The overlap with metabolic dysfunction-associated steatotic liver disease negatively affects outcomes of primary biliary cholangitis.

BACKGROUND AND AIMS: The relationship between primary biliary cholangitis (PBC) and metabolic dysfunction-associated steatotic liver disease, and its impact on treatment response and prognosis, remains underexplored. METHODS: Patient cohort from two centres comprising long-term follow-up data. All patients had histologically confirmed PBC. Biopsies were classified according to Non-Alcoholic Steatohepatitis Clinical Research Network. Diagnosis of metabolic dysfunction-associated steatotic liver disease was established when steatosis exceeded 5%, along with at least one metabolic risk factor. Patients with specific aetiologies of steatosis, other liver diseases, incomplete results and inadequate treatment with ursodeoxycholic acid were excluded. Data from patients initiating second-line treatment were censored. Treatment response was assessed using the Toronto, Paris II and AST-to-platelet at 12-month criteria. The UK PBC and Globe scores, and liver events were utilized as outcome measures. RESULTS: The study included 129 patients, 36 showing histologically confirmed overlap between PBC and steatosis. Patients with overlap showed worse prognosis according to Paris II (61.1% vs. 33.3%, p = 0.004), Toronto (52.5% vs. 24.7%, p = 0.002), AST-to-platelet 12-month >0.54 (36.1% vs. 17.2%, p = 0.021), Globe >0.30 (49.2% vs. 29.2%, p = 0.033) and UK PBC at 5, 10 and 15 years (p ≤ 0.001). Liver-related mortality and liver transplant were more prevalent in the overlap group (p = 0.001). In the multivariate analysis, steatosis, dyslipidaemia and advanced fibrosis were independently associated to worse outcomes. CONCLUSIONS: Our findings suggest that metabolic dysfunction-associated steatotic liver disease worsens the prognosis of PBC.

Clinical and pathological features of Merkel cell carcinoma: A 4-year follow-up observational retrospective study in Spain.

BACKGROUND: Merkel cell carcinoma (MCC) is a malignant skin cancer with a 5-year survival rate of approximately 50%. Knowledge of MCC has increased in recent years mostly due to improved diagnosis techniques. In Spain there is lack of information regarding the incidence and tumour characteristics, and the treatment approaches are not standardised. The objective of this study was to provide information of the clinical and epidemiological characteristics of MCC patients in Spain. METHODS: Retrospective, observational study involving 192 patients from 25 Spanish hospitals. Evaluated variables included overall survival and incidence rate of Merkel cell polyomavirus, in patients diagnosed from 2012 to 2016. RESULTS: The Spanish incidence rate was estimated 0.32/100,000 inhabitants/year, with variations according to geographical regions, being slightly higher in areas with greater sunlight exposure. In total, 61.5% of tumours showed expansive growth (progressive growth of the tumour), 78.6% showed localisation in UV-exposed skin. 97.4% of patients were diagnosed by excisional biopsy. Surgery was the first line treatment in 96.6% of patients, radiotherapy in 24.6%, and chemotherapy in 6.3%. These treatments were not mutually exclusive. Median overall survival was 38.3 months (78.4% at 12 months and 60% at 24 months). MCPyV was present in 33.8% of patients. CONCLUSION: The incidence of MCC in Spain is one of the highest in Europe, with a slight predominance in men. The sample has shown that a biopsy is available for diagnosis in most cases. Moreover, the treatment is surgical when the tumour is localized and is associated with lymphadenectomy, and/or it is radiotherapy if widespread.

Lesión miocárdica en una paciente con lupus eritematoso sistémico: Un reto diagnóstico / Myocardial lesion in a patient with systemic lupus erythematosus: A diagnostic challenge

