Nodular Lymphocyte-Predominant Hodgkin Lymphoma: A Rare Lymphoma with Isolated Hepatic Presentation.

Primary hepatic lymphoma (PHL) is extremely rare, accounting for less than 1% of all lymphomas, and is limited to the liver without extrahepatic involvement. A 30-year-old male was admitted in the Emergency Department complaining of weakness, fever, night sweats, significant weight loss, discrete ring alopecia, hepatomegaly, right axillary adenopathy and oedema of both legs. Laboratory evaluation showed normocytic normochromic anaemia, thrombocytosis, hyperbilirubinemia, cholestasis and increased international normalised ratio (INR). A computed tomography (CT) scan found an enlarged liver with a heterogeneous structure and moderate ascites. After admission in our ward further investigation revealed increased sedimentation velocity, ferritin and serum lactate dehydrogenase. A hepatic biopsy was performed which confirmed the diagnosis as a nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL). The patient was transferred to a haematological ward and underwent chemotherapy with six cycles of R-CHOP. He is in complete remission after a year and half since the beginning of treatment. NLPHL, a very rare lymphoma, is more common in men between the third and fifth decades of life. Usually, the symptoms are very unspecific; a few patients have B symptoms at admission. This kind of presentation is also common in infectious, metabolic and autoimmune diseases, which were excluded in this case. Due to technical issues the final diagnosis was only possible due to the liver biopsy. Treatment with standard Hodgkin lymphoma protocols leads to complete remission in more that 95% of patients with NLPHL. LEARNING POINTS: Differential diagnosis of fever, especially in young patients, is very complex and complete investigation takes time, which can delay the diagnosis of malignancies such as primary hepatic lymphoma (PHL).PHL is very rare, and overlapping symptoms with other liver diseases can make the diagnosis very challenging.When the suspicion of PHL is very high, only the hepatic biopsy can lead to the correct diagnosis because the disease has no extrahepatic involvement.

Aortoenteric Fistula: A Differential Diagnosis of Anemia.

Aortoenteric fistulas (AEFs) are a rare and deadly cause of gastrointestinal bleeding that can be easily overlooked, leading to massive bleeding. Secondary AEFs are more common than primary AEFs. An example of a secondary cause of anemia is postoperative hemorrhage due to a surgically placed aortic graft or after endovascular aneurysm repair. This report aims to increase the awareness of AEF as a differential diagnosis when anemia is detected. The clinical report presents a case of anemia in a 79-year-old man due to a secondary AEF, which occurred in a patient who had undergone abdominal aortic aneurysm surgery 10 years before. Surgical repair is considered the gold standard for AEF treatment; however, in this case, the patient was managed with medical therapy and discharged after two months.

conTemporary reflectiOns regarding heart failure manaGEmenT - How to ovERcome the PorTuguese barriers (TOGETHER-PT).

INTRODUCTION AND OBJECTIVES: Heart failure (HF) is a complex clinical syndrome that is a significant burden in hospitalisations, morbidity, and mortality. Although a significant effort has been made to better understand its consequences and current barriers in its management, there are still several gaps to address. The present work aimed to identify the views of a multidisciplinary group of health care professionals on HF awareness and literacy, diagnosis, treatment and organization of care, identifying current challenges and providing insights into the future. METHODS: A steering committee was established, including members of the Heart Failure Study Group of the Portuguese Society of Cardiology (GEIC-SPC), the Heart Failure Study Group of the Portuguese Society of Internal Medicine (NEIC-SPMI) and the Cardiovascular Study Group (GEsDCard) of the Portuguese Association of General and Family Medicine (APMGF). This steering committee produced a 16-statement questionnaire regarding different HF domains that was answered to by a diversified group of 152 cardiologists, internists, general practitioners, and nurses with an interest or dedicated to HF using a five-level Likert scale. Full agreement was defined as ≥80% of level 5 (fully agree) responses. RESULTS: Globally, consensus was achieved in all but one of the 16 statements. Full agreement was registered in seven statements, namely 3 of 4 statements for patient education and HF awareness and 2 in 4 statements of both HF diagnosis and healthcare organization, with proportions of fully agree responses ranging from 82.9% to 96.7%. None of the HF treatment statements registered full agreement but 3 of 4 achieved ≥80% of level 4 (agree) responses. CONCLUSION: This document aims to be a call-to-action to improve HF patients' quality of life and prognosis, by promoting a change in HF care in Portugal.

