Nuclear Envelope Alterations in Myotonic Dystrophy Type 1 Patient-Derived Fibroblasts

Myotonic dystrophy type 1 (DM1) is a hereditary and multisystemic disease characterized by myotonia, progressive distal muscle weakness and atrophy. The molecular mechanisms underlying this disease are still poorly characterized, although there are some hypotheses that envisage to explain the multisystemic features observed in DM1. An emergent hypothesis is that nuclear envelope (NE) dysfunction may contribute to muscular dystrophies, particularly to DM1. Therefore, the main objective of the present study was to evaluate the nuclear profile of DM1 patient-derived and control fibroblasts and to determine the protein levels and subcellular distribution of relevant NE proteins in these cell lines. Our results demonstrated that DM1 patient-derived fibroblasts exhibited altered intracellular protein levels of lamin A/C, LAP1, SUN1, nesprin-1 and nesprin-2 when compared with the control fibroblasts. In addition, the results showed an altered location of these NE proteins accompanied by the presence of nuclear deformations (blebs, lobes and/or invaginations) and an increased number of nuclear inclusions. Regarding the nuclear profile, DM1 patient-derived fibroblasts had a larger nuclear area and a higher number of deformed nuclei and micronuclei than control-derived fibroblasts. These results reinforce the evidence that NE dysfunction is a highly relevant pathological characteristic observed in DM1.

A Rare Case of Adult-onset Still's Disease Revealed by Acute Myopericarditis

Background: Still's disease in adults is a systemic inflammatory pathology of unknown aetiology, characterized by clinical manifestations associating feverish peaks, arthritis or arthtralgia, transient rashes and hyperferritinemia. Currently, this disease remains a multisystemic disease with generally poor outcome, poorly described in the literature with very few studies unlike other rheumatic diseases, probably underdiagnosed due to its clinical polymorphism. Cardiac forms are quite rare and among the manifestations described, pericarditis remains the most reported entity, myocardial involvement is exceptional. The aim of our observation is to report an exceptional case of discovery of stille disease following a myo-pericarditis mimicking a coronary Sd initially.

A Rare Case: IgG4-Related Chronic Inflammatory Disease with Kidney Involvement

IgG4 related disease is an immune-mediated chronic inflammatory disease. It is a multisystemic disease that can lead to retroperitoneal fibrosis with involvement of the pancreas, glands, thyroid, lymph nodes, etc. and characterized histopathologically by lymphoplasmocytic cell infiltration. We evaluated a patient diagnosed with IGG4 related disease impaired kidney function.

Hereditary hemorrhagic telangiectasia diagnosed by enteroscopy: a case report

Hereditary hemorrhagic telangiectasia (HHT) is a very rare autosomal dominant multisystemic disease. Patients with this disease usually present with punctate mucocutaneous telangiectasias and arteriovenous malformations. The diagnostic criteria currently in use are the Curaçao criteria. HHT is considered a clinical diagnosis; thus, no imaging or preclinical laboratory is mandatory, and diagnosis and management are performed according to the experience of the treating team. We herein describe a 58-year-old man with no significant medical history who presented with a 15-day history of intermittent hematochezia. He was admitted to the hospital and underwent a series of laboratory tests, including colonoscopy, which showed normal results. Therefore, the patient was discharged with a diagnosis of gastrointestinal bleeding. During his second visit to the emergency room, the doctors requested video capsule endoscopy because of the patient’s history, and a diagnosis of HHT was made. The entire approach and treatment were completed with antegrade double-balloon enteroscopy. This case highlights the importance of endoscopic methods for timely diagnosis and proper management.

The BPH/5 Mouse Model of Superimposed Preeclampsia Is Not a Model of HELLP Syndrome

Preeclampsia (PE) is a multisystemic disease of pregnancy affecting 2–8% of women worldwide. PE-induced liver disease is a rare but important complication of pregnancy. The pathogenesis of liver dysfunction in PE is poorly understood, but is correlated with dysregulated angiogenic, inflammatory, and hypoxic events in the early phase of placental development. Because BPH/5 mice develop the maternal and fetal hallmarks of PE during pregnancy, we hypothesized that they may also share the clinicopathologic findings of the human PE-associated hemolysis elevated liver transaminases low platelets (HELLP) syndrome. Using this model, we determined that microangiopathic hemolysis, thrombocytopenia, and elevated liver enzymes do not occur in mid to late gestation. Pregnant BPH/5 mice do not develop histologic evidence of hepatic inflammation, but they do have increased microsteatosis scores at preconception and in mid to late gestation that progress to macrosteatosis in a subset of mice in late gestation. The transcriptional upregulation of TNF-α, CXCL-10, and TLR-2 occurs in mid gestation prior to the onset of macrosteatosis. The BPH/5 female mouse is not a model of HELLP syndrome, but may be a model of fatty liver disease associated with pregnancy.

Bowel Ischemia in COVID-19 Infection: One-Year Surgical Experience

Background COVID-19 is a deadly multisystemic disease, and bowel ischemia, the most consequential gastrointestinal manifestation, remains poorly described. Our goal is to describe our institution’s surgical experience with management of bowel ischemia due to COVID-19 infection over a one-year period. Methods All patients admitted to our institution between March 2020 and March 2021 for treatment of COVID-19 infection and who underwent exploratory laparotomy with intra-operative confirmation of bowel ischemia were included. Data from the medical records were analyzed. Results Twenty patients were included. Eighty percent had a new or increasing vasopressor requirement, 70% had abdominal distension, and 50% had increased gastric residuals. Intra-operatively, ischemia affected the large bowel in 80% of cases, the small bowel in 60%, and both in 40%. Sixty five percent had an initial damage control laparotomy. Most of the resected bowel specimens had a characteristic appearance at the time of surgery, with a yellow discoloration, small areas of antimesenteric necrosis, and very sharp borders. Histologically, the bowel specimens frequently have fibrin thrombi in the small submucosal and mucosal blood vessels in areas of mucosal necrosis. Overall mortality in this cohort was 33%. Forty percent of patients had a thromboembolic complication overall with 88% of these developing a thromboembolic phenomenon despite being on prophylactic pre-operative anticoagulation. Conclusion Bowel ischemia is a potentially lethal complication of COVID-19 infection with typical gross and histologic characteristics. Suspicious clinical features that should trigger surgical evaluation include a new or increasing vasopressor requirement, abdominal distension, and intolerance of gastric feeds.

