Epidemiologic correlates of malnutrition among under-three children in the rural community of Northern India.

Context: Worldwide malnutrition is identified as a major health and nutrition problem. Undernutrition contributes to an estimated 45% of child deaths globally. The prevalence of underweight among children in India is among the highest in the world. Our children also bear a tremendous double burden of malnutrition. Aims: To find out the prevalence and determinants of malnutrition among six months to three-year-old children in the rural community of Northern India. Settings and Design: A community-based cross-sectional study conducted among children aged six months to three years in a rural area of Ludhiana district, Methods and Material: A total of 662 children in the age group of six months to three years from a population of 30,000 were identified and included in the study. All the relevant information regarding these children was collected from family folders. Socioeconomic status was assessed using the modified Udai Pareek scale (MUP). Statistical analysis used: The data collected was entered in MS Excel and was analyzed using SPSS version 26 and WHO Anthro Survey Analyzer. Results: Out of 662 children, 16% were underweight. Almost 50% of the children in the two-three years category were underweight. The prevalence of stunting in the study population was 20.7% and that of overweight was 4.8%. The prevalence of underweight was higher in children of low socioeconomic status than in children from upper socioeconomic status (P = 0.000). There was a significant association between birth order and increasing cases of underweight (P = 0.000). Conclusions: The causes of malnutrition in children are complex and involve multiple factors. There is a need for vigorous monitoring for early detection of malnutrition for children aged two-three years. The improvement of maternal education will improve the nutritional status of the child.

Tofacitinib Versus Oral Prednisolone for Induction of Remission in Moderately Active Ulcerative Colitis [ORCHID]: A Prospective, Open-Label, Randomized, Pilot Study.

BACKGROUND: Oral corticosteroids are first-line agents to induce remission in moderately active ulcerative colitis [UC], but are associated with adverse effects. We compared the efficacy and safety of tofacitinib and prednisolone for induction of remission in moderately active UC. METHODS: This was a single-centre, prospective, open-label, randomized, active-controlled pilot study. Eligible patients [aged ≥18 years] had moderately active UC. Participants were randomly assigned to receive either prednisolone [40 mg daily, tapered by 5 mg every week] or tofacitinib [10 mg twice daily] for 8 weeks. The primary endpoint was composite remission [defined as total Mayo clinic score ≤2, with endoscopic sub-score of 0 and faecal calprotectin <100 µg/g] at 8 weeks. RESULTS: Seventy-eight patients were randomly assigned to either of the treatment groups. At week 8, the proportion of patients achieving composite remission in the tofacitinib [7/43, 16.28%] and prednisolone groups [3/35, 8.57%] were not significantly different (odds ratio [OR] 2.07, 95% confidence interval [CI] 0.49-8.70; p = 0.31). The time to achieve symptomatic remission [normal stool frequency with absence of rectal bleeding] was similar (10 days, interquartile range [IQR 7-18.75] and 10 days [IQR 5-12.5] for tofacitinib and prednisolone, respectively; p = 0.25) in the two groups. One patient each in the tofacitinib and prednisolone group discontinued treatment due to development of pulmonary tuberculosis and pustular acne, respectively. One patient receiving tofacitinib developed herpes zoster, but did not require cessation of therapy. No serious adverse events or major adverse cardiovascular events were observed. CONCLUSION: In patients with moderately active UC, there was no difference in the efficacy and safety of tofacitinib and oral prednisolone for induction of remission at 8 weeks. TRAIL REGISTRATION: Clinical Trials Registry of India [CTRI/2021/10/037641].

Unmasking Sarcoidosis as the Culprit Behind Hypercalcemia-Induced Acute Pancreatitis: A Diagnostic Conundrum.

