Bergenin inhibits growth of human cervical cancer cells by decreasing Galectin-3 and MMP-9 expression.

Cervical cancer is still the leading cause of cancer mortality worldwide even after introduction of vaccine against Human papillomavirus (HPV), due to low vaccine coverage, especially in the developing world. Cervical cancer is primarily treated by Chemo/Radiotherapy, depending on the disease stage, with Carboplatin/Cisplatin-based drug regime. These drugs being non-specific, target rapidly dividing cells, including normal cells, so safer options are needed for lower off-target toxicity. Natural products offer an attractive option compared to synthetic drugs due to their well-established safety profile and capacity to target multiple oncogenic hallmarks of cancer like inflammation, angiogenesis, etc. In the current study, we investigated the effect of Bergenin (C-glycoside of 4-O-methylgallic acid), a natural polyphenol compound that is isolated from medicinal plants such as Bergenia crassifolia, Caesalpinia digyna, and Flueggea leucopyrus. Bergenin has been shown to have anti-inflammatory, anti-ulcerogenic, and wound healing properties but its anticancer potential has been realized only recently. We performed a proteomic analysis of cervical carcinoma cells treated with bergenin and found it to influence multiple hallmarks of cancers, including apoptosis, angiogenesis, and tumor suppressor proteins. It was also involved in many different cellular processes unrelated to cancer, as shown by our proteomic analysis. Further analysis showed bergenin to be a potent-angiogenic agent by reducing key angiogenic proteins like Galectin 3 and MMP-9 (Matrix Metalloprotease 9) in cervical carcinoma cells. Further understanding of this interaction was carried out using molecular docking analysis, which indicated MMP-9 has more affinity for bergenin as compared to Galectin-3. Cumulatively, our data provide novel insight into the anti-angiogenic mechanism of bergenin in cervical carcinoma cells by modulation of multiple angiogenic proteins like Galectin-3 and MMP-9 which warrant its further development as an anticancer agent in cervical cancer.

Use of ultrasound to estimate the prevalence of occult spinal dysraphism in children undergoing urogenital and anorectal surgeries: A cross-sectional study.

Background and Aim: The use of ultrasound has immensely increased the safety toward regional blocks and central venous access and has been considered as the standard of care for securing central access. The aim of this study is to estimate the prevalence of occult spinal dysraphism using ultrasound in children less than 2 years of age undergoing elective urogenital or anorectal surgery. Material and Methods: The lumbosacral region of 159 American Society of Anesthesiologists (ASA) category I/II patients, posted for elective urogenital and anorectal surgery was scanned with ultrasound, prior to giving caudal block. Results: The prevalence of occult spina bifida was 3% in our study. There was no statistically significant association of cutaneous marker with abnormal scan. Conclusion: Prevalence of occult spina bifida was ten-times higher in our study than in the general population. Perioperative ultrasound screening of the lower spinal anatomy by anesthesiologist done prior to performing neuraxial block is worthwhile in ruling out occult spinal anomalies in high-risk children of occult spinal dysraphism.

Advancing pediatric perioperative care in India: A contemporary overview.

BACKGROUND: In the last 30 years, significant advances have been made in pediatric medical care globally. However, there is a persistent urban-rural gap which is more pronounced in low middle-income countries than high-income countries, similar urban-rural gap exists in India. While on one hand, health care is on par or better than healthier nations thriving international medical tourism industry, some rural parts have reduced access to high-quality care. AIM: With this background, we aim to provide an overview of the present and future of healthcare in India. METHODOLOGY: With the cumulative health experience of the authors or more than 100 years, we have provided our experience and expertise about healthcare in India in this narrative educational review. This is supplemented by the government plans and non government plans as appropriate. References are used to justify as applicable. RESULTS: With the high percentage of pediatric population like other low to middle-income countries, India faces challenges in pediatric surgery and anesthesia due to limited resources and paucity of specialized training, especially in rural areas. Data on the access and quality of care is scarce, and the vast rural population and uneven resource distribution add to the challenges along with the shortage of pediatric surgeons in these areas of specialized care . Addressing these challenges requires a multi faceted strategy that targets both immediate and long-term healthcare needs, focusing on improving the facilities and training healthcare professionals. Solutions could include compulsory rural service, district residency programs, increasing postgraduate or residency positions, and safety courses offered by national and international organizations like Safer Anesthesia from Education Pediatrics, Vital Anesthesia Simulation Training, and World Federation of Society of Anesthesiologists pediatric fellowships. CONCLUSION: India has achieved great strides in perioperative health care and safety. It has become the major international medical industry due to high-quality care, access and costs. Crucially, India needs to establish local hubs for pediatric perioperative care training to enhance healthcare delivery for children.

