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"De Novo" Hypercapnic Respiratory Failure Unmasking Neuromuscular Disorders: Experiences From a Tertiary Care Center and Review of Literature.
Nair, AV, Kandagaddala, M, Sivadasan, A, Prabhakar, AT, Nair, S, Mathew, V, Aaron, S, Alexander, M
Journal of clinical neuromuscular disease. 2024;(3):122-131
Abstract
OBJECTIVES Neuromuscular disorders could have respiratory involvement early or late into illness. Rarely, patients may present with a hypercapnic respiratory failure (with minimal motor signs) unmasking an underlying disease. There are hardly any studies which have addressed the spectrum and challenges involved in management of this subset, especially in the real-world scenario. METHODS A retrospective study comprising consecutive patients hospitalized with hypercapnic respiratory failure as the sole/dominant manifestation. The clinical-electrophysiological spectrum, phrenic conductions, diaphragm thickness, and outcomes were analyzed. RESULTS Twenty-seven patients were included, the mean age was 47.29 (SD 15.22) years, and the median duration of respiratory symptoms was 2 months (interquartile range [IQR] 1-4). Orthopnea was present in 23 patients (85.2%) and encephalopathy in 8 patients (29.6%). Phrenic nerve latencies and amplitudes were abnormal in 83.3% and 95.6%, respectively. Abnormal diaphragm thickness was noted in 78.5%. Based on a comprehensive electrophysiological strategy and paraclinical tests, an etiology was established in all. Reversible etiologies were identified in 17 patients (62.9%). These included myasthenia gravis (anti-AChR and MuSK), inflammatory myopathy, riboflavin transporter deficiency neuronopathy, Pompe disease, bilateral phrenic neuritis, and thyrotoxicosis. Respiratory onset motor neuron disease was diagnosed in 8 patients (29.6%). Despite diaphragmatic involvement, a functional respiratory recovery was noted at discharge (45%) and last follow-up (60%). Predictors for good outcomes included female sex, normal nerve conductions, and recent-onset respiratory symptoms. DISCUSSION A good functional recovery was noted in most of the patients including respiratory onset motor neuron disease. A systematic algorithmic approach helps in proper triaging, early diagnosis, and treatment. Clinical and electrodiagnostic challenges and observations from a tertiary care referral center are discussed.
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Physiologic Insulin Resensitization as a Treatment Modality for Insulin Resistance Pathophysiology.
Greenway, F, Loveridge, B, Grimes, RM, Tucker, TR, Alexander, M, Hepford, SA, Fontenot, J, Nobles-James, C, Wilson, C, Starr, AM, et al
International journal of molecular sciences. 2022;(3)
Abstract
Prevalence of type 2 diabetes increased from 2.5% of the US population in 1990 to 10.5% in 2018. This creates a major public health problem, due to increases in long-term complications of diabetes, including neuropathy, retinopathy, nephropathy, skin ulcers, amputations, and atherosclerotic cardiovascular disease. In this review, we evaluated the scientific basis that supports the use of physiologic insulin resensitization. Insulin resistance is the primary cause of type 2 diabetes. Insulin resistance leads to increasing insulin secretion, leading to beta-cell exhaustion or burnout. This triggers a cascade leading to islet cell destruction and the long-term complications of type 2 diabetes. Concurrent with insulin resistance, the regular bursts of insulin from the pancreas become irregular. This has been treated by the precise administration of insulin more physiologically. There is consistent evidence that this treatment modality can reverse the diabetes-associated complications of neuropathy, diabetic ulcers, nephropathy, and retinopathy, and that it lowers HbA1c. In conclusion, physiologic insulin resensitization has a persuasive scientific basis, significant treatment potential, and likely cost benefits.
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Living Your Best Life: Lifestyle Medicine for All Women.
McHugh, J, Alexander, M, Kudesia, R, Krant, J, Comander, A, Tollefson, M, Geyer, C
American journal of lifestyle medicine. 2022;(5):577-588
Abstract
In an era of ever-increasing healthcare expenditures, yet simultaneously worsening outcomes, many of our patients choose between traditional medical care or often unproven alternative therapies. While the recognition of lifestyle change in addressing cardiovascular and metabolic disease grows, there is less understanding of the impact of lifestyle change on issues facing women every day. Millions of women around the globe struggle with infertility, cancer, sexual dysfunction, and dermatologic needs. Yet, research on the benefits of lifestyle change on these conditions is scarce, and gaps exist both in our understanding of evidence-based approaches to address these issues, as well as adequate provider education when evidence exists. The Women's Health Member Interest Group convened medical experts in these areas that affect women's lives to provide insights and meaningful education applicable not only for our patients, but also in our own lives.
