Degree of COVID-19 severity and mortality in stroke: correlation of clinical and laboratory parameters.

BACKGROUND: Stroke is one of the neurological manifestations of COVID-19, leading to a significant risk of morbidity and mortality. Clinical manifestations and laboratory parameters were investigated to determine mortality predictors in this case. METHOD: The case control study was conducted at Dr. Sardjito General Hospital,Yogyakarta, Indonesia, with data collected between July 2020 and August 2021. All recorded clinical and laboratory data from acute stroke patients with confirmed COVID-19 were collected. Baseline characteristics, bivariate, and multivariate analyses were assessed to determine significant predictors for mortality. RESULT: This study involved 72 subjects with COVID-19 and stroke. The majority experienced ischemic stroke, with hypertension as the most prevalent comorbidity. Notably, 45.8% of subjects (p < 0.05) loss of consciousness and 72.2% of exhibited motor deficits (p < 0.05). Severe degree of COVID-19 was observed in 52.8% of patients, with respiratory distress and death rates of 56.9% and 58.3%. Comparison of surviving and deceased groups highlighted significant differences in various clinical and laboratory characteristics differences. Hazard ratio (HR) analysis identified loss of consciousness (HR = 2.68; p = 0.01), motor deficit (HR = 2.34; p = 0.03), respiratory distress (HR = 81.51; p < 0.001), and monocyte count (HR:1.002; p = 0.04) as significant predictors of mortality. CONCLUSION: Mortality in COVID-19 patients with stroke was significantly associated with loss of consciousness, motor deficit, respiratory distress, and raised monocyte count. The risk of mortality is heightened when multiple factors coexist.

Concomitant Cerebral Venous Thrombosis and Intracranial Hemorrhages in Presentation of a Patient with Secondary Polycythemia: A Case Report.

BACKGROUND Cerebral ischemia and hemorrhages were reported to be the main complications of polycythemia vera (PV). The relationship between PV and increased risk of the cerebrovascular events has been established. Some patients with secondary polycythemia have thromboembolic events comparable to those of PV. However, secondary polycythemia that leads to cerebrovascular events is uncommon. CASE REPORT A 35-year-old man without any prior medical history presented with mild clinical acute ischemic stroke and polycythemia. The patient then showed worsening neurological deficits that were later attributed to the concurrent cerebral venous thrombosis, which led to malignant cerebral infarction with hemorrhagic transformation, and subarachnoid hemorrhage. His polycythemia appeared to be secondary to bacterial infection. The treatments for the secondary polycythemia were first phlebotomy and intravenous hydration, followed by intravenous broad-spectrum antibiotics. PV was excluded because the JAK2 V617F mutation was absent, the patient's peripheral blood smear suggested secondary polycythemia due to bacterial infection, and there were improvements in hemoglobin, erythrocyte count, and hematocrit after intravenous antibiotics. At the 1-month follow-up, he was moderately dependent, and hemoglobin, erythrocyte count, and hematocrit were within normal limits, without receiving any further phlebotomy or cytoreductive agents. CONCLUSIONS This case highlights the plausible causation of secondary polycythemia that could lead to concomitant cerebral thrombosis and hemorrhagic events. The diagnosis of cerebral venous thrombosis should be considered in a patient who presents with headache, focal neurological deficits, polycythemia, and normal head computed tomography scan.

Severe Abdominal Pain and Multi-Organ Involvement in a Young Woman With Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by diverse clinical manifestations and a broad spectrum of disease course and prognosis. Often presenting over an extended period, delays in diagnosis can significantly influence patient management and survival, particularly when faced with rare complications such as digestive system manifestations. This case report uniquely highlights the diagnostic and therapeutic challenges posed by severe abdominal pain in a young woman suspected of SLE, with a symptom often masked by steroid therapy or immunosuppression. The diagnostic journey, which led to the identification of SLE as the cause of abdominal pain, involved differentiating SLE from various abdominal pathologies including abdominal vasculitis, gastrointestinal syndrome, antiphospholipid antibody syndrome, pancreatitis, urinary tract infections, and obstetric-gynecological abnormalities. This case underlines the critical need for accurate, timely diagnosis, and targeted therapy in managing SLE, emphasizing the potential implications of such complexities on patient outcomes.

