Department of Biochemistry, Chemistry Institute, University of SĆ£o Paulo, SP 05508-000, Brazil.
Published: April 2022
AI Article Synopsis
Article Abstract
Chronic pain is a major health issue, and the search for new analgesics has become increasingly important because of the addictive properties and unwanted side effects of opioids. To explore potentially new drug targets, we investigated mutations in the gene found in individuals with congenital insensitivity to pain with anhidrosis (CIPA). encodes tropomyosin receptor kinase A (TrkA), the receptor for nerve growth factor (NGF) and that contributes to nociception. Molecular modeling and biochemical analysis identified mutations that decreased the interaction between TrkA and one of its substrates and signaling effectors, phospholipase CĪ³ (PLCĪ³). We developed a cell-permeable phosphopeptide derived from TrkA (TAT-pQYP) that bound the Src homology domain 2 (SH2) of PLCĪ³. In HEK-293T cells, TAT-pQYP inhibited the binding of heterologously expressed TrkA to PLCĪ³ and decreased NGF-induced, TrkA-mediated PLCĪ³ activation and signaling. In mice, intraplantar administration of TAT-pQYP decreased mechanical sensitivity in an inflammatory pain model, suggesting that targeting this interaction may be analgesic. The findings demonstrate a strategy to identify new targets for pain relief by analyzing the signaling pathways that are perturbed in CIPA.
Background: Previous studies suggest the relationship between activation time (AT) and action potential duration (APD) in the heart is dependent on electrotonic coupling, but this has not been directly tested. This study assessed whether acute changes in electrical coupling, or other determinants of conduction or repolarization, modulate APD heterogeneity.
Methods And Results: Langendorff-perfused guinea pig hearts were epicardially paced and optically mapped after treatment with the gap junction uncoupler carbenoxolone, ephaptic uncoupler mannitol, ephaptic enhancer dextran 2MDa, sodium channel inhibitor flecainide, or rapid component of the delayed rectifier potassium channel inhibitor E4031.
Mayer-Rokitansky-KĆ¼ster-Hauser syndrome (MRKHS) is a rare congenital disorder characterized by agenesis of the uterus and upper two-thirds of the vagina. It affects around 1 in 4000-5000 females and is of two types: type 1, also known as isolated MĆ¼llerian aplasia or Rokitansky, which involves only uterovaginal agenesis, and type 2, presents as uterovaginal agenesis along with renal, cardiac, and other organ anomalies. Despite the absence of vaginal and uterine structures, individuals with MRKHS typically present with normal secondary sexual characteristics and ovarian functions.
Congenital insensitivity to pain with anhidrosis (CIPA) is a rare autosomal recessive disorder because of NTRK1 gene mutations, leading to an inability to perceive pain and temperature and lack of sweating. Its rarity and unique clinical challenges, such as severe injuries from the inability to sense pain, make reporting cases critical. A 5-year-old boy, the third child of consanguineous parents, was referred for a fractured femur.
Complete androgen insensitivity syndrome (CAIS) can lead to challenges in diagnosing individuals with a 46, XY karyotype who appear female due to their inability to respond to androgens.
A case report details how a patient was misdiagnosed during surgery and later incorrectly identified as having another syndrome, but was ultimately given the correct diagnosis and a management plan that postponed surgery until after puberty.
The report emphasizes the need for a multidisciplinary approach in managing CAIS, calling for improved awareness and personalized treatment plans to provide effective, patient-centered care.
Objective: To explore the genetic etiology of a child featuring multiple fractures and congenital insensitivity to pain (CIP).
Methods: A child who had presented at the West China Hospital of Sichuan University on March 16, 2023 for recurrent fractures and CIP was selected as the study subject. Peripheral blood samples of the child and his parents was collected.
