Bile Acids in Pancreatic Carcinogenesis.

Pancreatic cancer (PC) is a dangerous digestive tract tumor that is becoming increasingly common and fatal. The most common form of PC is pancreatic ductal adenocarcinoma (PDAC). Bile acids (BAs) are closely linked to the growth and progression of PC. They can change the intestinal flora, increasing intestinal permeability and allowing gut microbes to enter the bloodstream, leading to chronic inflammation. High dietary lipids can increase BA secretion into the duodenum and fecal BA levels. BAs can cause genetic mutations, mitochondrial dysfunction, abnormal activation of intracellular trypsin, cytoskeletal damage, activation of NF-κB, acute pancreatitis, cell injury, and cell necrosis. They can act on different types of pancreatic cells and receptors, altering Ca2+ and iron levels, and related signals. Elevated levels of Ca2+ and iron are associated with cell necrosis and ferroptosis. Bile reflux into the pancreatic ducts can speed up the kinetics of epithelial cells, promoting the development of pancreatic intraductal papillary carcinoma. BAs can cause the enormous secretion of Glucagon-like peptide-1 (GLP-1), leading to the proliferation of pancreatic ß-cells. Using Glucagon-like peptide-1 receptor agonist (GLP-1RA) increases the risk of pancreatitis and PC. Therefore, our objective was to explore various studies and thoroughly examine the role of BAs in PC.

Mucormycosis and Its Upsurge During COVID-19 Epidemic: An Updated Review.

Although mucormycosis may have reached an epidemic situation during the COVID-19 pandemic, the term was much more familiar even before the COVID-19 period. The year 2020 showed an outbreak of novel coronavirus (SARS-CoV-2) which affected millions of people all over the world. One of the noticeable complications observed to be associated with this disease is mucormycosis. It is an opportunistic infection caused by members of the Order Mucorales existing worldwide and has been commonly reported as a laboratory contaminant for a long time. However, nowadays due to the changes in the host environment, they have been emerging as potent opportunistic pathogens responsible for causing primary infections or coinfections with other diseases eventually resulting in morbidity and even mortality in severe cases. Although immunocompromised patients are more susceptible to this infection, few cases have been reported in immunocompetent individuals. Various risk factors which are responsible for the acquisition of mucormycosis include diabetes mellitus type 2, ketoacidosis, hematological malignancies, organ transplants, and chemotherapy recipients. Among the various etiological agents, Rhizopus is found to be the most common, and rhino-cerebral to be the most frequent clinical presentation. As far as pathogenesis is concerned, host cell invasion, thrombosis, and necrosis are the main events in the progression of this disease. The aim of the present review is to address a complete spectrum of mucormycosis and COVID-19-associated mucormycosis (CAM) in a single article. Both global and Indian scenarios of mucormycosis are taken into account while framing this review.

Tolerability and efficacy of a reduced dose adenosine stress cardiac magnetic resonance protocol under general anesthesia in infants and children.