Recurrent Reversible Stroke-Like Encephalopathy After 5-Fluorouracil (5-FU) Chemotherapy: A Case Report and Literature Review.

BACKGROUND Chemotherapy based on 5-fluorouracil (5-FU) is a well-established treatment for solid cancers, including metastatic or advanced colon cancer. Despite its efficacy, 5-FU can cause rare but serious adverse events such as acute neurotoxicity, which presents as symptoms similar to stroke. CASE REPORT We report the case of a patient who was diagnosed with stage IV colorectal cancer and who underwent chemotherapy with a high dose of 5-FU as part of the FOLFIRI (Folinic Acid, Fluorouracil, Irinotecan) treatment plan. During the seventh, eighth, and ninth cycles of chemotherapy, the patient suffered from severe encephalopathy, and the cause of this condition was determined to the 46-hour continuous intravenous infusion of 5-FU, which was part of the FOLFIRI regimen. CONCLUSIONS 5-FU-induced hyperammonemic encephalopathy is a rare but serious adverse event that requires immediate recognition and treatment. The first step in managing this condition is to halt the 5-FU infusion and provide the patient with high volumes of fluid. Although most cases of 5-FU-induced encephalopathy resolve spontaneously, recurrence is possible if the drug is re-administered to the same patient. Therefore, it is crucial for healthcare providers to closely monitor patients receiving 5-FU chemotherapy and be aware of the signs and symptoms of hyperammonemic encephalopathy. Early intervention can prevent further complications and ensure the best possible outcome for the patient. It is important to note that while 5-FU-induced hyperammonemic encephalopathy is rare, it highlights the importance of closely monitoring patients receiving chemotherapy to identify and treat adverse events promptly. This can help improve patient outcomes and prevent serious long-term complications.

ChGn-2 Plays a Cardioprotective Role in Heart Failure Caused by Acute Pressure Overload.

Background Cardiac extracellular matrix is critically involved in cardiac homeostasis, and accumulation of chondroitin sulfate glycosaminoglycans (CS-GAGs) was previously shown to exacerbate heart failure by augmenting inflammation and fibrosis at the chronic phase. However, the mechanism by which CS-GAGs affect cardiac functions remains unclear, especially at the acute phase. Methods and Results We explored a role of CS-GAG in heart failure using mice with target deletion of ChGn-2 (chondroitin sulfate N-acetylgalactosaminyltransferase-2) that elongates CS chains of glycosaminoglycans. Heart failure was induced by transverse aortic constriction in mice. The role of CS-GAG derived from cardiac fibroblasts in cardiomyocyte death was analyzed. Cardiac fibroblasts were subjected to cyclic mechanical stretch that mimics increased workload in the heart. Significant CS-GAGs accumulation was detected in the heart of wild-type mice after transverse aortic constriction, which was substantially reduced in ChGn-2-/- mice. Loss of ChGn-2 deteriorated the cardiac dysfunction caused by pressure overload, accompanied by augmented cardiac hypertrophy and increased cardiomyocyte apoptosis. Cyclic mechanical stretch increased ChGn-2 expression and enhanced glycosaminoglycan production in cardiac fibroblasts. Conditioned medium derived from the stretched cardiac fibroblasts showed cardioprotective effects, which was abolished by CS-GAGs degradation. We found that CS-GAGs elicits cardioprotective effects via dual pathway; direct pathway through interaction with CD44, and indirect pathway through binding to and activating insulin-like growth factor-1. Conclusions Our data revealed the cardioprotective effects of CS-GAGs; therefore, CS-GAGs may play biphasic role in the development of heart failure; cardioprotective role at acute phase despite its possible unfavorable role in the advanced phase.

Publisher Correction: Endothelial progeria induces adipose tissue senescence and impairs insulin sensitivity through senescence associated secretory phenotype.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Loss of Family with Sequence Similarity 13, Member A Exacerbates Pulmonary Fibrosis Potentially by Promoting Epithelial to Mesenchymal Transition.