Reprogramming iPSCs to study age-related diseases: Models, therapeutics, and clinical trials.

The unprecedented rise in life expectancy observed in the last decades is leading to a global increase in the ageing population, and age-associated diseases became an increasing societal, economic, and medical burden. This has boosted major efforts in the scientific and medical research communities to develop and improve therapies to delay ageing and age-associated functional decline and diseases, and to expand health span. The establishment of induced pluripotent stem cells (iPSCs) by reprogramming human somatic cells has revolutionised the modelling and understanding of human diseases. iPSCs have a major advantage relative to other human pluripotent stem cells as their obtention does not require the destruction of embryos like embryonic stem cells do, and do not have a limited proliferation or differentiation potential as adult stem cells. Besides, iPSCs can be generated from somatic cells from healthy individuals or patients, which makes iPSC technology a promising approach to model and decipher the mechanisms underlying the ageing process and age-associated diseases, study drug effects, and develop new therapeutic approaches. This review discusses the advances made in the last decade using iPSC technology to study the most common age-associated diseases, including age-related macular degeneration (AMD), neurodegenerative and cardiovascular diseases, brain stroke, cancer, diabetes, and osteoarthritis.

Matrisomal components involved in regenerative wound healing in axolotl and Acomys: implications for biomaterial development.

Achieving regeneration in humans has been a long-standing goal of many researchers. Whereas amphibians like the axolotl (Ambystoma mexicanum) are capable of regenerating whole organs and even limbs, most mammals heal their wounds via fibrotic scarring. Recently, the African spiny mouse (Acomys sp.) has been shown to be injury resistant and capable of regenerating several tissue types. A major focal point of research with Acomys has been the identification of drivers of regeneration. In this search, the matrisome components related to the extracellular matrix (ECM) are often overlooked. In this review, we compare Acomys and axolotl skin wound healing and blastema-mediated regeneration by examining their wound healing responses and comparing the expression pattern of matrisome genes, including glycosaminoglycan (GAG) related genes. The goal of this review is to identify matrisome genes that are upregulated during regeneration and could be potential candidates for inclusion in pro-regenerative biomaterials. Research papers describing transcriptomic or proteomic coverage of either skin regeneration or blastema formation in Acomys and axolotl were selected. Matrisome and GAG related genes were extracted from each dataset and the resulting lists of genes were compared. In our analysis, we found several genes that were consistently upregulated, suggesting possible involvement in regenerative processes. Most of the components have been implicated in regulation of cell behavior, extracellular matrix remodeling and wound healing. Incorporation of such pro-regenerative factors into biomaterials may help to shift pro-fibrotic processes to regenerative responses in treated wounds.

Regulation of Ras Signaling by S-Nitrosylation.

Ras are a family of small GTPases that function as signal transduction mediators and are involved in cell proliferation, migration, differentiation and survival. The significance of Ras is further evidenced by the fact that Ras genes are among the most mutated oncogenes in different types of cancers. After translation, Ras proteins can be targets of post-translational modifications (PTM), which can alter the intracellular dynamics of the protein. In this review, we will focus on how S-nitrosylation of Ras affects the way these proteins interact with membranes, its cellular localization, and its activity. S-Nitrosylation occurs when a nitrosyl moiety of nitric oxide (NO) is covalently attached to a thiol group of a cysteine residue in a target protein. In Ras, the conserved Cys118 is the most surface-exposed Cys and the preferable residue for NO action, leading to the initiation of transduction events. Ras transduces the mitogen-activated protein kinases (MAPK), the phosphoinositide-3 kinase (PI3K) and the RalGEF cellular pathways. S-Nitrosylation of elements of the RalGEF cascade remains to be identified. On the contrary, it is well established that several components of the MAPK and PI3K pathways, as well as different proteins associated with these cascades, can be modified by S-nitrosylation. Overall, this review presents a better understanding of Ras S-nitrosylation, increasing the knowledge on the dynamics of these proteins in the presence of NO and the underlying implications in cellular signaling.

Measuring healthy ageing: current and future tools.

