scholarly journals Molecular Mechanisms Underlying Remodeling of Ductus Arteriosus: Looking beyond the Prostaglandin Pathway

2021 ◽  
Vol 22 (6) ◽  
pp. 3238
Author(s):  
Ho-Wei Hsu ◽  
Ting-Yi Lin ◽  
Yi-Ching Liu ◽  
Jwu-Lai Yeh ◽  
Jong-Hau Hsu
Keyword(s):  
Adverse Effect ◽  
Clinical Management ◽  
Vascular Remodeling ◽  
Molecular Mechanisms ◽  
Surgical Intervention ◽  
Ductus Arteriosus ◽  
Clinical Problem ◽  
Cyclooxygenase Inhibitors ◽  
Medical Patients ◽  
Fetal Circulation

The ductus arteriosus (DA) is a physiologic vessel crucial for fetal circulation. As a major regulating factor, the prostaglandin pathway has long been the target for DA patency maintenance or closure. However, the adverse effect of prostaglandins and their inhibitors has been a major unsolved clinical problem. Furthermore, a significant portion of patients with patent DA fail to respond to cyclooxygenase inhibitors that target the prostaglandin pathway. These unresponsive medical patients ultimately require surgical intervention and highlight the importance of exploring pathways independent from this well-recognized prostaglandin pathway. The clinical limitations of prostaglandin-targeting therapeutics prompted us to investigate molecules beyond the prostaglandin pathway. Thus, this article introduces molecules independent from the prostaglandin pathway based on their correlating mechanisms contributing to vascular remodeling. These molecules may serve as potential targets for future DA patency clinical management.

scholarly journals SURGICAL TREATMENT OF OPEN DUCTUS ARTERIOSUS IN PREMATURE INFANTS

2018 ◽  
Vol 22 (6) ◽  
pp. 301-305
Author(s):  
V. V. Aleksi-Meskhishvili ◽  
Yury A. Kozlov
Keyword(s):  
Surgical Treatment ◽  
Surgical Intervention ◽  
Ductus Arteriosus ◽  
Cyclooxygenase Inhibitors ◽  
Recurrent Nerve ◽  
Low Birth Weight Infants ◽  
Leading Role ◽  
Lymphatic Duct ◽  
Great Vessels ◽  
Prophylactic Use

The choice of tactics for the treatment of open arterial duct (OAD) in newborns is one of the most controversial and debatable topics in neonatal medicine. There are several approaches in the treatment of OAD in small infants: 1) the prophylactic use of cyclooxygenase inhibitors; 2) treatment on the background of maintenance therapy without the medical and surgical intervention; 3) drug stimulation of the closure of the AOA; 4) surgical intervention. Surgical treatment, which can be done with the aid of the open surgery and thoracoscopy, still plays a leading role. Complications associated directly with the operation are minimal. In this study, we present a review of the literature, including current information on the most frequent complications arising from the surgical treatment of OAD in newborns - damage to the lungs with the development of pneumothorax, damage to the great vessels with circulatory disorders, wound to the left phrenic nerve followed by paresis of the left diaphragm dome, damage to the recurrent nerve with impaired function of the left vocal cords, damage to the thoracic lymphatic duct with the development of chylothorax, damage to the muscles with development of functional scoliosis. Special attention is paid to the prognosis of the course of the disease and the survival rate of low birth weight infants.

scholarly journals Transcriptional evaluation of the ductus arteriosus at the single-cell level uncovers a requirement for vimentin for complete closure

2021 ◽  
Author(s):  
Jocelynda Salvador ◽  
Gloria E Hernandez ◽  
Feiyang Ma ◽  
Cyrus W Abrahamson ◽  
Robert D Goldman ◽  
...  
Keyword(s):  
Single Cell ◽  
Rna Sequencing ◽  
Vascular Remodeling ◽  
Molecular Mechanisms ◽  
Heart Defects ◽  
Ductus Arteriosus ◽  
Fibroblast Cell ◽  
Management Options ◽  
Complete Closure ◽  
Single Cell Rna Sequencing

