[Correction to the Article "Hansen's Disease: An Unusual Manifestation of an Ancient Disease", Published on Acta Med Port 2024 Mar;37(3):215-219]. / Errata ao Artigo "Doença de Hansen: Apresentação Incomum de uma Doença Antiga", Publicado em Acta Med Port 2024 Mar;37(3):215-219.

On page 215, list of authors, where it reads (in red): Mário FERREIRA1, Carlos GRIJÓ2, Joana PAULO1, Marta FONSECA1, Zélia NEVES1 It should read (in bold): Mário FERREIRA1, Carlos GRIJÓ2, Joana PAULO1, Marta FONSECA1, Zélia NEVES1, Rita BOUCEIRO MENDES3, Pedro VASCONCELOS3 On the same page 215, footer (authors affiliation), where it reads (in red): 1. Medicina III. Hospital Fernando Fonseca. Amadora. Portugal. 2. Serviço de Medicina Interna. Centro Hospitalar Universitário de São João. Porto. Portugal. It should read (in bold): 1. Medicina III. Hospital Fernando Fonseca. Amadora. Portugal. 2. Serviço de Medicina Interna. Centro Hospitalar Universitário de São João. Porto. Portugal. 3. Serviço de Dermatologia. Hospital de Santa Maria. Centro Hospitalar Universitário Lisboa Norte. Lisboa. Portugal. Article published with errors: https://www.actamedicaportuguesa.com/revista/index.php/amp/article/view/20599.

Na página 215, na linha de autoria onde se lê, (a vermelho): Mário FERREIRA1, Carlos GRIJÓ2, Joana PAULO1, Marta FONSECA1, Zélia NEVES1 Deverá ler-se (a negrito): Mário FERREIRA1, Carlos GRIJÓ2, Joana PAULO1, Marta FONSECA1, Zélia NEVES1, Rita BOUCEIRO MENDES3, Pedro VASCONCELOS3 Na mesma página 215, em rodapé (afiliação dos autores), onde se lê (a vermelho): 1. Medicina III. Hospital Fernando Fonseca. Amadora. Portugal. 2. Serviço de Medicina Interna. Centro Hospitalar Universitário de São João. Porto. Portugal. Deverá ler-se (a negrito): 1. Medicina III. Hospital Fernando Fonseca. Amadora. Portugal. 2. Serviço de Medicina Interna. Centro Hospitalar Universitário de São João. Porto. Portugal. 3. Serviço de Dermatologia. Hospital de Santa Maria. Centro Hospitalar Universitário Lisboa Norte. Lisboa. Portugal. Artigo publicado com erros: https://www.actamedicaportuguesa.com/revista/index.php/amp/article/view/20599.

T-large Granular Lymphocytic Leukemia: A Rare Diagnosis in a Young Woman With Fever, Necrotic Skin Lesions and Cytopenias.

T-large granular lymphocytic leukemia (T-LGLL) is a rare lymphoproliferative disorder. The diagnosis is established by identifying an abnormally high number of clonal granular T lymphocytes in the peripheral blood and eventually in the bone marrow, in cases with medullary infiltration. The majority of patients present with symptoms related to neutropenia and this condition may be associated with autoimmune diseases in up to a third of cases. The authors describe the case of a 26-year-old patient admitted with subacute high fever and bullous dermatitis with necrotic lesions with central bullae. Analytically, she presented anemia and leukopenia with severe neutropenia of 200 cells/L. Skin lesions were compatible with ecthyma and the skin biopsy revealed aspects compatible with leukocytoclastic vasculitis. The myelogram and bone biopsy revealed hypoplasia of the myeloid line and a pathological T population of CD8+, TIA-1+ and granzyme B+, which were associated with compatible flow cytometry (CD3+, T-cell receptor (TCR) Alpha-Beta+, CD5+, CD2+, with loss of CD7 antigen expression) established the diagnosis of T-LGLL. The patient had a favorable evolution, with cytopenias almost returning to normal after two months. She began follow-up at a Hematology Reference Center, remaining asymptomatic without specific treatment considering the indolent course of the disease.

[Hansen's Disease: An Unusual Manifestation of an Ancient Disease]. / Doença de Hansen: Apresentação Incomum de uma Doença Antiga.

