Severe Form Research Articles

A Severe Form of Atypical Hemolytic Uremic Syndrome in a Two-Year-Old Girl: A Case Report

A Severe Form of Atypical Hemolytic Uremic Syndrome in a Two-Year-Old Girl: A Case Report

Biomechanical activation of keloid fibroblasts promotes lysosomal remodelling and exocytosis.

Keloids are a severe form of scarring for which the underlying mechanisms are poorly understood, and treatment options are limited or inconsistent. While biomechanical forces are potential drivers of keloid scarring, the direct cellular responses to mechanical cues have yet to be defined. The aim of this study was to examine the distinct responses of normal dermal fibroblasts (NDFs) and keloid-derived fibroblasts (KDFs) to changes in extracellular matrix (ECM) stiffness. When cultured on hydrogels mimicking the elasticity of normal or scarred skin, KDFs displayed greater stiffness-dependent increases in cell spreading, F-actin stress fibre formation, and focal adhesion assembly. Elevated acto-myosin contractility in KDFs disrupted the normal mechanical regulation of ECM deposition and conferred resistance myosin inhibitors. Transcriptional profiling identified mechanically-regulated pathways in NDFs and KDFs, including the actin cytoskeleton, Hippo signalling, and autophagy. Further analysis of the autophagy pathway revealed that autophagic flux was intact in both fibroblast populations and depended on acto-myosin contractility. However, KDFs displayed marked changes in lysosome organisation and an increase in lysosomal exocytosis, which was mediated by acto-myosin contractility. Together, these findings demonstrate that KDFs possess an intrinsic increase in cytoskeletal tension, which heightens the response to ECM mechanics and promotes lysosomal exocytosis.

Management of the Devastated Bladder Outlet after Prostate CANCER Treatment.

Devastating complications of the bladder outlet resulting from prostate cancer treatments are relatively uncommon. However, the combination of the high incidence of prostate cancer and patient longevity after treatment have raised awareness of adverse outcomes deteriorating patients' quality of life. This narrative review discusses the diagnostic work-up and management options for bladder outlet obstruction resulting from prostate cancer treatments, including those that require urinary diversion. The devastated bladder outlet can be a consequence of the treatment of benign conditions, but more frequently from complications of pelvic cancer treatments. Regardless of etiology, the initial treatment ladder involves endoluminal options such as dilation and direct vision internal urethrotomy, with or without intralesional injection of anti-fibrotic agents. If these conservative strategies fail, surgical reconstruction should be considered. Although surgical reconstruction provides the best prospect of durable success, reconstructive procedures are also associated with serious complications. In the worst circumstances, such as prior radiotherapy, failed reconstruction, devastated bladder outlet with end-stage bladders, or patient's severe comorbidities, reconstruction may neither be realistic nor justified. Urinary diversion with or without cystectomy may be the best option for these patients. Thorough patient counseling before treatment selection is of utmost importance. Outcomes and repercussions on quality of life vary extensively with management options. Meticulous preoperative diagnostic evaluation is paramount in selecting the right treatment strategy for each individual patient. The risk of bladder outlet obstruction, and its severest form, devastated bladder outlet, after treatment of prostate cancer is not negligible, especially following radiation. Management includes endoluminal treatment, open or robot-assisted laparoscopic reconstruction, and urinary diversion in the worst circumstances, with varying success rates.

Genomic analysis of severe COVID-19 considering or not asthma comorbidity: GWAS insights from the BQC19 cohort

