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Neurobiology of Disease Oct 2023De novo somatic (post-zygotic) gene mutations affecting neuroglial progenitor cell types in embryonic cerebral cortex are increasingly identified in patients with drug... (Review)
Review
De novo somatic (post-zygotic) gene mutations affecting neuroglial progenitor cell types in embryonic cerebral cortex are increasingly identified in patients with drug resistant epilepsy (DRE) associated with malformations of cortical development, in particular, focal cortical dysplasias (FCD). Somatic variants in at least 16 genes have been linked to FCD type II, all encoding components of the mechanistic target of rapamycin (mTOR) pathway. FCD type II is characterized histopathologically by cytomegalic dysmorphic neurons and balloon cells. In contrast, the molecular pathogenesis of FCD I subtypes is less well understood, and histological features are characterized by alterations in columnar or laminar organization without cytomegalic dysmorphic neurons or balloon cells. In 2018, we reported somatic mutations in Solute Carrier Family 35 member A2 (SLC35A2) linked to DRE underlying FCD type I and subsequently to a new histopathological phenotype: excess oligodendrocytes and heterotopic neurons in subcortical white matter known as MOGHE (mild malformation of cortical development with oligodendroglial hyperplasia). These discoveries opened the door to studies linking somatic mutations to FCD. In this review, we discuss the biology of SLC35A2 somatic mutations in epilepsy in FCD and MOGHE, and insights into SLC35A2 epilepsy pathogenesis, describing progress to date and critical areas for investigation.
Topics: Humans; Drug Resistant Epilepsy; Focal Cortical Dysplasia; Epilepsy; Malformations of Cortical Development, Group I; Malformations of Cortical Development
PubMed: 37739137
DOI: 10.1016/j.nbd.2023.106299 -
Journal of Crohn's & Colitis Nov 2023Colonic bacterial biofilms are frequently present in ulcerative colitis [UC] and may increase dysplasia risk through pathogens expressing oncotraits. This prospective...
BACKGROUND AND AIMS
Colonic bacterial biofilms are frequently present in ulcerative colitis [UC] and may increase dysplasia risk through pathogens expressing oncotraits. This prospective cohort study aimed to determine [1] the association of oncotraits and longitudinal biofilm presence with dysplasia risk in UC, and [2] the relation of bacterial composition with biofilms and dysplasia risk.
METHODS
Faeces and left- and right-sided colonic biopsies were collected from 80 UC patients and 35 controls. Oncotraits [FadA of Fusobacterium, BFT of Bacteroides fragilis, colibactin [ClbB] and Intimin [Eae] of Escherichia coli] were assessed in faecal DNA with multiplex quantitative polymerase chain reaction [qPCR]. Biopsies were screened for biofilms [n = 873] with 16S rRNA fluorescent in situ hybridiation. Shotgun metagenomic sequencing [n = 265], and ki67-immunohistochemistry were performed. Associations were determined with a mixed-effects regression model.
RESULTS
Biofilms were highly prevalent in UC patients [90.8%] with a median persistence of 3 years (interquartile range [IQR] 2-5 years). Biofilm-positive biopsies showed increased epithelial hypertrophy [p = 0.025] and a reduced Shannon diversity independent of disease status [p = 0.015], but were not significantly associated with dysplasia in UC: adjusted odds ratio [aOR] 1.45, 95% confidence interval [CI] 0.63-3.40. In contrast, ClbB independently associated with dysplasia [aOR 7.16, 95% CI 1.75-29.28], and FadA and Fusobacteriales were associated with a decreased dysplasia risk in UC [aOR 0.23, 95% CI 0.06-0.83, p <0.01].
CONCLUSIONS
Biofilms are a hallmark of UC; however, because of their high prevalence are a poor biomarker for dysplasia. In contrast, colibactin presence and FadA absence independently associate with dysplasia in UC and might therefore be valuable biomarkers for future risk stratification and intervention strategies.
