Progeria-based vascular model identifies networks associated with cardiovascular aging and disease.

Hutchinson-Gilford Progeria syndrome (HGPS) is a lethal premature aging disorder caused by a de novo heterozygous mutation that leads to the accumulation of a splicing isoform of Lamin A termed progerin. Progerin expression deregulates the organization of the nuclear lamina and the epigenetic landscape. Progerin has also been observed to accumulate at low levels during normal aging in cardiovascular cells of adults that do not carry genetic mutations linked with HGPS. Therefore, the molecular mechanisms that lead to vascular dysfunction in HGPS may also play a role in vascular aging-associated diseases, such as myocardial infarction and stroke. Here, we show that HGPS patient-derived vascular smooth muscle cells (VSMCs) recapitulate HGPS molecular hallmarks. Transcriptional profiling revealed cardiovascular disease remodeling and reactive oxidative stress response activation in HGPS VSMCs. Proteomic analyses identified abnormal acetylation programs in HGPS VSMC replication fork complexes, resulting in reduced H4K16 acetylation. Analysis of acetylation kinetics revealed both upregulation of K16 deacetylation and downregulation of K16 acetylation. This correlates with abnormal accumulation of error-prone nonhomologous end joining (NHEJ) repair proteins on newly replicated chromatin. The knockdown of the histone acetyltransferase MOF recapitulates preferential engagement of NHEJ repair activity in control VSMCs. Additionally, we find that primary donor-derived coronary artery vascular smooth muscle cells from aged individuals show similar defects to HGPS VSMCs, including loss of H4K16 acetylation. Altogether, we provide insight into the molecular mechanisms underlying vascular complications associated with HGPS patients and normative aging.

Targeting CD73 with flavonoids inhibits cancer stem cells and increases lymphocyte infiltration in a triple-negative breast cancer mouse model.

Introduction: Chemotherapy remains the mainstay treatment for triple-negative breast cancer (TNBC) due to the lack of specific targets. Given a modest response of immune checkpoint inhibitors in TNBC patients, improving immunotherapy is an urgent and crucial task in this field. CD73 has emerged as a novel immunotherapeutic target, given its elevated expression on tumor, stromal, and specific immune cells, and its established role in inhibiting anti-cancer immunity. CD73-generated adenosine suppresses immunity by attenuating tumor-infiltrating T- and NK-cell activation, while amplifying regulatory T cell activation. Chemotherapy often leads to increased CD73 expression and activity, further suppressing anti-tumor immunity. While debulking the tumor mass, chemotherapy also enriches heterogenous cancer stem cells (CSC), potentially leading to tumor relapse. Therefore, drugs targeting both CD73, and CSCs hold promise for enhancing chemotherapy efficacy, overcoming treatment resistance, and improving clinical outcomes. However, safe and effective inhibitors of CD73 have not been developed as of now. Methods: We used in silico docking to screen compounds that may be repurposed for inhibiting CD73. The efficacy of these compounds was investigated through flow cytometry, RT-qPCR, CD73 activity, cell viability, tumorsphere formation, and other in vitro functional assays. For assessment of clinical translatability, TNBC patient-derived xenograft organotypic cultures were utilized. We also employed the ovalbumin-expressing AT3 TNBC mouse model to evaluate tumor-specific lymphocyte responses. Results: We identified quercetin and luteolin, currently used as over-the-counter supplements, to have high in silico complementarity with CD73. When quercetin and luteolin were combined with the chemotherapeutic paclitaxel in a triple-drug regimen, we found an effective downregulation in paclitaxel-enhanced CD73 and CSC-promoting pathways YAP and Wnt. We found that CD73 expression was required for the maintenance of CD44highCD24low CSCs, and co-targeting CD73, YAP, and Wnt effectively suppressed the growth of human TNBC cell lines and patient-derived xenograft organotypic cultures. Furthermore, triple-drug combination inhibited paclitaxel-enriched CSCs and simultaneously improved lymphocyte infiltration in syngeneic TNBC mouse tumors. Discussion: Conclusively, our findings elucidate the significance of CSCs in impairing anti-tumor immunity. The high efficacy of our triple-drug regimen in clinically relevant platforms not only underscores the importance for further mechanistic investigations but also paves the way for potential development of new, safe, and cost-effective therapeutic strategies for TNBC.