Human ageing is a complex, multifactorial process characterised by physiological damage, increased risk of age-related diseases and inevitable functional deterioration. As the population of the world grows older, placing significant strain on social and healthcare resources, there is a growing need to identify reliable and easy-to-employ markers of healthy ageing for early detection of ageing trajectories and disease risk. Such markers would allow for the targeted implementation of strategies or treatments that can lessen suffering, disability, and dependence in old age. In this review, we summarise the healthy ageing scores reported in the literature, with a focus on the past 5 years, and compare and contrast the variables employed. The use of approaches to determine biological age, molecular biomarkers, ageing trajectories, and multi-omics ageing scores are reviewed. We conclude that the ideal healthy ageing score is multisystemic and able to encompass all of the potential alterations associated with ageing. It should also be longitudinal and able to accurately predict ageing complications at an early stage in order to maximize the chances of successful early intervention.

How can we modulate aging through nutrition and physical exercise? An epigenetic approach.

The World Health Organization predicts that by 2050, 2.1 billion people worldwide will be over 60 years old, a drastic increase from only 1 billion in 2019. Considering these numbers, strategies to ensure an extended "healthspan" or healthy longevity are urgently needed. The present study approaches the promotion of healthspan from an epigenetic perspective. Epigenetic phenomena are modifiable in response to an individual's environmental exposures, and therefore link an individual's environment to their gene expression pattern. Epigenetic studies demonstrate that aging is associated with decondensation of the chromatin, leading to an altered heterochromatin structure, which promotes the accumulation of errors. In this review, we describe how aging impacts epigenetics and how nutrition and physical exercise can positively impact the aging process, from an epigenetic point of view. Canonical histones are replaced by histone variants, concomitant with an increase in histone post-translational modifications. A slight increase in DNA methylation at promoters has been observed, which represses transcription of previously active genes, in parallel with global genome hypomethylation. Aging is also associated with deregulation of gene expression - usually provided by non-coding RNAs - leading to both the repression of previously transcribed genes and to the transcription of previously repressed genes. Age-associated epigenetic events are less common in individuals with a healthy lifestyle, including balanced nutrition, caloric restriction and physical exercise. Healthy aging is associated with more tightly condensed chromatin, fewer PTMs and greater regulation by ncRNAs.

Real-Life Data on Readmissions of Worsening Heart Failure Outpatients in a Heart Failure Clinic.

Introduction Recurrent hospitalizations for worsening heart failure (WHF) represent a major global public health concern, resulting in significant individual morbimortality and socioeconomic costs. This real-life study aimed to determine the rate and predictors of readmission for WHF in a cohort of outpatients with chronic heart failure (CHF) followed in a heart failure clinic (HFC) at a university hospital. Methods We conducted a longitudinal, observational, and retrospective study of all consecutive CHF patients seen at the HFC of the São Francisco Xavier Hospital, Lisbon, by a multidisciplinary team in 2019. The patients were followed for one year and were on optimized therapy. The inclusion criteria for the study were patients who had been hospitalized and subsequently discharged at least three months prior to their enrollment. Patient demographics, heart failure (HF) characterization, comorbidities, pharmacological treatment, treatments of decompensated HF in the day hospital (DH), hospitalizations for WHF, and death were recorded. We applied logistic regression analysis to assess predictors of hospital readmission for HF. Results A total of 351 patients were included: 90 patients (26%) had WHF requiring treatment with intravenous diuretics in the DH; 45 patients (mean age: 79.1 ± 9.0 years) were readmitted for decompensated HF within one year (12.8%) with no gender difference, while 87.2% of the patients (mean age: 74.9 ± 12.1 years) were never readmitted. Readmitted patients were significantly older than those who were not (p=0.031). Additionally, they had a higher New York Heart Association (NYHA) functional classification (p<.001), were on a higher daily dose of furosemide (p=0.008) at the time of the inclusion visit, were more frequently affected by the chronic obstructive pulmonary disease (COPD) (p=0.004); had been treated more often in the DH for WHF (p<.001) and had a higher mortality rate (p<.001) at one year. Conclusions This study aimed to determine WHF patient readmission rates and predictors. According to our results, a higher NYHA class, the need for treatment in the DH for WHF, a daily dose of furosemide equal to or greater than 80 mg, and COPD were predictors of readmission for WHF. CHF patients continue to experience WHF and recurrent hospitalizations despite therapeutic advances and close follow-up in the HFC with the multidisciplinary team. Besides COPD, the HF readmission risk factors found were mainly related to advanced disease. Furthermore, the structured and multidisciplinary approach of our disease management program likely contributed to our relatively low rate of readmissions.