BACKGROUND: Intravenous adenosine induces pharmacological stress by causing vasodilatation and thus carries the risk of severe hypotension when combined with vasodilatory effects of anesthetic agents. OBJECTIVE: This study describes our experience with a reduced dose adenosine cardiac magnetic resonance imaging (MRI) protocol in young children under general anesthesia (GA). MATERIALS AND METHODS: This is a retrospective report of all patients from birth to 18 years who underwent adenosine stress cardiac MRI under GA between August 2018 and November 2022. Based on our anecdotal experience of severe adverse effects in patients receiving adenosine infusion under GA and in discussion with the pediatric anesthesia team, we developed a modified protocol starting at a dose of 110 mcg/kg/min with incremental escalation to a full dose of 140 mcg/kg/min to achieve desired hemodynamic effect. RESULTS: Twenty-two children (mean age 6.5 years, mean weight 28 kg) satisfied the inclusion criteria. The diagnoses included Kawasaki disease (7), anomalous aortic origin of left coronary artery (3), anomalous aortic origin of right coronary artery (2), coronary fistula (3), repaired d-transposition of great arteries (2), repaired anomalous left coronary artery from pulmonary artery (2), repaired truncus arteriosus with left coronary artery occlusion (1), extracardiac-Fontan with left coronary artery myocardial bridge (1), and post heart transplantation (1). Nine patients needed dose escalation beyond 110 mcg/kg/min. Two patients had transient hypotension during testing (systemic blood pressure drop > 25 mmHg). No patient developed significant heart block or bronchospasm. Six patients (repeat study in one) demonstrated inducible perfusion defects (27%) on stress perfusion sequences-5 of whom had confirmed significant coronary abnormalities on angiography or direct surgical inspection. CONCLUSION: A reduced/incremental dose adenosine stress cardiac MRI protocol under GA in children is safe and feasible. This avoids severe hypotension which is both unsafe and may result in inaccurate data.

Astigmatic reduction after dermoid excision in a child with Goldenhar syndrome.

Goldenhar syndrome is a rare congenital disorder. Limbal dermoid associated with this syndrome can cause high astigmatism and amblyopia in children. We report significant reduction in astigmatism, after limbal dermoid excision with lamellar keratoplasty, in a rare case of Goldenhar syndrome. A three-year-old female patient, with left-sided limbal dermoid with high astigmatism and amblyopia, was referred to us for visual rehabilitation. The patient had left-sided limbal dermoid and preauricular appendages. Oral examination revealed bifid labial frenum, a deep antegonial notch on the left side of the mandible and missing left upper central incisor teeth. She was diagnosed as a case of Goldenhar syndrome. Her best-corrected visual acuity was 20 of 20 in the right eye and 20 of 200 in the left eye. Refraction showed astigmatism of 10 diopters in her left eye. She underwent limbal dermoid excision with lamellar keratoplasty in her left eye, after which her astigmatism reduced considerably. Early surgical intervention is recommended in cases of limbal dermoid with high astigmatism as it provides not only good cosmetic but also good visual benefits by early institution of treatment for amblyopia.

Impact of Conditioning Regimen and Graft-versus-Host Disease Prophylaxis on The Outcome of Haploidentical Peripheral Blood Stem Cell Transplantation for High-Risk Severe Aplastic Anemia in Children and Young Adults: A Report from the Pediatric Severe Aplastic Anemia Consortium of India.

Allogenic hematopoietic cell transplantation (HCT) is the best curative approach for patients with severe aplastic anemia (SAA). The outcomes of HCT from haploidentical family donors (HFDs) have improved, making it a feasible option for patients lacking an HLA-identical donor. However, data on HFD-HCT for younger patients with SAA is sparse. In this multicenter retrospective study, we evaluated the outcomes of 79 patients undergoing HFD-HCT for SAA. All the patients were heavily pretransfused, the median time to HCT was >12 months, and 67% had failed previous therapies. Conditioning was based on fludarabine (Flu)-cyclophosphamide (Cy)-antithymocyte globulin (ATG)/total body irradiation (TBI) with or without thiotepa/melphalan (TT/Mel). Post-transplantation Cy (PTCy) and calcineurin inhibitors (CNIs)/sirolimus were used as graft-versus-host disease (GVHD) prophylaxis with or without abatacept. The rate of primary graft failure (PGF) was 16.43% overall, lower in patients conditioned with TT/Mel. The incidences of acute and chronic GVHD were 26.4% and 18.9%, respectively. At a median follow-up of 48 months, the overall survival (OS) and event-free survival (EFS) were 61.6% and 58.1%, respectively. Both OS and EFS were better in the TT/Mel recipients and with abatacept as GVHD prophylaxis. On multivariate analysis, the use of abatacept was found to favorably impact the outcome variables, including GVHD and EFS. Our study suggests that PTCy-based HFD-HCT is a reasonable option for young patients with high-risk SAA, in whom optimization of conditioning and GVHD prophylaxis might further improve outcomes.