Delivery of Safe Pediatric Anesthesia Care in the First 8000 days: Realities, Challenges, and Solutions in Low- and Middle-Income Countries.

BACKGROUND: Worldwide, perioperative mortality has declined over the past 50 years, but the reduction is skewed toward high-income countries (HICs). Currently, pediatric perioperative mortality is much higher in low- and middle-income countries (LMICs) compared to HICs, despite studied cohorts being predominantly low-risk. These disparities must be studied and addressed. METHODS: A narrative review of the literature was undertaken to identify contributing factors and potential knowledge gaps. Interventions aimed at alleviating the outcomes disparities are discussed, and recommendations are made for future directions. RESULTS AND CONCLUSIONS: There is a lack of adequately trained pediatric anesthesia providers in LMICs, and the number must be bolstered by making such training available. Essential anesthesia medications and equipment, in pediatric-appropriate sizes, are often not available; neither are essential infrastructure items. Perioperative staff are underprepared for emergent situations that may arise and simulation training may help to ameliorate this. The global anesthesia community has implemented several solutions to address these issues. The World Federation of Societies of Anaesthesiologists (WFSA) and Global Initiative for Children's Surgery have published standards that outline essential items for the provision of safe perioperative pediatric care. Several short educational courses have been developed and introduced in LMICs that either specifically address pediatric patients, or contain a pediatric component. The WFSA also maintains a collection of discrete tutorials for educational purposes. Finally, in Africa, large-scale, prospective data collection is underway to examine pediatric perioperative outcomes. More work needs to be done, though, to improve perioperative outcomes for pediatric patients in LMICs.

A cross-sectional observation study to evaluate the efficacy and complications of epidural analgesia in paediatric population.

Background and Aims: With advances in pediatric surgery, pediatric epidurals are increasingly being used for analgesia. As there is scarcity of data in India about the pediatric epidurals, we sought to determine the efficacy and complications of epidural analgesia. The aim of this study was to determine the efficacy of pediatric epidural analgesia and the incidence of complications aimed at improving the quality of care. Material and Methods: It was a prospective observational study in tertiary care hospital in the Southern part of India. Newborns to children aged 18 years in whom continuous epidural analgesia was planned were recruited. They were followed up postoperatively at specified intervals wherein pain scores were used to determine analgesic efficacy. Complications were noted in a specified format and the level of satisfaction of patient and surgeon was noted objectively. All the statistical analyses were performed using SPSS 25.0. Results: 100 children were recruited of which 63 received thoracic epidurals and 37 lumbar epidurals. Overall efficacy of epidural in pain management was 90.96% with the highest efficacy for lower abdominal epidurals (94.9%). Kinking of a catheter was the most common complication encountered (11%), followed by migration of catheter, occlusion of pump, and motor block. Conclusion: Continuous epidural analgesia has proven to be a safe and effective method to provide analgesia to the children in a protected environment and experienced hands.

Cost-effective Whole Exome Sequencing discovers pathogenic variant causing Neurofibromatosis type 1 in a family from Jammu and Kashmir, India.

