Autopsy-based all-cause unnatural mortality during pre-pandemic and pandemic of COVID-19 in Varanasi, India: a retrospective analysis.

The COVID-19 pandemic has led to significant disruptions in healthcare systems worldwide, with Varanasi, India, experiencing profound challenges in managing mortality rates. In order to inform public health initiatives, it is important to comprehend how the pandemic has affected all-cause unnatural death in comparison to pre-pandemic patterns. This retrospective study intended to investigate patterns of all-cause unnatural mortality employing autopsy records of cases from Varanasi's Institute of Medical Sciences, Banaras Hindu University during the pre-pandemic and pandemic period (First and Second wave) of COVID-19. The analysis included 2694 cases of unnatural mortality, such as road traffic accident (RTA), poisoning, hanging and other causes. Demographic, clinical, and circumstantial data were collected and compared between the two time periods, that revealed significant as well as non-significant shifts in all-cause unnatural mortality rates. Whilst certain types of unnatural deaths, such as RTAs, witnessed a non-significant 2.03% (p = 0.34722) decrease, others like hanging exhibited an unexpected significant 3.17% (p = 0.01732) rise, burning and poisoning witnessed a significant 4.18% (p = 0.00026) and 2.37% (p = 0.0271) decline respectively. RTA was the leading cause of mortality both during and before pandemic. Male deaths (79.18%) outweighed female deaths (20.82%) by a more substantial amount throughout research periods. Additionally, variations in demographic characteristics, circumstances surrounding deaths, and healthcare utilization were observed during the pandemic period. The majority of unnatural fatalities occur in the age group of 21-30 years old in both pre-pandemic (22.62%) and pandemic conditions (26.65%). This study provides important insights into the secondary effects of the pandemic on unnatural mortality and emphasizes the need for individualized public health. Furthermore, research is warranted to explore the long-term implications and address the associated challenges for healthcare systems and public health initiatives.

Seaweed-derived fucoidans and rhamnan sulfates serve as potent anti-SARS-CoV-2 agents with potential for prophylaxis.

Seaweeds represent a rich source of sulfated polysaccharides with similarity to heparan sulfate, a facilitator of myriad virus host cell attachment. For this reason, attention has been drawn to their antiviral activity, including the potential for anti-SARS-CoV-2 activity. We have identified and structurally characterized several fucoidan extracts, including those from different species of brown macroalga, and a rhamnan sulfate from a green macroalga species. A high molecular weight fucoidan extracted from Saccharina japonica (FSjRPI-27), and a rhamnan sulfate extracted from Monostroma nitidum (RSMn), showed potent competitive inhibition of spike glycoprotein receptor binding to a heparin-coated SPR chip. This inhibition was also observed in cell-based assays using hACE2 HEK-293 T cells infected by pseudotyped SARS-CoV-2 virus with IC50 values <1 µg/mL. Effectiveness was demonstrated in vivo using hACE2-transgenic mice. Intranasal administration of FSjRPI-27 showed protection when dosed 6 h prior to and at infection, and then every 2 days post-infection, with 100 % survival and no toxicity at 104 plaque-forming units per mouse vs. buffer control. At 5-fold higher virus dose, FSjRPI-27 reduced mortality and yielded reduced viral titers in bronchioalveolar fluid and lung homogenates vs. buffer control. These findings suggest the potential application of seaweed-based sulfated polysaccharides as promising anti-SARS-CoV-2 prophylactics.

Mitochondrial Acyl Carrier Protein of Leishmania major Displays Features Distinct from the Canonical Type II ACP.

