Treatment of severe atopic dermatitis with tralokinumab in clinical practice: short-term effectiveness and safety results.

BACKGROUND: Tralokinumab was recently approved for the treatment of moderate-to-severe atopic dermatitis (AD) and is the first selective interleukin (IL)-13 inhibitor that specifically neutralizes IL-13 with high affinity. OBJECTIVES: To determine the real-life short-term effectiveness and safety of tralokinumab treatment in patients with moderate-to-severe AD. METHODS: A multicentre retrospective study was conducted including adult patients with moderate-to-severe AD who started tralokinumab treatment from 1 April to 30 June 2022 in 16 Spanish hospitals. Demographic and disease characteristics, severity and quality of life scales were collected at the baseline visit and at weeks 4 and 16. RESULTS: Eighty-five patients were included. Twenty-seven patients (32%) were non-naive to advanced therapy (biological or Janus kinase inhibitors inhibitors). All included patients had severe disease with baseline Eczema Area and Severity Index (EASI) scores of 25.4 (SD 8.1), Dermatology Life Quality Index (DLQI) 15.8 (5.4) and peak pruritus numerical rating scale (PP-NRS) 8.1 (1.8) and 65% had an Investigator's Global Assessment (IGA) of 4. At week 16, there was improvement on all scales. The mean EASI decreased to 7.5 (SD 6.9, 70% improvement), SCORing Atopic Dermatitis improved 64% and PP-NRS, 57%. Also, 82%, 58% and 21% of the patients achieved EASI 50, 75 and 90, respectively. The percentage of EASI 75 responders was significantly higher among the naive vs. non-naive groups (67% vs. 41%). The safety profile was acceptable. CONCLUSIONS: Patients, with a long history of disease and prior multidrug failure, showed a good response to tralokinumab, confirming clinical trial results.

Clinically Inspired Skin Lesion Classification through the Detection of Dermoscopic Criteria for Basal Cell Carcinoma.

Background and Objective. Skin cancer is the most common cancer worldwide. One of the most common non-melanoma tumors is basal cell carcinoma (BCC), which accounts for 75% of all skin cancers. There are many benign lesions that can be confused with these types of cancers, leading to unnecessary biopsies. In this paper, a new method to identify the different BCC dermoscopic patterns present in a skin lesion is presented. In addition, this information is applied to classify skin lesions into BCC and non-BCC. Methods. The proposed method combines the information provided by the original dermoscopic image, introduced in a convolutional neural network (CNN), with deep and handcrafted features extracted from color and texture analysis of the image. This color analysis is performed by transforming the image into a uniform color space and into a color appearance model. To demonstrate the validity of the method, a comparison between the classification obtained employing exclusively a CNN with the original image as input and the classification with additional color and texture features is presented. Furthermore, an exhaustive comparison of classification employing different color and texture measures derived from different color spaces is presented. Results. Results show that the classifier with additional color and texture features outperforms a CNN whose input is only the original image. Another important achievement is that a new color cooccurrence matrix, proposed in this paper, improves the results obtained with other texture measures. Finally, sensitivity of 0.99, specificity of 0.94 and accuracy of 0.97 are achieved when lesions are classified into BCC or non-BCC. Conclusions. To the best of our knowledge, this is the first time that a methodology to detect all the possible patterns that can be present in a BCC lesion is proposed. This detection leads to a clinically explainable classification into BCC and non-BCC lesions. In this sense, the classification of the proposed tool is based on the detection of the dermoscopic features that dermatologists employ for their diagnosis.

The Deubiquitinase OTUB1 Is a Key Regulator of Energy Metabolism.

Dysregulated energy metabolism is a major contributor to a multitude of pathologies, including obesity and diabetes. Understanding the regulation of metabolic homeostasis is of utmost importance for the identification of therapeutic targets for the treatment of metabolically driven diseases. We previously identified the deubiquitinase OTUB1 as substrate for the cellular oxygen sensor factor-inhibiting HIF (FIH) with regulatory effects on cellular energy metabolism, but the physiological relevance of OTUB1 is unclear. Here, we report that the induced global deletion of OTUB1 in adult mice (Otub1 iKO) elevated energy expenditure, reduced age-dependent body weight gain, facilitated blood glucose clearance and lowered basal plasma insulin levels. The respiratory exchange ratio was maintained, indicating an unaltered nutrient oxidation. In addition, Otub1 deletion in cells enhanced AKT activity, leading to a larger cell size, higher ATP levels and reduced AMPK phosphorylation. AKT is an integral part of insulin-mediated signaling and Otub1 iKO mice presented with increased AKT phosphorylation following acute insulin administration combined with insulin hypersensitivity. We conclude that OTUB1 is an important regulator of metabolic homeostasis.

