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1.
Development of Novel Anti-Leishmanials: The Case for Structure-Based Approaches.
Soni, M, Pratap, JV
Pathogens (Basel, Switzerland). 2022;(8)
Abstract
The neglected tropical disease (NTD) leishmaniasis is the collective name given to a diverse group of illnesses caused by ~20 species belonging to the genus Leishmania, a majority of which are vector borne and associated with complex life cycles that cause immense health, social, and economic burdens locally, but individually are not a major global health priority. Therapeutic approaches against leishmaniasis have various inadequacies including drug resistance and a lack of effective control and eradication of the disease spread. Therefore, the development of a rationale-driven, target based approaches towards novel therapeutics against leishmaniasis is an emergent need. The utilization of Artificial Intelligence/Machine Learning methods, which have made significant advances in drug discovery applications, would benefit the discovery process. In this review, following a summary of the disease epidemiology and available therapies, we consider three important leishmanial metabolic pathways that can be attractive targets for a structure-based drug discovery approach towards the development of novel anti-leishmanials. The folate biosynthesis pathway is critical, as Leishmania is auxotrophic for folates that are essential in many metabolic pathways. Leishmania can not synthesize purines de novo, and salvage them from the host, making the purine salvage pathway an attractive target for novel therapeutics. Leishmania also possesses an organelle glycosome, evolutionarily related to peroxisomes of higher eukaryotes, which is essential for the survival of the parasite. Research towards therapeutics is underway against enzymes from the first two pathways, while the third is as yet unexplored.
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2.
Coronary Artery Calcium Score - A Reliable Indicator of Coronary Artery Disease?
Shreya, D, Zamora, DI, Patel, GS, Grossmann, I, Rodriguez, K, Soni, M, Joshi, PK, Patel, SC, Sange, I
Cureus. 2021;(12):e20149
Abstract
Coronary artery disease (CAD) is caused by atheromatous blockage of coronary vessels leading to acute coronary events that usually occur when a plaque ruptures and a thrombus forms. CAD is a known cause of significant cardiovascular events, accounting for more than 50% of the deaths in western countries, and most of the patients with CAD remain asymptomatic. The coronary artery calcium (CAC) score has been created as a measure of coronary atherosclerosis. This article has compiled various studies that conclude the clinical relationship between coronary artery calcium and the development of cardiovascular (CV) events by using the CAC score as a reliable indicator of CAD. This article has reviewed the pathophysiology and risk factors of CAD, along with various methods of CAC scoring. It also underlined the reliability of CAC scoring for early detection of CAD in asymptomatic individuals. We emphasized the importance of age-dependent risk factor analysis combined with practical screening tools like CAC scoring for early diagnosis of CAD can help direct the treatment and prevent deaths in asymptomatic individuals.
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3.
Celiac Disease, Beyond the Bowel: A Review of Its Neurological Manifestations.
Patel, SC, Shreya, D, Zamora, DI, Patel, GS, Grossmann, I, Rodriguez, K, Soni, M, Joshi, PK, Sange, I
Cureus. 2021;13(12):e20112
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Plain language summary
Coeliac disease (CD) is an autoimmune condition in which genetically predisposed individuals develop an immunologic reaction to ingested gluten, a protein found in barley, wheat, and rye, destroying the intestinal villi. The aims of this review are to: (i) underline the pathogenic mechanism of the involvement of CD and its neurological manifestations; (ii) establish a clinical relationship between CD and its neurological manifestations; (iii) explore the existing screening and upcoming management guidelines of CD. This review shows that: - the most common neurological manifestations of CD include gluten ataxia, gluten neuropathy, and epilepsy. These conditions are strongly associated with a lower quality of life and a higher rate of hospitalisation. - neurological features of CD should be kept in mind in order to raise an adequate amount of clinical suspicion to perform screening for gluten sensitivity with the aim of reducing the time it takes for diagnosis, and thus patient suffering is kept to a minimum. Authors conclude that further thorough studies about neurological manifestations of CD are needed so that alternative treatment modalities are offered to provide a more holistic treatment approach to a patient with CD.