Neurofibromatosis type 1 (NF1) is a multisystemic hereditary disorder associated with an increased risk of benign and malignant tumor formation predominantly on the skin, bone, and peripheral nervous system. It has been reported that out of all the NF1 cases, more than 95% cases develop the disease due to heterozygous loss-of-function variants in Neurofibromin (NF1) gene. However, identification of NF1 causative variants by presently recommended method of gene-targeted Sanger sequencing is challenging and cost-intensive due to the large size of the NF1gene with 60 exons spanning about 350 kb. Further, conducting the genetic studies is difficult in low resource regions and among families with the limited financial capabilities, restricting them from availing diagnostic as well as proper disease management measures. Here, we studied a three-generation family from Jammu and Kashmir state in India, with multiple affected family members showing clinical indications of NF1. We combinedly used two applications, Whole Exome Sequencing (WES) and Sanger sequencing, for this study and discovered a nonsense variant NM_000267.3:c.2041C>T (NP_000258.1:p.Arg681Ter*) in exon 18 of NF1 gene in a cost effective manner. In silico analyses further substantiated the pathogenicity of this novel variant. The study also emphasized on the role of Next Generation Sequencing (NGS) as a cost-effective method for the discovery of pathogenic variants in disorders with known phenotypes found in large sized candidate genes. The current study is the first study based on the genetic characterization of NF1 from Jammu and Kashmir-India, highlighting the importance of the described methodology adopted for the identification and understanding of the disease in low resource region. The early diagnosis of genetic disorders would open the door to appropriate genetic counseling, reducing the disease burden in the affected families and the general population at large.

Recent advances in paediatric anaesthesia.

Recent development in science has led to a significant improvement in safety for the anaesthetic management of children. Enhanced recovery after surgery is one of the novel approaches aiming to enhance paediatric surgical outcomes and their quick recovery. Preoperative counselling, minimal fasting, and no routine pharmacological premedication are critical components of enhanced recovery after surgery. As anaesthetists, management of airway is our priority and introduction of paraoxygenation in addition to preoxygenation has resulted in reduction in desaturation episodes during periods of apnoea. Safe care has been made possible by improvements in monitoring, equipment, medications, techniques, and resuscitation protocols. We are motivated to collect more evidence regarding ongoing disputes and issues, such as the effect of anaesthesia on neurodevelopment.

Surgical and anaesthetic outcomes of paediatric splenectomies at a tertiary care institution in South India: a retrospective cohort.

PURPOSE: Splenectomies though well-established in the successful management of several resistant haemoglobinopathies, have not been studied in detail in the paediatric population to assess the outcomes. We conducted this review to primarily assess the surgical and anaesthetic outcomes of paediatric splenectomies and secondarily highlight factors predictive for a high-risk splenectomy. METHODS: A 5 year retrospective chart review was made, and patient follow-up was done jointly using the hospital electronic medical records and telephonic calls. A p value of < 0.05 was considered significant. RESULTS: Among the 69 splenectomised children, 61% were male and the overall mean age was 10.2 years. The cohort consisted of patients with thalassemia (46%), ITP (30%), haemolytic anemia (19%) and 1 child each with lymphoma, splenic cyst and Kassabach Meritt syndrome. Most (96%) were electively operated and 23% were performed laparoscopically. 61% received intravenous analgesia and the mean volume of fluid administered intra-operatively was 21 ml/kg. There was no documented OPSI, and there was one mortality. The mean follow-up period was 43 months and the overall survival rate was 98.5%. CONCLUSIONS: Splenectomy was associated with a promising overall outcome. A greater pre-operative transfusion requirement, a larger sized spleen and increased fluid administration intra-operatively, were associated with a worse outcome.

Delivering Essential Surgical Care for Lower-limb Musculoskeletal disorders in the Low-Resource Setting.

BACKGROUND: Mismatched surgeon-anesthesiologist ratios often exist in low-resource settings making safe emergency essential surgical care challenging. This study is an audit of emergency essential procedures performed for lower-limb (LL) musculoskeletal disorders (MSD) when an anesthesiologist was unavailable. It aims to identify strategies for safe anesthesia. METHODS: A 5-year retrospective audit of emergency essential LL orthopedic procedures performed at remote mission hospital in Central India was performed. Out of necessity, a regional anesthesia (RA) protocol was developed in collaboration with anesthesiologists familiar with the setting. The incidence of intraoperative surgical and perioperative anesthesia complications when RA was administered by a surgeon was evaluated. RESULTS: During this period, 766 emergency essential LL MSDs procedures were performed. An anesthesiologist was available for only 6/766. RA was administered by a surgeon for 283/766. This included spinal anesthesia (SA) for 267/283 patients, peripheral nerve blocks for 16/283. Local infiltration and/or sedation was administered to 477/766. There were 17 intraoperative surgical complications. Anesthesia-related complications included 37/267 patients who required multiple attempts to localize subarachnoid space and SA failure in 9/267 patients all of whom had successful re-administration. Additional sedation and infiltration of local anesthetic was required in 5/267 patients. CONCLUSION: Remote pre-anesthesia consultation for high-risk patients, local surgeon-anesthesiologist networking, protocol-guided management, and dedicated short duration of training in anesthesia may be considered as an alternative for delivering RA for emergency essential surgery for LL MSDs due to unavailability of anesthesiologists.