BackgroundThe severity of COVID-19 is influenced by various factors including the presence of respiratory diseases. Studies have indicated a potential relationship between asthma and COVID-19 severity.ObjectiveThis study aimed to conduct a genome-wide association study (GWAS) to identify genetic and clinical variants associated with the severity of COVID-19, both among patients with and without asthma.MethodsWe analyzed data from 2131 samples sourced from the Biobanque québécoise de la COVID-19 (BQC19), with 1499 samples from patients who tested positive for COVID-19. Among these, 1110 exhibited mild-to-moderate symptoms, 389 had severe symptoms, and 58 had asthma. We conducted a comparative analysis of clinical data from individuals in these three groups and GWAS using a logistic regression model. Phenotypic data analysis resulted in the refined covariates integrated into logistic models for genetic studies.ResultsConsidering a significance threshold of 1 × 10−6, seven genetic variants were associated with severe COVID-19. These variants were located proximal to five genes: sodium voltage-gated channel alpha subunit 1 (SCN10A), desmoplakin (DSP), RP1 axonemal microtubule associated (RP1), IGF like family member 1 (IGFL1), and docking protein 5 (DOK5). The GWAS comparing individuals with severe COVID-19 with asthma to those without asthma revealed four genetic variants in transmembrane protein with EGF like and two follistatin like domains 2 (TMEFF2) and huntingtin interacting protein-1 (HIP1) genes.ConclusionThis study provides significant insights into the genetic profiles of patients with severe forms of the disease, whether accompanied by asthma or not. These findings enhance our comprehension of the genetic factors that affect COVID-19 severity.Key messagesSeven genetic variants were associated with the severe form of COVID-19;Four genetic variants were associated with the severe form of COVID-19 in individuals with comorbid asthma;These findings help define the genetic component of the severe form of COVID-19 in relation to asthma as a comorbidity.

The efficacy of anterior vertebral body tethering in lenke type 6 curves for adolescent idiopathic scoliosis.

Spinal fusion is the standard treatment for severe forms of adolescent idiopathic scoliosis (AIS). However, with the lowest instrumented vertebra that is usually located at L3 or L4, patients are prone to develop adjacent segment degeneration in the long term. Vertebral body tethering (VBT) as motion preserving technique has become an alternative for select patients with AIS. Several studies have presented the outcome after thoracic VBT but no study has analyzed the outcome after VBT for Lenke type 6 curves. This is a retrospective single center data analysis of patients who have had bilateral VBT for Lenke type 6 curves and a minimum follow up of 24months. Radiographic analysis was performed on several time points. Suspected tether breakages were additionally analyzed with respect to location and time at occurrence. 25 patients were included. Immediate thoracic curve correction was 55.4% and 71.7% for TL/L curves. Loss of correction was higher for TL/L curves and resulted in a correction rate of 48.3% for thoracic curves and 48.9% for TL/L curves at 24months post-operatively. 22 patients were suspected to have at least one segment with a tether breakage. Three patients required a re-VBT but no patient received posterior spinal fusion. Bilateral VBT for Lenke type 6 curves is feasible and shows a significant curve correction for thoracic and TL/L curves at a minimum of 24months post-operatively. Tether breakage rate and loss of correction remain an unfavorable observation that needs to be improved in the future.

Peritoneal Dialysis-Induced Encapsulating Peritonitis: Diagnostic and Therapeutic Challenges in Women with Benign Gynecological Pathology

Background: Peritoneal sclerosis (PS) and its most severe form, encapsulating PS (EPS), are rare entities that can occur in various procedures (liver transplantation, intraperitoneal chemotherapy) or secondary to medications (beta-blockers); however, PS or EPS typically occur in patients undergoing peritoneal dialysis as a form of renal function substitution. Medical or surgical treatments can be applied, but morbidity and mortality have high rates. This condition typically presents clinically as an intestinal obstruction caused by the inclusion of the intestinal loops in the peritoneal fibrous membrane. Methods: Herein, we present data from a single tertiary surgery center that has dedicated teams for patients receiving dialysis. Over 12 years, we analyzed a group of 63 patients admitted for catheter replacement/removal or for acute surgical pathology. In five cases (7.9%), we diagnosed EPS. Two patients with EPS presented with atypical abdominal pathologies requiring emergency surgery: one case of hemoperitoneum caused by a ruptured ovarian cyst and one case of uterine fibroids and metrorrhagia. Results: The definitive diagnoses were established intraoperatively and by analyzing the morpho-pathological changes in the peritoneum. The possible intraoperative challenges included laborious dissection, difficulties in restoring the correct anatomical landmarks, an increased duration of the surgical intervention and a high rate of incidents and accidents. Conclusions: The aim of the present study was to emphasize the possibility of other surgical pathologies overlapping with EPS, increasing the complexity of the surgical intervention.