Abstract
Celiac disease (CD) is a multi-systemic autoimmune condition that causes a hyperinflammatory response when gluten is ingested. There has been a shift in the clinical presentation of CD from a mere malabsorption disorder to an autoimmune condition that affects multiple organ systems, which could increase the rate of hospitalizations and a decreased quality of life. This article has compiled various studies that have explored the neurological manifestations of celiac disease, their epidemiology, possible pathogenic mechanisms, diagnosis, and treatment. The most common neurological conditions include gluten ataxia (GA), gluten neuropathy, gluten encephalopathy, and epilepsy which usually present as sporadic diseases which are difficult to diagnose in the absence of gastrointestinal (GI) symptoms. The treatment for most of these conditions is a gluten-free diet (GFD) regardless of GI involvement.
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Clinical Management of Hypertriglyceridemia in the Prevention of Cardiovascular Disease and Pancreatitis.
Hernandez, P, Passi, N, Modarressi, T, Kulkarni, V, Soni, M, Burke, F, Bajaj, A, Soffer, D
Current atherosclerosis reports. 2021;(11):72
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Abstract
PURPOSE OF REVIEW Hypertriglyceridemia (HTG) is common and is a significant contributor to atherosclerosis and pancreatitis risk. Specific HTG treatments have had variable success in reducing atherosclerosis risk. Novel therapies for severe HTG treatment and pancreatitis risk reduction are likely to be available soon. These novel therapies are expected to have broader applications for more moderate HTG and atherosclerosis risk reduction as well. RECENT FINDINGS NHANES 2012 data has confirmed a reduction in average triglyceride (TG) levels in the US population. Dietary modification and weight reduction when needed remain the core treatment elements for all individuals with HTG, while statin therapy is a foundational pharmacologic care for atherosclerotic cardiovascular disease (ASCVD) event risk reduction. In addition, the REDUCE-IT study provides evidence for additional benefit from the use of high-dose icosapent ethyl (IPE) on top of background medical therapy in adults with moderate HTG and ASCVD or type 2 diabetes mellitus (T2D) and additional ASCVD risk factors. However, treatment with eicosapentaenoic acid (EPA) combined with docosahexanoic acid (DHA) did not reduce ASCVD in a similar population studied in the STRENGTH trial. Furthermore, novel therapeutics targeting PPAR-ɑ, as well as ApoC-III and AngPTL3, effectively lower TG levels in individuals with moderate and severe HTG, respectively. These treatments may have applicability for reducing risk from ASCVD among individuals with chylomicronemia; in addition, ApoC-III and AngPTL3 treatments may have a role in treating individuals with the rare monogenic familial chylomicronemia syndrome (FCS) at risk for acute pancreatitis (AP). Residual ASCVD risk in individuals treated with contemporary care may be due in part to non-LDL lipid abnormalities including HTG. The findings from REDUCE-IT, but not STRENGTH, confirm that consumption of high-dose EPA may reduce ASCVD risk, while combination therapy of EPA plus DHA does not reduce ASCVD in a similar population. TG lowering likely reduces ASCVD risk in individuals with HTG, but ASCVD risk is multifactorial; the added benefit of IPE to contemporary preventive therapy is the consequence of differential non-TG biologic properties between the two fatty acids. Acute pancreatitis is more difficult to study prospectively since it is less common; however, TG lowering is likely critical for the care of at-risk individuals. Additional benefit from novel therapy that has an impact on this otherwise refractory condition is anticipated.
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5.
The Use of Subclinical Atherosclerosis Imaging to Guide Preventive Cardiology Management.
Soni, M, Ambrosino, M, Jacoby, DS
Current cardiology reports. 2021;(6):61
Abstract
PURPOSE OF THE REVIEW Clinical atherosclerotic cardiovascular disease (ASCVD) requires years to manifest, providing a window of opportunity for preventive cardiovascular management. Subclinical atherosclerosis imaging leverages this long latency period to estimate and improve future ASCVD risk. RECENT FINDINGS Coronary artery calcium (CAC) scoring has the most robust data in the detection of subclinical atherosclerosis. CAC scan significantly enhances cardiovascular risk stratification in addition to traditional risk models. Coronary computed tomography angiography data show similar strengths in subclinical atherosclerosis detection in addition to plaque morphology characterization with inherent limitations. Carotid intima-media thickness and ankle-brachial index are other modalities whose predictive value becomes incremental when added to the aforementioned modalities. When added to traditional risk models, subclinical atherosclerosis imaging modalities personalize future ASCVD risk stratification and assist in the initiation and rate of intensification of preventive therapies. Emerging imaging techniques exist but further research is required for primetime clinical use.
