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Chemistry & Biodiversity Jun 2024Acute lung injury (ALI) is a prevalent organ injury in sepsis, characterized by an inflammatory reactive disorder. Both the incidence and mortality rates of ALI have...
Acute lung injury (ALI) is a prevalent organ injury in sepsis, characterized by an inflammatory reactive disorder. Both the incidence and mortality rates of ALI have been steadily increasing. Isothiazolinone derivatives have displayed anti-inflammatory activity and have shown effectiveness in treating pneumonia. The objective of the study is to assess the effects and mechanisms of the isothiazolinone derivative 4-benzoyl-2-butyl-5-(ethylsulfinyl)isothiazol-3(2H)-one (C6) on sepsis-induced ALI. The analysis of biological function and signal pathway enrichment demonstrated that C6 primarily exhibited anti-inflammatory effects. Administration of different doses of C6 through intraperitoneal injection significantly improved the survival rate, body temperature, and body mass of mice with ALI induced by cecal ligation and puncture (CLP). Additionally, it mitigated lung tissue injury, pulmonary edema, lung permeability, inflammatory cell infiltration, apoptosis, and the expression of inflammatory cytokines. Network targeting analysis and experimental validation in mouse leukemia cells of monocyte macrophage (RAW264.7) cells and CLP-induced ALI mice revealed that the anti-inflammatory effect of C6 was mediated by the inhibition of the PI3K-AKT signaling pathway. The research suggest that C6 has protective effects against ALI by inhibiting the phosphatidylinositol 3 kinase -protein kinase B (PI3K-AKT) signaling pathway. This information could be valuable in developing potential treatments for ALI.
PubMed: 38924251
DOI: 10.1002/cbdv.202400892 -
Prenatal Diagnosis Jun 2024Exome sequencing in prenatal context confronts with pathogenic variants associated with phenotypes that are not detectable prenatally.
BACKGROUND
Exome sequencing in prenatal context confronts with pathogenic variants associated with phenotypes that are not detectable prenatally.
MATERIALS AND METHODS
A consanguineous couple was referred at 24 weeks of gestation for prenatal genetic investigations after ultrasonography findings including decreased fetal movements, hypoplastic male external genitalia, retrognathia, prefrontal edema, anomalies of the great vessels with pulmonary atresia and dilated tortuous aorta.
RESULT
Prenatal trio exome sequencing identified two homozygous likely pathogenic variants, i.e. a missense in EFEMP2 involved in cutis laxa and a nonsense in RAG1 involved in several types of severe combined immunodeficiency.
DISCUSSION
The fetal ultrasonographic phenotype was partially compatible with previously reported prenatal presentations secondary to EFEMP2 biallelic variants, but prenatal presentations have never been reported for RAG1 related disorders because the RAG1 phenotype is undetectable during pregnancy.
CONCLUSION
Both EFEMP2 and RAG1 variants were disclosed to the couple because the EFEMP2 variant was considered causative for the fetal ultrasonographic phenotype and the RAG1 variant was considered a finding of strong interest for genetic counselling and monitoring of future pregnancies following the American College of Medical Genetics and Genomics recommendations about the discovery of incidental findings in fetal exome sequencing in prenatal diagnosis.
PubMed: 38923535
DOI: 10.1002/pd.6629 -
Hospital Pharmacy Aug 2024Naloxone, an opioid receptor antagonist, effectively reverses opioid overdose and opioid-induced respiratory depression. A few side effects were reported after naloxone...
Naloxone, an opioid receptor antagonist, effectively reverses opioid overdose and opioid-induced respiratory depression. A few side effects were reported after naloxone administration, including arrhythmia and pulmonary edema. Although rare, naloxone-induced pulmonary edema can be a severe and sometimes life-threatening complication requiring mechanical ventilation. This condition is predominantly linked to an upsurge in catecholamines after opioid reversal as part of acute withdrawal syndrome, especially seen in patients who chronically use opioids. In this report, we present a case of a 66-year-old patient who developed pulmonary edema following the administration of multiple doses of intravenous and intranasal naloxone for opioid overdose. This case highlights the potential adverse effects associated with naloxone use and discusses how to employ this life-saving medication with minimal side effects.