Tuberculosis-diabetes comorbidities: Mechanistic insights for clinical considerations and treatment challenges.

Tuberculosis (TB) remains a leading cause of death among infectious diseases, particularly in poor countries. Viral infections, multidrug-resistant and ex-tensively drug-resistant TB strains, as well as the coexistence of chronic illnesses such as diabetes mellitus (DM) greatly aggravate TB morbidity and mortality. DM [particularly type 2 DM (T2DM)] and TB have converged making their control even more challenging. Two contemporary global epidemics, TB-DM behaves like a syndemic, a synergistic confluence of two highly prevalent diseases. T2DM is a risk factor for developing more severe forms of multi-drug resistant-TB and TB recurrence after preventive treatment. Since a bidirectional relationship exists between TB and DM, it is necessary to concurrently treat both, and promote recommendations for the joint management of both diseases. There are also some drug-drug interactions resulting in adverse treatment outcomes in TB-DM patients including treatment failure, and reinfection. In addition, autophagy may play a role in these comorbidities. Therefore, the TB-DM comorbidities present several health challenges, requiring a focus on multidisciplinary collaboration and integrated strategies, to effectively deal with this double burden. To effectively manage the comorbidity, further screening in affected countries, more suitable drugs, and better treatment strategies are required.

Effects of ozone exposure on lung injury, inflammation, and oxidative stress in a murine model of non-pneumonic endotoxemia.

Recent studies have identified exposure to environmental levels of ozone as a risk factor for the development of acute respiratory distress syndrome (ARDS), a severe form of acute lung injury (ALI) that can develop in humans with sepsis. The aim of this study was to develop a murine model of ALI to mechanistically explore the impact of ozone exposure on ARDS development. Mice were exposed to ozone (0.8 ppm, 3 hr) or air control followed 24 hr later by intravenous administration of 3 mg/kg lipopolysaccharide (LPS) or PBS. Exposure of mice to ozone + LPS caused alveolar hyperplasia; increased BAL levels of albumin, IgM, phospholipids, and proinflammatory mediators including surfactant protein D and soluble receptor for advanced glycation end products were also detected in BAL, along with markers of oxidative and nitrosative stress. Administration of ozone + LPS resulted in an increase in neutrophils and anti-inflammatory macrophages in the lung, with no effects on proinflammatory macrophages. Conversely, numbers of resident alveolar macrophages decreased after ozone + LPS; however, expression of Nos2, Arg1, Cxcl1, Cxcl2, Ccl2 by these cells increased, indicating that they are activated. These findings demonstrate that ozone sensitizes the lung to respond to endotoxin, resulting in ALI, oxidative stress and exacerbated pulmonary inflammation, and provide support for the epidemiologic association between ozone exposure and ARDS incidence.

Pre-existing cell populations with cytotoxic activity against SARS-CoV-2 in people with HIV and normal CD4/CD8 ratio previously unexposed to the virus

IntroductionHIV-1 infection may produce a detrimental effect on the immune response. Early start of antiretroviral therapy (ART) is recommended to preserve the integrity of the immune system. In fact, people with HIV (PWH) and normal CD4/CD8 ratio appear not to be more susceptible to severe forms of COVID-19 than the general population and they usually present a good seroconversion rate in response to vaccination against SARS-CoV-2. However, few studies have fully characterized the development of cytotoxic immune populations in response to COVID-19 vaccination in these individuals.MethodsIn this study, we recruited PWH with median time of HIV-1 infection of 6 years, median CD4/CD8 ratio of 1.0, good adherence to ART, persistently undetectable viral load, and negative serology against SARS-CoV-2, who then received the complete vaccination schedule against COVID-19. Blood samples were taken before vaccination against COVID-19 and one month after receiving the complete vaccination schedule. ResultsPWH produced high levels of IgG against SARS-CoV-2 in response to vaccination that were comparable to healthy donors, with a significantly higher neutralization capacity. Interestingly, the cytotoxic activity of PBMCs from PWH against SARS-CoV-2-infected cells was higher than healthy donors before receiving the vaccination schedule, pointing out the pre-existence of activated cell populations with likely unspecific antiviral activity. The characterization of these cytotoxic cell populations revealed high levels of Tgd cells with degranulation capacity against SARS-CoV-2-infected cells. In response to vaccination, the degranulation capacity of CD8+ T cells also increased in PWH but not in healthy donors.DiscussionThe full vaccination schedule against COVID-19 did not modify the ability to respond against HIV-1-infected cells in PWH and these individuals did not show more susceptibility to breakthrough infection with SARS-CoV-2 than healthy donors after 12 months of follow-up. These results revealed the development of protective cell populations with broad-spectrum antiviral activity in PWH with normal CD4/CD8 ratio and confirmed the importance of early ART and treatment adherence to avoid immune dysfunctions.