Virchow’s Triad and the Role of Thrombosis in COVID-Related Stroke

In December 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was identified as a virally transmitted disease. Three months later, SARS-CoV-2 became one of the largest pandemics in recent times, causing more than 235 million cases globally, and accounting for at least 4.8 million deaths to date. SARS-COV-2 infection was initially classified as a respiratory tract infection, but later was recognized as a multisystemic disease compromising gastrointestinal, hematological, cardiac, and neurological systems. With this Review, we aim to describe the epidemiology, risk factors, mechanisms, and management of cerebrovascular events in patients infected with COVID-19. Neurological manifestations related to thromboembolic cerebrovascular events in patients infected with COVID-19 have been frequent and associated with poor prognosis in the majority of cases. A better understanding of the mechanisms of thrombosis and etiologies of this new disease process are necessary to determine how to prevent and treat patients to reduce their length of stay, morbidity, and mortality.

ALK+ histiocytosis: a new clinicopathologic spectrum highlighting neurologic involvement and responses to ALK inhibition

ALK-related histiocytosis (formerly ALK-positive histiocytosis) is a rare subtype of histiocytic neoplasm first described in 2008 in three infants with multisystemic disease involving the liver and hematopoietic system. This entity has subsequently been documented in case reports and series to occupy a wider clinicopathologic spectrum with recurrent KIF5B-ALK fusions. The full clinicopathologic and molecular spectra of ALK-related histiocytosis remain, however, poorly characterized. Here, we describe the largest study of ALK-related histiocytosis to date, with detailed clinicopathologic data of 39 cases, including 37 cases with confirmed ALK rearrangements. The clinical spectrum comprised distinct clinical phenotypic groups: infants with multisystemic disease with liver and hematopoietic involvement, as originally described (Group 1A: 6/39), other patients with multisystemic disease (Group 1B: 10/39), and patients with single-system disease (Group 2: 23/39). Nineteen patients of the entire cohort (49%) had neurologic involvement (seven and twelve from Groups 1B and 2, respectively). Histology included classic xanthogranuloma features in almost one third of cases, whereas the majority displayed a more densely cellular, monomorphic appearance without lipidized histiocytes but sometimes more spindled or epithelioid morphology. Neoplastic histiocytes were positive for macrophage markers and ALK, and often conferred strong expression of phosphorylated-ERK, confirming MAPK pathway activation. KIF5B-ALK fusions were detected in 27 patients, while CLTC-ALK, TPM3-ALK, TFG-ALK, EML4-ALK and DCTN1-ALK fusions were identified in single cases. Robust and durable responses were observed in 11/11 patients treated with ALK inhibition, ten with neurologic involvement. This study presents the existing clinicopathologic and molecular landscape of ALK-related histiocytosis, and provides guidance for the clinical management of this emerging histiocytic entity.

Leveraging internet search data to assess prevalence, interest, and unmet needs of sarcoidosis in Germany

Sarcoidosis is a multisystemic disease of connective tissue with granuloma formation of unknown etiology and unclear prevalence. Internet search data has been shown to correlate with disease incidences and the population’s interest as well as seasonal variations. Accordingly, aim of this study was to leverage internet search data on sarcoidosis-related keywords to identify unmet needs, geographical and seasonal factors influencing sarcoidosis and estimating its prevalence. In this retrospective longitudinal study, Google Ads Keyword Planner was used to determine the internet search volume of terms related to sarcoidosis across Germany as a whole and in 17 major German cities between July 2015 and June 2019. Identified keywords were qualitatively categorized, converted into number of searches per 100,000 inhabitants and analyzed including regional and seasonal differences. With 3,068,200 queries and 425 different sarcoidosis-related search terms in the studied time period, the search volume was very high for a rare disease. Most searches (67.9%) related to general disease information with “sarcoidosis”, "Löfgren's syndrome", "sarcoidosis lung", "Morbus Boeck" and "neurosarcoidosis" as the top five keywords. Searches per 100,000 inhabitants were comparable in all 17 cities but higher than in Germany as a whole. Overall, the search volume increased from 2015 to 2019 and peaked annually in European springtime with annual lows in European autumn and winter months. The overall high search volume suggests an unmet need for sarcoidosis-related information and a diagnostic gap. Seasonal fluctuations indicate environmental as well as climatic factors that may influence sarcoidosis.

Neuroradiological findings in Alagille syndrome

Alagille syndrome (ALGS) is a multisystemic disease caused by mutations in genes of Notch pathway, which regulates embryonic cell differentiation and angiogenesis. Clinically, ALGS is characterized by cholestasis, cardiac defects, characteristic facial features, skeletal and ophthalmologic abnormalities. The aim of this review is to illustrate neuroradiological findings in ALGS, which are less well-known and prevalent, including cerebrovascular anomalies (such as aneurysms, dolichoectasia, Moyamoya syndrome and venous peculiarities), Chiari 1 malformation, craniosynostosis, intracranial hypertension, and vertebral anomalies (namely butterfly vertebra, hemivertebra, and craniocervical junction anomalies). Rarer cerebral midline malformations and temporal bone anomalies have also been described.