Hansen's disease, commonly known as leprosy, is an infectious disease caused by Mycobacterium leprae. Being rare in developed countries, it is an increasingly common imported disease due to the migratory flow from countries where it is endemic. We present the case of a 21-year-old man who went to the emergency department with complaints of additive polyarthralgia involving large joints, papules, and erythematous plaques on the limbs with bullae and central necrosis and fever with chills for one week. Skin biopsy was performed revealing neutrophilic infiltrate with perineural granulomas. The bacilloscopy detected acid-alcohol resistant bacilli. The diagnosis of multibacillary HD with type 2 lepromatous reaction (erythema nodosum leprosum - ENL) was established, showing clinical improvement under corticosteroid therapy. ENL usually presents with painful lesions, being an atypical presentation of leprosy, especially in the presence of bullae and necrosis, making diagnosis difficult and challenging. Social stigma is often present making it difficult to accept the disease as well as adherence to treatment.

A doença de Hansen, vulgarmente conhecida como lepra, é uma doença infecciosa causada por Mycobacterium leprae. Sendo rara nos países desenvolvidos, configura uma doença de importação cada vez mais frequente considerando o fluxo migratório de países onde é endémica. Apresentamos o caso de um homem de 21 anos que recorreu ao serviço de urgência por poliartralgias de caráter aditivo envolvendo grandes articulações, pápulas e placas eritematosas nos membros com bolhas e necrose central e febre com calafrio com uma semana de evolução. Foi realizada biópsia cutânea que revelou infiltrado neutrofílico com granulomas de distribuição perineural e baciloscopia com deteção de bacilos ácido-álcool resistentes. Foi estabelecido o diagnóstico de DH multibacilar com reação lepromatosa tipo 2 (eritema nodoso leproso), apresentando melhoria clínica sob corticoterapia. O eritema nodoso leproso cursa habitualmente com lesões dolorosas, configurando uma apresentação atípica de lepra, sobretudo na presença de bolhas e necrose, tornando este diagnóstico altamente desafiante. O estigma social é frequentemente limitativo na aceitação da doença e adesão ao tratamento.

COVID-19-associated secondary sclerosing cholangitis - A case series of 4 patients.

We report a case series of four patients diagnosed with COVID-19-associated secondary sclerosing cholangitis (SSC), a recently described rare late complication of severe COVID-19. Following prolonged stays in the intensive care unit, these patients developed marked sustained cholestasis and jaundice despite clinical improvement. Cholangiography showed beaded appearance of intra-hepatic bile ducts and bile casts were removed in one patient. None of the patients reached normalization of liver enzymes and at least one progressed to liver cirrhosis (follow-up time of 11 to 16 months). COVID-19-associated SSC has a dismal prognosis with rapid progression to advanced chronic liver disease.

A Refractory Case of Amiodarone Thyrotoxicosis.

Amiodarone is frequently used to control cardiac arrhythmias, like atrial fibrillation. Despite its benefits, it has many adverse effects, particularly on the thyroid gland. We describe the case of a patient treated with amiodarone for paroxysmal atrial fibrillation, admitted to the emergency room with atrial fibrillation with a rapid ventricular response. Type II thyrotoxicosis was identified as the cause of the refractory arrhythmia. Since its refractoriness to both pharmacological and electrical therapy, there was a need to proceed with plasmapheresis and total thyroidectomy for hormonal and cardiac rhythm control. Therefore, it is essential to monitor the toxicity of amiodarone, a drug that can have both beneficial and devastating effects.

Structural Basis for Dityrosine-Mediated Inhibition of α-Synuclein Fibrillization.

α-Synuclein (α-Syn) is an intrinsically disordered protein which self-assembles into highly organized ß-sheet structures that accumulate in plaques in brains of Parkinson's disease patients. Oxidative stress influences α-Syn structure and self-assembly; however, the basis for this remains unclear. Here we characterize the chemical and physical effects of mild oxidation on monomeric α-Syn and its aggregation. Using a combination of biophysical methods, small-angle X-ray scattering, and native ion mobility mass spectrometry, we find that oxidation leads to formation of intramolecular dityrosine cross-linkages and a compaction of the α-Syn monomer by a factor of √2. Oxidation-induced compaction is shown to inhibit ordered self-assembly and amyloid formation by steric hindrance, suggesting an important role of mild oxidation in preventing amyloid formation.

Cytoreductive Surgery With Hyperthermic Intraperitoneal Chemotherapy: Analysis of Perioperative Risk Factors and Impact on Outcome.