On the issue of the effectiveness and bioequivalence of isotretinoin Lidose

BACKGROUND: Acne is one of the most common dermatoses. The most effective drug for the treatment of severe forms of acne is systemic isotretinoin, which affects all links in the pathogenesis of acne. The article presents scientific data on the innovative drug Aknecutan, which uses the patented Lidose technology in its production. The use of isotretinoin in the composition of innovative product with Lidose technology makes it possible to reduce the amount of isotretinoin taken by the patient by 20% without compromising the therapeutic effectiveness of the drug. AIM: to analyze comparative studies of bioavailability and relevant pharmacokinetic parameters, which made it possible to prove that the initial dosages of 8 and 16 mg with Lidose technology are bioequivalent to dosages of 10 and 20 mg of the usual form of isotretinoin. MATERIALS AND METHODS: Over the past 7 years, 1044 patients have received acne treatment for moderate to severe acne (651; 62.4% women and 393; 37.6% men) in a daily dose of 0.4–0.8 mg per 1 kg of body weight with a total dose of the drug ― 100–120 mg/kg per course of therapy. RESULTS: After therapy, clinical remission was achieved in all patients, which required from 7 to 12 months of treatment, depending on the daily dose of the drug. Among the side effects in all patients, cheilitis and retinoic dermatitis of the face were noted, which were completely resolved when using moisturizers and sticks. An increase in liver enzymes, triglycerides and lipoproteins was noted in 5–10% and did not exceed 20–30% of the norm and did not require discontinuation of therapy. At the end of treatment, these indicators returned to normal. Other side effects were extremely rare. Relapses of the disease are most often caused by a low total dose of the drug or the presence of endocrinological and gynecological diseases. CONCLUSION: Thus, innovative product with Lidose technology is one of the most highly effective and safe systemic retinoids for the treatment of moderate to severe acne. Comparative studies of bioavailability and corresponding pharmacokinetic parameters have demonstrated the bioequivalence of isotretinoin in the composition of innovative product with Lidose technology, which fully corresponds to that in the original preparation.

Case Report: A neonatal case of cryopyrin-associated periodic syndrome with severe funisitis and neonatal asphyxia

Cryopyrin-associated periodic syndrome (CAPS) is a genetic disorder and autoinflammatory disease characterized by chronic inflammation throughout the body. The most severe form of CAPS, Chronic Infantile Neurologic Cutaneous, and Articular (CINCA) syndrome, also known as Neonatal Onset Multisystem Inflammatory Disease (NOMID), has three main features: skin rash, CNS involvement, and joint symptoms. Although these symptoms are typically reported shortly after birth, there have been a few reports of prenatal inflammation. Here, we report our experience managing a case of a CAPS infant born in severe neonatal asphyxia due to a ruptured cord associated with severe funisitis. The baby was born at 38 weeks and 6 days of gestation, weighing 2,898 g, through an ultra-emergency Caesarian section prompted by variable deceleration. The Apgar score was 1 point at 1 min and 4 points at 5 min, necessitating intensive care due to hypoxic-ischemic encephalopathy. Upon delivery, it was observed that the umbilical cord had partially ruptured at the site of attachment to the baby, accompanied by arterial hemorrhage. Umbilical cord rupture was considered to be the cause of the sudden decrease in fetal heart rate. Pathological examination also showed that the inflammation of the cord was more severe on the side attached to the fetus and on the arterial side, suggesting that the inflammation had extended from the fetus. The father carried a genetic mutation associated with CINCA syndrome/NOMID (NLRP3 c.2068G>A p.Glu690Lys Hetero), which was also found in the child. Histopathologic examination of the placenta and umbilical cord can provide crucial insights into the intrauterine onset of inflammation, which is the first manifestation of CINCA syndrome/NOMID in newborns. It should be noted that births with a genetic predisposition to CAPS may have complications related to the placenta and umbilical cord.