Elucidating the anatomy of a rare communicating bronchopulmonary foregut malformation (CBPFM) in a preschool child.

Communicating bronchopulmonary foregut malformations (CBPFMs) are complex and rare anomalies. Their characteristic feature is an anomalous communication between the respiratory system (trachea, lung or bronchus) on one side and the gastrointestinal tract (oesophagus or stomach) on the other. Though acquired CBPFMs are known, the large majority of them are congenital and single. CBPFMs often go undetected even at surgery and require more than one operation before they are successfully addressed. This is because the symptomatology of CBPFM resembles the more common oesophageal atresia (OA) with tracheoesophageal fistula, wherein it may coexist. We report a patient with OA who had a rare form of CBPFM where the upper lobe of the right lung communicated with the upper oesophagus. This account highlights a novel method of working out the uncertain anatomy, in such cases. There may be associated anomalies of the lung parenchyma and vasculature usually involving the pulmonary arterial supply to the affected lung. Clinical, radiological, endoscopic and pathological characterisation permit precise diagnosis in most instances, with an occasional case that defies definition.

Massive gingival bleed: a rare manifestation of cyclosporine toxicity.

A 12-year-old patient of thalassaemia major developed autoimmune cytopaenia after undergoing haematopoietic stem cell transplantation. She was started on cyclosporine (CsA) in view of poor response to steroids. She developed CsA toxicity manifesting as gum hyperplasia with multiple episodes of gum bleed. During endotracheal intubation for an elective splenectomy, she developed significant bleeding from gums requiring massive transfusion. Postoperatively the gum bleed persisted even after embolisation of facial artery and multiple transfusions. The catastrophic sequelae include transfusion-related lung injury, acute circulatory failure with subsequent cardiac arrest and death. Gum hyperplasia is a commonly reported toxic effect of CsA. Lethal presentations of this toxicity with such severity are limited in the medical literature. Evaluation of the patient's medical and laboratory records, along with a review of literature, was very helpful in understanding more about the toxicity of CsA.

LRFN2 gene variant rs2494938 provides susceptibility to esophageal cancer in the population of Jammu and Kashmir.

BACKGROUND: Leucine-rich repeat and fibronectin type 2 gene (LRFN2) variant rs2494938 has recently been found associated with esophageal cancer in a genome-wide association study in an Asian population. However, this association has not been replicated in any Indian population despite high incidence of the disease. MATERIALS AND METHODS: In the present case-control study, 166 cases and 459 controls were included. Taqman assay technique using real-time PCR was employed to investigate the association of the variant with esophageal cancer in the population of Jammu and Kashmir (J&K). The Hardy-Weinberg equilibrium for rs2494938 was assessed using the Chi-square test. The allele- and genotype-specific risk was estimated by odds ratio (OR) with 95% confidence interval (CI). RESULTS: Variant rs2494938 was observed to be significantly associated with esophageal cancer with an allelic OR of 1.59 (1.23-2.04 at 95% CI, P = 0.0003). CONCLUSION: The study highlights LRFN2 as a candidate gene for esophageal cancer susceptibility in the population of J&K and calls for a detailed study with a large sample size and involving more ethnic groups of India.

Operative fasting guidelines and postoperative feeding in paediatric anaesthesia-current concepts.

