Search

Familial Dysautonomia (FD) is an autosomal recessive disorder caused by a splice site mutation in the gene ELP1, which disproportionally affects neurons. While classically characterized by deficits in sensory and autonomic neurons, neuronal defects in the central nervous system have also been described. Although ELP1 expression remains high in the normal developing and adult cerebellum, its role in cerebellar development is unknown. To explore the role of Elp1 in the cerebellum, we knocked out Elp1 in cerebellar granule cell progenitors (GCPs) and examined the outcome on animal behavior and cellular composition. We found that GCP-specific conditional knockout of Elp1 (Elp1cKO) resulted in ataxia by 8 weeks of age. Cellular characterization showed that the animals had smaller cerebella with fewer granule cells. This defect was already apparent as early as 7 days after birth, when Elp1cKO animals also had fewer mitotic GCPs and shorter Purkinje dendrites. Through molecular characterization, we found that loss of Elp1 was associated with an increase in apoptotic cell death and cell stress pathways in GCPs. Our study demonstrates the importance of ELP1 in the developing cerebellum, and suggests that loss of Elp1 in the GC lineage may also play a role in the progressive ataxia phenotypes of FD patients.

Background: Degenerative cervical radiculopathy results from nerve root compression in the cervical neural foramina, often due to a herniated disc, osteophyte, or facetal/ligamentum flavum hypertrophy. Typically, 80% of patients show improvement within the initial 12 weeks through nonoperative measures, with surgical intervention considered for non-responders. This study aimed to compare clinical and radiological outcomes in cervical radiculopathy patients undergoing prolonged conservative care, anterior cervical discectomy and fusion (ACDF), or anterior cervical disc replacement (ACDR) after a 1‐year follow‐up. Materials and Methods: Our study was a retrospective single‐center study involving 780 cervical radiculopathy patients from January 2012 to December 2021. About 80.12% found relief with conservative management within 12 weeks. Remaining 155 patients were offered surgery, with 73 opting for continued conservative care, and 82 undergoing surgery (55 with ACDF and 27 with ACDR). Evaluation was done using visual analogue scale (VAS), Neck Disability Index (NDI), and radiographic parameters. Results: The mean follow‐up was 11.58 ± 6.7 months. ACDR group: Mean age 43.38 ± 8.56, VAS 7.81 ± 1.04 preoperatively, improved significantly to 2.07 ± 1.34 (P < 0.05) at 1‐year follow‐up. ACDF group: Mean age 44.85 ± 10.65, VAS 8.22 ± 1.21 preoperatively, improved significantly to 2.09 ± 1.01 (P < 0.05) at 1‐year follow‐up. Conservative group: Mean age 45.04 ± 11.19, VAS 7.77 ± 1.86 preoperatively, improved significantly to 2.08 ± 1.40 (P < 0.05) at 1‐year follow‐up. Radiographic parameters significantly improved in all groups at 1‐year follow‐up (P < 0.05). Range of motion (ROM) changes varied across groups. Miyazaki’s grading and Kim’s score showed comparable results. Conclusion: Comparable clinical and radiological outcomes were observed among conservative, ACDF, and ACDR approaches. ACDR approach demonstrated a better NDI score outcome. Neck ROM was better maintained or improved in the ACDR approach, decreased in ACDF, and remained almost similar in the conservative group.

Abstract Medulloblastomas with extensive nodularity are cerebellar tumors characterized by two distinct compartments and variable disease progression. The mechanisms governing the balance between proliferation and differentiation in MBEN remain poorly understood. Here, we employ a multi-modal single cell transcriptome analysis to dissect this process. In the internodular compartment, we identify proliferating cerebellar granular neuronal precursor-like malignant cells, along with stromal, vascular, and immune cells. In contrast, the nodular compartment comprises postmitotic, neuronally differentiated malignant cells. Both compartments are connected through an intermediate cell stage resembling actively migrating CGNPs. Notably, we also discover astrocytic-like malignant cells, found in proximity to migrating and differentiated cells at the transition zone between the two compartments. Our study sheds light on the spatial tissue organization and its link to the developmental trajectory, resulting in a more benign tumor phenotype. This integrative approach holds promise to explore intercompartmental interactions in other cancers with varying histology.