Hypercalcemia-induced pancreatitis is a rare and challenging complication, particularly when secondary to sarcoidosis. This case report discusses the clinical presentation, diagnostic workup, and management of a 61-year-old patient diagnosed with hypercalcemia-induced pancreatitis secondary to sarcoidosis. The abstract highlights the complexities of diagnosing pancreatitis linked to elevated calcium levels and underscores the importance of recognizing underlying conditions such as sarcoidosis in these cases. Through this case, we aim to enhance awareness among clinicians regarding the association between sarcoidosis, hypercalcemia, and pancreatitis, ultimately contributing to improved diagnostic accuracy and patient care strategies.

Vitamin D Toxicity Masquerading as Acute Pancreatitis.

Patients and medical professionals are showing renewed interest in vitamin D supplementation as a result of increased knowledge of the positive health effects of vitamin D supplementation, the prevalence of vitamin D deficiency, and the easy availability of over-the-counter vitamin D pills. We present a case of acute pancreatitis following vitamin D toxicity due to the administration of doses exceeding the recommended dosage. A 61-year-old man presented to us with elevated pancreatic enzymes, increased 25-hydroxyvitamin D (25-OHD) levels, and deranged renal function tests. He was kept nil per oral and managed with intravenous fluids and denosumab injection. We advocate educating medical professionals about the frequently disregarded side effect of vitamin D supplementation. At the same time, it is critical to create awareness among the public about the harmful effects of self-medication.

Biophysical studies of HIV-1 glycoprotein-41 interactions with peptides and small molecules - Effect of lipids and detergents.

BACKGROUND: The hydrophobic pocket (HP) of HIV-1 glycoprotein-41 ectodomain is defined by two chains of the N-heptad repeat trimer, within the protein-protein interface that mediates 6HB formation. It is a potential target for inhibitors of viral fusion, but its hydrophobic nature and proximity to membrane in situ has precluded ready analysis of inhibitor interactions. METHODS: We evaluated the sensitivity of 19F NMR and fluorescence for detecting peptide and small molecule binding to the HP and explored the effect of non-denaturing detergent or phospholipid as cosolvents and potential mimics of the membrane environment surrounding gp41. RESULTS: Chemical shifts of aromatic fluorines were found to be sensitive to changes in the hydrogen bonding network that occurred when inhibitors transitioned from solvent into the HP or into ordered detergent micelles. Fluorescence intensities and emission maxima of autofluorescent compounds responded to changes in the local environment. CONCLUSIONS: Gp41 - ligand binding occurred under all conditions, but was diminished in the presence of detergents. NMR and fluorescence studies revealed that dodecylphosphocholine (DPC) was a poor substitute for membrane in this system, while liposomes could mimic the membrane surroundings. GENERAL SIGNIFICANCE: Our findings suggest that development of high potency small molecule binders to the HP may be frustrated by competition between binding to the HP and binding to the bilayer membrane.

Sulfated quaternary amine lipids: a new class of inverse charge zwitterlipids.

We describe a new class of charge inverted zwitterionic sulfated lipids (AS) with a cationic quaternary amine anchored at the membrane interface and an anionic sulfate moiety extended into the aqueous phase. These lipids have exceptionally high transition temperatures and assemble into lipid aggregates when dispersed in aqueous solutions.

Designer lipids for drug delivery: from heads to tails.

For four decades, liposomes composed of both naturally occurring and synthetic lipids have been investigated as delivery vehicles for low molecular weight and macromolecular drugs. These studies paved the way for the clinical and commercial success of a number of liposomal drugs, each of which required a tailored formulation; one liposome size does not fit all drugs! Instead, the physicochemical properties of the liposome must be matched to the pharmacology of the drug. An extensive biophysical literature demonstrates that varying lipid composition can influence the size, membrane stability, in vivo interactions, and drug release properties of a liposome. In this review we focus on recently described synthetic lipid headgroups, linkers and hydrophobic domains that can provide control over the intermolecular forces, phase preference, and macroscopic behavior of liposomes. These synthetic lipids further our understanding of lipid biophysics, promote targeted drug delivery and improve liposome stability. We further highlight the immune reactivity of novel synthetic headgroups as a key design consideration. For instance it was originally thought that synthetic PEGylated lipids were immunologically inert; however, it's been observed that under certain conditions PEGylated lipids induce humoral immunity. Such immune activation may be a limitation to the use of other engineered lipid headgroups for drug delivery. In addition to the potential immunogenicity of engineered lipids, future investigations on liposome drugs in vivo should pay particular attention to the location and dynamics of payload release.