Antimicrobial Agents Based on Metal Complexes: Present Situation and Future Prospects.

The rise in antimicrobial resistance is a cause of serious concern since the ages. Therefore, a dire need to explore new antimicrobial entities that can combat against the increasing threat of antibiotic resistance is realized. Studies have shown that the activity of the strongest antibiotics has reduced drastically against many microbes such as microfungi and bacteria (Gram-positive and Gram-negative). A ray of hope, however, was witnessed in early 1940s with the development of new drug discovery and use of metal complexes as antibiotics. Many new metal-based drugs were developed from the metal complexes which are potentially active against a number of ailments such as cancer, malaria, and neurodegenerative diseases. Therefore, this review is an attempt to describe the present scenario and future development of metal complexes as antibiotics against wide array of microbes.

Metabolomics and Network Pharmacology in the Exploration of the Multi-Targeted Therapeutic Approach of Traditional Medicinal Plants.

Metabolomic is generally characterized as a comprehensive and the most copious analytical technique for the identification of targeted and untargeted metabolite diversity in a biological system. Recently, it has exponentially been used for phytochemical analysis and variability among plant metabolites, followed by chemometric analysis. Network pharmacology analysis is a computational technique used for the determination of multi-mechanistic and therapeutic evaluation of chemicals via interaction with the genomes involved in targeted or untargeted diseases. In considering the facts, the present review aims to explore the role of metabolomics and network pharmacology in the scientific validation of therapeutic claims as well as to evaluate the multi-targeted therapeutic approach of traditional Indian medicinal plants. The data was collected from different electronic scientific databases such as Google Scholar, Science Direct, ACS publication, PubMed, Springer, etc., using different keywords such as metabolomics, techniques used in metabolomics, chemometric analysis, a bioinformatic tool for drug discovery and development, network pharmacology, methodology and its role in biological evaluation of chemicals, etc. The screened articles were gathered and evaluated by different experts for their exclusion and inclusion in the final draft of the manuscript. The review findings suggest that metabolomics is one of the recent most precious and effective techniques for metabolite identification in the plant matrix. Various chemometric techniques are copiously used for metabolites discrimination analysis hence validating the unique characteristic of herbal medicines and their derived products concerning their authenticity. Network pharmacology remains the only option for the unique and effective analysis of hundreds of chemicals or metabolites via genomic interaction and thus validating the multi-mechanistic and therapeutic approach to explore the pharmacological aspects of herbal medicines for the management of the disease.

Refractive Outcomes of Simultaneous Pterygium and Cataract Surgery With Fibrin Glue.

Introduction Pterygium is commonly reported in India because of its tropical location. It is often accompanied by senile cataract. The current study aimed to evaluate the refractive outcomes of patients undergoing simultaneous pterygium and cataract surgery. Materials and methods A total of 12 patients with cataract and pterygium underwent simultaneous phacoemulsification with a foldable intraocular lens (IOL) followed by pterygium excision with conjunctival limbal autograft secured with fibrin glue under peribulbar anesthesia. Nasal pterygium was present in all the cases, and its size ranged from 2.5 to 3.5 mm from the limbus. All the patients exhibited nuclear sclerotic cataract of grades 2 and 3. Results The results of the patients were analyzed retrospectively. We determined the best-corrected visual acuity ([BCVA] in logMAR), manifest astigmatism, and mean corneal astigmatism before operation and after 12 months of surgery. We also analyzed the correlation between the prediction error (calculated by subtracting the predicted postoperative refraction from the actual postoperative spherical equivalent) and changes in the mean keratometry and prediction errors and pterygium size. The mean age of the patients was 61.9 ± 7.14 years (range: 50-70 years). The mean BCVA at presentation was 0.67 ± 0.24 logMAR units, which significantly increased after surgery to 0.01 ± 0.03 logMAR units (p < 0.001, Wilcoxon signed-rank test). The mean manifest corneal astigmatism significantly reduced from -1.98 ± 0.84 diopters (D) preoperatively to -0.54 ± 0.18 D postoperatively (p < 0.001). Mean corneal keratometry increased from 43.81 ± 1.77 D preoperatively to 44.19 ± 1.76 D postoperatively (p < 0.05). At 12 months, 58.33% and 41.66% of the eyes were within  ±0.5 D and  ±1.0 D, respectively. A significant correlation was observed between the prediction errors and changes in the mean keratometry (Spearman signed-rank test, r = -0.65, p < 0.05) and pterygium size (Spearman correlation coefficient, r = -0.75, p < 0.05). Conclusion The simultaneous pterygium and cataract surgery with conjunctival autograft and fibrin glue was safe and effective in providing excellent and predictable refractive outcomes. Steepening of the cornea after combined surgery results in myopia; therefore, the IOL power should be selected appropriately. The use of fibrin glue in surgeries reduces the operative time and postoperative pain and results in early postoperative rehabilitation of patients.