Background Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy (CRS + HIPEC) is an effective treatment option for appropriately selected patients with peritoneal carcinomatosis. Our aim was to analyze a multidisciplinary approach and to study the perioperative risk factors associated with morbidity and mortality. Methods We reviewed all patients who underwent CRS + HIPEC from January 2019 till December 2020 at our oncologic center. Patient demographics, risk scores, intraoperative variables, postoperative care, analgesia protocol, and adverse events (AE) within 30 days after treatment were collected and statistically analyzed. Results Of the 98 patients evaluated preoperatively by a multidisciplinary team, 39 patients required active optimization. The median age was 61 years, and 67 were women. Most tumors were appendiceal in origin. The median peritoneal cancer index (PCI) score was 12, and the median operative time length (OTL) was 400 minutes. Body mass index, Physiological and Operative Severity Score for the enUmeration of morbidity, PCI score, crystalloid volume, cell concentrates, and OTL were associated with postoperative intensive care unit admission (p <0.05). Epidural analgesia was given to 74 patients. AEs occurred in 39 patients, and 25 of the AEs were classified as mild or moderate. The intraoperative variables associated with development of AEs were anesthesia technique, estimated blood loss, crystalloid volume, cell concentrates, OTL, and analgesia protocol (p <0.05). On multivariate analysis, crystalloid volume >6 L, intravenous sufentanil analgesic protocol, and OTL were associated with 67%, 38%, and 15% increased risk of AE, respectively. Conclusion Our study highlighted the importance of a perioperative protocol with a standardized multidisciplinary approach in order to decrease the incidence of postoperative AE.

Charge Engineering Reveals the Roles of Ionizable Side Chains in Electrospray Ionization Mass Spectrometry.

In solution, the charge of a protein is intricately linked to its stability, but electrospray ionization distorts this connection, potentially limiting the ability of native mass spectrometry to inform about protein structure and dynamics. How the behavior of intact proteins in the gas phase depends on the presence and distribution of ionizable surface residues has been difficult to answer because multiple chargeable sites are present in virtually all proteins. Turning to protein engineering, we show that ionizable side chains are completely dispensable for charging under native conditions, but if present, they are preferential protonation sites. The absence of ionizable side chains results in identical charge state distributions under native-like and denaturing conditions, while coexisting conformers can be distinguished using ion mobility separation. An excess of ionizable side chains, on the other hand, effectively modulates protein ion stability. In fact, moving a single ionizable group can dramatically alter the gas-phase conformation of a protein ion. We conclude that although the sum of the charges is governed solely by Coulombic terms, their locations affect the stability of the protein in the gas phase.

A subset of functional adaptation mutations alter propensity for α-helical conformation in the intrinsically disordered glucocorticoid receptor tau1core activation domain.

BACKGROUND: Adaptive mutations that alter protein functionality are enriched within intrinsically disordered protein regions (IDRs), thus conformational flexibility correlates with evolvability. Pre-structured motifs (PreSMos) with transient propensity for secondary structure conformation are believed to be important for IDR function. The glucocorticoid receptor tau1core transcriptional activation domain (GR tau1core) domain contains three α-helical PreSMos in physiological buffer conditions. METHODS: Sixty change-of-function mutants affecting the intrinsically disordered 58-residue GR tau1core were studied using disorder prediction and molecular dynamics simulations. RESULTS: Change-of-function mutations were partitioned into seven clusters based on their effect on IDR predictions and gene activation activity. Some mutations selected from clusters characterized by mutations altering the IDR prediction score, altered the apparent stability of the α-helical form of one of the PreSMos in molecular dynamics simulations, suggesting PreSMo stabilization or destabilization as strategies for functional adaptation. Indeed all tested gain-of-function mutations affecting this PreSMo were associated with increased stability of the α-helical PreSMo conformation, suggesting that PreSMo stabilization may be the main mechanism by which adaptive mutations can increase the activity of this IDR type. Some mutations did not appear to affect PreSMo stability. CONCLUSIONS: Changes in PreSMo stability account for the effects of a subset of change-of-function mutants affecting the GR tau1core IDR. GENERAL SIGNIFICANCE: Long IDRs occur in about 50% of human proteins. They are poorly characterized despite much recent attention. Our results suggest the importance of a subtle balance between PreSMo stability and IDR activity, which may provide a novel target for future pharmaceutical intervention.

Lipids Shape the Electron Acceptor-Binding Site of the Peripheral Membrane Protein Dihydroorotate Dehydrogenase.

The interactions between proteins and biological membranes are important for drug development, but remain notoriously refractory to structural investigation. We combine non-denaturing mass spectrometry (MS) with molecular dynamics (MD) simulations to unravel the connections among co-factor, lipid, and inhibitor binding in the peripheral membrane protein dihydroorotate dehydrogenase (DHODH), a key anticancer target. Interrogation of intact DHODH complexes by MS reveals that phospholipids bind via their charged head groups at a limited number of sites, while binding of the inhibitor brequinar involves simultaneous association with detergent molecules. MD simulations show that lipids support flexible segments in the membrane-binding domain and position the inhibitor and electron acceptor-binding site away from the membrane surface, similar to the electron acceptor-binding site in respiratory chain complex I. By complementing MS with MD simulations, we demonstrate how a peripheral membrane protein uses lipids to modulate its structure in a similar manner as integral membrane proteins.