Preoperative fasting period is the prescribed time prior to any procedure done either under general anaesthesia, regional anaesthesia or sedation, when oral intake of liquids or solids are not allowed. This mandatory fasting is a safety precaution that helps to protect from pulmonary aspiration of gastric contents which may occur any time during anaesthesia. We searched PUBMED for English language articles using keywords including child, paediatric, anaesthesia, fasting, preoperative, gastric emptying. We also hand searched references from relevant review articles and major society guidelines. Association of Paediatric Anaesthesiologists of Great Britain and Ireland (APAGBI), the French Language Society of Paediatric Anaesthesiologists and the European Society of Paediatric Anesthetists recommends clear fluid intake upto one hour prior to elective surgery unless specific contraindications exists. Current guidelines recommend fasting duration of 4 hours for breastmilk, 6 hours for milk and light meals and 8 hours for fatty meals. The European Society for Clinical Nutrition and Metabolism (ESPEN) guidelines recommend that oral intake can be initiated within hours of surgery in most patients. While fluids can be started almost immediately, the introduction of solids should be done more cautiously.

Evaluation of anesthesia informed consent in pediatric practice - An observation cohort study.

BACKGROUND AND AIMS: An informed consent requires active participation by both physicians and patients. It is the responsibility of the physician to give the complete disclosure of information in easy language for the parent to understand. An informed consent process can be a challenge especially for the anesthetists when time is a limiting factor for patient-anesthetist interaction especially in same day admission and day surgery. The aim of this study was to subjectively evaluate the understanding and recall of the informed consent by the parents. MATERIAL AND METHODS: The validated survey was conducted over 10 weeks and was limited to one parent per child and to the parent who was directly involved in the consent process. RESULTS: Majority of parents rated positively for adequate disclosure of all items of information. Consent process done on day of surgery was found to be associated with lower parental rating in adequacy of disclosure of pain relief options. Seniority of anesthetists was associated with higher parental rating of adequacy of information regarding post operative plan, specific risk of child and overall consent process. Consent for minor surgeries, on day of surgery, did not significantly affect the parental performance in their recall of disclosed information but was associated with significant lower rating of adequacy of postoperative plan. Postoperative pain is among the areas for improvement especially in day surgery cases. CONCLUSION: Consent taken on day of surgery was found to be associated with lower parental rating. Postoperative plan for pain required improvement especially in day surgery cases.

A case report on a novel MT-ATP6 gene variation in atypical mitochondrial Leigh syndrome associated with bilateral basal ganglia calcifications.

Leigh Syndrome (LS) is a rare, hereditary progressive neurodegenerative disorder of infancy or early childhood associated with a highly variable clinical presentation even among siblings. Further, genetic heterogeneity makes its diagnosis complicated. Its causative genetic variations are notified in some of the mitochondrial and nuclear genes. Here, we report an atypical case of LS in a 9-year-old boy associated with a novel variation in MT-ATP6 gene. The atypical findings were Bilateral Basal Ganglia Calcification (BGC) and late survival age in the patient. Analyses of the Whole Mitochondrial Genome Sequencing (WMGS) results of the recruited patient and his mother at different read coverage, first at 100× and later repeated at 500×, revealed a novel disease-associated variation in the already known disease-associated MT-ATP6 gene. In conclusion, the present study indicates amalgamation of both neuro-imaging and Next Generation Sequencing (NGS) Technologies aiding the proper diagnosis of LS in atypical cases.

Whole Exome Screening Identifies Novel and Recurrent WISP3 Mutations Causing Progressive Pseudorheumatoid Dysplasia in Jammu and Kashmir-India.

We report identification and genetic characterization of a rare skeletal disorder that remained unidentified for decades in a village of Jammu and Kashmir, India. The population residing in this region is highly consanguineous and a lack of understanding of the disorder has hindered clinical management and genetic counseling for the many affected individuals in the region. We collected familial information and identified two large extended multiplex pedigrees displaying apparent autosomal recessive inheritance of an uncharacterized skeletal dysplasia. Whole exome sequencing (WES) in members of one pedigree revealed a rare mutation in WISP3:c.156C > A (NP_003871.1:p.Cys52Ter), that perfectly segregated with the disease in the family. To our surprise, Sanger sequencing the WISP3 gene in the second family identified a distinct, novel splice site mutation c.643 + 1G > A, that perfectly segregated with the disease. Combining our next generation sequencing data with careful clinical documentation (familial histories, genetic data, clinical and radiological findings), we have diagnosed the families with Progressive Pseudorheumatoid Dysplasia (PPD). Our results underscore the utility of WES in arriving at definitive diagnoses for rare skeletal dysplasias. This genetic characterization will aid in genetic counseling and management, critically required to curb this rare disorder in the families.

mtDNA G10398A variation provides risk to type 2 diabetes in population group from the Jammu region of India.