Segawa Syndrome, a Dramatic Response to Dopamine.

Segawa syndrome usually manifests as dystonia, disturbance of gait with fatigue, and may be confused with spasticity. Also known as dopamine-responsive dystonia (DRD), it should be considered in any child who presents with paroxysmal or progressive hypertonia of unknown etiology, which responds dramatically to levodopa. It is a clinical diagnosis, but the level of pterins in cerebrospinal fluid and guanosine triphosphate cyclohydrolase-1 (GTCH 1) gene mutation testing done by molecular genetic testing are confirmatory. Our case is a 45-year female with a family history of similar illness expressed as autosomal recessive inheritance pattern. She had symptoms onset at an early age of 13 years with features of dystonia of predominantly lower limbs, hence the inability to maintain posture and walk. Dramatic improvement with levodopa but sudden deterioration to dystonia due to noncompliance was evident in our patient with troublesome features of concomitant adjustment disorder during presentation.

Knowledge and Attitude about Labor Epidural Analgesia among Pregnant Women Attending Antenatal Clinic.

BACKGROUND: Labour pain is one of the most painful experiences that a woman faces in her lifetime. There are various options for labour pain management. Epidural analgesia is the gold standard method for pain management during labour. In developing and under-developed countries there are many challenges to provide this service, a very important one being knowledge about epidural analgesia among the parturients and the physicians. METHODS: A prospective cross-sectional study was carried out among 384 pregnant women attending Antenatal clinic of a tertiary level teaching hospital using pretested structured questionnaire prepared by a team of anaesthesiologists and obstetricians. Non-probability purposive sampling technique was used. The data was analysed by using SPSS version 20.0. Descriptive and inferential statistical methods were used for analysis. RESULTS: Of the 384 pregnant women, only 29.4% had knowledge about some form of labour analgesia techniques and only 16% of the participants were aware of labour epidural analgesia. Also, only 6.2% were aware that epidural service is available at our hospital. Regarding acceptance, only 42.4% were willing to use epidural analgesia in their present pregnancy. CONCLUSIONS: The present study findings revealed that a significant number of participants had very limited knowledge about labour epidural analgesia and were also unaware of the availability of the service in our hospital. Educational programs need to be provided to all the pregnant women for enhancement of knowledge and awareness about epidural labour analgesia to increase its acceptability among them.

Citrullination and the protein code: crosstalk between post-translational modifications in cancer.

Post-translational modifications (PTMs) of proteins are central to epigenetic regulation and cellular signalling, playing an important role in the pathogenesis and progression of numerous diseases. Growing evidence indicates that protein arginine citrullination, catalysed by peptidylarginine deiminases (PADs), is involved in many aspects of molecular and cell biology and is emerging as a potential druggable target in multiple diseases including cancer. However, we are only just beginning to understand the molecular activities of PADs, and their underlying mechanistic details in vivo under both physiological and pathological conditions. Many questions still remain regarding the dynamic cellular functions of citrullination and its interplay with other types of PTMs. This review, therefore, discusses the known functions of PADs with a focus on cancer biology, highlighting the cross-talk between citrullination and other types of PTMs, and how this interplay regulates downstream biological events. This article is part of the Theo Murphy meeting issue 'The virtues and vices of protein citrullination'.

Levetiracetam-Induced Acute Psychosis in an Adolescent.

Levetiracetam (LEV), a second-generation antiepileptic, is used as an adjunct therapy in primary generalized tonic-clonic seizures, refractory partial-onset seizures, and seizure prophylaxis after brain surgery. It is well tolerated, effective and has a convenient dosing regimen. As any other drugs, it has some adverse drug effects, including neuropsychiatric adverse effects ranging from agitation and mood symptoms to psychosis and suicide. Strong diagnostics guidelines are yet to be formulated for LEV-induced psychosis; however, complete recovery from psychotic symptoms after stopping LEV supports the possible adverse reaction from Naranjo's algorithm and, hence, the diagnosis. This case report presents a 16 years boy with focal onset generalized tonic-clonic seizure, whose drug regimen was switched to LEV, following which he had the delusion of persecution, second-person auditory hallucination, and aggressive behavior, which decreased on the 2nd day of cessation of LEV.

