As of 2021, the National Kala-azar Elimination Programme (NKAEP) in India has achieved visceral leishmaniasis (VL) elimination (<1 case / 10,000 population/year per block) in 625 of the 633 endemic ...blocks (subdistricts) in four states. The programme needs to sustain this achievement and target interventions in the remaining blocks to achieve the WHO 2030 target of VL elimination as a public health problem. An effective tool to analyse programme data and predict/ forecast the spatial and temporal trends of VL incidence, elimination threshold, and risk of resurgence will be of use to the programme management at this juncture.
We employed spatiotemporal models incorporating environment, climatic and demographic factors as covariates to describe monthly VL cases for 8-years (2013-2020) in 491 and 27 endemic and non-endemic blocks of Bihar and Jharkhand states. We fitted 37 models of spatial, temporal, and spatiotemporal interaction random effects with covariates to monthly VL cases for 6-years (2013-2018, training data) using Bayesian inference via Integrated Nested Laplace Approximation (INLA) approach. The best-fitting model was selected based on deviance information criterion (DIC) and Watanabe-Akaike Information Criterion (WAIC) and was validated with monthly cases for 2019-2020 (test data). The model could describe observed spatial and temporal patterns of VL incidence in the two states having widely differing incidence trajectories, with >93% and 99% coverage probability (proportion of observations falling inside 95% Bayesian credible interval for the predicted number of VL cases per month) during the training and testing periods. PIT (probability integral transform) histograms confirmed consistency between prediction and observation for the test period. Forecasting for 2021-2023 showed that the annual VL incidence is likely to exceed elimination threshold in 16-18 blocks in 4 districts of Jharkhand and 33-38 blocks in 10 districts of Bihar. The risk of VL in non-endemic neighbouring blocks of both Bihar and Jharkhand are less than 0.5 during the training and test periods, and for 2021-2023, the probability that the risk greater than 1 is negligible (P<0.1). Fitted model showed that VL occurrence was positively associated with mean temperature, minimum temperature, enhanced vegetation index, precipitation, and isothermality, and negatively with maximum temperature, land surface temperature, soil moisture and population density.
The spatiotemporal model incorporating environmental, bioclimatic, and demographic factors demonstrated that the KAMIS database of the national programmme can be used for block level predictions of long-term spatial and temporal trends in VL incidence and risk of outbreak / resurgence in endemic and non-endemic settings. The database integrated with the modelling framework and a dashboard facility can facilitate such analysis and predictions. This could aid the programme to monitor progress of VL elimination at least one-year ahead, assess risk of resurgence or outbreak in post-elimination settings, and implement timely and targeted interventions or preventive measures so that the NKAEP meet the target of achieving elimination by 2030.
COVID-19 and diabetes: What do we know so far? Gangadaran, Prakash; Padinjarathil, Himabindu; Rajendran, Shri Hari Subhashri ...
Experimental Biology and Medicine,
08/2022, Letnik:
247, Številka:
15
Book Review, Journal Article
Recenzirano
Odprti dostop
Coronavirus disease 2019 (COVID-19) management has been challenging for patients with comorbidities. Patients with diabetes and COVID-19, in particular, have shown severe symptoms and rapid ...progression of the disease. They also have a high mortality rate compared to the non-diabetic population. The high mortality rate is caused in people with diabetes who are in a pro-inflammatory condition; this could worsen COVID-19. In addition, people with diabetes have circulatory issues and COVID-19 infection can lead to further clotting problems. It is critical to understand the mechanisms underlying the adverse clinical outcomes in patients with diabetes and COVID-19. This review discusses various disease conditions contributing to poor prognosis in diabetic COVID-19 patients such as hyperglycemia, insulin resistance, impaired pancreatic function, and production of advanced glycation end products.