Diuretic-resistant heart failure and the role of ultrafiltration: A proposed protocol.

Acute heart failure (HF) decompensation generally manifests with signs and symptoms of congestion that strongly predict poor poor patient outcome. Loop diuretics are the cornerstone of therapy to counteract fluid overload and are widely used for acute management and chronic stabilization of HF. However, a diminished response to loop diuretics is a common problem, affecting the patient's clinical course and potentially prolonging hospitalization. Diuretic resistance is defined as failure to decongest despite appropriate and escalating loop diuretic therapy. We propose a protocol for the management of diuretic resistance. The initial approach should include an assessment of causes of pseudo-diuretic resistance. Adjustments to loop diuretic therapy, such as increasing doses and frequency of administration and sequential nephron blockade, may be successful. For hospitalized patients with progressive disease there are more invasive methods for fluid removal. Switching from oral to intravenous loop diuretics is essential to avoid variable absorption and for symptomatic relief. Extracorporeal ultrafiltration is also an option since this technique is highly effective at removing plasma fluid from blood. While extracorporeal ultrafiltration is an invasive solution, peritoneal dialysis is a home-based, intermittent therapeutic option that can enable efficient management of fluid overload, preventing HF-related hospital admission, and improving quality of life. As a last resort for fluid removal, a peritoneal dialysis regimen should fully exploit its decongestive properties and should be tailored to the patient's characteristics and clinical needs.

Acute kidney injury patterns in acute heart failure: The prognostic value of worsening renal function and its timing.

INTRODUCTION: Acute decompensated heart failure (ADHF) admissions are frequently complicated by different patterns of serum creatinine (SCr) elevation. We aimed to assess the prognostic impact of worsening renal function (WRF) based on the timing of its occurrence. METHODS: This was a retrospective cohort of patients admitted for ADHF. Standard WRF was defined as an increase in SCr of ≥0.3 mg/dl during hospitalization. WRF timing was classified as early (within 48 hours of admission) or late (>48 hours). Acute kidney injury (AKI) at admission was defined as a rise in SCr of ≥0.3 mg/dl from outpatient baseline measurement to first measurement at admission. The primary endpoint was a composite of all-cause mortality or hospitalization for cardiovascular events at one-year follow-up. RESULTS: Overall, 249 patients were included (mean age 77±11 years, 62% with preserved left ventricular ejection fraction). Early WRF occurred in 49 patients (19.7%) and was associated with a higher risk of the primary outcome (HR 2.49; 95% CI 1.66-3.73), whereas late WRF was not (p=0.411). After stratification for the presence of early WRF and/or AKI at admission, only patients with early WRF but no AKI at admission and patients with both AKI at admission and early WRF showed a higher risk of the primary outcome after multivariate Cox regression. CONCLUSION: Early WRF was associated with a higher risk of the primary outcome. The timing of WRF seems to be an important factor to take into account when considering the prognostic impact of creatinine variations during hospitalization for ADHF.

Co-Administration of Albumin and Furosemide in Acute Heart Failure with Diuretics Resistance.

Acute heart failure is a frequent cause of hospital admission in Portugal, and has an increasing tendency given the aging population. Although most admissions for acute heart failure are caused by congestive conditions, not all patients have a congestive phenotype, reflecting the complexity of a process with multiple pathophysiological pathways. The use of diuretics, usually loop diuretics, is the mainstay of treatment for congestion. However, many patients develop resistance, thus constituting a challenge with no consensual solution to date, despite extensive debate over the years. Despite its frequent use in clinical practice, the co-administration of albumin and furosemide remains controversial in the management of patients with acute heart failure, hypoalbuminemia, and diuretic resistance. This review addresses the pathophysiological mechanisms of congestion in patients with acute heart failure and explores the theoretical basis that supports the co-administration of albumin and furosemide in this clinical context. It is intended to clarify the potential benefit of the combined approach in this specific population and identify possible gaps in the literature that could be the subject of future studies.