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6.
Hereditary Hemochromatosis: A Cardiac Perspective.
Joshi, PK, Patel, SC, Shreya, D, Zamora, DI, Patel, GS, Grossmann, I, Rodriguez, K, Soni, M, Sange, I
Cureus. 2021;(11):e20009
Abstract
Hereditary hemochromatosis (HH) is a common genetic metabolic disorder characterized by excessive iron absorption and elevated serum iron levels, which accumulate in various organs, such as the heart, pancreas, gonads, and damage these organs. There are only a few articles and clinical studies describing the characteristics of cardiac involvement in HH along with the significance of early diagnosis and management in preventing complications. In this review article, we have reviewed multiple pieces of literature and gathered available information regarding the subject. We compiled the data to investigate the importance of early detection of symptoms, regular monitoring, and prompt management with strict adherence to reverse or prevent complications. This article has reviewed different aspects of cardiac hemochromatosis, such as pathogenesis, clinical presentation, diagnosis, and management. Recognition of early symptoms, diagnosis of cardiac involvement with various modalities, and implementation of early treatment are essentially the foundation of better outcomes in HH.
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7.
Vitamin D and Memory Decline: Two Population-Based Prospective Studies.
Kuźma, E, Soni, M, Littlejohns, TJ, Ranson, JM, van Schoor, NM, Deeg, DJ, Comijs, H, Chaves, PH, Kestenbaum, BR, Kuller, LH, et al
Journal of Alzheimer's disease : JAD. 2016;(4):1099-108
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Abstract
BACKGROUND Vitamin D deficiency has been linked with dementia risk, cognitive decline, and executive dysfunction. However, the association with memory remains largely unknown. OBJECTIVE To investigate whether low serum 25-hydroxyvitamin D (25(OH)D) concentrations are associated with memory decline. METHODS We used data on 1,291 participants from the US Cardiovascular Health Study (CHS) and 915 participants from the Dutch Longitudinal Aging Study Amsterdam (LASA) who were dementia-free at baseline, had valid vitamin D measurements, and follow-up memory assessments. The Benton Visual Retention Test (in the CHS) and Rey's Auditory Verbal Learning Test (in the LASA) were used to assess visual and verbal memory, respectively. RESULTS In the CHS, those moderately and severely deficient in serum 25(OH)D changed -0.03 SD (95% CI: -0.06 to 0.01) and -0.10 SD (95% CI: -0.19 to -0.02) per year respectively in visual memory compared to those sufficient (p = 0.02). In the LASA, moderate and severe deficiency in serum 25(OH)D was associated with a mean change of 0.01 SD (95% CI: -0.01 to 0.02) and -0.01 SD (95% CI: -0.04 to 0.02) per year respectively in verbal memory compared to sufficiency (p = 0.34). CONCLUSIONS Our findings suggest an association between severe vitamin D deficiency and visual memory decline but no association with verbal memory decline. They warrant further investigation in prospective studies assessing different memory subtypes.
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Parathyroid hormone, cognitive function and dementia: a systematic review.
