uniformity of content.

IFN-γ secretion of PBMC from non-drug-allergic control persons: Considerations for the validity of a positive lymphocyte transformation test.

BACKGROUND: The lymphocyte transformation test (LTT) is used for the in vitro detection of a drug sensitization in assumed drug allergic patients. It is based on the detection of antigen (drug)-specific activation of T cells indicated by e.g. proliferation or cytokine secretion. However, occasional stimulatory effects of the drug unrelated to specific drug-allergic mechanisms can only be detected if a larger number of non-drug allergic control persons are tested with this specific drug. In this respect, the overall specificity of the LTT with ELISA read-out is summarized in several review articles, but the impact of a specific drug on the specificity has not yet been analyzed in a larger set of control persons. OBJECTIVE: Do amoxicillin, cefuroxime and clindamycin induce an interferon (IFN)-y or interleukin (IL)-5 secretion of PBMC from control persons using the LTT with ELISA read-out? METHODS: We performed LTTs with amoxicillin, cefuroxime and clindamycin and determined drug-specific IFN-γ and IL-5 secretion measured by ELISA read-out. We included PBMC from 60 non-drug allergic control persons, who were unexposed to the tested drug at the time of blood donation. RESULTS: PBMC from 12 out of 23 control persons tested with amoxicillin gave a positive stimulation index (SI > 3.0) for IFN-γ resulting in a specificity of 47.8%. The corresponding specificity was 75% for cefuroxime (5/20 if SI > 3.0) and 58.8% for clindamycin (7/17, if SI > 2.0), respectively. In a next step, we calculated the Δ IFN-γ concentration by subtracting the background IFN-γ concentration in the unstimulated sample from the stimulated sample. After stimulation with amoxicillin, a mean concentration of 21.0 pg/mL IFN-γ was secreted. The less outlier prone median concentration was 7.4 pg/mL and much higher than for cefuroxime (1.7 pg/mL) and clindamycin (1.0 pg/mL). Remarkably, IL-5 concentrations were below the detection limit (< 1 pg/mL) for all drugs in all control persons who responded to TT. CONCLUSION: Consideration of these observations may be helpful since a positive LTT result in a control patient may challenge the validity of a positive LTT result in the same experiment for a patient with assumed drug allergy.

Amplified sinus-P-wave analysis predicts outcomes of cryoballoon ablation in patients with persistent and long-standing persistent atrial fibrillation: A multicentre study.

Introduction: Outcomes of catheter ablation for non-paroxysmal atrial fibrillation (AF) remain suboptimal. Non-invasive stratification of patients based on the presence of atrial cardiomyopathy (ACM) could allow to identify the best responders to pulmonary vein isolation (PVI). Methods: Observational multicentre retrospective study in patients undergoing cryoballoon-PVI for non-paroxysmal AF. The duration of amplified P-wave (APW) was measured from a digitally recorded 12-lead electrocardiogram during the procedure. If patients were in AF, direct-current cardioversion was performed to allow APW measurement in sinus rhythm. An APW cut-off of 150 ms was used to identify patients with significant ACM. We assessed freedom from arrhythmia recurrence at long-term follow-up in patients with APW ≥ 150 ms vs. APW < 150 ms. Results: We included 295 patients (mean age 62.3 ± 10.6), of whom 193 (65.4%) suffered from persistent AF and the remaining 102 (34.6%) from long-standing persistent AF. One-hundred-forty-two patients (50.2%) experienced arrhythmia recurrence during a mean follow-up of 793 ± 604 days. Patients with APW ≥ 150 ms had a significantly higher recurrence rate post ablation compared to those with APW < 150 ms (57.0% vs. 41.6%; log-rank p < 0.001). On a multivariable Cox-regression analysis, APW≥150 ms was the only independent predictor of arrhythmia recurrence post ablation (HR 2.03 CI95% 1.28-3.21; p = 0.002). Conclusion: APW duration predicts arrhythmia recurrence post cryoballoon-PVI in persistent and long-standing persistent AF. An APW cut-off of 150 ms allows to identify patients with significant ACM who have worse outcomes post PVI. Analysis of APW represents an easy, non-invasive and highly reproducible diagnostic tool which allows to identify patients who are the most likely to benefit from PVI-only approach.