Topics: Humans; Colitis, Ulcerative; Prospective Studies; RNA, Ribosomal, 16S; Hyperplasia; Biomarkers
PubMed: 37243505
DOI: 10.1093/ecco-jcc/jjad092 -
Clinics in Colon and Rectal Surgery Jan 2024Patients with inflammatory bowel disease (IBD) have increased risk of colorectal cancer (CRC). The risk for CRC is positively correlated to the duration of disease,... (Review)
Review
Patients with inflammatory bowel disease (IBD) have increased risk of colorectal cancer (CRC). The risk for CRC is positively correlated to the duration of disease, extent of colonic involvement, and severity of inflammation. After 8 to 10 years of IBD diagnosis, the risk for CRC rises substantially and screening colonoscopy is recommended. Surveillance colonoscopy interval ranges from 1 to 5 years depending on patient and disease-specific risk factors. IBD patients with high risk factors such as having concomitant primary sclerosing cholangitis, moderate-to-severe inflammation, first-degree relative with CRC at early age, or history of invisible dysplasia or high-risk visible dysplasia should undergo surveillance colonoscopy in 1 year. Meanwhile, those with minimal colonic involvement or ≥2 consecutive unremarkable examinations while in continuous remission may consider extending the surveillance interval to 5 years. Advance in colonoscopy technique such as chromoendoscopy using dyes and/or image digital processing (virtual chromoendoscopy) may enhance dysplasia detection and is the preferred method for IBD surveillance. In the era of high-definition colonoscope, the practice of obtaining extensive biopsies throughout the colon remains controversial but is generally recommended to improve the detection rate of invisible dysplasia. Endoscopic surveillance in IBD has been shown to result in earlier detection of CRC and improved prognosis.
PubMed: 38188071
DOI: 10.1055/s-0043-1762558 -
Orthopaedic Journal of Sports Medicine Oct 2023Developmental dysplasia of the hip (DDH) and trochlear dysplasia (TD) are distinct pathologies with several important features in common. In addition to shared risk...
BACKGROUND
Developmental dysplasia of the hip (DDH) and trochlear dysplasia (TD) are distinct pathologies with several important features in common. In addition to shared risk factors, both forms of dysplasia cause abnormal joint kinematics and force transmission, predisposing patients to pain, injuries to cartilage and soft tissue stabilizers, and ultimately arthritis.
PURPOSE
To evaluate for an association between hip dysplasia and TD in skeletally mature patients with symptomatic hip dysplasia.
STUDY DESIGN
Cross-sectional study; Level of evidence, 3.
METHODS
A total of 48 patients with DDH who underwent periacetabular osteotomy were compared with 48 sex-matched patients who underwent hip arthroscopy for femoroacetabular impingement (FAI) between July 2014 and February 2021. All patients were skeletally mature. The Tönnis angle and lateral center-edge angle were measured on preoperative pelvis radiographs. Femoral version, trochlear depth, lateral trochlear inclination (LTI), tibial tubercle-trochlear groove distance (TTTG-d), and posterior lateral condylar angle (PLCA) were measured on preoperative magnetic resonance imaging scans of the symptomatic hip and ipsilateral knee. Continuous variables were compared between the patient groups using 2-sample tests. Interobserver reliability was measured using the intraclass correlation coefficient.
RESULTS
Patients with DDH demonstrated a reduced trochlear depth compared with patients with FAI (3.6 vs 4.6 mm; < .001). There were no differences between groups in femoral anteversion, LTI, TTTG-d, or PLCA. Two (4.2%) patients with FAI and 17 (35.4%) patients with DDH had a trochlear depth <3 mm ( < .001). One (2.1%) patient with FAI and 7 (14.6%) patients with DDH had an LTI <11° ( = .027). There was no difference between groups in frequency of a convex proximal trochlea, patient-reported ipsilateral knee pain, or ipsilateral knee procedures.
CONCLUSION
Patients with DDH had reduced trochlear depth compared with patients with FAI, demonstrating a higher incidence of dysplastic trochlear features that may predispose patients to patellofemoral joint disease. Further research is needed to determine whether screening at-risk patients and treating TD will help to prevent symptomatic patellofemoral disease.
PubMed: 37822419
DOI: 10.1177/23259671231200805 -
Clinical Medicine Insights. Arthritis... 2023Hip osteoarthritis (HOA) is a growing burden and one of the leading causes of hip pain. The relationship between the HOA and the alignment of the spinopelvic region has...
BACKGROUND
Hip osteoarthritis (HOA) is a growing burden and one of the leading causes of hip pain. The relationship between the HOA and the alignment of the spinopelvic region has been intensively studied, however the issue remains controversial. Spinopelvic imbalance, HOA, and dysplasia were investigated in relation to sagittal spinopelvic parameters in this study.