Correlation of Body Mass Index and Oxygen Saturation in Chronic Obstructive Pulmonary Disease Patients at a Tertiary Care Center in Nepal: A Cross-Sectional Study.

Purpose: Chronic obstructive pulmonary disease (COPD) is a major cause of mortality and morbidity worldwide. COPD is associated with clinically relevant pulmonary and extrapulmonary manifestations, including hypoxemia and weight loss. The correlation of body mass index (BMI) and oxygen saturation (SpO2) with COPD grades may provide a useful additional marker for understanding and managing the disease. The aim of the study was to study the correlation of BMI and oxygen saturation with COPD in patients presenting to a tertiary care center in Nepal. Patients and Methods: A descriptive cross-sectional study was conducted among 145 COPD patients visiting the Department of Medicine in Shree Birendra Hospital between 1 March 2019 and 28 February 2020. A non-probability purposive sampling method was used and data were analyzed using SPSS version 21. A p-value of <0.05 was considered significant. Results: Out of 145 COPD patients, 58 (40%) were underweight, 53 (36.55%) were of normal weight, 20 (13.79%) were overweight, and 14 (9.6%) were obese. The number of underweight patients was highest in COPD grade 4 and lowest in COPD grade 1. The proportion of subjects with underweight BMI and hypoxia increased with COPD severity, and both were statistically significant (p-values <0.01). Conclusion: Our study shows that BMI and oxygen saturation have an inverse association with COPD severity. The correlation of BMI and oxygen saturation with COPD grade could provide a supplementary marker of disease severity, which could be useful in the understanding of the disease process and subsequent management of COPD.

Mean Brixia Severity Scores among Symptomatic COVID-19 Patients in a Tertiary Care Centre: A Descriptive Cross-sectional Study.

Introduction: COVID-19 is a highly contagious viral disease which escalated into a global pandemic since its outbreak on 31 December 2019. Chest X-rays are the most common investigation in suspected cases to diagnose and manage pneumonia. The aim of this study was to find out the mean Brixia severity scores among symptomatic COVID-19 patients in a tertiary care centre. Methods: A descriptive cross-sectional study was conducted among the chest X-rays of symptomatic COVID-19-positive patients of a tertiary care centre. Data from 1 May 2021 to 31 July 2021 were collected between 1 August 2022 and 1 January 2023 from the hospital records. Ethical approval was taken from Institutional Review Committee (Reference number: 01-079/080). Patients with reverse transcriptase polymerase chain reaction with symptoms of COVID-19 were included in this study. Convenience sampling method was used. Point estimate and 95% Confidence Interval were calculated. Results: Among the total of 300 patients, the mean Brixia severity score was 7.15±5.07 and out of 235 patients with abnormal chest X-ray, the mean Brixia severity score was 9.13±3.84. A total of 68 (22.66%) patients had mild, 115 (38.33%) had moderate and 52 (17.33%) had severe scores. Conclusions: The mean Brixia severity score among symptomatic COVID-19 patients was found to be higher than the other studies done in similar settings. Keywords: COVID-19; Nepal; pneumonia; prevalence; x-ray.

Molecular Understanding of Adhesion of Epoxy Resin to Graphene and Graphene Oxide Surfaces in Terms of Orbital Interactions.

The adhesion mechanism of epoxy resin (ER) cured material consisting of diglycidyl ether of bisphenol A (DGEBA) and 4,4'-diaminodiphenyl sulfone (DDS) to pristine graphene and graphene oxide (GO) surfaces is investigated on the basis of first-principles density functional theory (DFT) with dispersion correction. Graphene is often used as a reinforcing filler incorporated into ER polymer matrices. The adhesion strength is significantly improved by using GO obtained by the oxidation of graphene. The interfacial interactions at the ER/graphene and ER/GO interfaces were analyzed to clarify the origin of this adhesion. The contribution of dispersion interaction to the adhesive stress at the two interfaces is almost identical. In contrast, the DFT energy contribution is found to be more significant at the ER/GO interface. Crystal orbital Hamiltonian population (COHP) analysis suggests the existence of hydrogen bonding (H-bonding) between the hydroxyl, epoxide, amine, and sulfonyl groups of the ER cured with DDS and the hydroxyl groups of the GO surface, in addition to the OH-π interaction between the benzene rings of ER and the hydroxyl groups of the GO surface. The H-bond has a large orbital interaction energy, which is found to contribute significantly to the adhesive strength at the ER/GO interface. The overall interaction at the ER/graphene is much weaker due to antibonding type interactions just below the Fermi level. This finding indicates that only dispersion interaction is significant when ER is adsorbed on the graphene surface.