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Dietary Approaches to Women's Sexual and Reproductive Health.
Kudesia, R, Alexander, M, Gulati, M, Kennard, A, Tollefson, M
American journal of lifestyle medicine. 2021;(4):414-424
Abstract
Over the course of the reproductive life span, it is common for women to experience one or more of the most common gynecologic conditions, including sexual dysfunction, polycystic ovary syndrome, fibroids, endometriosis, and infertility. Although current management guidelines often turn to the established pharmaceutical approaches for each of these diagnoses, the scientific literature also supports an evidence-based approach rooted in the paradigm of food as medicine. Achieving healthy dietary patterns is a core goal of lifestyle medicine, and a plant-forward approach akin to the Mediterranean diet holds great promise for improving many chronic gynecologic diseases. Furthermore, creating an optimal preconception environment from a nutritional standpoint may facilitate epigenetic signaling, thus improving the health of future generations. This state-of-the-art review explores the literature connecting diet with sexual and reproductive health in premenopausal women.
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Undergraduate Medical Education: Lifestyle Medicine Curriculum Implementation Standards.
Trilk, JL, Worthman, S, Shetty, P, Studer, KR, Wilson, A, Wetherill, M, Whelan, L, Bansal, S, Alexander, M, Frates, B, et al
American journal of lifestyle medicine. 2021;(5):526-530
Abstract
Lifestyle medicine (LM) is an emerging specialty that is gaining momentum and support from around the world. The American Medical Association passed a resolution to support incorporating LM curricula in medical schools in 2017. Since then, the American College of Lifestyle Medicine Undergraduate Medical Education Task Force has created a framework for incorporating LM into medical school curricula. This article provides competencies for medical school LM curriculum implementation and illustrates how they relate to the Association of American Medical College's Core Entrustable Professional Activities and the LM Certification Competencies from the American Board of Lifestyle Medicine. Finally, standards are presented for how medical schools may receive certification for integrating LM into their curriculum and how medical students can work toward becoming board certified in LM through an educational pathway.
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A comprehensive review of histopathological findings of infections induced by COVID-19.
Balaky, STJ, Zaki Abdullah, SM, Alexander, M, Maashi, MS, Alkaim, AF, Shahriyari, S, Tabari, F, Kazemi, E
Cellular and molecular biology (Noisy-le-Grand, France). 2020;(7):143-151
Abstract
The severe acute respiratory syndrome (SARS)-Coronavirus (CoV2) virus, first identified in Wuhan, China, caused the coronavirus disease 2019 (COVID-19) which soon became a global pandemic, as labelled by the World Health Organization (WHO). The transmission method of the infection is primarily through droplets of various sizes. The SARS-CoV2 virus leads to a severe respiratory illness which in the first place causes the simulation of the acute respiratory syndrome. In order to diagnose of COVID-19 efficiently, samples with infection probability need to be examined through histopathological methods. Survival chances of the infected can remarkably increase if the virus is diagnosed timely by reverse transcription-polymerase chain reaction (RT-PCR) or computed tomography (CT) scan of the chest. One of the destructive effects of COVID-19 is the formation of ground-glass opacity (GGO) in the lungs which might be regarded to be equivalent to high-altitude pulmonary edema (HAPE). COVID-19 acts very similarly to SARS and Middle East Respiratory Syndrome (MERS) which can be inactivated by the chemical compounds of ethanol and sodium hypochlorite. Epidemiologic characteristics of COVID-19 have been indicated by numerous studies; however, there is still a lack of details of pathologic changes in the lung. The present comprehensive review is an attempt to assess and cover the current state of knowledge on COVID-19 disease based on the histopathologic studies conducted before May 2020.
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Deconstructing Mechanisms of Diet-Microbiome-Immune Interactions.
Alexander, M, Turnbaugh, PJ
Immunity. 2020;(2):264-276
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Abstract
Emerging evidence suggests that the effect of dietary intake on human health and disease is linked to both the immune system and the microbiota. Yet, we lack an integrated mechanistic model for how these three complex systems relate, limiting our ability to understand and treat chronic and infectious disease. Here, we review recent findings at the interface of microbiology, immunology, and nutrition, with an emphasis on experimentally tractable models and hypothesis-driven mechanistic work. We outline emerging mechanistic concepts and generalizable approaches to bridge the gap between microbial ecology and molecular mechanism. These set the stage for a new era of precision human nutrition informed by a deep and comprehensive knowledge of the diverse cell types in and on the human body.