Rapid Identification of SARS-CoV-2 Variants of Concern Using a Portable peakPCR Platform.

The need for tools that facilitate rapid detection and continuous monitoring of SARS-CoV-2 variants of concern (VOCs) is greater than ever, as these variants are more transmissible and therefore increase the pressure of COVID-19 on healthcare systems. To address this demand, we aimed at developing and evaluating a robust and fast diagnostic approach for the identification of SARS-CoV-2 VOC-associated spike gene mutations. Our diagnostic assays detect the E484K and N501Y single-nucleotide polymorphisms (SNPs) as well as a spike gene deletion (HV69/70) and can be run on standard laboratory equipment or on the portable rapid diagnostic technology platform peakPCR. The assays achieved excellent diagnostic performance when tested with RNA extracted from culture-derived SARS-CoV-2 VOC lineages and clinical samples collected in Equatorial Guinea, Central-West Africa. Simplicity of usage and the relatively low cost are advantages that make our approach well suitable for decentralized and rapid testing, especially in resource-limited settings.

OTUB1 regulates lung development, adult lung tissue homeostasis, and respiratory control.

OTUB1 is one of the most highly expressed deubiquitinases, counter-regulating the two most abundant ubiquitin chain types. OTUB1 expression is linked to the development and progression of lung cancer and idiopathic pulmonary fibrosis in humans. However, the physiological function of OTUB1 is unknown. Here, we show that constitutive whole-body Otub1 deletion in mice leads to perinatal lethality by asphyxiation. Analysis of (single-cell) RNA sequencing and proteome data demonstrated that OTUB1 is expressed in all lung cell types with a particularly high expression during late-stage lung development (E16.5, E18.5). At E18.5, the lungs of animals with Otub1 deletion presented with increased cell proliferation that decreased saccular air space and prevented inhalation. Flow cytometry-based analysis of E18.5 lung tissue revealed that Otub1 deletion increased proliferation of major lung parenchymal and mesenchymal/other non-hematopoietic cell types. Adult mice with conditional whole-body Otub1 deletion (wbOtub1del/del ) also displayed increased lung cell proliferation in addition to hyperventilation and failure to adapt the respiratory pattern to hypoxia. On the molecular level, Otub1 deletion enhanced mTOR signaling in embryonic and adult lung tissues. Based on these results, we propose that OTUB1 is a negative regulator of mTOR signaling with essential functions for lung cell proliferation, lung development, adult lung tissue homeostasis, and respiratory regulation.

Possible Role of Leptin in Atopic Dermatitis: A Literature Review.

Atopic dermatitis (AD) is the most frequent chronic inflammatory skin disease, and its incidence has been rapidly increasing in developed countries in the last years. AD presents a high degree of heterogeneity due to biases and confounding factors such as age range, sex, or ethnicity. For those reasons, the search for new biomarkers is crucial. At the same time, obesity, which is a global health problem, has also increased over the years. It has been associated with many pathophysiological states, including skin diseases such as AD, mostly in childhood. Obesity promotes a low grade inflammation driven by many different cytokines and adipokines, including leptin, which has a key role in many other diseases due to its pleiotropic effects. Leptin also has a role in both skin and allergic diseases very related to AD. Thus, this adipokine could have an important role in the pathogenesis of AD, especially in its chronicity. Despite the limited literature available, there is some evidence that leads us to consider leptin as an important adipokine in this skin disease. For this reason, here we have reviewed the role of leptin in the pathophysiology of AD.

Oxygen-dependent bond formation with FIH regulates the activity of the client protein OTUB1.