Epidermal growth factor receptor inhibitors as potential anticancer agents: An update of recent progress.

Epidermal growth factor receptor (EGFR) is a vital intermediate in cell signaling pathway including cell proliferation, angiogenesis, apoptosis, and metastatic spread and also having four divergent members with similar structural features, such as EGFR (HER1/ErbB1), ErbB2 (HER2/neu), ErbB3 (HER3), and ErbB4 (HER4). Despite this, clinically exploited inhibitors of EGFR (including erlotinib, lapatinib, gefitinib, selumetinib, etc.) are not specific thus provoking unenviable adverse effects. Some of the paramount obstacles to generate and develop new lead molecules of EGFR inhibitors are drug resistance, mutation, and also selectivity which inspire medicinal chemists to generate novel chemotypes. The discovery of therapeutic agents that inhibit the precise stage in tumorous cells such as EGFR is one of the chief successful targets in many cancer therapies, including lung and breast cancers. This review aims to compile the various recent progressions (2016-2021) in the discovery and development of diverse epidermal growth factor receptor (EGFR) inhibitors belonging to distinct structural classes like pyrazoline, pyrazole, imidazole, pyrimidine, coumarin, benzothiazole, etc. We have summarized preclinical and clinical data, structure-activity relationships (SAR) containing mechanistic and in silico studies to provide proposals for the design and invention of new EGFR inhibitors with therapeutic significance. The detailed progress of the work in the field will provide inexorable scope for the development of novel drug candidates with greater selectivity and efficacy.

Recent developments in mitogen activated protein kinase inhibitors as potential anticancer agents.

The mitogen activated protein kinase (MAPK) belongs to group of kinase that links the extracellular stimuli to intracellular response. The MAPK signalling pathway (RAS-RAF-MEK-ERK) involved in different pathological conditions like cancer, caused due to genetic or any other factor such as physical or environmental. Many studies have been conducted on the pathological view of MAPK cascade and its associated element like RAS, RAF, MEK, ERK or its isoforms, and still the research is going on particularly with respect to its activation, regulation and inhibition. The MAPK signalling pathway has become the area of research to identify new target for the management of cancer. A number of heterocyclics are key to fight with the cancer associated with these enzymes thus give some hope in the management of cancer by inhibiting MAPK cascade. In the present article, we have focussed on MAPK signalling pathway and role of different heterocyclic scaffolds bearing nitrogen, sulphur and oxygen and about their potential to block MAPK signalling pathway. The heterocyclics are gaining importance due to high potency and selectivity with less off-target effects against different targets involved in the MAPK signalling pathway. We have tried to cover recent advancements in the MAPK signalling pathway inhibitors with an aim to get better understanding of the mechanism of action of the compounds. Several compounds in the preclinical and clinical studies have been thoroughly dealt with. In addition to the synthetic compounds, a significant number of natural products containing heterocyclic moieties as MAPK signalling pathway inhibitors have been put together. The structure activity relationship along with docking studies have been discussed to apprehend the mechanistic studies of various compounds that will ultimately help to design and develop more MAPK signalling pathway inhibitors.