The HDAC inhibitor zabadinostat is a systemic regulator of adaptive immunity.

Protein acetylation plays a key role in regulating cellular processes and is subject to aberrant control in diverse pathologies. Although histone deacetylase (HDAC) inhibitors are approved drugs for certain cancers, it is not known whether they can be deployed in other therapeutic contexts. We have explored the clinical HDAC inhibitor, zabadinostat/CXD101, and found that it is a stand-alone regulator of the adaptive immune response. Zabadinostat treatment increased expression of MHC class I and II genes in a variety of cells, including dendritic cells (DCs) and healthy tissue. Remarkably, zabadinostat enhanced the activity of DCs, and CD4 and CD8 T lymphocytes. Using an antigenic peptide presented to the immune system by MHC class I, zabadinostat caused an increase in antigen-specific CD8 T lymphocytes. Further, mice immunised with covid19 spike protein and treated with zabadinostat exhibit enhanced covid19 neutralising antibodies and an increased level of T lymphocytes. The enhanced humoral response reflected increased activity of T follicular helper (Tfh) cells and germinal centre (GC) B cells. Our results argue strongly that zabadinostat has potential to augment diverse therapeutic agents that act through the immune system.

Intrauterine pregnancy with copper intrauterine contraceptive device in situ: A case report from Nepal.

Introduction: and importance: Intrauterine pregnancy on the background of intrauterine devices heralds its rare but possible failure. Despite having an excellent contraceptive pearl index, clients with copper-T may present with typical pregnancy symptoms. Case presentation: We present a case of a 22 year primigravida who after 42 months of successful use of copper-T, conceived an intrauterine pregnancy diagnosed at 7 weeks period of gestation.Clinical Findings and Investigations: A positive urine pregnancy test following cessation of menstruation for 2 months was reported by the patient on presentation. Urgent transabdominal ultrasound of the abdomen and pelvis revealed a gravid uterus containing a single gestational sac corresponding to 7 weeks of gestation. After a thorough explanation about possibility of viable pregnancy and also its pros and cons, she decided to terminate the pregnancy. Manual vacuum aspiration was done with removal of copper-T. Conclusion: Although ectopic pregnancy is a relatively common complication of intrauterine contraceptive device, it is necessary to consider the possibility of intrauterine pregnancy as a potential complication as well. Although, term pregnancies with excellent prognosis have been demonstrated in many studies after removal of intrauterine devices, close follow up is needed to identify misplaced copper-T and keep unwanted pregnancy at bay.

UltraSound Axillary Vein Access (USAA): Learning curve and randomized comparison to traditional venous access for cardiac device implantation.

BACKGROUND: Many techniques exist for venous access (VA) during cardiac implantable electronic device (CIED) implantation. OBJECTIVE: We sought to evaluate the learning curve with ultrasound (US) guided axillary vein access (USAA). METHODS: Single-center prospective randomized controlled trial of patients undergoing CIED implantation. Patients were randomized in a 2:1 fashion to USAA versus conventional VA techniques. The primary outcomes were the success rates, VA times and 30-day complication rates. RESULTS: The study included 100 patients (age 68 ± 14 years, BMI 27 ± 4 kg/m2 ). USAA was successful in 66/70 implants (94%). Initial attempts at conventional VA included 47% axillary (n = 14), 30% (n = 9) cephalic, and 23% (n = 7) subclavian. The median access time was longer for USAA than conventional access (8.3 IQR 4.2-15.3 min vs. 5.2 IQR 3.4-8.6 min, p = .009). Among the five inexperienced USAA implanters, there was a significant improvement in median access time from first to last tertile of USAA implants (17.0 IQR 7.0-21.0 min to 8.6 IQR 4.5-10.8 min, p = .038). The experienced USAA implanter had similar access times with USAA compared with conventional access (4.0 IQR 3.3-4.7 min vs. 5.2 IQR 3.4-8.6 min, p = .15). Venograms were less common with USAA than conventional access (2% vs. 33%, p < .0001). The 30-day complication rate was similar with USAA (n = 4/70, 6%) versus conventional (n = 3/30, 10%, p = .44). CONCLUSION: Although the success rate with USAA was high, there was a significant learning curve. Once experienced with the USAA technique, there is the potential for reduced complications without adding to the procedure duration.