PubMed: 38919766
DOI: 10.1177/00185787241230074 -
Frontiers in Aging Neuroscience 2024Necroptosis is implicated in the pathogenesis of ischemic stroke. However, the mechanism underlying the sequential recruitment of receptor-interacting protein kinase 1...
Necroptosis is implicated in the pathogenesis of ischemic stroke. However, the mechanism underlying the sequential recruitment of receptor-interacting protein kinase 1 (RIPK1) and N-ethylmaleimide-sensitive fusion ATPase (NSF) in initiating necroptosis remains poorly understood, and the role of NSF in ischemic stroke is a subject of controversy. Here, we utilized a recently emerging RNA-targeting CRISPR system known as CasRx, delivered by AAVs, to knockdown mRNA and mRNA around the ischemic brain tissue. This approach resulted in a reduction in infarct and edema volume, as well as an improvement in neurological deficits assessed by Bederson score, RotaRod test, and Adhesive removal test, which were achieved by RIPK1/receptor-interacting protein kinase 3/mixed lineage kinase domain-like protein signaling pathway involved in neuronal necroptosis. In conclusion, the downregulation of mRNA and mRNA mediated by CRISPR-CasRx holds promise for future therapeutic applications aimed at ameliorating cerebral lesions and neurological deficits following the ischemic stroke.
PubMed: 38919602
DOI: 10.3389/fnagi.2024.1401038 -
European Heart Journal. Case Reports Jun 2024There is limited evidence for the use of an intra-aortic balloon pump (IABP) in adult patients with a total cavopulmonary, or Fontan circulation.
BACKGROUND
There is limited evidence for the use of an intra-aortic balloon pump (IABP) in adult patients with a total cavopulmonary, or Fontan circulation.
CASE SUMMARY
A patient in his twenties with a Fontan circulation presented with sepsis, pneumonia, and pulmonary oedema. He was born with a hypoplastic left ventricle, atrioventricular septal defect, and hypoplastic aortic arch, and a total cavopulmonary circulation had been established within his first years of life. Standard of care treatment with antibiotics, non-invasive ventilatory support, loop diuretics, and vasopressors was initiated. Due to persistent pulmonary congestion and increasing general fatigue, an IABP was placed via a femoral artery to offload the failing systemic ventricle. Secondary to IABP treatment, mean arterial pressure rose, and vasodilatory nitroprusside could be introduced. Over 4 days of IABP treatment, the patient's general condition and ventricular systolic function improved significantly.
DISCUSSION
This case suggests that IABP treatment was important in the recovery of our patient with a Fontan circulation, pneumonia, and heart failure. We propose that during IABP treatment, an increase in stroke volume and a reduction in ventricular filling pressure is achieved, thereby increasing the transpulmonary pressure gradient that is central to pulmonary blood flow in Fontan patients. More definitive evidence is necessary to confirm our hypotheses.
PubMed: 38912116
DOI: 10.1093/ehjcr/ytae289 -
Pulmonary Circulation Apr 2024Pulmonary hypertension (PH) adds a substantial disease burden, including higher mortality, when associated with interstitial lung disease (ILD), a severe, chronic,...
Pulmonary hypertension (PH) adds a substantial disease burden, including higher mortality, when associated with interstitial lung disease (ILD), a severe, chronic, progressive condition. Yet little is known of the lived experiences, perspectives, priorities, and viewpoints of patients and carers living with PH-ILD. The Voice of the Patient meeting at the center of this qualitative research study aims to provide these difficult-to-obtain insights from a European perspective for the first time. The multistakeholder approach brought together four PH-ILD patients, three primary caregivers, two patient associations, clinical experts, sponsor representatives, and a facilitator. Of the six major themes identified in the thematic analysis, symptoms, and physical limitations were the most impactful. Shortness of breath was the most bothersome symptom affecting patients daily. Further symptoms included fatigue, cough, dizziness, syncope, edema, and palpitations. Physical limitations focused on reduced mobility, impacting patients' ability to perform daily tasks, hobbies, sports, and to enjoy travel. Existing antifibrotic and pulmonary arterial hypertension-targeted treatments were perceived as beneficial. However, despite advances in treatment, severe disease burdens and high unmet medical needs persist from the perspectives of patients. Most meaningful to patients' daily wellbeing was supplemental oxygen, enabling greater mobility. Patients and carers reported difficulties and barriers in navigating the healthcare system and obtaining adequate information to reduce their considerable uncertainties, documenting the substantial challenges that rare and complex conditions such as PH-ILD pose for routine clinical practice beyond PH expert centers and indicating an urgent need for high-quality patient- and clinician-directed information to support patient-centered care.