Idiopathic pulmonary fibrosis (IPF) is a devastating disease with poor prognosis due to limited clinical treatment options. IPF is characterized by the augmented deposition of extracellular matrix driven by myofibroblasts, and the epithelial-mesenchymal transition (EMT) has been known to play an essential role in the mechanism of pulmonary fibrosis. Previous genome-wide association study identified Fam13a as one of genes that showed genetic link with IPF and chronic obstructive pulmonary disease. Here, we analyzed the role of Fam13a in the pathogenesis of pulmonary fibrosis using Fam13a-deficient mice. We found that Fam13a was down-regulated in mouse lungs of bleomycin-induced pulmonary fibrosis model. Of note, genetic deletion of Fam13a exacerbated the lung fibrosis induced by bleomycin in association with enhanced EMT in mice. Moreover, silencing of Fam13a accelerated EMT induced by TGF-ß and TNF-α in alveolar epithelial cells, accompanied by increased active ß-catenin and its nuclear accumulation. Our data revealed a crucial role of Fam13a in the development of pulmonary fibrosis potentially through inhibiting EMT, and thus Fam13a has a therapeutic potential in the treatment of IPF.

Endothelial progeria induces adipose tissue senescence and impairs insulin sensitivity through senescence associated secretory phenotype.

Vascular senescence is thought to play a crucial role in an ageing-associated decline of organ functions; however, whether vascular senescence is causally implicated in age-related disease remains unclear. Here we show that endothelial cell (EC) senescence induces metabolic disorders through the senescence-associated secretory phenotype. Senescence-messaging secretomes from senescent ECs induced a senescence-like state and reduced insulin receptor substrate-1 in adipocytes, which thereby impaired insulin signaling. We generated EC-specific progeroid mice that overexpressed the dominant negative form of telomeric repeat-binding factor 2 under the control of the Tie2 promoter. EC-specific progeria impaired systemic metabolic health in mice in association with adipose tissue dysfunction even while consuming normal chow. Notably, shared circulation with EC-specific progeroid mice by parabiosis sufficiently transmitted the metabolic disorders into wild-type recipient mice. Our data provides direct evidence that EC senescence impairs systemic metabolic health, and thus establishes EC senescence as a bona fide risk for age-related metabolic disease.

Activation of neuregulin-4 in adipocytes improves metabolic health by enhancing adipose tissue angiogenesis.

Obesity often causes systemic metabolic disorders in close association with adipose tissue dysfunction. Adipose tissue contains well-developed vasculatures, and obesity mediates vascular rarefaction that causes hypoxia and triggers inflammation in adipose tissue. Adipose tissue-derived neuregulin-4 (Nrg4) is an immerging factor that is critically involved in metabolic homeostasis. We recently identified that Nrg4 is an angiogenic adipokine that plays an important role in maintaining adipose tissue vasculature. Here, we further validated its beneficial role in metabolic health primarily by enhancing adipose tissue angiogenesis. Targeted activation of Nrg4 in adipocytes improved metabolic health in mice under both normal and high fat dietary condition without changes in body weight. Activation of Nrg4 increased blood vessels in white adipose tissue, and ameliorated adipose tissue hypoxia under obese condition. Of note, inhibition of angiogenesis by sugen-treatment abolished the beneficial effects of Nrg4 on systemic metabolic health. Furthermore, targeted inhibition of Nrg4-ErbB signaling in adipose tissue vasculature using prohibitin binding peptide-conjugated nanocarrier abrogated the enhanced adipose tissue angiogenesis, and canceled the improved metabolic health induced by Nrg4 activation. These data further support a crucial role of Nrg4 in maintaining systemic metabolic homeostasis at least partially through enhancing adipose tissue angiogenesis.

Neuregulin-4 is an angiogenic factor that is critically involved in the maintenance of adipose tissue vasculature.

