Management of Pediatric Constipation

Constipation is a common problem in children. It accounts for 20–30% of pediatric outdoor office. It is common in both rich and poor countries despite the belief that developing countries consume food rich in fiber. Normal bowel movement in breastfed babies may range from several times a day to once in every 10 days. Constipation can be both functional and pathological. Functional constipation has no underlying cause and is the most common type of constipation found in children. My main focus will be on this common type of constipation. In functional constipation routine, digital rectal examination is not recommended unless impaction is suspected. Abdominal radiography is recommended only in equivocal clinical examination or if impaction is suspected and examination not conclusive. Dietary and behavior modifications, toilet training, and parent education are important in the management of functional constipation. Initial management of functional constipation includes disimpaction of stools. Lactulose is safe in all age groups. Polyethylene glycol is more effective than lactulose but is costly. Maintenance therapy may take some time till constipation improves. Some rare situations such as refractory and slow transient constipation are also discussed in this chapter

Mesenchymal Stromal Cell-Derived Tailored Exosomes Treat Bacteria-Associated Diabetes Foot Ulcers: A Customized Approach From Bench to Bed

Exosomes are nano-vesicles of endosomal origin inherited with characteristics of drug delivery and cargo loading. Exosomes offer a diverse range of opportunities that can be exploited in the treatment of various diseases post-functionalization. This membrane engineering is recently being used in the management of bacteria-associated diabetic foot ulcers (DFUs). Diabetes mellitus (DM) is among the most crippling disease of society with a large share of its imposing economic burden. DM in a chronic state is associated with the development of micro- and macrovascular complications. DFU is among the diabetic microvascular complications with the consequent occurrence of diabetic peripheral neuropathy. Mesenchymal stromal cell (MSC)-derived exosomes post-tailoring hold promise to accelerate the diabetic wound repair in DFU associated with bacterial inhabitant. These exosomes promote the antibacterial properties with regenerative activity by loading bioactive molecules like growth factors, nucleic acids, and proteins, and non-bioactive substances like antibiotics. Functionalization of MSC-derived exosomes is mediated by various physical, chemical, and biological processes that effectively load the desired cargo into the exosomes for targeted delivery at specific bacterial DFUs and wound. The present study focused on the application of the cargo-loaded exosomes in the treatment of DFU and also emphasizes the different approaches for loading the desired cargo/drug inside exosomes. However, more studies and clinical trials are needed in the domain to explore this membrane engineering

Newer Horizon of Mesenchymal Stem Cell-Based Therapy in the Management of SARS-CoV-2-Associated Mucormycosis: A Safe Hope for Future Medicine

SARS-CoV-2-infected patients are reported to show immunocompromised behavior that gives rise to a wide variety of complications due to impaired innate immune response, cytokine storm, and thrombo-inflammation. Prolonged use of steroids, diabetes mellitus, and diabetic ketoacidosis (DKA) are some of the factors responsible for the growth of Mucorales in such immunocompromised patients and, thus, can lead to a life-threatening condition referred to as mucormycosis. Therefore, an early diagnosis and cell-based management cosis is the need of the hour to help affected patients overcome this severe condition. In addition, extended exposure to antifungal drugs/therapeutics is found to initiate hormonal and neurological complications. More recently, mesenchymal stem cells (MSCs) have been used to exhibit immunomodulatory function and proven to be beneficial in a clinical cell-based regenerative approach. The immunomodulation ability of MSCs in mucormycosis patient boosts the immunity by the release of chemotactic proteins. MSC-based therapy in mucormycosis along with the combination of short-term antifungal drugs can be utilized as a prospective approach for mucormycosis treatment with promising outcomes. However, preclinical and in mucormyIn mucormycosis, the hyphae of clinical trials are needed to establish the precise mechanism of MSCs in mucormycosis treatment

EZH2 inhibition reactivates epigenetically silenced FMR1 and normalizes molecular and electrophysiological abnormalities in fragile X syndrome neurons

Fragile X Syndrome (FXS) is a neurological disorder caused by epigenetic silencing of the FMR1 gene. Reactivation of FMR1 is a potential therapeutic approach for FXS that would correct the root cause of the disease. Here, using a candidate-based shRNA screen, we identify nine epigenetic repressors that promote silencing of FMR1 in FXS cells (called FMR1 Silencing Factors, or FMR1- SFs). Inhibition of FMR1-SFs with shRNAs or small molecules reactivates FMR1 in cultured undifferentiated induced pluripotent stem cells, neural progenitor cells (NPCs) and post-mitotic neurons derived from FXS patients. One of the FMR1-SFs is the histone methyltransferase EZH2, for which an FDA-approved small molecule inhibitor, EPZ6438 (also known as tazemetostat), is available. We show that EPZ6438 substantially corrects the characteristic molecular and electrophysiological abnormalities of cultured FXS neurons. Unfortunately, EZH2 inhibitors do not efficiently cross the blood-brain barrier, limiting their therapeutic use for FXS. Recently, antisense oligonucleotide (ASO)-based approaches have been developed as effective treatment options for certain central nervous system disorders. We therefore derived efficacious ASOs targeting EZH2 and demonstrate that they reactivate FMR1 expression and correct molecular and electrophysiological abnormalities in cultured FXS neurons, and reactivate FMR1 expression in human FXS NPCs engrafted within the brains of mice. Collectively, our results establish EZH2 inhibition in general, and EZH2 ASOs in particular, as a therapeutic approach for FXS