Pharmacological properties, therapeutic potential, and legal status of Cannabis sativa L.: An overview.

Marijuana, or Cannabis sativa L., is a common psychoactive plant used for both recreational and medicinal purposes. In many countries, cannabis-based medicines have been legalized under certain conditions because of their immense prospects in medicinal applications. With a comprehensive insight into the prospects and challenges associated with the pharmacological use and global trade of C. sativa, this mini-review focuses on the medicinal importance of the plant and its legal status worldwide; the pharmacological compounds and its therapeutic potential along with the underlying public health concerns and future perspective are herein discussed. The existence of major compounds including Δ9 -tetrahydrocannabinol (Δ9 -THC), cannabidiol, cannabinol, and cannabichromene contributes to the medicinal effects of the cannabis plant. These compounds are also involved in the treatment of various types of cancer, epilepsy, and Parkinson's disease displaying several mechanisms of action. Cannabis sativa is a plant with significant pharmacological potential. However, several aspects of the plant need an in-depth understanding of the drug mechanism and its interaction with other drugs. Only after addressing these health concerns, legalization of cannabis could be utilized to its full potential as a future medicine.

Occurrence, Impact on Agriculture, Human Health, and Management Strategies of Zearalenone in Food and Feed: A Review.

Mycotoxins represent an assorted range of secondary fungal metabolites that extensively occur in numerous food and feed ingredients at any stage during pre- and post-harvest conditions. Zearalenone (ZEN), a mycotoxin categorized as a xenoestrogen poses structural similarity with natural estrogens that enables its binding to the estrogen receptors leading to hormonal misbalance and numerous reproductive diseases. ZEN is mainly found in crops belonging to temperate regions, primarily in maize and other cereal crops that form an important part of various food and feed. Because of the significant adverse effects of ZEN on both human and animal, there is an alarming need for effective detection, mitigation, and management strategies to assure food and feed safety and security. The present review tends to provide an updated overview of the different sources, occurrence and biosynthetic mechanisms of ZEN in various food and feed. It also provides insight to its harmful effects on human health and agriculture along with its effective detection, management, and control strategies.

Ochratoxins in food and feed: Occurrence and its impact on human health and management strategies.

Ochratoxins (OTs) are a group of mycotoxins produced by Aspergillus and Penicillium spp. which are ubiquitous. They infect the crops during pre- and post-harvest conditions and contaminate various food and feed. Among all the OTs produced, ochratoxin A (OTA) poses serious health issues like neurotoxicity and carcinogenesis. The harmful impact of the toxins is observed in both humans and animals. The toxins get accumulated in the organs of animals through the contaminated animal-feed which further contaminate the products derived from them, such as milk and meat-based products. Therefore, sensitive and robust identification, detection, and quantification methods along with efficient management and control measures are crucial. Spectrometric and spectroscopy techniques are quite sensitive and lead to better detection of the toxin in the food products. Control and preventive measures during harvesting, storage and transportation are found to be effective in managing the production of such toxins. This review insight on the occurrence, chemistry, biosynthesis, effects on human health and agriculture, detections, management, and control strategies of ochratoxins.

Resolution of Corneal Dellen After an Uneventful Pterygium Surgery with Punctal Cautery.