Management of relapses and refractory rheumatoid arthritis (RA) patients is complex and difficult. Even after the administration of new biological disease-modifying anti-rheumatic drugs (DMARDs), ...only a few patients achieve the complete remission phase. DMARDs help only in modifying the disease activity, which sooner or later fails. They do not manage the disease at the patho-etiological level. There are some serious side effects as well as drug interaction with DMARDs. There are few subsets of RA patients who do not respond to DMARDs, reasons unknown. Mesenchymal stem cells (MSCs) provide a promising alternative, especially in such cases. This review elaborates on the studies pertaining to the application of MSCs in rheumatoid arthritis over the last two decades. A total of 14 studies (one review article) including 447 patients were included in the study. Most of the studies administered MSCs in refractory RA patients through the intravenous route with varied dosages and frequency of administration. MSCs help in RA treatment via various mechanisms including paracrine effects. All the studies depicted a better clinical outcome with minimal adverse events. The functional scores including the VAS scores improved significantly in all studies irrespective of dosage and source of MSCs. The majority of the studies depicted no complications. Although the use of MSCs in RA is still in the early stages requiring further refinement in the source of MSCs, dosage, and frequency. The role of MSCs in the management of RA has a promising prospect. MSCs target the RA at the molecular level and has the potential to manage refractory RA cases not responding to conventional treatment. Multicentric, large sample populations, and long-term studies are required to ascertain efficacy and safety.
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Alzheimer’s disease (AD), a multi-factorial neurodegenerative disorder has affected over 30 million individuals globally and these numbers are expected to increase in the coming decades. Current ...therapeutic interventions are largely ineffective as they focus on a single target. Development of an effective drug therapy requires a deep understanding of the various factors influencing the onset and progression of the disease. Aging and genetic factors exert a major influence on the development of AD. Other factors like post-viral infections, iron overload, gut dysbiosis, and vascular dysfunction also exacerbate the onset and progression of AD. Further, post-translational modifications in tau, DRP1, CREB, and p65 proteins increase the disease severity through triggering mitochondrial dysfunction, synaptic loss, and differential interaction of amyloid beta with different receptors leading to impaired intracellular signalling. With advancements in neuroscience tools, new inter-relations that aggravate AD are being discovered including pre-existing diseases and exposure to other pathogens. Simultaneously, new therapeutic strategies involving modulation of gene expression through targeted delivery or modulation with light, harnessing the immune response to promote clearance of amyloid deposits, introduction of stem cells and extracellular vesicles to replace the destroyed neurons, exploring new therapeutic molecules from plant, marine and biological sources delivered in the free state or through nanoparticles and use of non-pharmacological interventions like music, transcranial stimulation and yoga. Polypharmacology approaches involving combination of therapeutic agents are also under active investigation for superior therapeutic outcomes. This review elaborates on various disease-causing factors, their underlying mechanisms, the inter-play between different disease-causing players, and emerging therapeutic options including those under clinical trials, for treatment of AD. The challenges involved in AD therapy and the way forward have also been discussed.
•Secondary pathological changes involving mitochondria, and co-morbidities are associated with severity of Alzheimer’s disease.•Molecular targets related to the emerging pathological events associated with AD may prove beneficial.•New insights on co-morbidities associated with AD reveal extensive cross-talk between signalling pathways.•Emerging therapeutic strategies are shifting towards harnessing cells, nanotechnology, immune system, phytotherapy, non-pharmacological interventions and combinational therapy.•Summary of clinical trial findings (2016–2023) using AD drug pipeline data shows a shift towards new molecular targets.
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The industrial and technological advancements in the world have also contributed to the rapid deterioration in the environment quality through introduction of obnoxious pollutants ...that threaten to destroy the subtle balance in the ecosystem. The environment contaminants cause severe adverse effects to humans, flora and fauna that are mostly irreversible. Chief among these toxicants is arsenic, a metalloid, which is considered among the most dangerous environmental toxins that leads to various diseases which affect the quality of life even when present in small quantities. Treatment of arsenic-mediated disorders still remains a challenge due to lack of effective options. Chelation therapy has been the most widely used method to detoxify arsenic. But this method is associated with deleterious effects leading various toxicities such as hepatotoxicity, neurotoxicity and other adverse effects. It has been discovered that indigenous drugs of plant origin display effective and progressive relief from arsenic-mediated toxicity without any side-effects. Further, these phytochemicals have also been found to aid the elimination of arsenic from the biological system and therefore can be more effective than conventional therapeutic agents in ameliorating arsenic-mediated toxicity. This review presents an overview of the toxic effects of arsenic and the therapeutic strategies that are available to mitigate the toxic effects with emphasis on chelation as well as protective and detoxifying activities of different phytochemicals and herbal drugs against arsenic. This information may serve as a primer in identifying novel prophylactic as well as therapeutic formulations against arsenic-induced toxicity.
