Survey on Etiology of Stevens-Johnson syndrome and Toxic Epidermal Necrolysis in Pediatric Patients: A Six-Year Study from Iran

Background Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are among the most severe dermatologic reactions to the drugs. Data about SJS and TEN among pediatric population especially in Iran is limited. This study aimed to investigate the clinical and para-clinical characteristics of pediatric patients with SJS/TEN. Materials and Methods From 2010 to 2016, all SJS and TEN children from three teaching hospitals in Mashhad-Iran with age less than 15 years were included in the study. Patients’ catechistic, history, physical examinations, progress notes, laboratory findings, medical consults, treatments taken and the final outcome were extracted from medical records by researcher. Data were further analyzed by SPSS (version 17.0). Results Among 165 records, 48 children (58.3% male; mean age of 9.1 years) were among the SJS and TEN spectrum. Anticonvulsants (50%; including lamotrigine, phenobarbital, phenytoin, carbamazepine, valproate and clobazam) were the most common drugs followed by antibiotics (38.1%; including cefixime, penicillin, azithromycin, co-amoxiclav, cephalexin, co-trimoxazole and ceftriaxone), and analgesics (9.5%; including acetaminophen, ibuprofen and naproxen). Infectious agents were the possible cause of SJS/TEN in two patients. WBC counts, liver function tests, renal and electrolyte tests were significantly different in SJS and TEN groups. Conclusion The main suspected medications found in this study were anticonvulsants and antibiotics and the mortality rate was 12.5%. The main suspected medications found in this study were anticonvulsants and antibiotics and the mortality rate was 12.5%

Activated microglia and neuroinflammation as a pathogenic mechanism in Leigh syndrome

Neuroinflammation is one of the main mechanisms leading to neuronal death and dysfunction in neurodegenerative diseases. The role of microglia as primary mediators of inflammation is unclear in Leigh syndrome (LS) patients. This study aims to elucidate the role of microglia in LS progression by a detailed multipronged analysis of LS neuropathology, mouse and human induced pluripotent stem cells models of Leigh syndrome. We described brain pathology in three cases of Leigh syndrome and performed immunohistochemical staining of autopsy brain of LS patients. We used mouse model of LS (Ndufs4−/−) to study the effect of microglial partial ablation using pharmacologic approach. Genetically modified human induced pluripotent stem cell (iPS) derived neurons and brain organoid with Ndufs4 mutation were used to investigate the neuroinflammation in LS. We reported a novel observation of marked increased in Iba1+ cells with features of activated microglia, in various parts of brain in postmortem neuropathological examinations of three Leigh syndrome patients. Using an Ndufs4−/− mouse model for Leigh syndrome, we showed that partial ablation of microglia by Pexidartinib initiated at the symptom onset improved neurological function and significantly extended lifespan. Ndufs4 mutant LS brain organoid had elevated NLRP3 and IL6 pro-inflammatory pathways. Ndufs4-mutant LS iPSC neurons were more susceptible to glutamate excitotoxicity, which was further potentiated by IL-6. Our findings of LS human brain pathology, Ndufs4-deficient mouse and iPSC models of LS suggest a critical role of activated microglia in the progression of LS encephalopathy. This study suggests a potential clinical application of microglial ablation and immunosuppression during the active phase of Leigh syndrome

TOR Signaling Pathway in Cardiac Aging and Heart Failure

Mechanistic Target of Rapamycin (mTOR) signaling is a key regulator of cellular metabolism, integrating nutrient sensing with cell growth. Over the past two decades, studies on the mTOR pathway have revealed that mTOR complex 1 controls life span, health span, and aging by modulating key cellular processes such as protein synthesis, autophagy, and mitochondrial function, mainly through its downstream substrates. Thus, the mTOR pathway regulates both physiological and pathological processes in the heart from embryonic cardiovascular development to maintenance of cardiac homeostasis in postnatal life. In this regard, the dysregulation of mTOR signaling has been linked to many age-related pathologies, including heart failure and age-related cardiac dysfunction. In this review, we highlight recent advances of the impact of mTOR complex 1 pathway and its regulators on aging and, more specifically, cardiac aging and heart failure