Lourida, I, Thompson-Coon, J, Dickens, CM, Soni, M, Kuźma, E, Kos, K, Llewellyn, DJ
PloS one. 2015;(5):e0127574
Abstract
BACKGROUND Metabolic factors are increasingly recognized to play an important role in the pathogenesis of Alzheimer's disease and dementia. Abnormal parathyroid hormone (PTH) levels play a role in neuronal calcium dysregulation, hypoperfusion and disrupted neuronal signaling. Some studies support a significant link between PTH levels and dementia whereas others do not. METHODS We conducted a systematic review through January 2014 to evaluate the association between PTH and parathyroid conditions, cognitive function and dementia. Eleven electronic databases and citation indexes were searched including Medline, Embase and the Cochrane Library. Hand searches of selected journals, reference lists of primary studies and reviews were also conducted along with websites of key organizations. Two reviewers independently screened titles and abstracts of identified studies. Data extraction and study quality were performed by one and checked by a second reviewer using predefined criteria. A narrative synthesis was performed due to the heterogeneity of included studies. RESULTS The twenty-seven studies identified were of low and moderate quality, and challenging to synthesize due to inadequate reporting. Findings from six observational studies were mixed but suggest a link between higher serum PTH levels and increased odds of poor cognition or dementia. Two case-control studies of hypoparathyroidism provide limited evidence for a link with poorer cognitive function. Thirteen pre-post surgery studies for primary hyperparathyroidism show mixed evidence for improvements in memory though limited agreement in other cognitive domains. There was some degree of cognitive impairment and improvement postoperatively in observational studies of secondary hyperparathyroidism but no evident pattern of associations with specific cognitive domains. CONCLUSIONS Mixed evidence offers weak support for a link between PTH, cognition and dementia due to the paucity of high quality research in this area.
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Mediterranean diet, cognitive function, and dementia: a systematic review.
Lourida, I, Soni, M, Thompson-Coon, J, Purandare, N, Lang, IA, Ukoumunne, OC, Llewellyn, DJ
Epidemiology (Cambridge, Mass.). 2013;(4):479-89
Abstract
BACKGROUND Adherence to a Mediterranean diet has been associated with lower risk of various age-related diseases including dementia. Although narrative reviews have been published, no systematic review has synthesized studies on the association between Mediterranean diet adherence and cognitive function or dementia. METHODS We conducted a systematic review of 11 electronic databases (including Medline) of published articles up to January 2012. Reference lists, selected journal contents, and relevant websites were also searched. Study selection, data extraction, and quality assessment were performed independently by two reviewers using predefined criteria. Studies were included if they examined the association between a Mediterranean diet adherence score and cognitive function or dementia. RESULTS Twelve eligible papers (11 observational studies and one randomized controlled trial) were identified, describing seven unique cohorts. Despite methodological heterogeneity and limited statistical power in some studies, there was a reasonably consistent pattern of associations. Higher adherence to Mediterranean diet was associated with better cognitive function, lower rates of cognitive decline, and reduced risk of Alzheimer disease in nine out of 12 studies, whereas results for mild cognitive impairment were inconsistent. CONCLUSIONS Published studies suggest that greater adherence to Mediterranean diet is associated with slower cognitive decline and lower risk of developing Alzheimer disease. Further studies would be useful to clarify the association with mild cognitive impairment and vascular dementia. Long-term randomized controlled trials promoting a Mediterranean diet may help establish whether improved adherence helps to prevent or delay the onset of Alzheimer disease and dementia.
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Vitamin D effects on musculoskeletal health, immunity, autoimmunity, cardiovascular disease, cancer, fertility, pregnancy, dementia and mortality-a review of recent evidence.
Pludowski, P, Holick, MF, Pilz, S, Wagner, CL, Hollis, BW, Grant, WB, Shoenfeld, Y, Lerchbaum, E, Llewellyn, DJ, Kienreich, K, et al
Autoimmunity reviews. 2013;(10):976-89
Abstract
BACKGROUND Optimal vitamin D intake and its status are important not only for bone and calcium-phosphate metabolism, but also for overall health and well-being. Vitamin D deficiency and insufficiency as a global health problem are likely to be a risk for wide spectrum of acute and chronic illnesses. METHODS A review of randomized controlled trials, meta-analyses, and other evidence of vitamin D action on various health outcomes. RESULTS Adequate vitamin D status seems to be protective against musculoskeletal disorders (muscle weakness, falls, fractures), infectious diseases, autoimmune diseases, cardiovascular disease, type 1 and type 2 diabetes mellitus, several types of cancer, neurocognitive dysfunction and mental illness, and other diseases, as well as infertility and adverse pregnancy and birth outcomes. Vitamin D deficiency/insufficiency is associated with all-cause mortality. CONCLUSIONS Adequate vitamin D supplementation and sensible sunlight exposure to reach optimal vitamin D status are among the front line factors of prophylaxis for the spectrum of disorders. Supplementation guidance and population strategies for the eradication of vitamin D deficiency must be included in the priorities of physicians, medical professionals and healthcare policy-makers.