PubMed: 38911184
DOI: 10.1002/pul2.12405 -
Cardio-oncology (London, England) Jun 2024The anthracycline doxorubicin (DOX) is a highly effective anticancer agent, especially in breast cancer and lymphoma. However, DOX can cause cancer therapy-related...
BACKGROUND
The anthracycline doxorubicin (DOX) is a highly effective anticancer agent, especially in breast cancer and lymphoma. However, DOX can cause cancer therapy-related cardiovascular toxicity (CTR-CVT) in patients during treatment and in survivors. Current diagnostic criteria for CTR-CVT focus mainly on left ventricular systolic dysfunction, but a certain level of damage is required before it can be detected. As diastolic dysfunction often precedes systolic dysfunction, the current study aimed to identify functional and molecular markers of DOX-induced CTR-CVT with a focus on diastolic dysfunction.
METHODS
Male C57BL/6J mice were treated with saline or DOX (4 mg/kg, weekly i.p. injection) for 2 and 6 weeks (respectively cumulative dose of 8 and 24 mg/kg) (n = 8 per group at each time point). Cardiovascular function was longitudinally investigated using echocardiography and invasive left ventricular pressure measurements. Subsequently, at both timepoints, myocardial tissue was obtained for proteomics (liquid-chromatography with mass-spectrometry). A cohort of patients with CTR-CVT was used to complement the pre-clinical findings.
RESULTS
DOX-induced a reduction in left ventricular ejection fraction from 72 ± 2% to 55 ± 1% after 2 weeks (cumulative 8 mg/kg DOX). Diastolic dysfunction was demonstrated as prolonged relaxation (increased tau) and heart failure was evident from pulmonary edema after 6 weeks (cumulative 24 mg/kg DOX). Myocardial proteomic analysis revealed an increased expression of 12 proteins at week 6, with notable upregulation of SERPINA3N in the DOX-treated animals. The human ortholog SERPINA3 has previously been suggested as a marker in CTR-CVT. Upregulation of SERPINA3N was confirmed by western blot, immunohistochemistry, and qPCR in murine hearts. Thereby, SERPINA3N was most abundant in the endothelial cells. In patients, circulating SERPINA3 was increased in plasma of CTR-CVT patients but not in cardiac biopsies.
CONCLUSION
We showed that mice develop heart failure with impaired systolic and diastolic function as result of DOX treatment. Additionally, we could identify increased SERPINA3 levels in the mice as well as patients with DOX-induced CVT and demonstrated expression of SERPINA3 in the heart itself, suggesting that SERPINA3 could serve as a novel biomarker.
PubMed: 38909263
DOI: 10.1186/s40959-024-00241-1 -
Cell & Bioscience Jun 2024Clinical outcome after traumatic brain injury (TBI) is closely associated conditions of other organs, especially lungs as well as degree of brain injury. Even if there... (Review)
Review
Clinical outcome after traumatic brain injury (TBI) is closely associated conditions of other organs, especially lungs as well as degree of brain injury. Even if there is no direct lung damage, severe brain injury can enhance sympathetic tones on blood vessels and vascular resistance, resulting in neurogenic pulmonary edema. Conversely, lung damage can worsen brain damage by dysregulating immunity. These findings suggest the importance of brain-lung axis interactions in TBI. However, little research has been conducted on the topic. An advanced disease model using stem cell technology may be an alternative for investigating the brain and lungs simultaneously but separately, as they can be potential candidates for improving the clinical outcomes of TBI.In this review, we describe the importance of brain-lung axis interactions in TBI by focusing on the concepts and reproducibility of brain and lung organoids in vitro. We also summarize recent research using pluripotent stem cell-derived brain organoids and their preclinical applications in various brain disease conditions and explore how they mimic the brain-lung axis. Reviewing the current status and discussing the limitations and potential perspectives in organoid research may offer a better understanding of pathophysiological interactions between the brain and lung after TBI.