METHODS
We collected computerized tomography (CT) topograms of the pelvis or abdomen from 380 patients. In antero-posterior (AP) topograms, Tonnis grading, center-edge angle (CEA) and Sharp's acetabular angle (AA) measurements were performed on each patient. Lateral topograms were used to evaluate the following spinopelvic parameters for each patient: pelvic incidence (PI), pelvic tilt (PT), sacral slope (SS), sacral table angle (STA), lumbar lordosis (LL), proximal lumbar lordosis (PLL), distal lumbar lordosis (DLL), and PI-LL difference. Initially, the cohort was divided into two subgroups based on whether or not they had HOA. Then, they were divided into two subgroups based on whether or not they had dysplasia. Ultimately, it was divided in half based on the PI-LL imbalance. Statistical analyses were conducted to determine the likely correlations between the spinopelvic parameters of these subgroups. In addition, the correlations between spinopelvic parameters were investigated.
RESULTS
There were 380 patients evaluated. We found no association between HOA or dysplasia and spinopelvic parameters. In addition, there was no association between PI-LL imbalance and HOA or dysplasia.
CONCLUSION
There was no difference in constant PI and STA angle, besides other variable parameters, between groups having HOA and dysplasia or not. PI-LL imbalance has no effect on HOA and dysplasia.
PubMed: 37701625
DOI: 10.1177/11795441231191790 -
Current Reviews in Musculoskeletal... Nov 2023The most common and biomechanically influential pathoanatomic risk factor for recurrent patellofemoral instability is trochlear dysplasia. Sulcus-deepening... (Review)
Review
PURPOSE OF REVIEW
The most common and biomechanically influential pathoanatomic risk factor for recurrent patellofemoral instability is trochlear dysplasia. Sulcus-deepening trochleoplasty is a procedure developed to address high-grade trochlear dysplasia in the setting of patellofemoral instability. The purpose of this paper is to outline the current classification and surgical management of trochlear dysplasia as well as to review the current literature on the clinical outcomes and complications of sulcus-deepening trochleoplasty.
RECENT FINDINGS
This review outlines the most recent literature reporting evidence behind the decision-making to perform a trochleoplasty in the setting of patellofemoral instability and high-grade trochlear dysplasia. Critical parameters include grade of trochlear dysplasia, severity of symptoms, pertinent physical examination findings, surgical techniques, modifications for skeletally immature patients, and considerations for the revision setting. Historic studies have elicited concerns regarding high reported complication rates for trochleoplasty; however, recent studies consistently report good clinical outcomes and acceptable complication rates, similar to those of other patellar stabilizing procedures. The addition of a trochleoplasty in patients with high-grade dysplasia results in a lower re-dislocation rate, significant improvements in patient-reported outcome measures (PROMs) as well as high levels of patient satisfaction and return to sport. The use of sulcus-deepening trochleoplasty for the treatment of high-grade dysplasia and recurrent patellofemoral instability is a well-established technique with good outcomes and an acceptable complication profile. In patients with high-grade dysplasia, trochleoplasty results in lower re-dislocation rates, high patient satisfaction scores, and good clinical and functional outcomes. An understanding of trochleoplasty and its indications should be in the armamentarium of surgeons treating patellofemoral instability.
PubMed: 37698757
DOI: 10.1007/s12178-023-09868-6 -
Biomedicines Sep 2023Infants with the most severe forms of bronchopulmonary dysplasia (BPD) may require long-term invasive positive pressure ventilation for survival, therefore necessitating... (Review)
Review
Infants with the most severe forms of bronchopulmonary dysplasia (BPD) may require long-term invasive positive pressure ventilation for survival, therefore necessitating tracheostomy. Although life-saving, tracheostomy has also been associated with high mortality, postoperative complications, high readmission rates, neurodevelopmental impairment, and significant caregiver burden, making it a highly complex and challenging decision. However, for some infants tracheostomy may be necessary for survival and the only way to facilitate a timely and safe transition home. The specific indications for tracheostomy and the timing of the procedure in infants with severe BPD are currently unknown. Hence, centers and clinicians display broad variations in practice with regard to tracheostomy, which presents barriers to designing evidence-generating studies and establishing a consensus approach. As the incidence of severe BPD continues to rise, the question remains, how do we decide on tracheostomy to provide optimal outcomes for these patients?