Resumen Mujer de 37 años con antecedentes de lupus eritematoso sistémico (LES), tromboembolia pulmonar y trombosis venosa profunda, quien consultó por dolor torácico, con hallazgos de elevación de la troponina, disfunción sistólica del ventrículo izquierdo y alteraciones de la contractilidad segmentaria, además de anti-DNA elevado y complemento consumido. La angiografía coronaria mostró estenosis grave en el tercio medio de la arteria descendente anterior, que fue intervenida con angioplastia más stent medicado. La resonancia magnética cardiaca reveló infarto agudo de miocardio extenso en el territorio de la arteria descendente anterior, sin miocarditis. Se descartó compromiso cardiaco por LES, se continuó igual terapia inmunosupresora, se añadió manejo para enfermedad coronaria y egresó por buena evolución. El enfoque de las causas de lesión miocárdica en un paciente con LES supone un reto, dadas las múltiples posibilidades en el espectro de compromiso cardiaco, ya que varias estructuras se pueden ver afectadas. La miocarditis y la pericarditis se consideran las más frecuentes, pero el compromiso coronario no puede descartarse, independientemente de la edad y de la presencia de factores de riesgo tradicionales, puesto que el componente inflamatorio de la patología autoinmunitaria confiere un desarrollo acelerado de ateroesclerosis. La multimodalidad diagnóstica y el enfoque interdisciplinario son necesarios para aclarar el mecanismo de la lesión y así brindar un tratamiento dirigido.

Abstract A 37-year-old woman with a history of systemic lupus erythematosus (SLE), pulmonary thromboembolism and deep vein thrombosis consulted for chest pain, with findings of elevated troponin, left ventricular systolic dysfunction, and segmental contractility abnormalities, as well as elevated anti-DNA and complement consumption. Coronary angiography showed severe stenosis of the middle third of the anterior descending artery, which was treated with angioplasty plus a medicated stent. Cardiac magnetic resonance imaging revealed an extensive acute myocardial infarction in the area supplied by the anterior descending artery, without myocarditis. Cardiac involvement in SLE was ruled out, immunosuppressive treatment was maintained, coronary disease treatment was added, and she was discharged due to improvement. Identifying the causes of myocardial insult in a patient with SLE is challenging, given the multiple possibilities across the cardiac involvement spectrum, in which several structures may be affected. Myocarditis and pericarditis are considered to be the most frequent, but coronary involvement cannot be ruled out, regardless of age or the presence of traditional risk factors, since the inflammatory component of the autoimmune disease accelerates the development of atherosclerosis. Multimodal diagnostics and an interdisciplinary approach are necessary to clarify the mechanism of injury and provide targeted treatment.

SARS-CoV-2 Infection in Multiple Sclerosis: Results of the Spanish Neurology Society Registry.

OBJECTIVE: To understand COVID-19 characteristics in people with multiple sclerosis (MS) and identify high-risk individuals due to their immunocompromised state resulting from the use of disease-modifying treatments. METHODS: Retrospective and multicenter registry in patients with MS with suspected or confirmed COVID-19 diagnosis and available disease course (mild = ambulatory; severe = hospitalization; and critical = intensive care unit/death). Cases were analyzed for associations between MS characteristics and COVID-19 course and for identifying risk factors for a fatal outcome. RESULTS: Of the 326 patients analyzed, 120 were cases confirmed by real-time PCR, 34 by a serologic test, and 205 were suspected. Sixty-nine patients (21.3%) developed severe infection, 10 (3%) critical, and 7 (2.1%) died. Ambulatory patients were higher in relapsing MS forms, treated with injectables and oral first-line agents, whereas more severe cases were observed in patients on pulsed immunosuppressors and critical cases among patients with no therapy. Severe and critical infections were more likely to affect older males with comorbidities, with progressive MS forms, a longer disease course, and higher disability. Fifteen of 33 patients treated with rituximab were hospitalized. Four deceased patients have progressive MS, 5 were not receiving MS therapy, and 2 were treated (natalizumab and rituximab). Multivariate analysis showed age (OR 1.09, 95% CI, 1.04-1.17) as the only independent risk factor for a fatal outcome. CONCLUSIONS: This study has not demonstrated the presumed critical role of MS therapy in the course of COVID-19 but evidenced that people with MS with advanced age and disease, in progressive course, and those who are more disabled have a higher probability of severe and even fatal disease.

Association of traditional cardiovascular risk factors in adults younger than 55 years with coronary heart disease. Case-control study.