Prokaryotes synthesize fatty acids using a type II synthesis pathway (FAS). In this process, the central player, i.e., the acyl carrier protein (ACP), sequesters the growing acyl chain in its internal hydrophobic cavity. As the acyl chain length increases, the cavity expands in size, which is reflected in the NMR chemical shift perturbations and crystal structures of the acyl-ACP intermediates. A few eukaryotic organelles, such as plastids and mitochondria, also harbor type II fatty acid synthesis machinery. Plastid FAS from spinach and Plasmodium falciparum has been characterized at the molecular level, but the mitochondrial pathway remains unexplored. Here, we report NMR studies of the mitochondrial acyl-acyl carrier protein intermediates of Leishmania major (acyl-LmACP). Our studies show that LmACP experiences remarkably small conformational changes upon acylation, with perturbations confined to helices II and III only. CastP determined that the cavity size of apo-LmACP (PDB entry 5ZWT) is less than that of Escherichia coli ACP (PDB 1T8K). Thus, the small chemical shift perturbations observed in the LmACP intermediates, coupled with CastP results, suggest an unusually small cavity when fully expanded. The faster rate of C8-LmACP chain hydrolysis compared to E. coli ACP (EcACP) also supports these convictions. Structure comparison of LmACP with other type II ACP disclosed unique differences in the helix I and loop I conformations, as well as several residues present there. Numerous hydrophobic residues in helix I and loop I (conserved in all mitochondrial ACPs) are substituted with hydrophilic residues in the bacterial/plastid type II ACP. For instance, Phe and leucine at positions 14 and 34 in LmACP are substituted with a hydrophilic residue and Ala in bacterial/plastid type II ACP. Mutation of Leu 34 to Ala (corresponding residue in EcACP) resulted in a complete loss of structure, underscoring its importance in maintaining the ACP fold. Thus, our NMR studies, combined with insights from the crystal structure, highlight several unique features of LmACP, distinct from the prokaryote and plastid type II ACP. Given the high sequence identity, the features might be conserved in all mitochondrial ACPs.

Flexible, Thermally Stable, and Ultralightweight Polyimide-CNT Aerogel Composite Films for Energy Storage Applications.

Polyimide (PI) aerogels are promising in various fields of application, ranging from thermal insulators to aerospace. However, they are typically in the form of a bulk monolith, which suffers from a lack of conformability and drapability. Moreover, their electrical conductivity is limited, and they mainly display an insulative behavior. These shortcomings can limit the applications of PI aerogels in energy storage systems, which require ultralightweight flexible conductive films, which at the same time offer high thermal stability, ultralow density, and high surface area. To overcome these obstacles, the present study reports the fabrication of PI-carbon nanotube (PI-CNT) aerogel composite films with varying CNT content prepared through a sol-gel preparation method, followed by a supercritical drying procedure. Compared to pristine PI aerogels, which displayed a large shrinkage and density of 18.3% and 0.12 g cm-3, respectively, the incorporation of only 5 wt % CNTs resulted in a significant reduction of both shrinkage and density to only 11.5% and 0.10 g cm-3, respectively. This suggests the importance of CNTs in improving the dimensional stability of aerogels and creating a robust network. Further characterizations showed that incorporation of 5 wt % CNTs also resulted in the highest pore volume (1.25 cm3 g-1), highest surface area (324 m2 g-1), highest real permittivity (80), highest electrical conductivity (3 × 10-1 S m-1), and ultrahigh service temperature (575 °C). It was also shown that the aerogel films can withstand a large degree of bending, can be twisted, and can be fully rolled with no obvious cracks propagated in the structure. The combined outstanding properties of the developed aerogel composite films make them promising potential candidates for supercapacitor electrodes. Therefore, the electrochemical performance of the devices based on aerogel electrodes was further studied. The device demonstrated a high energy density of 2.6 Wh kg-1 at a power density of 303.8 W kg-1. The total capacitance after 5000 cycles was 91.8% of the initial capacitance, which indicated excellent stability and durability of the device. Overall, this work provides a facile yet effective methodology for the development of high-performance aerogel materials for energy storage applications.

Protein Cage Relaxivity Measurement for Magnetic Resonance Imaging Contrast Agents.