Adipose tissue (AT) contains well-developed vascular networks. Pathological AT expansion often accompany the reduction in AT blood vessels, which further exacerbates adipocyte dysfunction due to hypoxia; however, it remains unclear whether AT vascular rarefaction is simply secondary to adipocyte hypertrophy, or if there is an actively regulated pathway that mediates impaired AT angiogenesis in obesity. We searched for growth factors whose expression in AT is down-regulated in obesity; accordingly, we identified neuregulin-4 (Nrg4), a member of the EGF family of proteins. Nrg4 is highly and preferentially expressed in healthy adipocytes, while its expression was substantially reduced in obesity. Nrg4 activated endothelial angiogenic functions and angiogenesis both in vitro and in vivo. Genetic loss of Nrg4 caused reduction in brown and white AT blood vessels, and induced overweight even while consuming normal chow. Conditional knockout of Nrg4 in brown adipocytes caused blood vessel reduction in brown but not in white AT, and was sufficient to induce obese phenotype. Our data demonstrated that Nrg4 plays a critical role in maintaining AT vasculature and its metabolic functions. Considering the substantial reduction of Nrg4 in obesity, disruption of Nrg4-mediated angiogenesis could be an active mechanism for the obesity-associated vascular rarefaction in AT, and thus Nrg4 is an attracting pharmacotherapeutic target in the prevention and/or treatment of obesity-related metabolic disorders.

Systemic inhibition of Janus kinase induces browning of white adipose tissue and ameliorates obesity-related metabolic disorders.

Browning of white adipose tissue is a promising strategy to tackle obesity. Recently, Janus kinase (JAK) inhibition was shown to induce white-to-brown metabolic conversion of adipocytes in vitro; however effects of JAK inhibition on browning and systemic metabolic health in vivo remain to be elucidated. Here, we report that systemic administration of JAK inhibitor (JAKi) ameliorated obesity-related metabolic disorders. Administration of JAKi in mice fed a high-fat diet increased UCP-1 and PRDM16 expression in white adipose tissue, indicating the browning of white adipocyte. Food intake was increased in JAKi-treated mice, while the body weight and adiposity was similar between the JAKi- and vehicle-treated mice. In consistent with the browning, thermogenic capacity was enhanced in mice treated with JAKi. Chronic inflammation in white adipose tissue was not ameliorated by JAKi-treatment. Nevertheless, insulin sensitivity was well preserved in JAKi-treated mice comparing with that in vehicle-treated mice. Serum levels of triglyceride and free fatty acid were significantly reduced by JAKi-treatment, which is accompanied by ameliorated hepatosteatosis. Our data demonstrate that systemic administration of JAKi has beneficial effects in preserving metabolic health, and thus inhibition of JAK signaling has therapeutic potential for the treatment of obesity and its-related metabolic disorders.

Family with sequence similarity 13, member A modulates adipocyte insulin signaling and preserves systemic metabolic homeostasis.

Adipose tissue dysfunction is causally implicated in the impaired metabolic homeostasis associated with obesity; however, detailed mechanisms underlying dysregulated adipocyte functions in obesity remain to be elucidated. Here we searched for genes that provide a previously unknown mechanism in adipocyte metabolic functions and identified family with sequence similarity 13, member A (Fam13a) as a factor that modifies insulin signal cascade in adipocytes. Fam13a was highly expressed in adipose tissue, predominantly in mature adipocytes, and its expression was substantially reduced in adipose tissues of obese compared with lean mice. We revealed that Fam13a accentuated insulin signaling by recruiting protein phosphatase 2A with insulin receptor substrate 1 (IRS1), leading to protection of IRS1 from proteasomal degradation. We further demonstrated that genetic loss of Fam13a exacerbated obesity-related metabolic disorders, while targeted activation of Fam13a in adipocytes ameliorated it in association with altered adipose tissue insulin sensitivity in mice. Our data unveiled a previously unknown mechanism in the regulation of adipocyte insulin signaling by Fam13a and identified its significant role in systemic metabolic homeostasis, shedding light on Fam13a as a pharmacotherapeutic target to treat obesity-related metabolic disorders.