OBJECTIVES: The traditional cardiovascular risk factors associated with coronary artery disease in individuals younger than 55 years old was determined in this study. METHODS: A retrospective, paired case-control study comprised of patients younger than 55 years old who were admitted to the hospital due to acute coronary syndrome with coronary artery disease from 2011 to 2016. There were two controls per case, paired by age, gender, admission date, and health insurance. Data from patients were collected, such as sociodemographic information, cardiovascular risk factors, and drug therapy information. A conditional logistic regression model was created to evaluate the association between traditional cardiovascular risk factors and coronary artery disease. RESULTS: There were 171 cases and 342 controls included in the study. The median age was 49 years, with a predominance of male gender (80.12%). Nearly 66% of cases had at least one traditional cardiovascular risk factor. The most common risk factors were obesity (57.31%), arterial hypertension (45.62%), and smoking (28.97%). Independent risk factors of coronary artery disease in patients younger than 55 years were arterial hypertension (odds ratio, 2.52; 95% confidence interval, 1.48-4.20; p = 0.001) and smoking (odds ratio, 7.15; 95% confidence interval, 3.19-15.99; p = 0.00). No significant association between diabetes mellitus and coronary heart disease in the global group (odds ratio, 2.04; 95% confidence innterval, 0.91-4.58; p = 0.083) was found. CONCLUSION: For patients younger than 55 years, with a theoretically lower risk of coronary artery disease due to their age, having one or several traditional risk factors (smoking, arterial hypertension, dyslipidemia, or diabetes mellitus) confers an increased risk of coronary artery disease regardless of age.

Reflectance Confocal Microscopy of Pigmented Bowen's Disease: A Case Series of Difficult to Diagnose Lesions.

Pigmented Bowen's disease is a rare variant of in situ squamous skin cell carcinoma. It mainly affects patients between 60 and 70 years of age. Its clinical features include well-demarcated, pigmented plaque arising in photo-exposed areas of the body. The best-characterized feature of the disease by histological examination is the presence of atypical keratinocytes, hyperpigmentation of the epidermis with trans-epidermal elimination of melanin and dermal melanophages. Precise diagnosis is often difficult, both clinically and dermoscopically, as Bowen's disease is often mistaken with keratinocyte tumors such as solar lentigines, seborrheic keratosis, Bowenoid papulosis, pigmented basal cell carcinoma, pigmented actinic keratosis; or even melanocytic lesions such as melanocytic nevus, pigmented epithelioid melanocytoma, and melanoma. Precise diagnosis often requires biopsy and histopathological examination of the tissue. Reflectance confocal microscopy is a noninvasive technique to diagnose pigmented skin lesions. To date, not much data are available regarding its use in the diagnosis of pigmented Bowen's disease. Herein, we report a well-represented case series of pigmented Bowen's disease imaged using dermoscopy and reflectance confocal microscopy.

Aging dependent effect of nuclear tau.

Tau protein is characterized by a complex pattern of phosphorylation and is localized in the cytoplasm and nucleus in both neuronal and non-neuronal cells. Human AT100 nuclear tau, endowed by phosphorylation in Thr212/Ser214, was recently shown to decline in cornus ammonis 1 (CA1) and dentate gyrus (DG) in Alzheimer's disease (AD), but a defined function for this nuclear tau remains unclear. Here we show that AT100 progressively increases in the nuclei of neuronal and non-neuronal cells during aging, and decreases in the more severe AD stages, as recently shown, and in cancer cells (colorectal adenocarcinoma and breast cancer). AT100, in addition to a co-localization with the DAPI-positive heterochromatin, was detected in the nucleolus of pyramidal cells from the CA1 region, shown to be at its highest level in the more senescent cells and in the first stage of AD (ADI), and disappearing in the more severe AD cases (ADIV). Taking into account the nuclear distribution of AT100 during cell aging and its relation to the chromatin changes observed in degenerated neurons, as well as in cancerous cells, which are both cellular pathologies associated with age, we can consider the Thr212/Ser214 phosphorylated nuclear tau as a molecular marker of cell aging.