The emergence of new lifestyle disorders and pharmaco-resistant variants of diseases has necessitated the search for effective therapeutic moieties and approaches that could overcome the limitations ...in the existing treatment modalities. In this context, bioactives such as flavonoids, polyphenols, tannins, terpenoids and alkaloids have demonstrated promise in therapy owing to their ability to scavenge free radicals and modulate the mitochondrial function as well as regulate metabolic pathways. However, their clinical applicability is low owing to their poor bioavailability and aqueous solubility. The encapsulation of bioactives in nanodimensional particles has overcome these limitations to a large extent while simultaneously conferring additional advantages of improved circulation time, enhanced cell uptake and target specific release. A wide range of nanocarriers derived from biopolymers such as polysaccharides, lipids and proteins, have been explored for encapsulation of different bioactives and have reported significant improvement of the bioavailability and therapeutic efficacy of the encapsulated cargo. However, incorporation of cell-specific and mitochondria-specific elements on the nanocarriers has been relatively less explored. This review summarizes some of the recent attempts to treat different disorders using bioactives encapsulated in biopolymer nanostructures and few instances of mitochondria-specific delivery.
Background
Brahmi Nei (BN), an Indian traditional phytoformulation composed of eleven plant constituents has been traditionally used for treating various psychiatric disorders, hypertension and ...cerebral palsy. Some of the key phytoconstituents in this formulation have been explored for their potential role in plaque disruption, crossing the blood‐brain barrier, reversing the cognitive deficit and promoting tau dephosphorylation independently as a mono‐drug. Since Alzheimer’s disease (AD) is a multifactorial disorder affecting various signaling pathways, we hypothesize that BN formulation may be an effective option to treat AD.
Method
The major constituents in BN were identified using LC‐MS/MS technique. The Alzheimer’s model was created using scopolamine hydrobromide in animals through intra‐hippocampal injection at a concentration of 10 µg/µL. After seven days of post‐operative care, treatment was started with three different doses BN1 (0.5 of therapeutic dose, n=5), BN2 (Therapeutic dose, n=5), BN3 (twice the therapeutic dose, n=5) for a period of 28 days. The cognition and spatial learning were assessed using Morris water maze, radial arm maze and elevated plus maze. RT‐PCR, Western blots, biochemical assays analysis were performed to evaluate the therapeutic efficacy of BN against various signaling pathways deregulated in AD. Neuritic plaque deposits were detected using Bielchowsky silver staining while dendritic morphology and spine types were studied using Golgi‐Cox staining.
Result
Our results reveal that BN treatment influences the working memory and hippocampal‐dependent learning pattern in AD‐induced rodents. BN reduced acetylcholine esterase and malondialdehyde concentration in hippocampal tissues. It significantly regulates dephosphorylation of tau, inflammatory pathway and also inhibits the BBB disruption by activating YAP/TAZ. At the cellular level, synaptic degeneration and hippocampal neuronal loss were reversed by BN treatment which also regenerated neurons and increased spine density that is reflected in the superior cognitive improvement displayed by the BN2 and BN3 treated animals in the behavioral studies.
Conclusion
The BN formulation is an efficient therapeutic option in treating the multiple pathways involved in AD when compared to conventional mono‐drug treatment.