OBJECTIVE: Failure to close the ductus arteriosus immediately post-birth, patent ductus arteriosus (PDA), accounts for up to 10% of all congenital heart defects. Despite significant advances in PDA management options, including pharmacological treatment targeting the prostaglandin pathway, a proportion of patients fail to respond and must undergo surgical intervention. Thus, further refinement of the cellular and molecular mechanisms that govern vascular remodeling of this vessel is required. APPROACH AND RESULTS: As anticipated, single-cell RNA sequencing on the ductus arteriosus in mouse embryos at E18.5, P0.5, and P5, revealed broad transcriptional alterations in the endothelial, smooth muscle, and fibroblast cell compartments. Making use of these data sets, vimentin emerged as an interesting candidate for further investigation. Subsequent studies demonstrated that, in fact, mice with genetic deletion of vimentin fail to complete vascular remodeling of the ductus arteriosus, as per presence of a functional lumen. CONCLUSIONS: Through single-cell RNA-sequencing and by tracking closure of the ductus arteriosus postnatally in mice, we uncovered the unexpected contribution of vimentin in driving complete closure of the ductus arteriosus potentially through regulation of the Notch signaling pathway.

Articulation and Nasality Changes Resulting from Sustained Palatal Fistula Obturation

1998 ◽  
Vol 35 (1) ◽  
pp. 81-87 ◽  
Author(s):  
Judith Pinborough-Zimmerman ◽  
Claudia Canady ◽  
Duane K. Yamashiro ◽  
Louis Morales
Keyword(s):  
Adverse Effect ◽  
Clinical Management ◽  
Surgical Intervention ◽  
Palatal Fistula ◽  
Department Of Health ◽  
Unique Shape ◽  
Molar Teeth ◽  
And Performance ◽  
Nasal Emission ◽  
Over Time

Objective The purpose of the study was to determine differences in articulation and nasality with obturation over time in children with a palatal fistula. Design Articulation and nasality were measured with the fistula open, immediately after obturation, and 4 to 7 weeks postobturation. Setting, Patients, Participants Subjects were 15 patients with a palatal fistula secondary to a repaired cleft palate who were seen through the Orofacial Program, Utah Department of Health, ranging in age from 4 years 6 months to 13 years 1 month. Interventions Acrylic palatal obturators were designed to provide coverage specific to the unique shape and location of each child's fistula. Obturators were cemented to molar teeth using wire clasps for control of usage. Main outcome Measures Measurements consisted of listener judgments of hypernasality, hyponasality, and nasal emissions; instrumental ratings of nasalance using the Nasometer 6200-2; and performance on a standardized articulation test. Results Significant improvement occurred only on nasal emission measures from the preobturation condition to immediate postobturation. However, significant improvement was found in articulation, listener judgments of hypernasality, nasal emissions, and Nasometric Nasal Sentence mean scores from the preobturation condition to 4 to 7 weeks postobturation and from the immediate postobturation condition to 4 to 7 weeks postobturation. No significant differences were found between conditions for listener judgments of hyponasality and Nasometric Zoo and Rainbow Passage scores. Obturation of the palatal fistula over a 4- to 7-week period resulted in no adverse effect on articulation ability, perceptual ratings of nasality, or instrumental ratings of nasalance. Conclusions Clinical management of patients with a palatal fistula can be enhanced with treatment using obturation over time. For subjects who continue to exhibit hypernasality immediately postobturation, sustained obturation is advocated prior to consideration of surgical intervention for treatment of a palatal fistula and/or velopharyngeal dysfunction.