Incidencia de eventos cardiovasculares mayores asociada a la suspensión de doble terapia antiagregante en pacientes con enfermedad coronaria e implante de stent / Incidence of major adverse cardiovascular events associated to suspension of dual antiplatelet therapy in patients with coronary disease and stent implants

Resumen Objetivo: Determinar el riesgo de presentar eventos cardiovasculares mayores en pacientes con síndrome coronario agudo e implante de stent, que suspendieron la doble terapia antiagregante antes de un año de tratamiento. Métodos: Estudio analítico de pacientes con síndrome coronario agudo e implante de stent que recibieron doble terapia antiagregante al egreso hospitalario. Se describieron las características sociodemográficas, clínicas y paraclínicas. Se determinó la prevalencia de suspensión de doble terapia antiagregante antes de un año de tratamiento y el riesgo de eventos cardiovasculares mayores mediante un modelo de riesgos proporcionales Cox. Resultados: Se incluyeron 873 pacientes. La prevalencia de suspensión de doble terapia antiagregante fue 39,18%. El grupo que continuó la terapia por un año tuvo mayor frecuencia de enfermedad coronaria previa (19,13% p = 0,03). La principal indicación del procedimiento en los pacientes que suspendieron la terapia fue infarto sin ST elevado (36,8%). La suspensión de la doble terapia antiagregante antes del año estuvo asociada con mayor incidencia de MACE a un año (HR 1,31 95% IC 0,65-2,62 p = 0,45). La presencia de enfermedad arterial periférica, diabetes mellitus y más de un vaso enfermo se relacionó con eventos adversos cardiovasculares a un año. Conclusiones: La suspensión antes de los doce meses de la doble terapia antiagregante en pacientes con implante de stent posterior a un síndrome coronario agudo, es frecuente y parece no estar asociada con mayor incidencia de desenlaces cardiovasculares mayores; sin embargo, la causa de la interrupción puede influir en los desenlaces clínicos y debe tenerse en cuenta en la práctica clínica.

Abstract Objective: To determine the risk of developing major adverse cardiovascular events (MACEs) in patients with acute coronary syndrome and stent implant who suspended dual antiplatelet therapy before one year of treatment. Methods: Analytical study of patients with acute coronary syndrome and stent implant who received dual antiplatelet therapy upon hospital admission. Sociodemographic, clinical and paraclinical features were described. The prevalence of dual antiplatelet therapy suspensión before one year of treatment was determined, and for assessing the risk of major adverse cardiovascular events a Cox proportional hazard regression model was used. Results: 873 patients were included. Prevalence of dual antiplatelet therapy suspension was 39.18%. The group who continued the therapy during a year had a higher frequency of previous coronary disease (19.13%, p = 0.03). The main indication for the procedure in patients who interrupted their treatment was infarction without ST elevation (36.8%). Dual therapy suspensión before one year was not related to a higher incidence of MACEs after one year (HR1.31, CI 95% 0.65-2.62 p = 0.45). The presence of peripheral arterial disease, diabetes mellitus and more than one abnormal vessel was related to adverse cardiovascular effects within one year. Conclusions: The suspension of dual antiplatelet therapy before twelve months in patients with a stent implant posterior to an acute coronary syndrome is frequent and does not seem to be associated to a higher incidence of major adverse cardiovascular events; nevertheless, the reason for the interruption could influence the clinical outcome and must be taken into account for clinical practice.

Clear Cell Atypical Fibroxanthoma: Clinicopathological Study of 6 Cases and Review of the Literature With Special Emphasis on the Differential Diagnosis.

Atypical fibroxanthoma (AFX) is an uncommon dermal-based neoplasm arising on the sun-damaged skin of elderly people. Clear cell AFX is a rare variant with only 12 cases reported until the present date, all of them as case reports, except for 1 small series of 3 cases. The authors report 6 new cases and review the literature with special emphasis on the differential diagnosis. The clear cell variant represents 5% of AFX from their files. Histopathologically, it consists of sheets of epithelioid, pleomorphic cells, intermixed with a varying number of giant multinucleated and spindle cells, the latter arranged in a fascicular pattern. All cell types predominantly exhibit a clear, microvacuolated cytoplasm with well-demarcated cell borders. The clinical and immunohistochemical features of this variant are similar to those of the classic type. Clear cell AFX must be differentiated from other cutaneous clear cell neoplasms, some of them with an aggressive clinical behavior, including clear cell melanoma, primary cutaneous and metastatic clear cell carcinomas, clear cell sarcoma, pleomorphic liposarcoma, tumor of perivascular epithelioid cells, and distinctive dermal clear cell mesenchymal neoplasm. The clinical presentation and immunohistochemical profile play a key role in the differential diagnosis.