Aspiration of a Row of Artificial Dentures in an Adult: A Case Report.

Clinical findings of foreign body aspiration, generally, are subtle. Scrutinous clinical suspicion is always recommended. Here, we present a rare case of an adult male, who under the influence of alcohol had aspirated a row of his artificial denture without his conscience of where his denture got missing and presented to our outpatient department with non-specific symptoms. With clinical examination and advanced diagnostics, he was successfully managed with rigid bronchoscopy. With the advancement in diagnostic techniques and our widened knowledge of the condition, utmost early detection has been possible and our case report reinforces the need for a low threshold for foreign body aspiration suspicion, especially in adults with dentures, and the use of rigid bronchoscopy as a plausible tool for the prompt management of the aspiration. Keywords: bronchoscopy; case reports; dentures; foreign bodies.

Sinusitis among Patients Undergoing CT Scan of Paranasal Sinuses in a Tertiary Care Centre: A Descriptive Cross-sectional Study.

Introduction: Computed tomography imaging provides detailed information about the paranasal sinuses and is now well established as an alternative to standard radiographs in evaluating patients with sinusitis. Sinusitis can have dangerous complications which can even lead to death if not diagnosed and treated on time. This study aimed to find the prevalence of sinusitis among the patients undergoing Computed Tomography scan of paranasal sinuses in a tertiary care centre. Methods: A descriptive cross-sectional study was conducted in the Department of Radiology at a tertiary care hospital from 1 October 2021 to 30 April 2022 after taking ethical approval from the Institutional Review Committee (Reference Number: 023-078/079). The patients undergoing Computed Tomography paranasal sinuses and meeting the eligibility criteria were enrolled for the study after taking informed consent. Convenience sampling was done. Point estimate and 95% Confidence Interval were calculated. Results: Among 113 patients, 109 (96.46%) (93.05-99.87, 95% Confidence Interval) patients had sinusitis. The most common subtype was found to be acute sinusitis in 63 (57.79%) individuals. Conclusions: The prevalence of sinusitis was higher than in other studies done in similar settings. Keywords: computed tomography; paranasal sinuses; sinusitis.

Increased Great Saphenous Vein Diameter at the Level of Knee among Patients with Varicose Veins in a Tertiary Care Centre: A Descriptive Cross-sectional Study.

Introduction: Colour Doppler ultrasonography plays an important role in determining the morphological and hemodynamic information of the venous system. This study aimed to find out the prevalence of increased great saphenous vein diameter at the level of the knee among patients with varicose veins in a tertiary care centre. Methods: A descriptive cross-sectional study was carried out in the Department of Radiology at a tertiary care centre from 30 October 2021 to 31 March 2022 after taking ethical approval from the Institutional Review Committee (Reference number: 028-077/078). A convenience sampling technique was used for the study. The study group consisted of patients over 18 years, coming for ultrasonography examination of the lower limb with the clinical symptoms and signs of varicose veins. The great saphenous vein diameter was measured at the level of the medial femoral condyle of the knee using the software in the ultrasonography unit. B mode, colour Doppler and spectral analysis were done. A cut-off value of 5 mm for the diameter of the great saphenous vein was taken to indicate the presence or absence of varicosity and saphenofemoral reflux. Point estimate and 90% Confidence Interval were calculated. Results: Among 72 patients with varicose veins, the diameter of the great saphenous vein was increased in 59 (81.94%) (74.50-89.38, 90% Confidence Interval) patients. Conclusions: The mean diameter of the great saphenous vein in our study was similar when compared to other studies conducted in similar settings. Keywords: saphenous vein; ultrasonography; varicose veins.