Molecular Correlates of Imatinib Resistance in Gastrointestinal Stromal Tumors

2006 ◽  
Vol 24 (29) ◽  
pp. 4764-4774 ◽  
Author(s):  
Michael C. Heinrich ◽  
Christopher L. Corless ◽  
Charles D. Blanke ◽  
George D. Demetri ◽  
Heikki Joensuu ◽  
...  
Keyword(s):  
Gastrointestinal Stromal Tumors ◽  
Molecular Mechanisms ◽  
Clonal Evolution ◽  
Clinical Problem ◽  
Primary Resistance ◽  
Imatinib Resistance ◽  
Secondary Resistance ◽  
Stromal Tumors ◽  
Rnai Technology ◽  
Imatinib Resistant

Purpose Gastrointestinal stromal tumors (GISTs) commonly harbor oncogenic mutations of the KIT or platelet-derived growth factor alpha (PDGFRA) kinases, which are targets for imatinib. In clinical studies, 75% to 90% of patients with advanced GISTs experience clinical benefit from imatinib. However, imatinib resistance is an increasing clinical problem. Patients and Methods One hundred forty-seven patients with advanced, unresectable GISTs were enrolled onto a randomized, phase II clinical study of imatinib. Specimens from pretreatment and/or imatinib-resistant tumors were analyzed to identify molecular correlates of imatinib resistance. Secondary kinase mutations of KIT or PDGFRA that were identified in imatinib-resistant GISTs were biochemically profiled for imatinib sensitivity. Results Molecular studies were performed using specimens from 10 patients with primary and 33 patients with secondary resistance. Imatinib-resistant tumors had levels of activated KIT that were similar to or greater than those typically found in untreated GISTs. Secondary kinase mutations were rare in GISTs with primary resistance but frequently found in GISTs with secondary resistance (10% v 67%; P = .002). Evidence for clonal evolution and/or polyclonal secondary kinase mutations was seen in three (18.8%) of 16 patients. Secondary kinase mutations were nonrandomly distributed and were associated with decreased imatinib sensitivity compared with typical KIT exon 11 mutations. Using RNAi technology, we demonstrated that imatinib-resistant GIST cells remain dependent on KIT kinase activity for activation of critical downstream signaling pathways. Conclusion Different molecular mechanisms are responsible for primary and secondary imatinib resistance in GISTs. These findings have implications for future approaches to the growing problem of imatinib resistance in patients with advanced GISTs.

scholarly journals When the Blood Hits Your Brain: The Neurotoxicity of Extravasated Blood

2021 ◽  
Vol 22 (10) ◽  
pp. 5132
Author(s):  
Jesse A. Stokum ◽  
Gregory J. Cannarsa ◽  
Aaron P. Wessell ◽  
Phelan Shea ◽  
Nicole Wenger ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Surgical Intervention ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Critical Factor ◽  
Mass Effect ◽  
Direct Role ◽  
Scientific Curiosity ◽  
Clot Removal ◽  
Clinical Literature ◽  
The Central Nervous System

Hemorrhage in the central nervous system (CNS), including intracerebral hemorrhage (ICH), intraventricular hemorrhage (IVH), and aneurysmal subarachnoid hemorrhage (aSAH), remains highly morbid. Trials of medical management for these conditions over recent decades have been largely unsuccessful in improving outcome and reducing mortality. Beyond its role in creating mass effect, the presence of extravasated blood in patients with CNS hemorrhage is generally overlooked. Since trials of surgical intervention to remove CNS hemorrhage have been generally unsuccessful, the potent neurotoxicity of blood is generally viewed as a basic scientific curiosity rather than a clinically meaningful factor. In this review, we evaluate the direct role of blood as a neurotoxin and its subsequent clinical relevance. We first describe the molecular mechanisms of blood neurotoxicity. We then evaluate the clinical literature that directly relates to the evacuation of CNS hemorrhage. We posit that the efficacy of clot removal is a critical factor in outcome following surgical intervention. Future interventions for CNS hemorrhage should be guided by the principle that blood is exquisitely toxic to the brain.

Predictors of Surgical Intervention in Patients with Inflammatory Bowel Disease

QJM ◽  
2021 ◽  
Vol 114 (Supplement_1) ◽  
Author(s):  
Khaled Hamdy Abd El Megeed ◽  
Shereen Abou Bakr Saleh ◽  
Christina Alphonse Anwar ◽  
Ahmed Elkattary Mohamed Elkattary
Keyword(s):  
Inflammatory Bowel Disease ◽  
Surgical Treatment ◽  
Bowel Disease ◽  
Surgical Intervention ◽  
High Sensitivity ◽  
Medical Patients ◽  
Mayo Score ◽  
Calprotectin Level ◽  
Inflammatory Bowel ◽  
The Mean