Abstract Introduction Cardiac resynchronization therapy (CRT) device insertion comprises of a transvenous pacing lead implanted in posterolateral branch of the coronary sinus (CS) for left ventricular (LV) pacing, in addition to leads in the right ventricle and right atrium. In patients undergoing CRT device implantation, failure of CS cannulation was earlier reported to be around 10% but has come down to about 4% in recent years. Although the use of electrophysiology (EP) catheter has been reported during CRT procedures but femoral approach to place decapolar catheter as fluoroscopic guide for CS ostium cannulation during LV lead implantation has not been evaluated. Materials and methods The aim of the study was to compare fluoroscopy time during CRT procedure between conventional technique and using decapolar EP catheter via femoral approach as fluoroscopic marker to cannulate CS. Results This study included 21 patients. Group 1 (using decapolar catheter) had 12 patients and group 2 (using the conventional technique) had 9 patients. CS cannulation was successful in all 21 cases. The mean fluoroscopy time for the CS cannulation and LV lead placement in group 1 was 10.7 (±1.03) min and in group 2 was 19.1 (±1.51) min. This difference in mean fluoroscopy time for the CS cannulation and LV lead placement was statistically significant with p

Introduction: Acute coronary syndrome (ACS) in very young adults with age ≤30 years is rare. In India, the prevalence of acute myocardial infarction (AMI) in this population is

Introduction: Left ventricular (LV) thrombus is a known complication of myocardial infarction (MI) and it usually occurs in areas of poorly contracting LV muscle as a result of endocardial injury with associated inflammation. There is a high risk of embolization within 3 months among patients with MI complicated by mural thrombus and this risk is maximum during the first 1–2 weeks. We report a case series of five patients who presented with acute coronary syndrome with LV apical thrombus and treated with triple anti-thrombotic therapy of rivaroxaban, aspirin, and clopidogrel. Case Series: Our series involves 5 cases who developed LV apical thrombus after acute coronary syndrome. Four patients had anterior wall ST-elevation MI (STEMI) whereas 1 patient had inferior wall STEMI. One of the patients with anterior STEMI also had COVID pneumonitis. All of these patients received triple anti-thrombotic therapy consisting of tab Aspirin 75 mg OD, tab clopidogrel 75 mg OD, and tab rivaroxaban 20 mg OD for 3 months duration. Repeat ECHO after 3 months showed complete resolution of LV thrombus in all of our cases. Discussion: LV thrombus reported in STEMI patients is from 1.6% up to 39% in various studies. The incidence of LV thrombus is on decreasing trend as a result of modern revascularization strategies. The role of novel oral anticoagulants (NOACs) in treating LV thrombus is scant as compared to oral Vitamin K antagonists (VKAs) like warfarin. The current recommendation for anticoagulation in the presence of a LV thrombus after acute coronary syndrome is with VKAs for up to 6 months. Conclusion: Although there is uncertainty in decision-making regarding antithrombotic therapy, our case series demonstrate that triple antithrombotic therapy with NOACs results in resolution of LV thrombus without any additional bleeding events in patients presenting with acute coronary syndrome. NOACs have an advantage of not requiring PT/INR monitoring and have less bleeding complications. Further large-scale research or randomized controlled trials are needed to find the optimal therapies in such cases.

Right ventricular outflow tract tachycardia is a type of monomorphic VT which originates from the outflow tract of the right ventricle or occasionally from the tricuspid annulus. It usually occurs in structurally normal heart but can also occur in patients with structural heart disease. A 45 year old male was referred to our hospital for EP study and RF ablation. Patient had multiple episodes of palpitations in the past 1 month and these were diagnosed as episode of ventricular tachycardia which were reverted each time with Direct Current Cardioversion in another hospital. Patient was diagnosed as case of RVOT VT, Double Chamber Right Ventricle, outlet VSD (restrictive) with RVOT aneurysm. He was managed conservatively and advised surgical repair.