Pleomorphic dermal sarcoma: a more aggressive neoplasm than previously estimated.

BACKGROUND: Pleomorphic dermal sarcoma (PDS) is a rare neoplasm sharing pathological features with atypical fibroxanthoma, but adding tumor necrosis, invasion beyond superficial subcutis or vascular or perineural infiltration. Although its metastatic risk has been estimated to be less than 5%, its real outcome is presently uncertain because of its rarity and to the lack of homogeneous criteria used in reported cases. METHODS: Retrospective clinicopathological study of 18 cases of PDS. RESULTS: The lesions presented as tumors or plaques (size: 7-70 mm) on the head of elderly patients (median: 81 years), without a gender predominance. Histopathologically, they consisted of spindle cells arranged in a fascicular pattern, containing pleomorphic epithelioid and giant multinucleated cells in varying proportions, and usually exhibiting numerous mitotic figures and infiltrative tumor margins. No immunoexpression for cytokeratins, S100 protein, desmin or CD34 was observed. Necrosis and venous invasion were found in three tumors each (17%). Follow-up was available in 15 cases (median: 33 months). Three patients (20%) had local recurrences, all with incomplete primary surgical resections. Three patients (20%) developed distant metastases in the skin, regional lymph nodes and/or lungs and died from the disease. CONCLUSION: Our data suggest that PDS may be a more aggressive neoplasm than previously estimated.

Association of C4d deposition with clinical outcomes in IgA nephropathy.

BACKGROUND AND OBJECTIVES: Several studies have suggested that activation of the complement system is a contributing pathogenic mechanism in IgA nephropathy (IgAN). C4d staining is an inexpensive and easy-to-perform method for the analysis of renal biopsies. This study aimed to assess the clinical and prognostic implications of C4d staining in IgAN. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This retrospective cohort study included 283 patients with IgAN in 11 hospitals in Spain who underwent a renal biopsy between 1979 and 2010. The primary predictor was mesangial C4d staining. Secondary predictors included demographic, clinical, and laboratory characteristics, and Oxford pathologic classification criteria. The primary end point was the cumulative percentage of patients who developed ESRD, defined as onset of chronic dialysis or renal transplantation. C4d was analyzed by immunohistochemical staining using a polyclonal antibody. Kaplan-Meier and Cox proportional hazards analyses were performed to evaluate the effect of C4d staining on renal survival. RESULTS: There were 109 patients (38.5%) and 174 patients (61.5%) who were classified as C4d positive and C4d negative, respectively. Renal survival at 20 years was 28% in C4d-positive patients versus 85% in C4d-negative patients (P<0.001). Independent risk factors associated with ESRD were as follows: proteinuria (hazard ratio [HR] per every 1 g/d increase. 1.16; 95% confidence interval [95% CI], 1.03 to 1.31; P=0.01), eGFR (HR per every 1 ml/min per 1.73 m(2) increase, 0.96; 95% CI, 0.94 to 0.97; P<0.001), T2 Oxford classification (tubular atrophy/interstitial fibrosis, >50%; HR, 4.42; 95% CI, 1.40 to 13.88; P=0.01), and C4d-positive staining (HR, 2.45; 95% CI, 1.30 to 4.64; P=0.01). CONCLUSIONS: C4d-positive staining is an independent risk factor for the development of ESRD in IgAN. This finding is consistent with the possibility that complement activation is involved in the pathogenesis of this disease.

Evolving brain functional abnormalities in PSEN1 mutation carriers: a resting and visual encoding fMRI study.