Abstract
Background
Brahmi Nei
(BN), an Indian traditional phytoformulation composed of eleven plant constituents has been traditionally used for treating various psychiatric disorders, hypertension ...and cerebral palsy. Some of the key phytoconstituents in this formulation have been explored for their potential role in plaque disruption, crossing the blood‐brain barrier, reversing the cognitive deficit and promoting tau dephosphorylation independently as a mono‐drug. Since Alzheimer’s disease (AD) is a multifactorial disorder affecting various signaling pathways, we hypothesize that BN formulation may be an effective option to treat AD.
Method
The major constituents in BN were identified using LC‐MS/MS technique. The Alzheimer’s model was created using scopolamine hydrobromide in animals through intra‐hippocampal injection at a concentration of 10 µg/µL. After seven days of post‐operative care, treatment was started with three different doses BN1 (0.5 of therapeutic dose, n=5), BN2 (Therapeutic dose, n=5), BN3 (twice the therapeutic dose, n=5) for a period of 28 days. The cognition and spatial learning were assessed using Morris water maze, radial arm maze and elevated plus maze. RT‐PCR, Western blots, biochemical assays analysis were performed to evaluate the therapeutic efficacy of BN against various signaling pathways deregulated in AD. Neuritic plaque deposits were detected using Bielchowsky silver staining while dendritic morphology and spine types were studied using Golgi‐Cox staining.
Result
Our results reveal that BN treatment influences the working memory and hippocampal‐dependent learning pattern in AD‐induced rodents. BN reduced acetylcholine esterase and malondialdehyde concentration in hippocampal tissues. It significantly regulates dephosphorylation of tau, inflammatory pathway and also inhibits the BBB disruption by activating YAP/TAZ. At the cellular level, synaptic degeneration and hippocampal neuronal loss were reversed by BN treatment which also regenerated neurons and increased spine density that is reflected in the superior cognitive improvement displayed by the BN2 and BN3 treated animals in the behavioral studies.
Conclusion
The BN formulation is an efficient therapeutic option in treating the multiple pathways involved in AD when compared to conventional mono‐drug treatment.
Background
Alzheimer’s disease (AD), a common form of dementia currently has no single disease‐modifying drug to halt disease progression. Environmental enrichment (EE) has emerged as an effective ...therapeutic strategy against various brain disorders. Our previous studies have revealed that the phytoformulation BN was effective in improving cognition and working memory in rodent models induced with cholinergic deficits. BN also inhibited tau hyperphosphorylation, increased dendritic arborization, and modulated AKT and MAPK pathways. In the present study, we propose to evaluate the combinatorial effect of BN and EE against AD.
Method
A rodent model of AD was created in Wistar rats through bilateral intra‐hippocampal injection of 100 µg/µL amyloid beta(1‐42). After ten days, the animals were randomly divided in to five groups (GII to GVI) and compared with normal animals (GI). The treatment regimen was commenced with GII acting as disease control, GIII receiving BN (844 mg/kg b.w), GIV receiving combined treatment of EE and BN, GV received only EE and GVI receiving the standard drug donepezil (4 mg/kg b.w.) for a period of 28 days. The cognition and spatial learning were assessed using behavioral studies. Gene and protein expression of key molecular targets were performed to gain insights into the molecular mechanism involved in the combination therapy. Amyloid plaque load was detected using thioflavin S, and dendritic morphology was studied using Golgi‐Cox staining. For EE, cages measuring 60×60×60 cm containing a running wheel, play tubes, ladder, balls, toys, and nesting material that are rearranged weekly, were used to study behavioral changes associated with cognitive stimulation.
Result
We found improved exploratory behaviour of the animals in EE when compared to their counterparts in normal cages. Other behavioral patterns like chewing, physical activity, sorting are significantly higher in animals subjected to the combination of EE and therapy when compared to animals treated in the conventional environment. The cognition and behavioral studies coupled with the histopathological results, gene and protein expression studies will help in establishing the molecular mechanism of the combination.
Conclusion
The results from this study open up new therapeutic directions involving environmental factors and multi‐targeted therapeutic agents against AD.
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