Improving the distribution of Doxil® in the tumor matrix by depletion of tumor hyaluronan.

Liposomes improve the pharmacokinetics and safety of rapidly cleared drugs, but have not yet improved the clinical efficacy compared to the non-encapsulated drug. This inability to improve efficacy may be partially due to the non-uniform distribution of liposomes in solid tumors. The tumor extra-cellular matrix is a barrier to distribution and includes the high molecular weight glycosaminoglycan, hyaluronan (HA). Strategies to remove HA or block its synthesis may improve drug delivery into solid tumors. Orally administered methylumbelliferone (MU) is an inhibitor of HA synthesis, but it is limited by low potency and limited solubility. In this study, we encapsulate a water-soluble phosphorylated prodrug of MU (MU-P) in a liposome (L-MU-P). We demonstrate that L-MU-P is a more potent inhibitor of HA synthesis than oral MU in the 4T1 murine mammary carcinoma model using both a quantitative ELISA and histochemistry. We show that HA depletion improves the tumor distribution of liposomes computed using Mander's colocalization analysis of liposomes with the tumor vasculature. Hyaluronan depletion also increases the fraction of the tumor area positive for liposomes. This improved distribution extends the overall survival of mice treated with Doxil®.

A robust and quantitative method for tracking liposome contents after intravenous administration.

We introduce a method for tracking the rate and extent of delivery of liposome contents in vivo based on encapsulation of 4-methylumbelliferyl phosphate (MU-P), a profluorophore of 4-methylumbelliferone (MU). MU-P is rapidly dephosphorylated by endogenous phosphatases in vivo to form MU after leakage from the liposome. The change in fluorescence spectra when MU-P is converted to MU allows for quantification of entrapped (MU-P) and released (MU) liposome contents by fluorescence or by a sensitive high performance liquid chromatography assay. We define the "cellular availability" of an agent encapsulated in a liposome as the ratio of the amount of released agent in the tissue to the total amount of agent in the tissue; this parameter quantifies the fraction of drug available for therapy. The advantage of this method over existing technologies is the ability to decouple the signals of entrapped and released liposome contents. We validate this method by tracking the circulation and tissue distribution of MU-P loaded liposomes after intravenous administration. We use this assay to compare the cellular availability of liposomes composed of engineered phosphocholine lipids with covalently attached cholesterol, sterol-modified lipids (SML), to liposomes composed of conventional phospholipids and cholesterol. The SML liposomes have similar pharmacokinetic and biodistribution patterns as conventional phospholipid-cholesterol liposomes but a slower rate of contents delivery into the tissue. Thus, MU-P enables the tracking of the rate and extent of liposome contents release in tissues and should facilitate a better understanding of the pharmacodynamics of liposome-encapsulated drugs in animals.

M13-templated magnetic nanoparticles for targeted in vivo imaging of prostate cancer.

Molecular imaging allows clinicians to visualize the progression of tumours and obtain relevant information for patient diagnosis and treatment. Owing to their intrinsic optical, electrical and magnetic properties, nanoparticles are promising contrast agents for imaging dynamic molecular and cellular processes such as protein-protein interactions, enzyme activity or gene expression. Until now, nanoparticles have been engineered with targeting ligands such as antibodies and peptides to improve tumour specificity and uptake. However, excessive loading of ligands can reduce the targeting capabilities of the ligand and reduce the ability of the nanoparticle to bind to a finite number of receptors on cells. Increasing the number of nanoparticles delivered to cells by each targeting molecule would lead to higher signal-to-noise ratios and would improve image contrast. Here, we show that M13 filamentous bacteriophage can be used as a scaffold to display targeting ligands and multiple nanoparticles for magnetic resonance imaging of cancer cells and tumours in mice. Monodisperse iron oxide magnetic nanoparticles assemble along the M13 coat, and its distal end is engineered to display a peptide that targets SPARC glycoprotein, which is overexpressed in various cancers. Compared with nanoparticles that are directly functionalized with targeting peptides, our approach improves contrast because each SPARC-targeting molecule delivers a large number of nanoparticles into the cells. Moreover, the targeting ligand and nanoparticles could be easily exchanged for others, making this platform attractive for in vivo high-throughput screening and molecular detection.