Abstract Lesch-Nyhan disease (LND) is an inherited disorder caused by pathogenic variants in the HPRT1 gene, which encodes the purine recycling enzyme hypoxanthine–guanine phosphoribosyltransferase (HGprt). We generated 6 induced pluripotent stem cell (iPSC) lines from 3 individuals with LND, along with 6 control lines from 3 normal individuals. All 12 lines had the characteristics of pluripotent stem cells, as assessed by immunostaining for pluripotency markers, expression of pluripotency genes, and differentiation into the 3 primary germ cell layers. Gene expression profiling with RNAseq demonstrated significant heterogeneity among the lines. Despite this heterogeneity, several anticipated abnormalities were readily detectable across all LND lines, including reduced HPRT1 mRNA. Several unexpected abnormalities were also consistently detectable across the LND lines, including decreases in FAR2P1 and increases in RNF39. Shotgun proteomics also demonstrated several expected abnormalities in the LND lines, such as absence of HGprt protein. The proteomics study also revealed several unexpected abnormalities across the LND lines, including increases in GNAO1 decreases in NSE4A. There was a good but partial correlation between abnormalities revealed by the RNAseq and proteomics methods. Finally, functional studies demonstrated LND lines had no HGprt enzyme activity and resistance to the toxic pro-drug 6-thioguanine. Intracellular purines in the LND lines were normal, but they did not recycle hypoxanthine. These cells provide a novel resource to reveal insights into the relevance of heterogeneity among iPSC lines and applications for modeling LND.

Renal medullary carcinomas (RMC) are rare aggressive tumors of the kidneys, characterized by a loss of SMARCB1. Characteristically, these tumors arise in patients with sickle cell trait or other hemoglobinopathies. Recent characterization efforts have unraveled oncogenic pathways that drive tumorigenesis. Among these, gene sets that characterize replicative stress and the innate immune response are upregulated in RMCs. Despite comprehensive genetic and transcriptomic characterizations, commonalities or differences to other SMARCB1 deficient entities so far have not been investigated. We analyzed the methylome of seven primary RMC and compared it to other SMARCB1 deficient entities such as rhabdoid tumors (RT) and epithelioid sarcomas using 850 K methylation arrays. Moreover, we evaluated the differential gene expression of RMC using RNA-sequencing in comparison to other rhabdoid tumors. In accordance with previous gene expression data, we found that RMCs separate from other SMARCB1 deficient entities, pointing to a potentially different cell of origin and a role of additional genetic aberrations that may drive tumorigenesis and thus alter the methylome when compared to rhabdoid tumors. In a focused analysis of genes that are important for nephrogenesis, we particularly detected genes that govern early nephrogenesis such as FOXI1 to be hypomethylated and expressed at high levels in RMC. Overall, our analyses underscore the fact that RMCs represent a separate entity with limited similarities to rhabdoid tumors, warranting specific treatment tailored to the aggressiveness of the disease.

Research in the stem cell field has traditionally focused on understanding key transcriptional factors that provide pluripotent cell identity. However, much less is known about other critical non-transcriptional signaling networks that govern stem cell identity. Although we continue to gain critical insights into the mechanisms underlying mitochondrial morphology and function during cellular reprogramming – the process of reverting the fate of a differentiated cell into a stem cell, many uncertainties remain. Recent studies suggest an emerging landscape in which mitochondrial morphology and function have an active role in maintaining and regulating changes in cell identity. In this review, we will focus on these emerging concepts as crucial modulators of cellular reprogramming. Recognition of the widespread applicability of these concepts will increase our understanding of the mitochondrial mechanisms involved in cell identity, cell fate and disease.

CUL9 is a non-canonical and poorly characterized member of the largest family of E3 ubiquitin ligases known as the Cullin RING ligases (CRLs). Most CRLs play a critical role in developmental processes, however, the role of CUL9 in neuronal development remains elusive. We determined that deletion or depletion of CUL9 protein causes aberrant formation of neural rosettes, an in vitro model of early neuralization. In this study, we applied mass spectrometric approaches in human pluripotent stem cells (hPSCs) and neural progenitor cells (hNPCs) to identify CUL9 related signaling pathways that may contribute to this phenotype. Through LC-MS/MS analysis of immunoprecipitated endogenous CUL9, we identified several subunits of the APC/C, a major cell cycle regulator, as potential CUL9 interacting proteins. Knockdown of the APC/C adapter protein FZR1 resulted in a significant increase in CUL9 protein levels, however, CUL9 does not appear to affect protein abundance of APC/C subunits and adapters or alter cell cycle progression. Quantitative proteomic analysis of CUL9 KO hPSCs and hNPCs identified protein networks related to metabolic, ubiquitin degradation, and transcriptional regulation pathways that are disrupted by CUL9 deletion in both hPSCs. No significant changes in oxygen consumption rates or ATP production were detected in either cell type. The results of our study build on current evidence that CUL9 may have unique functions in different cell types and that compensatory mechanisms may contribute to the difficulty of identifying CUL9 substrates.