Occupational Sun Exposure Among Physical Education Teachers in Primary and Secondary Schools in Andalusia, Spain.

Chronic sun exposure and sunburns are the main preventable causes of skin cancer. Due to the nature of their work, physical education teachers are at high risk for occupational skin cancer. This descriptive, cross-sectional study analyzes primary and secondary physical education teachers in Andalusia, Spain. All participants were invited to monitor their ultraviolet (UV) radiation exposure using individual biologic dosimeters and record their photoprotection practices over 3 workdays. The teachers spent an average of 2.7 h outdoors and the mean personal UV radiation exposure was 309.9 J/m2 per day, a value three times higher than international recommendations. Based on the photoprotection diary, it was determined that classes held outdoors were not scheduled outside the hours with the highest UV index and that the percentage of participants who followed the photoprotective practices of remaining in the shade or wearing a hat during outdoor lessons were less than 20% and 60%, respectively. The results on sun exposure and photoprotection practices show a need for organizational and educational intervention strategies to mitigate sun exposure and increase compliance with photoprotection measures to reduce skin cancer risk among these workers and promote early diagnosis of the disease.

Leprosy in a Patient With Lymphoma: A Challenge in the Twenty-First Century.

Leprosy, or Hansen's disease, mistakenly considered a disease from the past by some, is still common nowadays, especially in tropical and subtropical regions. In the absence of appropriate medical treatment, it may progress and cause permanent damage to multiple organs. This case report illustrates the diagnostic challenge of a south-american adult man who had been living in Europe for over 14 years. He was referred to the Hematology department due to persistent lymphocytosis and a CD5+ B-cell lymphoproliferative disorder was identified. During clinical surveillance, the patient developed skin lesions in his limbs with associated hypoesthesia. A histological diagnosis of lepromatous leprosy was made, and he underwent a long-term three-drug therapeutic regimen (dapsone, rifampicin, and clofazimine). Adding to the complexity of the case, the patient progressed with splenomegaly and constitutional symptoms, more than 7 years after development of lymphocytosis. Through a comprehensive evaluation, a definitive diagnosis of mantle cell lymphoma was established and received 6-cycle R-CHOP induction, followed by maintenance rituximab. Importantly, prophylaxis for leprosy reactivation was not administered as there were no recommendations in available guidelines. Eventually, the patient experienced a leprosy relapse while on maintenance therapy, 58 months after completing the initial anti-leprous treatment. Clinical response was attained with a new treatment regimen consisting of rifampicin, clofazimine, and minocycline.  Although leprosy is primarily observed in tropical and subtropical regions, the long incubation period of this disease combined with the global flow of migrants, made us consider it. Despite being rare, leprosy relapses can occur even after a few decades. The contribution of rituximab or previously administered chemotherapeutic agents is still unknown. The question remains whether antibiotic prophylaxis should be performed in patients undergoing immunochemotherapy for malignant diseases.

Seronegative Celiac Disease - A Challenging Case.

Celiac disease is an inflammatory disorder of the small intestine caused by sensitivity to gluten. This enteropathy results from the interaction between genetics, autoimmunity, and an environmental trigger (gluten). It can manifest at all ages. We present a case of a 76-year-old woman with nausea and vomiting for six months. She reported asthenia, weight loss, and a brief period of diarrhea without blood or mucus. The search for evidence of infection, tumours, and endocrinopathies was negative, as well as the immunological study, including antibodies for celiac disease. Upper endoscopy with biopsies revealed villous atrophy. Capsule endoscopy showed macroscopic features suggestive of celiac/Whipple's disease. Duodenal biopsies were reviewed, and Whipple's disease was considered unlikely. The genetic analysis was positive for HLA DR7-DQ2. After one year on a gluten-free diet, there was a clinical and histological improvement. The diagnosis of seronegative celiac disease is complex and requires the exclusion of other causes of villous atrophy, as well as a histological improvement after one year of treatment. The genetic test has a high negative predictive value.

Heart Failure: From Typical Clinical Manifestations to the Surprising Final Diagnosis.