Epidermolytic ichthyosis: Clinical spectrum and burden of disease in a large German cohort.

Keratinopathic ichthyoses are a group of hereditary skin disorders caused by pathogenic variants in keratin genes such as KRT1, KRT2 and KRT10, resulting in conditions such as epidermolytic ichthyosis (EI), autosomal-recessive EI, superficial EI and epidermal nevus. Case reports highlight the diversity of clinical manifestations, but only limited information exists regarding the quality of life and burden of disease. The objective of this study was to assess the clinical spectrum, genotype-phenotype correlations and burden of disease in patients with epidermolytic ichthyosis in Germany. We conducted an observational study involving 48 patients diagnosed with EI. Evaluations included the severity of skin involvement using the Investigator's Global Assessment (IGA), the modified Ichthyosis Area Severity Index (mIASI) and complications. The burden of disease was evaluated using the Dermatology Life Quality Index (DLQI) or the Children's Dermatology Life Quality Index (cDLQI). Based on clinical features, mIASI and IGA, EI can be categorized into localized, intermediate and severe forms. Patients with keratin 1 mutations tended to have severe EI, while the three forms were evenly distributed in those with keratin 10 mutations. The study highlights that around half of the patients with EI experienced itch and severe pain. Quality of life was affected, with daily life restrictions of 78% due to care and therapies. Reimbursement for moisturizing ointments by health insurance was insufficient for one-quarter of cases. The results emphasize the need for targeted interventions and comprehensive care strategies to enhance the quality of life for affected individuals.

Protective role of RIPK1 scaffolding against HDV-induced hepatocyte cell death and the significance of cytokines in mice.

Hepatitis delta virus (HDV) infection represents the most severe form of human viral hepatitis; however, the mechanisms underlying its pathology remain incompletely understood. We recently developed an HDV mouse model by injecting adeno-associated viral vectors (AAV) containing replication-competent HBV and HDV genomes. This model replicates many features of human infection, including liver injury. Notably, the extent of liver damage can be diminished with anti-TNF-α treatment. Here, we found that TNF-α is mainly produced by macrophages. Downstream of the TNF-α receptor (TNFR), the receptor-interacting serine/threonine-protein kinase 1 (RIPK1) serves as a cell fate regulator, playing roles in both cell survival and death pathways. In this study, we explored the function of RIPK1 and other host factors in HDV-induced cell death. We determined that the scaffolding function of RIPK1, and not its kinase activity, offers partial protection against HDV-induced apoptosis. A reduction in RIPK1 expression in hepatocytes through CRISPR-Cas9-mediated gene editing significantly intensifies HDV-induced damage. Contrary to our expectations, the protective effect of RIPK1 was not linked to TNF-α or macrophage activation, as their absence did not alter the extent of damage. Intriguingly, in the absence of RIPK1, macrophages confer a protective role. However, in animals unresponsive to type-I IFNs, RIPK1 downregulation did not exacerbate the damage, suggesting RIPK1's role in shielding hepatocytes from type-I IFN-induced cell death. Interestingly, while the damage extent is similar between IFNAR KO and WT mice in terms of transaminase elevation, their cell death mechanisms differ. In conclusion, our findings reveal that HDV-induced type-I IFN production is central to inducing hepatocyte death, and RIPK1's scaffolding function offers protective benefits. Thus, type-I IFN together with TNF-α, contribute to HDV-induced liver damage. These insights may guide the development of novel therapeutic strategies to mitigate HDV-induced liver damage and halt disease progression.