Protein:protein interactions are the basis of molecular communication and are usually of transient non-covalent nature, while covalent interactions other than ubiquitination are rare. For cellular adaptations, the cellular oxygen and peroxide sensor factor inhibiting HIF (FIH) confers oxygen and oxidant stress sensitivity to the hypoxia inducible factor (HIF) by asparagine hydroxylation. We investigated whether FIH contributes to hypoxia adaptation also through other mechanisms and identified a hypoxia sensitive, likely covalent, bond formation by FIH with several client proteins, including the deubiquitinase ovarian tumor domain containing ubiquitin aldehyde binding protein 1 (OTUB1). Biochemical analyses were consistent with a co-translational amide bond formation between FIH and OTUB1, occurring within mammalian and bacterial cells but not between separately purified proteins. Bond formation is catalysed by FIH and highly dependent on oxygen availability in the cellular microenvironment. Within cells, a heterotrimeric complex is formed, consisting of two FIH and one covalently linked OTUB1. Complexation of OTUB1 by FIH regulates OTUB1 deubiquitinase activity. Our findings reveal an alternative mechanism for hypoxia adaptation with remarkably high oxygen sensitivity, mediated through covalent protein-protein interactions catalysed by an asparagine modifying dioxygenase.

Statistical Detection of Colors in Dermoscopic Images With a Texton-Based Estimation of Probabilities.

Color has great diagnostic significance in dermatoscopy. Several diagnosis methods are based on the colors detected within a lesion. Malignant lesions frequently show more than three colors, whereas in benign lesions, three or fewer colors are usually observed. Black, red, white, and blue-gray are found more frequently in melanomas than in benign nevi. In this paper, a method to automatically identify the colors of a lesion is presented. A color label identification problem is proposed and solved by maximizing the posterior probability of a pixel to belong to a label, given its color value and the neighborhood color values. The main contribution of this paper is the estimation of the different terms involved in the computation of this probability. Two evaluations are performed on a database of 200 dermoscopic images. The first one evaluates if all the colors detected in a lesion are indeed present in it. The second analyzes if each pixel within a lesion is assigned the correct color label. The results show that the proposed method performs correctly and outperforms other methods, with an average F-measure of 0.89, an accuracy of 0.90, and a Spearman correlation of 0.831.

The functional interplay between the HIF pathway and the ubiquitin system - more than a one-way road.

The hypoxia inducible factor (HIF) pathway and the ubiquitin system represent major cellular processes that are involved in the regulation of a plethora of cellular signaling pathways and tissue functions. The ubiquitin system controls the ubiquitination of proteins, which is the covalent linkage of one or several ubiquitin molecules to specific targets. This ubiquitination is catalyzed by approximately 1000 different E3 ubiquitin ligases and can lead to different effects, depending on the type of internal ubiquitin chain linkage. The best-studied function is the targeting of proteins for proteasomal degradation. The activity of E3 ligases is antagonized by proteins called deubiquitinases (or deubiquitinating enzymes), which negatively regulate ubiquitin chains. This is performed in most cases by the catalytic removal of these chains from the targeted protein. The HIF pathway is regulated in an oxygen-dependent manner by oxygen-sensing hydroxylases. Covalent modification of HIFα subunits leads to the recruitment of an E3 ligase complex via the von Hippel-Lindau (VHL) protein and the subsequent polyubiquitination and proteasomal degradation of HIFα subunits, demonstrating the regulation of the HIF pathway by the ubiquitin system. This unidirectional effect of an E3 ligase on the HIF pathway is the best-studied example for the interplay between these two important cellular processes. However, additional regulatory mechanisms of the HIF pathway through the ubiquitin system are emerging and, more recently, also the reciprocal regulation of the ubiquitin system through components of the HIF pathway. Understanding these mechanisms and their relevance for the activity of each other is of major importance for the comprehensive elucidation of the oxygen-dependent regulation of cellular processes. This review describes the current knowledge of the functional bidirectional interplay between the HIF pathway and the ubiquitin system on the protein level.

Evaluación integral de la sensibilidad en los pies de las personas con diabetes mellitus tipo 2 / Avaliação integral da sensibilidade nos pés das pessoas com diabetes mellitus tipo 2 / Comprehensive evaluation of foot sensitivity of individuals with type 2 diabetes mellitus