Abstract Background Inflammatory bowel disease (IBD) is comprised of two major disorders: Ulcerative Colitis and Crohn’s disease. Ulcerative Colitis affects the colon, where as Crohn’s disease can involve any component of the gastrointestinal tract from the mouth to the perianal area. These disorders have somewhat different pathologic and clinical characteristics, but with substantial overlap; their pathogenesis remains poorly understood. Objective To determine & detect different predictors that help us to characterize patients with high probability of undergoing surgical intervention for inflammatory bowel diseases. Patients and Methods The present study was designed to detect & identify possible factors that can be used to predict surgical intervention in patients with IBD. The present study was a case control study that was conducted on 80 patients with inflammatory bowel disease (either controlled by medical treatment or needed surgical intervention as a part of disease control) who were recruited form Ain-Shams university hospitals and El Quabbary general hospital in Alexandria. In the present study, the mean age of the included patients was 36.67 ±8.5 years old and 50% of the patients were males. The mean age at the onset of the disease was 25.81 ±6.8 years old. Results In the present study, there were statistically significant differences between surgical and medical patients in terms of CDAI for CD (p < 0.001) and Mayo score for UC (p < 0.001). Surgical patients were more likely to have higher scores. CDAI and Mayo score were negative predictors of surgical treatment. CDAI score > 287 and Mayo score > 8.5 achieved high sensitivity and specificity for the detection of surgical treatment. In the present study, we found that there was statistically significant differences between surgical and medical patients in terms of Stool Calprotectin level. Surgical patients were more likely to have higher Stool Calprotectin level. Stool Calprotectin level was negative predictor of surgical treatment at a level of > 341.5 microgm/gm with high sensitivity and specificity. Conclusion Surgical treatment is a common outcome in IBD. Certain clinical features and the extent of disease are risk factors for surgical intervention. Our study indicates that smoking, Chron’s disease, perianal disease, granulomas, higher severity scores, higher stool Calprotectin level, CRP, and ESR were associated with higher risks of surgical intervention. In addition, smoking, peri-anal disease, CDAI, Mayo score, Stool Calprotectin level, and CRP level were predictors of surgical treatment. The findings of our analysis have implications for practice, particularly in the promotion of preoperative individualized risk prediction. The ability to predict which patients will need surgery and target more intensive, early treatment to that group would be invaluable. Further research through large prospective cohort studies is needed to confirm our findings and conclusions.

scholarly journals A concise review on advances in development of small molecule anti-inflammatory therapeutics emphasising AMPK: An emerging target

2016 ◽  
Vol 29 (4) ◽  
pp. 562-571 ◽  
Author(s):  
Chethan Gejjalagere Honnappa ◽  
Unnikrishnan Mazhuvancherry Kesavan
Keyword(s):  
Drug Targets ◽  
Molecular Mechanisms ◽  
Inflammatory Diseases ◽  
Cyclooxygenase Inhibitors ◽  
Evolutionarily Conserved ◽  
Inflammatory Drugs ◽  
Anti Inflammatory ◽  
Acid Pathway ◽  
Clinical Trial Results ◽  
Amp Activated Protein Kinase

Inflammatory diseases are complex, multi-factorial outcomes of evolutionarily conserved tissue repair processes. For decades, non-steroidal anti-inflammatory drugs and cyclooxygenase inhibitors, the primary drugs of choice for the management of inflammatory diseases, addressed individual targets in the arachidonic acid pathway. Unsatisfactory safety and efficacy profiles of the above have necessitated the development of multi-target agents to treat complex inflammatory diseases. Current anti-inflammatory therapies still fall short of clinical needs and the clinical trial results of multi-target therapeutics are anticipated. Additionally, new drug targets are emerging with improved understanding of molecular mechanisms controlling the pathophysiology of inflammation. This review presents an outline of small molecules and drug targets in anti-inflammatory therapeutics with a summary of a newly identified target AMP-activated protein kinase, which constitutes a novel therapeutic pathway in inflammatory pathology.

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