Neuropsychological profile associated with KAT6A syndrome: Emergent genotype-phenotype trends

BackgroundKAT6A (Arboleda-Tham) syndrome is a Mendelian disorder of the epigenetic machinery caused by pathogenic variants in the lysine acetyltransferase 6 A (KAT6A) gene. Intellectual disability and speech/language impairment (e.g., minimally verbal) are common features of the disorder, with late-truncating variants associated with a more severe form of intellectual disability. However, much of the cognitive phenotype remains elusive given the dearth of research.Participants and methodsThis study examined non-verbal and social skills of 15 individuals with molecularly-confirmed diagnoses of KAT6A syndrome (Mean age = 10.32 years, SD = 4.12). Participants completed select subtests from the DAS-II, the NEPSY-II, and the Beery Buktenica Developmental Test of Visual Motor Integration 6th Edition, and their caregivers completed an assortment of behavior rating inventories.ResultsFindings suggest global cognitive impairment with nonverbal cognition scores similar to those for receptive language. Autism-related features, particularly restricted interests and repetitive behaviors, and broad adaptive deficits were common in our sample juxtaposed with a relatively strong social drive and low frequency of internalizing and externalizing behavioral problems. A general trend of lower performance scores on nonverbal and receptive language measures was observed among those with protein-truncating variants vs. missense variants; however, no effect was observed on caregiver rating inventories of daily behaviors. Late and early truncating variants yielded comparable neuropsychological profiles.ConclusionsOverall, study results show the cognitive phenotype of KAT6A syndrome includes equally impaired nonverbal cognition and receptive language functioning, paired with relatively intact social drive and strengths in behavior regulation. Emergent genotype-phenotype correlations suggest cognition may be more affected in protein-truncating than missense mutations although similar neurobehavioral profiles were observed.

Holoprosencephaly: The Disease and Its Related Disabilities

AbstractHoloprosencephaly (HPE), the most prevalent developmental anomaly affecting the forebrain in humans, occurs in ∼1 in 16,000 liveborn neonates, with an incidence reaching 1 in 250 in conceptuses. This condition is distributed worldwide. HPE is etiologically heterogeneous, and its pathogenesis is variable. Environmental, teratogenic, genetic, or metabolic factors can contribute to the development of HPE. Notably, maternal insulin-dependent diabetes mellitus and maternal alcoholism are among the primary causative factors. HPE may be linked to various well-defined multiple malformation syndromes characterized by a normal karyotype, such as Smith–Lemli–Opitz's, Pallister–Hall's, or velocardiofacial syndrome. Alternatively, it can be associated with chromosomal abnormalities. (i.e., Patau's syndrome and, less frequently, Edwards' syndrome or Down's syndrome). The major genes implicated in HPE are SHH, ZIC2, SIX3, and TGIF. The range of HPE is extensive, covering diverse neuropathological phenotypes of varying severity. Three classical types of HPE can be distinguished in increasing order of severity: lobar HPE, characterized by separated right and left ventricles with some continuity across the frontal cortex; semilobar HPE, featuring a partial separation; and the most severe form, alobar HPE, where there is a single brain ventricle and the absence of an interhemispheric fissure. Additionally, there are other variations of HPE, ranging in severity, including the less severe interhemispheric median HPE (also known as middle interhemispheric variant). The phenotypic spectrum of HPE is highly extensive, encompassing severe cerebral malformations to microforms. Children with HPE often encounter numerous medical challenges; among them neurological disorders, craniofacial malformations, endocrine disorders, oral and motor dysfunction, and dysfunction of the autonomic nervous system. Neurologic problems, such as cerebral palsy and seizures, are common. The diagnosis of HPE is typically made prenatally, relying primarily on ultrasound and magnetic resonance imaging examinations. The prognosis for individuals with HPE is largely dependent on its underlying causes. Those with cytogenetic abnormalities, in particular, face a significantly poorer prognosis, with only 2% surviving beyond 1 year.

A case of granulomatos is with polyangiitis (Wegener’s) after a patient’s suffering from a new coronavirus infection COVID-19

A case of granulomatos is with polyangiitis (Wegener’s) after a patient’s suffering from a new coronavirus infection COVID-19

Edaravone Alleviates Traumatic Brain Injury by Inhibition of Ferroptosis via FSP1 Pathway.