Contrast agents are employed to enhance the differentiation of diseased cells or lesions from normal tissues in magnetic resonance imaging (MRI). Protein cages have been explored as templates to synthesize superparamagnetic MRI contrast agents for decades. The biological origin imparts natural precision in forming confined nano-sized reaction vessels. With natural capacity to bind divalent metal ions, ferritin protein cages have been used for the synthesis of nanoparticles containing MRI contrast agents inside their core. Furthermore, ferritin is known to bind transferrin receptor 1 (TfR1) which is overexpressed on specific cancer cell types and could be used for targeted cellular imaging. In addition to iron, other metal ions such as manganese and gadolinium have been encapsulated within the core of ferritin cages. To compare the magnetic properties of ferritin loaded with contrast agents, a protocol for calculating the contrast enhancement power of protein nanocage is required. The contrast enhancement power is demonstrated as relaxivity and can be measured using MRI and solution nuclear magnetic resonance (NMR) methods. In this chapter, we present methods for measuring and calculating the relaxivity of ferritin nanocages loaded with paramagnetic ions in solution (in tube) with NMR and MRI.

Oxygen-Vacancy Abundant Nanoporous Ni/NiMnO3/MnO2@NiMn Electrodes with Ultrahigh Capacitance and Energy Density for Supercapacitors.

High-performance energy storage devices (HPEDs) play a critical role in the realization of clean energy and thus enable the overarching pursuit of nonpolluting, green technologies. Supercapacitors are one class of such lucrative HPEDs; however, a serious limiting factor of supercapacitor technology is its sub-par energy density. This report presents hitherto unchartered pathway of physical deformation, chemical dealloying, and microstructure engineering to produce ultrahigh-capacitance, energy-dense NiMn alloy electrodes. The activated electrode delivered an ultrahigh specific-capacitance of 2700 F/cm3 at 0.5 A/cm3. The symmetric device showcased an excellent energy density of 96.94 Wh/L and a remarkable cycle life of 95% retention after 10,000 cycles. Transmission electron microscopy and atom probe tomography studies revealed the evolution of a unique hierarchical microstructure comprising fine Ni/NiMnO3 nanoligaments within MnO2-rich nanoflakes. Theoretical analysis using density functional theory showed semimetallic nature of the nanoscaled oxygen-vacancy-rich NiMnO3 structure, highlighting enhanced carrier concentration and electronic conductivity of the active region. Furthermore, the geometrical model of NiMnO3 crystals revealed relatively large voids, likely providing channels for the ion intercalation/de-intercalation. The current processing approach is highly adaptable and can be applied to a wide range of material systems for designing highly efficient electrodes for energy-storage devices.

Comprehensive spatio-temporal benchmarking of surface water quality of Hindon River, a tributary of river Yamuna, India: Adopting multivariate statistical approach.

The Hindon River is the main tributary of river Yamuna and it is a significant source of surface water, which flows through the major cities of western Uttar Pradesh, India. The indiscriminate development of industries and urbanization along river basin coupled with rapid population growths contribute various amounts of pollutant in the river. Therefore, the present study was conducted to assess the spatial-temporal variability of river water quality (seventeen physicochemical parameters and eight heavy metals) during pre- and post-monsoon seasons for 5 years data at 19 sampling sites along the river stretch. Indices associated with water quality and heavy metals were computed to scale the accurate state of risk associated to its use for drinking and irrigation. During the pre- and post-monsoon seasons, only four sites were found having safe water quality index (WQI) values. The mean heavy metal concentrations are found in order of Zn > Fe > Pb > Cu > Cr > Cd > Ni > Mn. Considering the spatial and temporal distribution, the study benchmarked the water quality of Hindon River for priority attention.

Correlative Multicentric Analysis of Dimensions of Nasopharynx and Adenoid Size, and its Burden in Otitis Media with Effusion: An Indian Scenario.