Mitochondrion plays an integral role in glucose metabolism and insulin secretion. Mitochondrial electron-transport chain (ETC) is involved in adenosine triphosphate (ATP) generation and ATP mediated insulin secretion in pancreatic ß-cells. ß-cell dysfunction is a critical component in the pathogenesis of type 2 diabetes (T2D). The mtDNA G10398A variation (amino acid change: Alanine â†’ Threonine) within the NADH dehydrogenase (ND3) subunit of complex I of mtDNA ETC, has emerged as a variation of clinical significance in various disorders including T2D. This variation is supposed to result in altered complex I function, leading to an increased rate of electron leakage and reactive oxygen species (ROS) production, which might cause ß-cell damage and impaired insulin secretion. The aim of the study was to explore the association of mtDNA G10398A variation with T2D in a total of 439 samples (196 T2D cases and 243 healthy controls) belonging to the Jammu region of Jammu and Kashmir (J&K). The candidate gene association analyses showed significant association of mtDNA G10398A variant with T2D and the estimated odds ratio (OR) was 2.83 (1.64-4.90 at 95% CI) in the studied population group. The extent of genetic heterogeneity in T2D and diversity of the Indian population groups, make such replication studies pertinent to understand the etiology of T2D in these population groups.

Mitochondrial DNA G10398A polymorphism imparts maternal Haplogroup N a risk for breast and esophageal cancer.

Mitochondria are the major source of Reactive Oxygen Species (ROS) and mtDNA G10398A (Ala-->Thr) polymorphism, proposed to be involved in increased ROS production, has been shown in association with invasive breast cancer in African-American (AA) women [J.A. Canter, A.R. Kallianpur, F.F. Parl, R.C. Millikan, Mitochondrial DNA G10398A polymorphism and invasive breast cancer in African-American women, Cancer Res. 65 (2005) 8028-8033] and prostate cancer in AA men [M.P. Mims, T.G. Hayes, S. Zheng, S.M. Leal, A. Frolov, M.M. Ittmann, et al., Mitochondrial DNA G10398A polymorphism and invasive breast cancer in African-American women, Cancer Res. 66 (2006) 1880; author reply 1880-1881]. The role of mitochondria, however, in cancer development has been in question recently [A. Salas, Y.G. Yao, V. Macaulay, A. Vega, A. Carracedo, H.J. Bandelt, A critical reassessment of the role of mitochondria in tumorigenesis, PLoS Med. 2 (2005) e296], which has made it pertinent to analyze the data and test the hypotheses by conducting fresh case-control studies. This study, therefore, makes an attempt to validate the exclusive presence of mtG10398A (Ala-->Thr) polymorphism in a haplotype constituting mtDNA haplogroup N and its sublineages, imparting this group a higher risk for breast cancer, based on the re-analyses of approximately 1000 complete human mtDNA sequences worldwide and collated information on 2334 individuals belonging to 18 regions in India. The conclusion drawn of mt10398A allele providing a risk towards cancer is confirmed in a case-control comparison study of 124 sporadic breast cancer patients and 273 controls; and 55 squamous cell carcinoma of esophagus, ESCC, and 163 controls, matched for age, ethnicity and sex from north India. It is further apparent from the study that such a mtDNA polymorphism background provides a higher risk for the cancers of the tissues which could be affected by environmental insults directly as in the ESCC, observed with a high acquired (somatic) rate of mutation in p53 when compared to the breast cancer, suggesting that the mtDNA variants that arose as energetic adaptations, influence our health differentially under different environment conditions and a given genetic background of the mt genome.