Traumatic brain injury (TBI) is a highly severe form of trauma with complex series of reactions in brain tissue which ultimately results in neuronal damage. Previous studies proved that neuronal ferroptosis, which was induced by intracranial haemorrhage and other reasons, was one of the most primary causes of neuronal damage following TBI. However, the association between neuronal mechanical injury and ferroptosis in TBI and relevant treatments remain unclear. In the present study, we first demonstrated the occurrence of neuronal ferroptosis in the early stage of TBI and preliminarily elucidated that edaravone (EDA), a cerebroprotective agent that eliminates oxygen radicals, was able to inhibit ferroptosis induced by TBI. A cell scratching model was established in PC12 cells, and it was confirmed that mechanical injury induced ferroptosis in neurons at the early stage of TBI. Ferroptosis suppressor protein 1 (FSP1) plays a significant role in inhibiting ferroptosis, and we found that iFSP, a ferroptosis agonist which is capable to inhibit FSP1 pathway, attenuated the anti-ferroptosis effect of EDA. In conclusion, our results suggested that EDA inhibited neuronal ferroptosis induced by mechanical injury in the early phase of TBI by activating FSP1 pathway, which could provide evidence for future research on prevention and treatment of TBI.

Protein Quality Control of NKCC2 in Bartter Syndrome and Blood Pressure Regulation

Mutations in NKCC2 generate antenatal Bartter syndrome type 1 (type 1 BS), a life-threatening salt-losing nephropathy characterized by arterial hypotension, as well as electrolyte abnormalities. In contrast to the genetic inactivation of NKCC2, inappropriate increased NKCC2 activity has been associated with salt-sensitive hypertension. Given the importance of NKCC2 in salt-sensitive hypertension and the pathophysiology of prenatal BS, studying the molecular regulation of this Na-K-2Cl cotransporter has attracted great interest. Therefore, several studies have addressed various aspects of NKCC2 regulation, such as phosphorylation and post-Golgi trafficking. However, the regulation of this cotransporter at the pre-Golgi level remained unknown for years. Similar to several transmembrane proteins, export from the ER appears to be the rate-limiting step in the cotransporter’s maturation and trafficking to the plasma membrane. The most compelling evidence comes from patients with type 5 BS, the most severe form of prenatal BS, in whom NKCC2 is not detectable in the apical membrane of thick ascending limb (TAL) cells due to ER retention and ER-associated degradation (ERAD) mechanisms. In addition, type 1 BS is one of the diseases linked to ERAD pathways. In recent years, several molecular determinants of NKCC2 export from the ER and protein quality control have been identified. The aim of this review is therefore to summarize recent data regarding the protein quality control of NKCC2 and to discuss their potential implications in BS and blood pressure regulation.

PCI Vs. CABG: Battle For Better Outcomes in Pakistani Triple Vessel Disease Patients