Diseases of adenoids are commonly observed in children. It indirectly leads to pathology in the middle ear cleft. It has been demonstrated both by radiological techniques and middle ear pressure studies that adenoids can and do obstruct the Eustachian Tube. The Adenoid-Nasopharyngeal Ratio (ANR), can offer a simple arithmetic measure of nasopharyngeal obstruction. Coupled with tympanometry, it also predicts the degree to which the middle ear is affected. Multicentric study done at two centres in India. 230 patients were studied. Children were in the age group of 5-14 years. The nasopharyngeal and adenoid dimensions were measured separately using the Fujioka method. The adenoid-nasopharyngeal ratio was derived by the arithmetic method. All patients were also subjected to tympanometry. ANR decreased from 0.728 to 0.663 with an increase in age from 5 to 12 years. ANR between 0.701-0.800 had maximum number of Type B (140) and Type C (71) Tympanogram whereas between 0.801 and 0.900, all Tympanogram were found to be of Type B or Type C with none belonging to Type A. Using ANR and Tympanometry, the effects of the adenoids on the middle ear can be quantified indirectly. Both these modalities are easily available, economical, safe and can be performed at the Out Patient Level. This aids in timely and appropriate management thus preventing discomforting symptoms caused by the adenoids locally and also the morbidity caused to the middle ear in the long term.

Alpha-Calcitonin Gene Related Peptide: New Therapeutic Strategies for the Treatment and Prevention of Cardiovascular Disease and Migraine.

Alpha-calcitonin gene-related peptide (α-CGRP) is a vasodilator neuropeptide of the calcitonin gene family. Pharmacological and gene knock-out studies have established a significant role of α-CGRP in normal and pathophysiological states, particularly in cardiovascular disease and migraines. α-CGRP knock-out mice with transverse aortic constriction (TAC)-induced pressure-overload heart failure have higher mortality rates and exhibit higher levels of cardiac fibrosis, inflammation, oxidative stress, and cell death compared to the wild-type TAC-mice. However, administration of α-CGRP, either in its native- or modified-form, improves cardiac function at the pathophysiological level, and significantly protects the heart from the adverse effects of heart failure and hypertension. Similar cardioprotective effects of the peptide were demonstrated in pressure-overload heart failure mice when α-CGRP was delivered using an alginate microcapsules-based drug delivery system. In contrast to cardiovascular disease, an elevated level of α-CGRP causes migraine-related headaches, thus the use of α-CGRP antagonists that block the interaction of the peptide to its receptor are beneficial in reducing chronic and episodic migraine headaches. Currently, several α-CGRP antagonists are being used as migraine treatments or in clinical trials for migraine pain management. Overall, agonists and antagonists of α-CGRP are clinically relevant to treat and prevent cardiovascular disease and migraine pain, respectively. This review focuses on the pharmacological and therapeutic significance of α-CGRP-agonists and -antagonists in various diseases, particularly in cardiac diseases and migraine pain.

Unusual Anterior Mediastinal Tumors Treated at a Tertiary Thoracic Center: A Case Series Analysis.

Several tumors arise from different structures within the mediastinum. Although each type of mediastinal tumor has a predilection for a specific compartment, the progression of growth from one compartment to another can occur. The anterior mediastinum is the site of several tumors that pose interesting diagnostic and therapeutic challenges to thoracic surgeons. The anterior mediastinum is the seat of the majority of neoplastic growths within the mediastinum. Thymomas and lymphomas are the most common pathologies of the anterior mediastinum. Tumors of mesenchymal origin (hemangioma, lymphangioma, lipomas) and their malignant counterparts may occur in any of the mediastinal compartments. Less common tumors of the anterior mediastinal compartment are ectopic thyroid and parathyroid tumors, germ cell tumors, mesenchymal origin tumors, hemangiomas, and cervicomediastinal hygromas. Most of the mediastinal growths usually remain clinically silent until they become large and cause compressive symptoms. Here, we present a case series of five anterior mediastinal tumors consisting of solitary benign teratoma, fibrous benign tumor, malignant fibrosarcoma, hamartomatous chondroma, and malignant thymoma.

Magnetoferritin enhances T2 contrast in magnetic resonance imaging of macrophages.