PubMed: 37761012
DOI: 10.3390/biomedicines11092572 -
Frontiers in Neurology 2024Lateral semicircular canal (LSCC) dysplasia is the most common inner ear malformation. The severity of dysplasia can appear in various spectrums, from a short and broad...
INTRODUCTION
Lateral semicircular canal (LSCC) dysplasia is the most common inner ear malformation. The severity of dysplasia can appear in various spectrums, from a short and broad LSCC with normal or small-sized central bony island (CBI) to a single fluid-filled cavity confluent with the vestibule without CBI. However, reports on the association between LSCC dysplasia and the loss of vestibular function are still lacking. In this study, the results of vestibular function tests [caloric test and video-head impulse test (vHIT)] in patients with LSCC dysplasia were analyzed and compared between groups with and without CBI.
METHODS
This study retrospectively enrolled 17 patients (23 ears) who had LSCC dysplasia following computed tomography or magnetic resonance imaging and underwent vestibular function tests.
RESULTS
LSCC dysplasia was observed unilaterally in 11 patients and bilaterally in six patients. Nine of 23 ears had CBIs, and 14 ears had no CBI. Three of 17 patients experienced dizziness. Abnormal caloric tests were detected in 11 of the 16 patients who underwent the caloric tests (69%); in contrast, 11 of 12 patients who underwent the vHIT (92%) had normal LSCC vestibulo-ocular reflex (VOR) gain on vHIT. A significant correlation was found between the maximum slow-phase velocity of the caloric test and LSCC VOR gain of the vHIT (correlation coefficient 0.792, = 0.004). The CBI-absent group showed significantly lower SPV and LSCC VOR gains than the CBI-present group ( = 0.001 and 0.004, respectively).
DISCUSSION
LSCC dysplasia impairs VOR function, especially in the absence of CBI.
PubMed: 38299016
DOI: 10.3389/fneur.2024.1341812 -
American Journal of Human Genetics Sep 2023Sclerosing skeletal dysplasias result from an imbalance between bone formation and resorption. We identified three homozygous, C-terminally truncating AXIN1 variants in...
Sclerosing skeletal dysplasias result from an imbalance between bone formation and resorption. We identified three homozygous, C-terminally truncating AXIN1 variants in seven individuals from four families affected by macrocephaly, cranial hyperostosis, and vertebral endplate sclerosis. Other frequent findings included hip dysplasia, heart malformations, variable developmental delay, and hematological anomalies. In line with AXIN1 being a central component of the β-catenin destruction complex, analyses of primary and genome-edited cells harboring the truncating variants revealed enhanced basal canonical Wnt pathway activity. All three AXIN1-truncating variants resulted in reduced protein levels and impaired AXIN1 polymerization mediated by its C-terminal DIX domain but partially retained Wnt-inhibitory function upon overexpression. Addition of a tankyrase inhibitor attenuated Wnt overactivity in the AXIN1-mutant model systems. Our data suggest that AXIN1 coordinates the action of osteoblasts and osteoclasts and that tankyrase inhibitors can attenuate the effects of AXIN1 hypomorphic variants.
Topics: Humans; Tankyrases; Hip Dislocation; Axin Protein; Wnt Signaling Pathway; Osteosclerosis; beta Catenin
PubMed: 37582359
DOI: 10.1016/j.ajhg.2023.07.011 -
World Journal of Orthopedics May 2024Combined femoral and acetabular anteversion is the sum of femoral and acetabular anteversion, representing their morphological relationship in the axial plane. Along...
Combined femoral and acetabular anteversion is the sum of femoral and acetabular anteversion, representing their morphological relationship in the axial plane. Along with the increasing understanding of hip dysplasia in recent years, numerous scholars have confirmed the role of combined femoral and acetabular anteversion in the pathological changes of hip dysplasia. At present, the reconstructive surgery for hip dysplasia includes total hip replacement and redirectional hip preservation surgery. As an important surgery index, combined femoral and acetabular anteversion have a crucial role in these surgeries. Herein, we discuss the role of combined femoral and acetabular anteversion in pathological changes of hip dysplasia, total hip replacement, and redirectional hip preservation surgery.
PubMed: 38835688
DOI: 10.5312/wjo.v15.i5.390