Medulloblastoma is the most common malignant pediatric brain tumor with high fatality rate. Recent large-scale studies utilizing genome-wide technologies have sub-grouped medulloblastomas into four major subgroups: wingless (WNT), sonic hedgehog (SHH), group 3, and group 4. However, there has yet to be a global analysis of long non-coding RNAs, a crucial part of the regulatory transcriptome, in medulloblastoma. Here, we performed bioinformatic analysis of RNA-seq data from 175 medulloblastoma patients. Differential lncRNA expression sub-grouped medulloblastomas into the four main molecular subgroups. Some of these lncRNAs were subgroup-specific, with a random forest-based machine-learning algorithm identifying an 11-lncRNA diagnostic signature. We also validated the diagnostic signature in patient derived xenograft (PDX) models. We further identified a 17-lncRNA prognostic model using LASSO based penalized Cox’ PH model (Score HR = 13.6301, 95% CI = 8.857–20.98, logrank p-value ≤ 2e-16). Our analysis represents the first global lncRNA analysis in medulloblastoma. Our results identify putative candidate lncRNAs that could be evaluated for their functional role in medulloblastoma genesis and progression or as diagnostic and prognostic biomarkers.

Cellular differentiation is a tightly regulated process under the control of intricate signaling and transcription factors interaction network working in coordination. These interactions make the systems dynamic, robust and stable but also difficult to dissect. In the spinal cord, recent work has shown that a network of FGF, WNT and Retinoic Acid (RA) signaling factors regulate neural maturation by directing the activity of a transcription factor network that contains CDX at its core. Here we have used partial and ordinary (Hill) differential equation based models to understand the spatiotemporal dynamics of the FGF/WNT/RA and the CDX/transcription factor networks, alone and in combination. We show that in both networks, the strength of interaction among network partners impacts the dynamics, behavior and output of the system. In the signaling network, interaction strength determine the position and size of discrete regions of cell differentiation and small changes in the strength of the interactions among networking partners can result in a signal overriding, balancing or oscillating with another signal. We also show that the spatiotemporal information generated by the signaling network can be conveyed to the CDX/transcription network to produces a transition zone that separates regions of high cell potency from regions of cell differentiation, in agreement with most in vivo observations. Importantly, one emerging property of the networks is their robustness to extrinsic disturbances, which allows the system to retain or canalize NP cells in developmental trajectories. This analysis provides a model for the interaction conditions underlying spinal cord cell maturation during embryonic axial elongation.

This paper proposes a no-reference quality assessment technique to assess the quality of images that is degraded due to blur and noise. The technique is motivated from the fact that when distortion occurs in a natural image, its naturalness gets disturbed. We analyze this disturbance using continuous-wavelet transform in order to assess the quality of the image. The proposed image quality estimation technique is free from training and prior knowledge of the distortion (noise or blur) present in the image. The technique is being evaluated on LIVE and CSIQ databases, and the obtained results are found very similar with subjective scores provided by the databases. It is observed from the obtained results that the proposed technique outperforms the latest state-of-the-art techniques.

Abstract Huntington’s disease is characterized by a complex and heterogeneous pathogenic profile. Studies have shown that disturbance in lipid homeostasis may represent a critical determinant in the progression of several neurodegenerative disorders. The recognition of perturbed lipid metabolism is only recently becoming evident in HD. In order to provide more insight into the nature of such a perturbation and into the effect its modulation may have in HD pathology, we investigated the metabolism of Sphingosine-1-phosphate (S1P), one of the most important bioactive lipids, in both animal models and patient samples. Here, we demonstrated that S1P metabolism is significantly disrupted in HD even at early stage of the disease and importantly, we revealed that such a dysfunction represents a common denominator among multiple disease models ranging from cells to humans through mouse models. Interestingly, the in vitro anti-apoptotic and the pro-survival actions seen after modulation of S1P-metabolizing enzymes allows this axis to emerge as a new druggable target and unfolds its promising therapeutic potential for the development of more effective and targeted interventions against this incurable condition.