Inverse-phosphocholine lipids: a remix of a common phospholipid.

Zwitterionic inverse-phosphocholine (iPC) lipids contain headgroups with an inverted charge orientation relative to phosphocholine (PC) lipids. The iPC lipid headgroup has a quaternary amine adjacent to the bilayer interface and a phosphate that extends into the aqueous phase. Neutral iPC lipids with ethylated phosphate groups (CPe) and anionic iPC lipids nonethylated phosphate groups (CP) were synthesized. The surface potential of CPe liposomes remains negative across a broad pH range and in the presence of up to 10 mM Ca(2+). CP liposomes aggregate in the presence of Ca(2+), but at a slower rate than other anionic lipids. Hydrolysis of CP lipids by alkaline phosphatases generates a cationic lipid. CPe liposomes release encapsulated anionic carboxyfluorescein (CF) 20 times faster than PC liposomes and release uncharged glucose twice as fast as PC liposomes. As such, iPC lipids afford a unique opportunity to investigate the biophysical and bioactivity-related ramifications of a charge inversion at the bilayer surface.

Synthesis and characterization of betaine-like diacyl lipids: zwitterionic lipids with the cationic amine at the bilayer interface.

We synthesized and characterized a series of zwitterionic, acetate-terminated, quaternized amine diacyl lipids (AQ). These lipids have an inverted headgroup orientation as compared to naturally occurring phosphatidylcholine (PC) lipids; the cationic group is anchored at the membrane interface, while the anionic group extends into the aqueous phase. AQ lipids preferentially interact with highly polarizable anions (ClO(4)(-)) over less polarizable ions (Cl(-)), in accord with the Hofmeister series, as measured by the change in zeta potential of AQ liposomes. Conversely, AQ lipids have a weaker association with calcium than do PC lipids. The transition temperatures (Tm) of the AQ lipids are similar to the Tm observed with phosphatidylethanolamine (PE) lipids of the same chain length. AQ lipids form large lipid sheets after heating and sonication; however, in the presence of cholesterol (Chol), these lipids form stable liposomes that encapsulate carboxyfluorescein. The AQ:Chol liposomes retain their contents in the presence of serum at 37°C, and when injected intravenously into mice, their organ biodistribution is similar to that observed with PC:Chol liposomes. AQ lipids demonstrate that modulating the headgroup charge orientation significantly alters the biophysical properties of liposomes. For the drug carrier field, these new materials provide a non-phosphate containing zwitterlipid for the production of lipid vesicles.

Refactored M13 bacteriophage as a platform for tumor cell imaging and drug delivery.

M13 bacteriophage is a well-characterized platform for peptide display. The utility of the M13 display platform is derived from the ability to encode phage protein fusions with display peptides at the genomic level. However, the genome of the phage is complicated by overlaps of key genetic elements. These overlaps directly couple the coding sequence of one gene to the coding or regulatory sequence of another, making it difficult to alter one gene without disrupting the other. Specifically, overlap of the end of gene VII and the beginning of gene IX has prevented the functional genomic modification of the N-terminus of p9. By redesigning the M13 genome to physically separate these overlapping genetic elements, a process known as "refactoring," we enabled independent manipulation of gene VII and gene IX and the construction of the first N-terminal genomic modification of p9 for peptide display. We demonstrate the utility of this refactored genome by developing an M13 bacteriophage-based platform for targeted imaging of and drug delivery to prostate cancer cells in vitro. This successful use of refactoring principles to re-engineer a natural biological system strengthens the suggestion that natural genomes can be rationally designed for a number of applications.