Corneal dellen are a rare and serious complication after primary pterygium surgery with conjunctival limbal autograft (CLAG) with fibrin glue without antimetabolites. Dellen are caused by interruptions of the tear film and local dehydration of the cornea. If untreated, they may lead to corneal perforation. We describe the case of a patient who developed corneal dellen 15 days after uneventful pterygium excision with CLAG with fibrin glue without the use of antimetabolites. There was no satisfactory response to lubricants and patching, and the patient had no associated systemic risk factors. As the thinning increased, cyanoacrylate glue with bandage contact lens was applied, but the dellen reappeared seven days after glue removal. Dellen finally resolved with thermal punctal cautery applied to both puncta. Dellen most commonly respond to artificial tears, antibiotic ointment, and patch application. However, in refractory cases, punctal cauterization can be considered as a good option to increase tear pooling in the area of dellen, thereby promoting healing.

Penicillium on the Iris! An Unusual Presentation and Cause of Postoperative Anterior Uveitis.

Intraocular fungal infections may not present solely as postoperative anterior uveitis or as a focal anterior segment lesion. The present study describes a 50-year-old woman with well-controlled diabetes who presented with postoperative anterior uveitis three months after uncomplicated cataract surgery. A fuzzy lesion was observed on her iris. The patient underwent an anterior chamber wash and removal of the lesion, followed by intracameral treatment with voriconazole. Culture of the lesion showed that it was a species of Penicillium. The patient has remained stable after treatment. Three aspects of this case were unusual: a fungal lesion of unusual etiology and location, inflammation restricted to the anterior segment despite a fungal background, and the excellent response to treatment with a very favorable outcome.

Update on Management of Polycystic Ovarian Syndrome for Dermatologists.

Polycystic ovarian syndrome (PCOS) is the commonest endocrine disorder in women having wide range of clinical manifestation. These women may present with reproductive, dermatological, metabolic, psychological, or neoplastic implications from adolescence to menopause. The common dermatological manifestations include hirsutism, acne, alopecia, or acanthosis nigricans. Women presenting with these dermatological manifestations must be evaluated for PCOS. A multidisciplinary team approach involving a reproductive endocrinologist, dermatologist, psychologist/psychiatrist, dietician, and sometimes a bariatric surgeon should be undertaken for long-term management of these patients. Unless metabolic and underlying endocrinal disturbances arecorrected and simultaneous life-style modification is adopted, cosmetic treatment would give only temporary relief.

Intraoperative customized double-patch device with twin sutures for multiple muscular septal defects.

OBJECTIVES: Closure of multiple muscular ventricular septal defects (VSDs) remains a challenge because of anatomical complexity. METHODS: We mapped all the VSDs using en face reconstruction of the right ventricular septal surface through echocardiography and then performed an 'Intraoperative Customized Double-Patch Device' technique to surgically close them in 39 patients (male:female = 25:14). The median age of the patients was 6 months (2 months-10 years), and mean weight was 5.98 ± 4.21 kg. A patch of polytetrafluoroethylene was placed on the left ventricular side of the defect and another on the right ventricular side, and they were anchored to each other using 2 polypropylene sutures. Residual shunts were evaluated using intraoperative echocardiography and measurements of right atrial-pulmonary arterial saturation were taken in all patients. RESULTS: The distribution of muscular VSDs was as follows: anterior muscular 12, posterior muscular 18, mid-muscular 11 and apical 9. The associated lesions included perimembranous VSD (n = 28), tetralogy of Fallot (n = 6), double-outlet right ventricle (n = 2) and supramitral membrane (n = 2). Mean clamp time and bypass time were 93 ± 19 min and 147 ± 26 min, respectively. Mean hospital stay was 11 ± 3.39 days with no in-hospital mortality. Five patients with significant residual shunts needed concomitant PA banding. All patients remained in New York Heart Association Class I. There was either no residual shunt (n = 3) or trivial shunt (n = 2) among the banded patients. All patients remained symptom-free and continued to thrive well at the most recent follow-up (3.48 ± 1.51 years). CONCLUSIONS: Muscular VSDs can be mapped through en face reconstruction and closed using intraoperative customized double-patch device technique in a variety of situations with satisfactory immediate and short-term results.