PubMed: 38909262
DOI: 10.1186/s13578-024-01252-2 -
Medicina 2024Takotsubo syndrome, was described in Japan in 1990, it is a stress cardiomyopathy, predominantly in women, usually postmenopausal. Cardiac hypokinesia occurs, with...
Takotsubo syndrome, was described in Japan in 1990, it is a stress cardiomyopathy, predominantly in women, usually postmenopausal. Cardiac hypokinesia occurs, with involvement of multiple coronary territories. In intensive care unit (ICU), it is considered underdiagnosed. Manifestations of severe dengue fever include cardiovascular involvement, mainly arrhythmias and systolic dysfunction. A case of a 72-year-old man is presented, who was hospitalized in ICU for dengue fever, with plateletopenia (15000 cells/mm3) and dehydration. After fluid management the patient reported respiratory discomfort, auscultating crackling rales. A pulmonary ultrasound was made where bilateral B lines were found with B7 pattern compatible with interstitial syndrome and pulmonary edema. Basal hyperkinesia, medial and apical hypokinesia with an image consistent with apical ballooning were observed in the transthoracic echocardiogram. The electrocardiogram showed complete right bundle branch block. Chagas serology was negative and quantitative troponin I was increased. In the context of severe dengue, a Takotsubo syndrome was diagnosed. The patient evolved favorably. After discharge, a normalization of the cardiac function was stated in ultrasound images. The case is of clinical importance due to the low association of these two diseases and the need to screen for cardiac involvement in severe dengue.
Topics: Humans; Takotsubo Cardiomyopathy; Aged; Male; Dengue; Electrocardiography; Severe Dengue; Echocardiography
PubMed: 38907979
DOI: No ID Found -
Cureus May 2024The Gerbode defect is a rare ventricular septal defect (VSD) between the left ventricle (LV) and right atrium (RA). We describe a challenging case of a rare acquired...
The Gerbode defect is a rare ventricular septal defect (VSD) between the left ventricle (LV) and right atrium (RA). We describe a challenging case of a rare acquired Gerbode defect from infective endocarditis. A 73-year-old male presented for left lower extremity edema and shortness of breath with exertion. He was discharged from the hospital one week prior after being diagnosed with right hip septic arthritis. A transthoracic echocardiogram (TTE) did not demonstrate an abscess or vegetation, but was significant for severely elevated tricuspid regurgitation velocity and pulmonary artery (PA) systolic pressure of 70 mm Hg without structural changes to the right ventricle or RA. A transesophageal echocardiogram (TEE) was performed due to these abnormal values and demonstrated a VSD between the LV and RA. This type of defect is known as a Gerbode defect, which is suggestive of an aortic root abscess. The patient ultimately was transferred to a tertiary care center, and the Gerbode defect with aortic root abscess was confirmed by direct visualization. This case reports a unique case of an acquired Gerbode defect secondary to infective endocarditis. Our patient's defect was noted to be above the tricuspid valve, which essentially confirmed the etiology as a VSD. Although the TEE did not demonstrate a clear aortic root abscess, direct visualization during the surgical intervention confirmed this suspicion. Prompt diagnosis of the Gerbode defect allowed the patient to receive urgent surgical intervention. Gerbode defects are rare but clinically important complications of infective endocarditis. This case highlights the importance of maintaining a high level of suspicion, especially if the values obtained during TTE do not fully explain a patient's clinical presentation. A high level of suspicion leading to a timely diagnosis of this condition is essential in preventing further valvular destruction and allowing prompt surgical intervention.
PubMed: 38903337
DOI: 10.7759/cureus.60677