Imaging of immune cells has wide implications in understanding disease progression and staging. While optical imaging is limited in penetration depth due to light properties, magnetic resonance (MR) imaging provides a more powerful tool for the imaging of deep tissues where immune cells reside. Due to poor MR signal to noise ratio, tracking of such cells typically requires contrast agents. This report presents an in-depth physical characterization and application of archaeal magnetoferritin for MR imaging of macrophages - an important component of the innate immune system that is the first line of defense and first responder in acute inflammation. Magnetoferritin is synthesized by loading iron in apoferritin in anaerobic condition at 65 °C. The loading method results in one order of magnitude enhancement of r1 and r2 relaxivities compared to standard ferritin synthesized by aerobic loading of iron at room temperature. Detailed characterizations of the magnetoferritin revealed a crystalline core structure that is distinct from previously reported ones indicating magnetite form. The magnetite core is more stable in the presence of reducing agents and has higher peroxidase-like activities compared to the core in standard loading. Co-incubation of macrophage cells with magnetoferritin in-vitro shows significantly higher enhancement in T2-MRI contrast of the immune cells compared to standard ferritin.

Assessment of eco-hydrological parameters for important sympodial bamboo species in Himalayan foothills.

Bamboos due to high soil water conservation potential are gaining increased attention in plantation programs across the globe. Large-scale plantation of fast-growing bamboo, however, can have important hydrological consequences. The study aims to quantify the eco-hydrological parameters, viz., throughfall (TF), stemflow (SF), and interception (I) in seven important sympodial bamboo species in north western Himalayan foothills of India. The species selected include Bambusa balcooa, Bambusa bambos, Bambusa vulgaris., Bambusa nutans, Dendrocalamus hamiltonii, Dendrocalamus stocksii, and Dendrocalamus strictus. Throughfall versus gross rainfall (GR) relationship in different species indicated high throughfall production during high rainfall events with r2 > 0.90. Average throughfall was lowest (62.1%) in D. hamiltonii and highest in B. vulgaris (74.6%). SF ranged from 1.32% in B. nutans to 3.39% in D. hamiltonii. The correlation coefficient (r) between leaf area index (LAI), number of culms, and crown area with the interception were 0.746, 0.691, and 0.585, respectively. The funneling ratio (F) was highest (27.0) in D. hamiltonii and least in B. nutans. Canopy storage capacity was highest in D. strictus (3.57 mm) and least in D. hamiltonii (1.09 mm). Interception loss was highest (34.4%) in D. hamiltonii and lowest in B. vulgaris (23.5%) and D. strictus (23.6%). Higher interception in bamboos make them suitable for soil conservation, but careful selection of species is required in low rainfall areas.

L. major apo-acyl carrier protein forms ordered aggregates due to an exposed phenylalanine, while phosphopantetheine inhibits aggregation in the holo-form.

L. major acyl carrier protein (ACP) is a mitochondrial protein, involved in fatty acid biosynthesis. The protein is expressed as an apo-protein, and post-translationally modified at Ser 37 by a 4'-Phosphopantetheinyl transferase. Crystal structure of the apo-form of the protein at pH 5.5 suggests a four helix bundle fold, typical of ACP's. However, upon lowering the pH to 5.0, it undergoes a conformational transition from α-helix to ß-sheet, and displays amyloid like properties. When left for a few days at room temperature at this pH, the protein forms fibrils, visible under Transmission electron microscopy (TEM). Using an approach combining NMR, biophysical techniques, and mutagenesis, we have identified a Phe residue present on helix II of ACP, liable for this change. Phosphopantetheinylation of LmACP, or mutation of Phe 45 to the corresponding residue in E. coli ACP (methionine), slows down the conformational change. Conversely, substitution of methionine 44 of E. coli ACP with a phenylalanine, causes enhanced ThT binding. Thus, we demonstrate the unique property of an exposed Phe in inducing, and phophopantetheine in inhibiting amyloidogenesis. Taken together, our study adds L. major acyl carrier protein to the list of ACPs that act as pH sensors.

Role of JAK/STAT in the Neuroinflammation and its Association with Neurological Disorders.