INTRODUCCIÓN: Actualmente la diabetes mellitus tipo 2 es considerada una epidemia en el mundo, es uno de los problemas de mayor trascendencia, por su alta prevalencia como por su enorme repercusión social y económica, por tal motivo el propósito del estudio fue evaluar de manera integral la sensibilidad en los pies de las personas con diabetes mellitus tipo 2, de Villahermosa, Tabasco, México. MATERIALES Y MÉTODOS: El diseño fue descriptivo correlacional, la muestra fue de 198 personas. Se utilizó el Test del Michigan Neuropathy Screening con monofilamento de Semme Weinstein, Diapasón, temperatura frío/calor y reflejo Aquileo. RESULTADOS Y DISCUSIÓN: El sexo femenino predominó con un 70.2% y el 29.8% hombres, el promedio de edad fue 56.44 años y 12.34 años promedio con la enfermedad. El 46% registró síntomas neuropáticos moderados, 26.3% graves; el 65.7% riesgo de neuropatía positiva (40.9% mujeres y 24.8% hombres), 41.1% con pérdida de sensibilidad moderada y 29.3% sensibilidad normal; el 74.7% tiene un control glucémico deficiente. Los factores de riesgo detectados con mayor prevalencia fueron helomas, hiperqueratosis y deformidades. CONCLUSIONES: Existe una correlación significativa entre la pérdida de la sensibilidad con los años con la enfermedad, con la hiperglucemia y síntomas de neuropatía, la pérdida de sensibilidad en mujeres es de moderada a grave y en los hombres la pérdida de la sensibilidad es moderada

INTRODUÇÃO: Atualmente a diabetes mellitus tipo 2 é considerada uma epidemia no mundo, é um dos problemas de maior transcendência, por sua alta prevalência, bem como sua enorme repercussão social e económica, por isso, o objetivo do estudo foi avaliar de forma integral a sensibilidade nos pés das pessoas com diabetes mellitus tipo 2, de Villahermosa, Tabasco, México. MATERIAIS E MÉTODOS: O desenho foi descritivo correlacional, a amostra foi de 198 pessoas. Utilizou-se o teste do Michigan Neuropathy Screening com monofilamento de Semme Weinstein, Diapasão, temperatura frio/calor e reflexo aquileu. RESULTADOS E DISCUSSÃO: O sexo feminino predominou com 70.2% e 29.8% o sexo masculino, a média de idade foi 56.44 anos, 12.34 anos em média com a doença. 46% relataram sintomas neuropáticos moderados, 26.3% graves; 65.7% com risco de neuropatia positiva (40.9% mulheres e 24.8% homens), 41.1% com perda da sensibilidade moderada e 29.3% com sensibilidade normal; 74.7% têm um controle glicêmico deficiente. Os fatores de risco foram detectados com maior prevalência foram helomas, hiperqueratose e deformidades. CONCLUSÕES: Ha uma correlação significativa entre a perda de sensibilidade ao longo dos anos com a doença, hiperglicemia e sintomas de neuropatia, a perda da sensibilidade nas mulheres é moderada a grave, e nos homens a perda da sensibilidade é moderada

INTRODUCTION: Currently, type 2 diabetes mellitus is considered a global epidemic. It is one of the most transcending problems due to its high prevalence and huge social and economic repercussion; for this reason, the purpose of this study was to comprehensively evaluate foot sensitivity in people participants. The Michigan Neuropathy Screening test was used with Semme-Weinstein monofilament testing, diapason, cold/hot temperature testing, and Achilles reflex. RESULTS AND DISCUSSION: Females prevailed with 70.2% and 29.8% for men; mean age was 56.44 years and an average of 12.34 years with the disease. Moderate neuropathic symptoms were registered in 46%, 26.3% severe; 65.7% showed risk of positive neuropathy (40.9% women and 24.8% men), 41.1% with moderate loss of sensitivity and 29.3% normal with type 2 diabetes mellitus in Villahermosa, Tabasco, Mexico. MATERIALS AND METHODS: The study design was descriptive correlational; the sample was comprised of 198 sensitivity; 74.7% have deficient glycemic control. The risk factors detected with greater prevalence were helomas, hyperkeratosis, and deformities. CONCLUSIONS: Significant correlation exists between sensitivity loss with years with the disease and hyperglycemia and neuropathy symptoms; sensitivity loss in women is from moderate to severe and in men it is moderate

Mucinosis eritematosa reticular / Reticular erythematous mucinosis

La mucinocis eritematosa reticular (MER) es una rara entidad que se caracteriza por placas eritematosas infiltradas en zonas de exposición de tórax y espalda. Se ha relacionado con exposición solar, alteraciones hormonales, procesos reumatológicos y cáncer de mama. Una mujer de 28 años presentaba una placa eritematosa infiltrada, de 4 años de evolución en la mama izquierda, que con el paso del tiempo fue extendiéndose por ambas mamas. El estudio histopatológico demostró la existencia de un infiltrado linfocitario perivascular y perianexial, que se acompañaba de evidentes depósitos de mucina en dermis superior y media. Se realizó tratamiento con colchicina e hidroxicloroquina, con regresión parcial de las lesiones (AU)

Isotretinoín y depresión: ¿una realidad? / Isotretinoin and depression: a fact?