Background: Cardiovascular diseases (CVDs) are the leading cause of mortality worldwide, with Triple Vessel Disease (TVD) representing a severe form that poses significant treatment challenges. In Pakistan, the burden of CVDs is high, exacerbated by genetic and lifestyle factors. Objective: To evaluate and compare the clinical outcomes of Percutaneous Coronary Intervention (PCI) and Coronary Artery Bypass Grafting (CABG) in patients diagnosed with Triple Vessel Disease (TVD) in a Pakistani cohort. Methods: This prospective cohort study was conducted at Lady Reading Hospital, Peshawar, from January 1, 2020, to December 31, 2021. A total of 400 patients diagnosed with TVD based on angiographic findings were enrolled. Inclusion criteria included age above 18 years, clinical diagnosis of stable angina or non-ST elevation myocardial infarction, and consent to participate. Exclusion criteria were previous revascularization procedures, concomitant valvular or congenital heart disease, and life expectancy less than a year due to non-cardiac conditions. Patients were assigned to either PCI or CABG based on clinical decisions by their managing cardiologists, considering anatomical considerations, comorbid conditions, and patient preferences. Baseline demographic and clinical data, including age, gender, smoking status, presence of diabetes, hypertension, and previous myocardial infarction (MI), were collected through patient interviews and medical record reviews. Clinical outcomes were monitored for 12 months post-procedure. Primary outcome measures included mortality, myocardial infarction, repeat revascularization, and stroke within 12 months. Secondary outcomes were hospital readmission rates and quality of life scores, measured using a standardized 10-point scale. Statistical analyses were performed using SPSS version 25, with continuous variables expressed as means and standard deviations and categorical variables as percentages. The chi-square test or Fisher’s exact test was used for categorical outcomes, and the student’s t-test or Mann-Whitney U test for continuous outcomes, with a p-value of less than 0.05 considered statistically significant. Results: The mean age of the participants was 62.5 ± 7.8 years, with 62 ± 8 years in the PCI group and 63 ± 7 years in the CABG group (p=0.45). Gender distribution was similar, with 255 males and 145 females overall (p=0.55). Smoking status, diabetes, hypertension, and previous MI were comparably distributed between the groups. Mortality was 5% in the PCI group and 3% in the CABG group (p=0.31). Myocardial infarction occurred in 10% of PCI patients compared to 5% of CABG patients (p=0.05). Repeat revascularization was required in 15% of the PCI group versus 7% of the CABG group (p=0.01). Stroke incidence was 2% in the PCI group and 1% in the CABG group (p=0.45). Hospital readmission rates were 20% for PCI and 15% for CABG (p=0.10). Quality of life scores were higher in the CABG group (8.0 ± 1.1) compared to the PCI group (7.5 ± 1.2) (p=0.04). Conclusion: CABG may offer superior outcomes compared to PCI in managing TVD among Pakistani patients, particularly in reducing myocardial infarction rates and repeat revascularization. Despite the invasive nature of CABG, its long-term benefits suggest it should be considered preferentially for patients with complex coronary anatomies. Clinical decisions should, however, be tailored to individual patient factors and preferences.

Acute mitral regurgitation complicating STEMI

Abstract Funding Acknowledgements None. Introduction Acute ischemic mitral regurgitation (aiMR) occurs in 17-40% of patients suffering an acute coronary syndrome. Although severe forms constitute less than 1% of the cases, this complication significantly increases mortality risk. While surgery has been traditionally considered the treatment of choice, heterogeneity in underlying mechanisms and lack of updated evidence questions optimal treatment. Purpose The aim of the present study was to describe baseline clinical characteristics, management and outcomes of a contemporary cohort of patients with aiMR. Methods A retrospective cohort including patients diagnosed with moderate to severe aiMR presenting from 2006 to 2019 at the National Institute of Cardiology "Ignacio Chavez" in Mexico City. Results A total of 10,434 patients presented to the study center with an ACS from 2006 to 2019, out of which 6,448 (61.8%) were diagnosed with STEMI and 3,986 (38.2%) with NSTEMI. Mechanical post-infarction complications occurred in 203 (1.9%). Among these, aiMR was observed in 132 patients (1.3%), categorized as moderate in 49 patients (37.2%) and severe in 83 patients (62.8%). 6 patients were excluded due to incomplete information. Acute ischemic mitral regurgitation was more frequent in patients with STEMI (79.4%) compared with NSTEMI (20.6%) and 88.9% were non-reperfused infarctions. 65.9% of patients were male and 57.1% had hypertension. In-hospital mortality was present in 40 patients (31.7%). Ischemia of the papillary muscle was the most commonly reported mechanism (38.1%), followed by alterations in the left ventricle's geometry (33.3%), mitral annular dilation (14.3%), papillary muscle rupture (7.1%) and chordae tendineae rupture (5.6%). The least frequently reported mechanism was pre existing non-ischemic mitral regurgitation (1.6%). There was no significant difference in mortality based on the mechanism responsible for aiMR. Patients with aiMR managed solely with medical therapy had a higher mortality rate (41.3%) compared to those undergoing mitral valve replacement (37%) (Figure 1). Timely reperfusion (thrombolysis/primary PCI) significantly reduced in-hospital mortality (85% survival) in contrast to those with a non-reperfused MI (66% survival). Conclusions Acute ischemic mitral regurgitation remains an entity with a high mortality rate. Early identification of underlying etiology, prompt reperfusion treatment and tailored surgery, if needed, are key to improve outcomes.