Background: Innate immunity is mediated by a variety of cell types, including microglia, macrophages, and neutrophils, and serves as the immune system's first line of defense. There are numerous pathways involved in innate immunity, including the interferon (IFN) pathway, TRK pathway, mitogen-activated protein kinase (MAPK) pathway, Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway, interleukin (IL) pathways, chemokine pathways (CCR5), GSK signaling, and Fas signaling. Summary: JAK/STAT is one of these important signaling pathways and this review focused on JAK/STAT signaling pathway only. The overactivation of microglia and astrocytes influences JAK/STAT's role in neuroinflammatory disease by initiating innate immunity, orchestrating adaptive immune mechanisms, and ultimately constraining inflammatory and immunological responses. The JAK/STAT signaling pathway is one of the critical factors that promotes neuroinflammation in neurodegenerative diseases. Key message: Given the importance of the JAK/STAT pathway in neurodegenerative disease, this review discussed the feasibility of targeting the JAK/STAT pathway as a neuroprotective therapy for neurodegenerative diseases in near future.

Rooting behaviour and soil properties in different bamboo species of Western Himalayan Foothills, India.

Due to extensive root system, connected rhizome bamboos are considered suitable for improving soil properties within a short period, though most of the claims are anecdotal and need to be supported with quantified data. The study evaluates seven bamboo species viz., Bambusa balcooa, Bambusa bambos, Bambusa vulgaris, Bambusa nutans, Dendrocalamus hamiltonii, Dendrocalamus stocksii and Dendrocalamus strictus for their rooting pattern and impact on soil health properties. Coarse and fine root intensity was maximum in B. vulgaris. Coarse root biomass ranged from 0.6 kg m-3 in B. nutans to 2.0 kg m-3 in B. vulgaris and B. bambos. Fine root biomass ranged from 1.1 kg m-3 in B. nutans to 4.5 kg m-3 in D. hamiltonii. Contribution of fine roots in terms of intensity and biomass was much higher than coarse roots. Fine root biomass showed declining trend with increase in soil depth in all the species. During sixth year, the litter fall ranged from 8.1 Mg ha-1 in D. stocksii to 12.4 Mg ha-1 in D. hamiltonii. Among soil physical properties significant improvement were recorded in hydraulic conductivity, water stable aggregates and mean weight diameter. Soil pH, organic carbon and available phosphorus under different species did not reveal any significant changes, while significant reduction was observed in total nitrogen and potassium. Significant positive correlation was observed between WSA and iron content. Soil microbial population and enzyme activities were higher in control plot. Considering root distribution, biomass, soil hydraulic conductivity and water stable aggregates, B. bambos, B. vulgaris and D. hamiltonii are recommended for rehabilitation of degraded lands prone to soil erosion.

A Novel Alginate-Based Delivery System for the Prevention and Treatment of Pressure-Overload Induced Heart Failure.