The authors report a case of an 80-year-old woman with multiple cardiovascular risk factors, with exuberant acute congestive heart failure at admission. Fever, anemia, and an increase in inflammatory parameters were present, with imaging suggesting a respiratory infection as the main reason for decompensation. Empirical antibiotic therapy was instituted, with no clinical improvement even after escalation to broad-spectrum antibiotics and non-invasive ventilation with high support pressures, with no possibility of weaning. Due to maintenance of symptoms, a transthoracic echocardiogram was performed, revealing a large left atrial myxoma, obstructing the mitral valve in diastole. This case illustrates the potential severity of these benign tumors and their ability to mimic symptoms that are often evaluated in the daily life of an internist. The high clinical suspicion led to a diagnosis that was surprising due to its rarity and severity, with the patient being urgently referred for cardiac surgery.

Coronal brain atlas in stereotaxic coordinates of the African spiny mouse, Acomys cahirinus.

The African spiny mouse (Acomys cahirinus) is an emerging model of mammalian epimorphic regeneration that has aroused the interest of the scientific community in the last decade. To date, studies on brain repair have been hindered by the lack of knowledge on the neuroanatomy of this species. Here, we present a coronal brain atlas in stereotaxic coordinates, which allows for three-dimensional identification and localization of the brain structures of this species. The brain of 12-week-old spiny mice was mapped in stereotaxic coordinates using cresyl violet-stained brain sections obtained from coronal cryosectioning of the brain after transcardial perfusion with fixative. The atlas is presented in 42 plates representing sections spaced 240 µm apart. Stereotaxic coordinates were validated using both a model of Parkinsonian lesion of the striatum with 6-hydroxydopamine and labeling of the corticospinal tract in the spiny mouse spinal cord using AAV1/2-GFP intracortical injections. This work presents a new tool in A. cahirinus neurobiology and opens new avenues of research for the investigation of the regenerative ability of A. cahirinus in models of brain disorders.

Predicting Prognosis in Internal Medicine: A Short and Long-Term Mortality Comparison Analysis.

Introduction The marked increase in life expectancy seen in Portugal in the last five decades led to a change in the profile of patients being most commonly admitted in internal medicine wards. In deciding the best care for these patients, prognostication models are needed in order to reduce readmissions, mortality, and adequate care. We aimed to study short and long-term mortality and predictors of all-cause mortality, independently of cause admission, of patients admitted in an internal medicine ward. Methods This two-part, single-center study enrolled patients from October 2013 to October 2014 with a follow-up of 60 months. Results A total of 681 patients were included; the mean age was 75.86 years with 60.4% females. The most frequent comorbidities were anemia, hypertension, and renal impairment. More than half of the population died in the follow-up period (51.5%). Deaths were significantly higher in the first six months after discharge (53% of all deaths) and then decreased abruptly to 11.6% in the second half-year after discharge. Based on the multivariate logistic regression model, with age over 80 years, anemia and neoplasm were independent predictors of short-term (p<0.001, p=0.001, p<0.001, respectively) and long-term (p<0.001 for the three conditions) mortality. Heart failure (p=0.018) and diabetes (p=0.025) were also predictors of long-term mortality. Conclusion High mortality, mainly in the first six months after discharge, elicits strategies targeting transition of care and close follow-up in the first months, which can be the key to improving outcomes. Identification of patients at higher risk may help design realistic models aiming to improve care for this frail population and decrease morbimortality.

Rewired glycosylation activity promotes scarless regeneration and functional recovery in spiny mice after complete spinal cord transection.

Regeneration of adult mammalian central nervous system (CNS) axons is abortive, resulting in inability to recover function after CNS lesion, including spinal cord injury (SCI). Here, we show that the spiny mouse (Acomys) is an exception to other mammals, being capable of spontaneous and fast restoration of function after severe SCI, re-establishing hind limb coordination. Remarkably, Acomys assembles a scarless pro-regenerative tissue at the injury site, providing a unique structural continuity of the initial spinal cord geometry. The Acomys SCI site shows robust axon regeneration of multiple tracts, synapse formation, and electrophysiological signal propagation. Transcriptomic analysis of the spinal cord following transcriptome reconstruction revealed that Acomys rewires glycosylation biosynthetic pathways, culminating in a specific pro-regenerative proteoglycan signature at SCI site. Our work uncovers that a glycosylation switch is critical for axon regeneration after SCI and identifies ß3gnt7, a crucial enzyme of keratan sulfate biosynthesis, as an enhancer of axon growth.