PSEN1 mutations are the most frequent cause of familial Alzheimer's disease and show nearly full penetrance. Here we studied alterations in brain function in a cohort of 19 PSEN1 mutation carriers: 8 symptomatic (SMC) and 11 asymptomatic (AMC). Asymptomatic carriers were, on average, 12 years younger than the predicted age of disease onset. Thirteen healthy subjects were used as a control group (CTR). Subjects underwent a 10-min resting-state functional magnetic resonance imaging (fMRI) scan and also performed a visual encoding task. The analysis of resting-state fMRI data revealed alterations in the default mode network, with increased frontal connectivity and reduced posterior connectivity in AMC and decreased frontal and increased posterior connectivity in SMC. During task-related fMRI, SMC showed reduced activity in regions of the left occipital and left prefrontal cortices, while both AMC and SMC showed increased activity in a region within the precuneus/posterior cingulate, all as compared to CTR. Our findings suggest that fMRI can detect evolving changes in brain mechanisms in PSEN1 mutation carriers and support the use of this technique as a biomarker in Alzheimer's disease, even before the appearance of clinical symptoms.

NADPH oxidase NOX4 mediates stellate cell activation and hepatocyte cell death during liver fibrosis development.

A role for the NADPH oxidases NOX1 and NOX2 in liver fibrosis has been proposed, but the implication of NOX4 is poorly understood yet. The aim of this work was to study the functional role of NOX4 in different cell populations implicated in liver fibrosis: hepatic stellate cells (HSC), myofibroblats (MFBs) and hepatocytes. Two different mice models that develop spontaneous fibrosis (Mdr2(-/-)/p19(ARF-/-), Stat3(Δhc)/Mdr2(-/-)) and a model of experimental induced fibrosis (CCl(4)) were used. In addition, gene expression in biopsies from chronic hepatitis C virus (HCV) patients or non-fibrotic liver samples was analyzed. Results have indicated that NOX4 expression was increased in the livers of all animal models, concomitantly with fibrosis development and TGF-ß pathway activation. In vitro TGF-ß-treated HSC increased NOX4 expression correlating with transdifferentiation to MFBs. Knockdown experiments revealed that NOX4 downstream TGF-ß is necessary for HSC activation as well as for the maintenance of the MFB phenotype. NOX4 was not necessary for TGF-ß-induced epithelial-mesenchymal transition (EMT), but was required for TGF-ß-induced apoptosis in hepatocytes. Finally, NOX4 expression was elevated in patients with hepatitis C virus (HCV)-derived fibrosis, increasing along the fibrosis degree. In summary, fibrosis progression both in vitro and in vivo (animal models and patients) is accompanied by increased NOX4 expression, which mediates acquisition and maintenance of the MFB phenotype, as well as TGF-ß-induced death of hepatocytes.

Long lasting interstitial generalized granuloma annulare on sun-exposed areas.

Granuloma annulare (GA) is a benign inflammatory dermatosis of unknown etiology and chronic course, with different clinical variants. The cases associated with a photodistributed pattern are rare and show a palisading histopathological pattern. We report a case of generalized GA affecting sun-exposed areas with an interstitial pattern. The patient has been followed-up for 6 years, presenting a recurrent course of the disease, with a good response to chloroquine and relapse when no treatment was prescribed.

[Acquired brain injury: a proposal for its definition, diagnostic criteria and classification]. / Dano cerebral sobrevenido: propuesta de definicion, criterios diagnosticos y clasificacion.

Acquired brain injury is a heterogeneous clinical concept that goes beyond the limits of the classical medical view, which tends to define processes and diseases on the grounds of a single causation. Although in the medical literature it appears fundamentally associated to traumatic brain injury, there are many other causes and management is similar in all of them, during the post-acute and chronic phases, as regards the measures to be taken concerning rehabilitation and attention to dependence. Yet, despite being an important health issue, today we do not have a set of diagnostic criteria or a classification for this condition. This is a serious handicap when it comes to carrying out epidemiological studies, designing specific care programmes and comparing results among different programmes and centres. Accordingly, the Extremadura Acquired Brain Injury Health Care Plan working group has drawn up these proposed diagnostic criteria, definition and classification. The proposal is intended to be essentially practical, its main purpose being to allow correct identification of the cases that must be attended to and to optimise the use of neurorehabilitation and attention to dependence resources, thereby ensuring attention is provided on a fair basis.