Growth-finance nexus: Empirical evidence from India

The relationship between financial development and economic growth has attracted considerable attention of policymakers and researchers alike. The present study aims to empirically examine the relationship between economic growth and financial development in the post-reform period, from 1992-1993 to 2014-2015. The period witnessed reforms towards financial liberalisation like deregulation of interest rates, lowering reserve requirements, removal of financial markets imperfections and the development of an efficient and sound financial sector. The indicators of financial development used in the study are Broad money to GDP ratio, Stock market capitalization to GDP ratio and Traded Value ratio. The study employs Johnson co-integration technique and finds long run relationship among the variables. Multivariate Granger causality test finds market capitalization and traded value ratio together granger cause GDP, and market capitalization and broad money together granger cause GDP. Also, the study finds causality running from GDP and traded value ratio to market capitalization. The results, therefore, indicate considerable interdependence among economic growth and financial development in the post reform period under study

Emerging Trends in Immunotherapy for Cancer

Recent advances in cancer immunology have enabled the discovery of promising immunotherapies for various malignancies that have shifted the cancer treatment paradigm. The innovative research and clinical advancements of immunotherapy approaches have prolonged the survival of patients with relapsed or refractory metastatic cancers. Since the U.S. FDA approved the first immune checkpoint inhibitor in 2011, the field of cancer immunotherapy has grown exponentially. Multiple therapeutic approaches or agents to manipulate different aspects of the immune system are currently in development. These include cancer vaccines, adoptive cell therapies (such as CAR-T or NK cell therapy), monoclonal antibodies, cytokine therapies, oncolytic viruses, and inhibitors targeting immune checkpoints that have demonstrated promising clinical efficacy. Multiple immunotherapeutic approaches have been approved for specific cancer treatments, while others are currently in preclinical and clinical trial stages. Given the success of immunotherapy, there has been a tremendous thrust to improve the clinical efficacy of various agents and strategies implemented so far. Here, we present a comprehensive overview of the development and clinical implementation of various immunotherapy approaches currently being used to treat cancer. We also highlight the latest developments, emerging trends, limitations, and future promises of cancer immunotherapy

Macrophages as a Potential Immunotherapeutic Target in Solid Cancers

The revolution in cancer immunotherapy over the last few decades has resulted in a paradigm shift in the clinical care of cancer. Most of the cancer immunotherapeutic regimens approved so far have relied on modulating the adaptive immune system. In recent years, strategies and approaches targeting the components of innate immunity have become widely recognized for their efficacy in targeting solid cancers. Macrophages are effector cells of the innate immune system, which can play a crucial role in the generation of anti-tumor immunity through their ability to phagocytose cancer cells and present tumor antigens to the cells of adaptive immunity. However, the macrophages that are recruited to the tumor microenvironment predominantly play pro-tumorigenic roles. Several strategies targeting pro-tumorigenic functions and harnessing the anti-tumorigenic properties of macrophages have shown promising results in preclinical studies, and a few of them have also advanced to clinical trials. In this review, we present a comprehensive overview of the pathobiology of TAMs and their role in the progression of solid malignancies. We discuss various mechanisms through which TAMs promote tumor progression, such as inflammation, genomic instability, tumor growth, cancer stem cell formation, angiogenesis, EMT and metastasis, tissue remodeling, and immunosuppression, etc. In addition, we also discuss potential therapeutic strategies for targeting TAMs and explore how macrophages can be used as a tool for next-generation immunotherapy for the treatment of solid malignancies

Posterior reversible encephalopathy syndrome after augmentation cystoplasty in a child with neurogenic bladder

Posterior reversible encephalopathy syndrome (PRES) or leukoencephalopathy syndrome was introduced into clinical practice in 1996 by Hinchey et al., to describe unique syndrome, clinically expressed during hypertensive and uremic encephalopathy, eclampsia, and immunosuppressive therapy. Hyperperfusion with resultant disruption of the blood–brain barrier results in vasogenic edema, but not infarction, most commonly in the parieto-occipital regions. The severity of this clinical symptom varies. For example, the visual disturbance can manifest as blurred vision, homonymous hemianopsia, or even cortical blindness.Patients may be mildly confused or agitated but can become comatose.Other symptoms less commonly seen include nausea, vomiting, seizures, and brainstem deficits.Chronic kidney disease (CKD) and acute kidney injury are both commonly present in patients with PRES. We are presenting a rare case of neurogenic bladder who developed PRES after augmentation cystoplasty due to underlying CKD

Loss of TDP-43 function contributes to genomic instability in amyotrophic lateral sclerosis.

A common pathological hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is the cytoplasmic mislocalization and aggregation of the DNA/RNA-binding protein TDP-43, but how loss of nuclear TDP-43 function contributes to ALS and FTD pathogenesis remains largely unknown. Here, using large-scale RNAi screening, we identify TARDBP, which encodes TDP-43, as a gene whose loss-of-function results in elevated DNA mutation rate and genomic instability. Consistent with this finding, we observe increased DNA damage in induced pluripotent stem cells (iPSCs) and iPSC-derived post-mitotic neurons generated from ALS patients harboring TARDBP mutations. We find that the increase in DNA damage in ALS iPSC-derived neurons is due to defects in two major pathways for DNA double-strand break repair: non-homologous end joining and homologous recombination. Cells with defects in DNA repair are sensitive to DNA damaging agents and, accordingly, we find that ALS iPSC-derived neurons show a marked reduction in survival following treatment with a DNA damaging agent. Importantly, we find that increased DNA damage is also observed in neurons with nuclear TDP-43 depletion from ALS/FTD patient brain tissues. Collectively, our results demonstrate that ALS neurons with loss of nuclear TDP-43 function have elevated levels of DNA damage and contribute to the idea that genomic instability is a defining pathological feature of ALS/FTD patients with TDP-43 pathology

Correction: Satam et al. Next-Generation Sequencing Technology: Current Trends and Advancements. <i>Biology</i> 2023, <i>12</i>, 997

We are very thankful to the commentator for pointing out the issues in the review article by Satam et al [...