Introducción: El isotretinoín es un fármaco de eficacia probada en el acné nódulo-quístico. En algunos estudios se ha especulado su relación con cuadros de depresión. Objetivos: Demostrar la posible asociación del isotretinoín con el desarrollo de depresión. Material y métodos: Se seleccionaron 877 pacientes con acné nódulo-quístico tratados con isotretinoín en el Hospital Virgen del Rocío en un período de tiempo de 10 años (1990-2000), la mayoría (88 por ciento) menores de 30 años. Se dividió a los pacientes en 2 grupos: A) 348 pacientes, tratados de 1990 a 1996, en los que no se excluyó a aquellos con antecedentes de depresión, y B) 529 pacientes, tratados de 1996 al 2000, del que se excluyeron los pacientes con antecedentes de depresión. Resultados: En el grupo A, el 1,1% de los pacientes con antecedentes de depresión que tomaban isotretinoín tuvieron una recaída de la enfermedad, pero un 1,1% de ellos mejoraron de la depresión tras el tratamiento. Así mismo, el 2% de los que no tenían antecedentes tuvieron depresión tras tomar el fármaco. En el grupo B, el 1,6% de los pacientes desarrollaron depresión. Conclusiones: No se demostró relación estadísticamente significativa entre isotretinoín y depresión (AU)

Thalidomide as elective treatment in persistent erythema multiforme; report of two cases.

Recurrent erythema multiforme is a rare disorder, clinically characterized by symmetrically distributed, erythematous, and bullous skin and mucous lesions, mainly precipitated by a preceding herpes simplex infection. In rare cases, EM presents continuous or persistent relapses, and has been related to an Epstein-Barr virus infection. We report 2 cases of severe, persistent erythema multiforme, treated with thalidomide, with complete disease suppression in both cases. Thalidomide induces immunomodulator, anti-inflammatory, and anti-angiogenic effects, and may be considered as the elective treatment of this rare variety of erythema multiforme. However, in order to avoid neuropathic side effects, patients under thalidomide therapy should be monitored every 6 months with nerve conduction studies while taking the drug.

Mixedema palpebral por amiodarona / Palpebral myxedema from amiodarone

El mixedema es el signo cutáneo más característico del déficit de hormonas tiroideas. La amiodarona, además de sus conocidos efectos de fotosensibilidad e hiperpigmentación, puede producir alteraciones cutáneas por hipotiroidismo inducido. Se presenta el caso de un varón de 57 años que tras 4 años de tratamiento con amiodarona por una fibrilación auricular crónica, fue diagnosticado de un hipotiroidismo tras la aparición de un mixedema localizado de forma unilateral en el párpado inferior derecho. El enfermo no presentó otros signos de hipotiroidismo. El estudio de hormonas tiroideas confirmó el diagnóstico de sospecha y la retirada del fármaco, junto con la terapia sustitutiva hicieron desaparecer la lesión, y las concentraciones hormonales volvieron a sus valores normales (AU)

Type III protein translocase: HrcN is a peripheral ATPase that is activated by oligomerization.

Type III protein secretion (TTS) is catalyzed by translocases that span both membranes of Gram-negative bacteria. A hydrophilic TTS component homologous to F1/V1-ATPases is ubiquitous and essential for secretion. We show that hrcN encodes the putative TTS ATPase of Pseudomonas syringae pathovar phaseolicola and that HrcN is a peripheral protein that assembles in clusters at the membrane. A decahistidinyl HrcN derivative was overexpressed in Escherichia coli and purified to homogeneity in a folded state. Hydrodynamic analysis, cross-linking, and electron microscopy revealed four distinct HrcN forms: I, 48 kDa (monomer); II, approximately 300 kDa (putative hexamer); III, 575 kDa (dodecamer); and IV, approximately 3.5 MDa. Form III is the predominant form of HrcN at the membrane, and its ATPase activity is dramatically stimulated (>700-fold) over the basal activity of Form I. We propose that TTS ATPases catalyze protein translocation as activated homo-oligomers at the plasma membrane.