Background: α-CGRP (alpha-calcitonin gene related peptide) is a cardioprotective neuropeptide. Our recent study demonstrated that the administration of native α-CGRP, using osmotic mini-pumps, protected against transverse aortic constriction (TAC) pressure-induced heart failure in mice. However, the short half-life of peptides and the non-applicability of osmotic pumps in humans limits the use of α-CGRP as a therapeutic agent for heart failure (HF). Here, we sought to comprehensively study a novel α-CGRP delivery system using alginate microcapsules to determine its bioavailability in vivo and to test for cardioprotective effects in HF mice. Methods: Native α-CGRP filled alginate microcapsules (200 µm diameter) were prepared using an electrospray method. The prepared alginate-α-CGRP microcapsules were incubated with rat cardiac H9c2 cells, mouse cardiac HL-1 cells, and human umbilical vein endothelial cells (HUVECs), and the cytotoxicity of the alginate-α-CGRP microcapsules was measured by a trypan-blue cell viability assay and a calcium dye fluorescent based assay. The efficacy of the alginate-α-CGRP microcapsules was tested in a TAC-pressure overload mouse model of heart failure. Male C57BL6 mice were divided into four groups: sham, sham-alginate-α-CGRP, TAC-only, and TAC-alginate-α-CGRP, and the TAC procedure was performed in the TAC-only and TAC-alginate-α-CGRP groups of mice to induce pressure-overload heart failure. After 2 or 15 days post-TAC, alginate-α-CGRP microcapsules (containing an α-CGRP dose of 6 mg/kg/mouse) were administered subcutaneously on alternate days, for 28 days, and echocardiography was performed weekly. After 28 days of peptide delivery, the mice were sacrificed and their hearts were collected for histological and biochemical analyses. Results: Our in vitro cell culture assays showed that alginate-α-CGRP microcapsules did not affect the viability of the cell lines tested. The alginate-α-CGRP microcapsules released their peptides for an extended period of time. Our echocardiography, biochemical, and histology data from HF mice demonstrated that the administration of alginate-α-CGRP microcapsules significantly improved all cardiac parameters examined in TAC-mice. When compared to sham mice, TAC significantly decreased cardiac functions (as determined by fraction shortening and ejection fraction) and markedly increased heart and lung weight, left ventricle (LV) cardiac cell size, cardiac apoptosis, and oxidative stress. In contrast, the administration of alginate-α-CGRP microcapsules significantly attenuated the increased heart and lung weight, LV cardiac cell size, apoptosis, and oxidative stress in TAC mice. Conclusion: Our results demonstrate that the encapsulation of α-CGRP in an alginate polymer is an effective strategy to improve peptide bioavailability in plasma and increase the duration of the therapeutic effect of the peptide throughout the treatment period. Furthermore, alginate mediates α-CGRP delivery, either prior to the onset or after the initiation of the symptom progression of pressure-overload, improves cardiac function, and protects hearts against pressure-induced HF.

Alpha-calcitonin gene-related peptide prevents pressure-overload induced heart failure: role of apoptosis and oxidative stress.

Alpha-calcitonin gene-related peptide (α-CGRP) is a 37-amino acid neuropeptide that plays an important protective role in modulating cardiovascular diseases. Deletion of the α-CGRP gene increases the vulnerability of the heart to pressure-induced heart failure and the administration of a modified α-CGRP agonist decreases this vulnerability. Systemic administration of α-CGRP decreases blood pressure in normotensive and hypertensive animals and humans. Here we examined the protective effect of long-term administration of native α-CGRP against pressure-overload heart failure and the likely mechanism(s) of its action. Transverse aortic constriction (TAC) was performed to induce pressure-overload heart failure in mice. We found that TAC significantly decreased left ventricular (LV) fractional shortening, ejection fraction, and α-CGRP content, and increased hypertrophy, dilation, and fibrosis compared to sham mice. Administration of α-CGRP-filled mini-osmotic pumps (4 mg/kg bwt/day) in TAC mice preserved cardiac function and LV α-CGRP levels, and reduced LV hypertrophy, dilation, and fibrosis to levels comparable to sham mice. Additionally, TAC pressure-overload significantly increased LV apoptosis and oxidative stress compared to the sham mice but these increases were prevented by α-CGRP administration. α-CGRP administration in TAC animals decreased LV AMPK phosphorylation levels and the expression of sirt1, both of which are regulatory markers of oxidative stress and energy metabolism. These results demonstrate that native α-CGRP is protective against pressure-overload induced heart failure. The mechanism of this cardio-protection is likely through the prevention of apoptosis and oxidative stress, possibly mediated by sirt1 and AMPK. Thus, α-CGRP is a potential therapeutic agent in preventing the progression to heart failure, and the cardio-protective action of α-CGRP is likely the result of a direct cellular effect; however, a partial vasodilatory blood pressure-dependent mechanism of α-CGRP cannot be excluded.

Abundant neuroprotective chaperone Lipocalin-type prostaglandin D synthase (L-PGDS) disassembles the Amyloid-ß fibrils.