Introduction: Screening mammography is used for detection of breast cancer and is interpreted using the Breast Image Reporting and Data System (BIRADS) convention. It is not routinely offered to women in countries which do not have a national screening programme resulting in a challenge for the radiologist who has to interpret these in the absence of previous mammograms. Aim: To analyse benign and probably benign lesions in screening mammograms in a hitherto unscreened population and suggest protocols to increase diagnostic confidence. Materials and Methods: Screening mammograms of 362 asymptomatic women in the age range of 40 to 60 years carried out over a two year period were retrospectively analysed. Patients of breast cancer and those who had palpable lumps were excluded from the study. All images were analysed in standard Mediolateral Oblique (MLO) and Craniocaudal (CC) projections with additional views wherever necessary. Corroborative ultrasound had been carried out wherever indicated in the opinion of the interpreting radiologist. The mammograms were finally classified according to the BIRADS convention. Results: Of the total number of 362 women screened, most of whom did not have any previous mammogram, 162 were reported as BIRADS I, 179 as BIRADS II and 18 as BIRADS III. The mammograms reported as BIRADS II had various findings including dystrophic calcification/macrocalcification, vascular calcification, simple cysts and fibroadenomas. Only 26 (16.04%) of the BIRADS I mammograms had undergone further evaluation with Ultrasound (US) due to dense breasts or asymmetrical involution of breast tissue whereas 76 (42.5%) of the BIRADS II mammograms had undergone further evaluation with US to characterize lesions like cysts and fibroadenomas, but occasionally also for benign clustered calcification. Of BIRADS III mammograms, 12 (66.6%) had required US correlation to exclude a mass in cases with dense breasts. The increased likelihood of ultrasound corroboration in BIRADS II and BIRADS III was analysed using the Chi square test and was statistically significant. Conclusion: In the absence of previous screening mammograms, a small number of BIRADS I mammograms and a significant number of BIRADS II and BIRADS III mammograms undergo a corroborative US examination. The addition of supplemental US to the evaluation of these lesions increase diagnostic confidence and lesion characterization in a population which is not subject to routine screening.

Proximal focal femoral deficiency (PFFD) is a rare congenital anomaly resulting in limb shortening and disability in young. The exact cause of the disease is not known and it may present as varying grades of affection involving the proximal femur and the acetabulum. Recognition of this rare abnormality on radiographs can help manage these cases better since early institution of therapy may help in achieving adequate growth of the femur.

Background: Image quality in an Intravenous Urogram (IVU) can occasionally be compromised by variables like bowel preparation, renal function and radiographic factors, posing a challenge to all Uroradiologists. The Computerised Tomography Urogram (CTU) yields better diagnostic information than an IVU, due to its inherent superior anatomic delineation and contrast sensitivity, against a trade-off involving radiation dose and cost. Our study was conducted to assess the utility and timing of performing a single-phase CTU, as a problem-solving tool, to clear the diagnostic dilemma in a selected subset of patients, in whom an ongoing IVU could potentially be inconclusive. Material and Methods: Five hundred and twelve patients who underwent IVU studies for urologic referrals at a tertiary care hospital, during the period of January to December 2009, formed the subject of the study, of whom 33 patients with inconclusive IVU findings after the first three radiographs underwent a single-phase CTU, to reach definitive imaging diagnoses. Results: The percentage of inconclusive IVU studies amounted to only 33 / 512 (6.4%), in whom a CTU study revealed definitive diagnoses in 30 patients and no abnormality in three patients, thus conclusively clearing the ambiguities raised on the IVU in all the selected patients. Conclusions: The concept of a CTU limited to a single-phase study to supplement an inconclusive IVU optimizes the contrast and radiation dose to the affected patients. It is a cost-effective, timely, and definitive ′imaging intervention′ and should be considered a viable hybrid technique to be utilized selectively and judiciously.