Are forest disturbances amplifying or canceling out climate change-induced productivity changes in European forests?

Recent studies projecting future climate change impacts on forests mainly consider either the effects of climate change on productivity or on disturbances. However, productivity and disturbances are intrinsically linked because 1) disturbances directly affect forest productivity (e.g. via a reduction in leaf area, growing stock or resource-use efficiency), and 2) disturbance susceptibility is often coupled to a certain development phase of the forest with productivity determining the time a forest is in this specific phase of susceptibility. The objective of this paper is to provide an overview of forest productivity changes in different forest regions in Europe under climate change, and partition these changes into effects induced by climate change alone and by climate change and disturbances. We present projections of climate change impacts on forest productivity from state-of-the-art forest models that dynamically simulate forest productivity and the effects of the main European disturbance agents (fire, storm, insects), driven by the same climate scenario in seven forest case studies along a large climatic gradient throughout Europe. Our study shows that, in most cases, including disturbances in the simulations exaggerate ongoing productivity declines or cancel out productivity gains in response to climate change. In fewer cases, disturbances also increase productivity or buffer climate-change induced productivity losses, e.g. because low severity fires can alleviate resource competition and increase fertilization. Even though our results cannot simply be extrapolated to other types of forests and disturbances, we argue that it is necessary to interpret climate change-induced productivity and disturbance changes jointly to capture the full range of climate change impacts on forests and to plan adaptation measures.

Effects of Detergent Micelles on Lipid Binding to Proteins in Electrospray Ionization Mass Spectrometry.

A wide variety of biological processes rely upon interactions between proteins and lipids, ranging from molecular transport to the organization of the cell membrane. It was recently established that electrospray ionization mass spectrometry (ESI-MS) is capable of capturing transient interactions between membrane proteins and their lipid environment, and a detailed understanding of the underlying processes is therefore of high importance. Here, we apply ESI-MS to investigate the factors that govern complex formation in solution and gas phases by comparing nonselective lipid binding with soluble and membrane proteins. We find that exogenously added lipids did not bind to soluble proteins, suggesting that lipids have a low propensity to form electrospray ionization adducts. The presence of detergents at increasing micelle concentrations, on the other hand, resulted in moderate lipid binding to soluble proteins. A direct ESI-MS comparison of lipid binding to the soluble protein serum albumin and to the integral membrane protein NapA shows that soluble proteins acquire fewer lipid adducts. Our results suggest that protein-lipid complexes form via contacts between proteins and mixed lipid/detergent micelles. For soluble proteins, these complexes arise from nonspecific contacts between the protein and detergent/lipid micelles in the electrospray droplet. For membrane proteins, lipids are incorporated into the surrounding micelle in solution, and complex formation occurs independently of the ESI process. We conclude that the lipids in the resulting complexes interact predominantly with sites located in the transmembrane segments, resulting in nativelike complexes that can be interrogated by MS.

A carbon footprint simulation model for the cork oak sector.

In the present study, a simulation model for the calculation of the carbon footprint of the cork oak sector (CCFM) is developed for the first time. A life cycle approach is adopted including the forest management, manufacturing, use and end-of-life stages. CCFM allows the user to insert the cork type used as raw material and its respective quantity and the distances in-between the various stages. The user can choose among different end-of-life destination options for the used cork products. The option of inserting different inputs, allows the use of the present simulation model for different cork oak systems, in different countries and with different conditions. CCFM allows the identification of the stages and products with the greatest carbon footprint and thus, a better management of the sector from an environmental perspective. The Portuguese cork oak sector is used as an application example of the model. The results obtained showed that the agglomeration industry is the hotspot for the carbon footprint of the cork sector mainly due to the production of the resins that are mixed with the cork granules for the production of agglomerated cork products. The consideration of the biogenic carbon emissions and sequestration of carbon at the forest in the carbon footprint, resulted to a great decrease of the sector's carbon footprint. Future actions for improvement are suggested in order to decrease the carbon footprint of the entire cork sector. It was found that by decreasing by 10% the emission factor of the agglomeration and transformation industries, substituting the transport trucks by more recent ones and by decreasing by 10% the cork products reaching the landfilling end-of-life destinations (while increasing the quantities reaching incineration and recycling), a decrease of the total CF (excluding the biogenic emissions and sequestration) of the entire cork industry by 10% can be achieved.