Oxidative Stress and Cardiovascular Risk Factors: The Coronary Artery Risk Development in Young Adults (CARDIA) Study.

Introduction-Oxidative stress is linked to cardiovascular diseases (CVD) and is suggested to vary by sex. However, few population-level studies have explored these associations and the majority comprise populations with advanced CVD. We assessed urinary isoprostane concentrations, a standard measure of oxidative stress, in a relatively young and healthy cohort, hypothesizing that higher oxidative stress is associated with an adverse cardiometabolic profile and female sex. Methods-Oxidative stress was measured in 475 women and 266 men, aged 48-55 years, from the Coronary Artery Risk Development in Young Adults (CARDIA) study using urinary 8-isoprostane (IsoP) and 2,3-dinor-8-isoprostane (IsoP-M). Multivariable-adjusted regression was used to evaluate cross-sectional associations. As secondary analysis, previously measured plasma F2-isoprostanes (plasma IsoP) from another CARDIA subset was similarly analyzed. Results-Mean (SD) ages for men and women were 52.1(2.3) and 52.2(2.2) years, respectively (p = 0.46), and 39% of the participants self-identified as Black (vs. White). Before adjustments, female sex was associated with higher median urinary IsoP (880 vs. 704 ng/g creatinine in men; p < 0.01) and IsoP m (1675 vs. 1284 ng/g creatinine in men; p < 0.01). Higher body mass index (BMI), high-density cholesterol (HDL-C), and triglycerides, current smoking, and less physical activity were associated with higher oxidative stress. Diabetes was not associated with urinary IsoP but was associated with lower IsoP m and plasma IsoP. Higher serum creatinine showed diverging associations with higher plasma and lower urinary isoprostane concentrations. Conclusions-Different isoprostane entities exhibit varying association patterns with CVD risk factors, and therefore are complementary, rather than interchangeable, in assessment of oxidative stress. Still, consistently higher isoprostanes among women, smokers, less active persons, and those with higher BMI and plasma triglycerides could reflect higher oxidative stress among these groups. While urinary isoprostanes are indexed to urinary creatinine due to variations in concentration, caution should be exercised when comparing groups with differing serum creatinine.

The NLRP1 inflammasome in skin diseases.

Healthy human skin is constantly exposed to sterile and microbial agents. The skin immune system plays an important role in immune surveillance between tolerance and immune activation. This is mainly mediated by neutrophils, macrophages and most importantly lymphocytes. Keratinocytes, which form the outer skin barrier (epidermis) are also critical for cutaneous homeostasis. Being a non-professional immune cell, recognition of danger signals in keratinocytes is mediated by innate immune receptors (pattern recognition receptors, PRR). While Toll-like receptors are located on the cell membrane or the endosomes, nucleotide-binding domain and leucine-rich repeat containing gene family receptors (NLR) are intracellular PRRs. Some of these, once activated, trigger the formation of inflammasomes. Inflammasomes are multiprotein complexes and serve as platforms that mediate the release of innate cytokines after successful recognition, thereby attracting immune cells. Moreover, they mediate the pro-inflammatory cell death pyroptosis. Best characterized is the NLRP3 inflammasome. The function of inflammasomes differs significantly between different cell types (keratinocytes versus immune cells) and between different species (human versus mouse). In recent years, great progress has been made in deciphering the activation mechanisms. Dysregulation of inflammasomes can lead to diseases with varying degrees of severity. Here we focus on the structure, function, and associated pathologies of the NLRP1 inflammasome, which is the most relevant inflammasome in keratinocytes.