Misfolding of Amyloid ß (Aß) peptides leads to the formation of extracellular amyloid plaques. Molecular chaperones can facilitate the refolding or degradation of such misfolded proteins. Here, for the first time, we report the unique ability of Lipocalin-type Prostaglandin D synthase (L-PGDS) protein to act as a disaggregase on the pre-formed fibrils of Aß(1-40), abbreviated as Aß40, and Aß(25-35) peptides, in addition to inhibiting the aggregation of Aß monomers. Furthermore, our proteomics results indicate that L-PGDS can facilitate extraction of several other proteins from the insoluble aggregates extracted from the brain of an Alzheimer's disease patient. In this study, we have established the mode of binding of L-PGDS with monomeric and fibrillar Aß using Nuclear Magnetic Resonance (NMR) Spectroscopy, Small Angle X-ray Scattering (SAXS), and Transmission Electron Microscopy (TEM). Our results confirm a direct interaction between L-PGDS and monomeric Aß40 and Aß(25-35), thereby inhibiting their spontaneous aggregation. The monomeric unstructured Aß40 binds to L-PGDS via its C-terminus, while the N-terminus remains free which is observed as a new domain in the L-PGDS-Aß40 complex model.

Protective Role of α-Calcitonin Gene-Related Peptide in Cardiovascular Diseases.

α-Calcitonin gene-related peptide (α-CGRP) is a regulatory neuropeptide of 37 amino acids. It is widely distributed in the central and peripheral nervous system, predominantly in cell bodies of the dorsal root ganglion (DRG). It is the most potent vasodilator known to date and has inotropic and chronotropic effects. Using pharmacological and genetic approaches, our laboratory and other research groups established the protective role of α-CGRP in various cardiovascular diseases such as heart failure, experimental hypertension, myocardial infarction, and myocardial ischemia/reperfusion injury (I/R injury). α-CGRP acts as a depressor to attenuate the rise in blood pressure in three different models of experimental hypertension: (1) DOC-salt, (2) subtotal nephrectomy-salt, and (3) L-NAME-induced hypertension during pregnancy. Subcutaneous administration of α-CGRP lowers the blood pressure in hypertensive and normotensive humans and rodents. Recent studies also demonstrated that an α-CGRP analog, acylated α-CGRP, with extended half-life (~7 h) reduces blood pressure in Ang-II-induced hypertensive mouse, and protects against abdominal aortic constriction (AAC)-induced heart failure. Together, these studies suggest that α-CGRP, native or a modified form, may be a potential therapeutic agent to treat patients suffering from cardiac diseases.

Prevalence of Psychiatric Illness among Residents of Old Age Homes in Northern India.

CONTEXT: There are many factors which compelled older adults to live in old age homes (OAHs) and vulnerable to psychological problems. Studies reported high prevalence of mental health problems (20%-60%) among elderlies of OAHs. Therefore, the study was conducted to explore prevalence of psychiatric illness (PI) among residents of OAHs of Northern India. SETTINGS AND DESIGN: The present study was conducted in OAHs of Districts Bareilly, Lucknow, Varanasi, Dehradun, and Haridwar, using cross-sectional descriptive study method. Sample Size were 306 (male - 98 [32.5%] and female n = 208 [68%]) residing in OAHs selected by means of purposive sampling. SUBJECTS AND METHODS: Inclusion criteria: (a) older adults aged 60 years and above residing in OAHs and able to communicate. (b) Staying in OAHs for 6 months or more. (c) Able to understand comprehends and reply to questions and (d) Giving written informed consent. Exclusion criteria: (a) Residents who declined/not interested to participate in the study. (b) Residents having any sensory impairment/physical health problem which can impede the interview. Research tools were (i) a semi-structured pro forma, (ii) Hindi Mental Status Examination, (iii) Survey psychiatric assessment schedule, and (iv) Schedules for clinical assessment in neuropsychiatry-based clinical interview for diagnosis of PIs according to International Classification of Disease 10. STATISTICAL ANALYSIS USED: The quantitative data obtained was analyzed by means of frequency tables. RESULTS: The results show overall prevalence of PI is 43% among residents of OAHs. The prevalence of PI was found to be higher among females compared to males. Depression was the most common among the residents of OAHs. CONCLUSIONS: There is an urgent need of trained professionals to provide professional help for highly prevalent psychiatric disorders among residents of OAHs.