Immune modulation underpins the anti-cancer activity of HDAC inhibitors.

Aberrant protein acetylation is strongly linked to tumorigenesis, and modulating acetylation through targeting histone deacetylase (HDAC) with small-molecule inhibitors has been the focus of clinical trials. However, clinical success on solid tumours, such as colorectal cancer (CRC), has been limited, in part because the cancer-relevant mechanisms through which HDAC inhibitors act remain largely unknown. Here, we have explored, at the genome-wide expression level, the effects of a novel HDAC inhibitor CXD101. In human CRC cell lines, a diverse set of differentially expressed genes were up- and downregulated upon CXD101 treatment. Functional profiling of the expression data highlighted immune-relevant concepts related to antigen processing and natural killer cell-mediated cytotoxicity. Similar profiles were apparent when gene expression was investigated in murine colon26 CRC cells treated with CXD101. Significantly, these changes were also apparent in syngeneic colon26 tumours growing in vivo. The ability of CXD101 to affect immune-relevant gene expression coincided with changes in the tumour microenvironment (TME), especially in the subgroups of CD4 and CD8 tumour-infiltrating T lymphocytes. The altered TME reflected enhanced antitumour activity when CXD101 was combined with immune checkpoint inhibitors (ICIs), such as anti-PD-1 and anti-CTLA4. The ability of CXD101 to reinstate immune-relevant gene expression in the TME and act together with ICIs provides a powerful rationale for exploring the combination therapy in human cancers.

Congenital absence of left circumflex artery with right coronary dominance.

Absent left circumflex coronary (LCX) artery though rare and benign should be considered in patients with chest pain and differentiated from atherosclerotic coronary artery disease for better management & prognosis.

Superior mesenteric artery syndrome.

Superior mesenteric artery (SMA) syndrome, though rare, should be considered in patients with duodenal obstruction with no other causes. History of recent weight loss and imaging modalities help in the diagnosis. Conservative management can be tried before going for surgery.

Multilineage murine stem cells generate complex organoids to model distal lung development and disease.

Organoids derived from mouse and human stem cells have recently emerged as a powerful tool to study organ development and disease. We here established a three-dimensional (3D) murine bronchioalveolar lung organoid (BALO) model that allows clonal expansion and self-organization of FACS-sorted bronchioalveolar stem cells (BASCs) upon co-culture with lung-resident mesenchymal cells. BALOs yield a highly branched 3D structure within 21 days of culture, mimicking the cellular composition of the bronchioalveolar compartment as defined by single-cell RNA sequencing and fluorescence as well as electron microscopic phenotyping. Additionally, BALOs support engraftment and maintenance of the cellular phenotype of injected tissue-resident macrophages. We also demonstrate that BALOs recapitulate lung developmental defects after knockdown of a critical regulatory gene, and permit modeling of viral infection. We conclude that the BALO model enables reconstruction of the epithelial-mesenchymal-myeloid unit of the distal lung, thereby opening numerous new avenues to study lung development, infection, and regenerative processes in vitro.

Targeting Bronchopulmonary Dysplasia-Associated Pulmonary Hypertension (BPD-PH): Potential Role of the FGF Signaling Pathway in the Development of the Pulmonary Vascular System.

More than 50 years after the first description of Bronchopulmonary dysplasia (BPD) by Northway, this chronic lung disease affecting many preterm infants is still poorly understood. Additonally, approximately 40% of preterm infants suffering from severe BPD also suffer from Bronchopulmonary dysplasia-associated pulmonary hypertension (BPD-PH), leading to a significant increase in total morbidity and mortality. Until today, there is no curative therapy for both BPD and BPD-PH available. It has become increasingly evident that growth factors are playing a central role in normal and pathologic development of the pulmonary vasculature. Thus, this review aims to summarize the recent evidence in our understanding of BPD-PH from a basic scientific point of view, focusing on the potential role of Fibroblast Growth Factor (FGF)/FGF10 signaling pathway contributing to disease development, progression and resolution.