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Association of Cerebral Amyloid-β Aggregation With Cognitive Functioning in Persons Without Dementia.
Jansen, WJ, Ossenkoppele, R, Tijms, BM, Fagan, AM, Hansson, O, Klunk, WE, van der Flier, WM, Villemagne, VL, Frisoni, GB, Fleisher, AS, et al
JAMA psychiatry. 2018;(1):84-95
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Abstract
IMPORTANCE Cerebral amyloid-β aggregation is an early event in Alzheimer disease (AD). Understanding the association between amyloid aggregation and cognitive manifestation in persons without dementia is important for a better understanding of the course of AD and for the design of prevention trials. OBJECTIVE To investigate whether amyloid-β aggregation is associated with cognitive functioning in persons without dementia. DESIGN, SETTING, AND PARTICIPANTS This cross-sectional study included 2908 participants with normal cognition and 4133 with mild cognitive impairment (MCI) from 53 studies in the multicenter Amyloid Biomarker Study. Normal cognition was defined as having no cognitive concerns for which medical help was sought and scores within the normal range on cognitive tests. Mild cognitive impairment was diagnosed according to published criteria. Study inclusion began in 2013 and is ongoing. Data analysis was performed in January 2017. MAIN OUTCOMES AND MEASURES Global cognitive performance as assessed by the Mini-Mental State Examination (MMSE) and episodic memory performance as assessed by a verbal word learning test. Amyloid aggregation was measured with positron emission tomography or cerebrospinal fluid biomarkers and dichotomized as negative (normal) or positive (abnormal) according to study-specific cutoffs. Generalized estimating equations were used to examine the association between amyloid aggregation and low cognitive scores (MMSE score ≤27 or memory z score≤-1.28) and to assess whether this association was moderated by age, sex, educational level, or apolipoprotein E genotype. RESULTS Among 2908 persons with normal cognition (mean [SD] age, 67.4 [12.8] years), amyloid positivity was associated with low memory scores after age 70 years (mean difference in amyloid positive vs negative, 4% [95% CI, 0%-7%] at 72 years and 21% [95% CI, 10%-33%] at 90 years) but was not associated with low MMSE scores (mean difference, 3% [95% CI, -1% to 6%], P = .16). Among 4133 patients with MCI (mean [SD] age, 70.2 [8.5] years), amyloid positivity was associated with low memory (mean difference, 16% [95% CI, 12%-20%], P < .001) and low MMSE (mean difference, 14% [95% CI, 12%-17%], P < .001) scores, and this association decreased with age. Low cognitive scores had limited utility for screening of amyloid positivity in persons with normal cognition and those with MCI. In persons with normal cognition, the age-related increase in low memory score paralleled the age-related increase in amyloid positivity with an intervening period of 10 to 15 years. CONCLUSIONS AND RELEVANCE Although low memory scores are an early marker of amyloid positivity, their value as a screening measure for early AD among persons without dementia is limited.
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Pesticides as estrogen disruptors: QSAR for selective ERα and ERβ binding of pesticides.
Agatonovic-Kustrin, S, Alexander, M, Morton, DW, Turner, JV
Combinatorial chemistry & high throughput screening. 2011;(2):85-92
Abstract
Evidence suggests that environmental exposure to estrogen-like compounds can cause adverse effects in humans and wildlife. The Endocrine Disruptor Screening and Testing Advisory Committee (EDSTAC) has advised screening of 87,000 compounds in the interest of human safety. This may best be accomplished by pre-screening using quantitative structure-activity relationship (QSAR) modelling. The present study aimed to develop in silico QSARs based on natural, semi-synthetic, synthetic, and phytoestrogens, to predict the potential estrogenic toxicity of pesticides. A diverse set of 170 compounds including steroidal-, synthetic- and phytoestrogens, as well as pesticides was used to construct the QSAR models using artificial neural networks (ANNs). Mean correlation coefficients between experimentally measured and predicted binding affinities were all greater than 0.7 and models had few false negative results, an important consideration for screening tools. This study demonstrated the utility of ANNs as QSAR models for pre-screening of potential endocrine disruptors.
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Single photon emission computed tomography experience with (S)-5-[(123)I]iodo-3-(2-azetidinylmethoxy)pyridine in the living human brain of smokers and nonsmokers.
Brasić, JR, Zhou, Y, Musachio, JL, Hilton, J, Fan, H, Crabb, A, Endres, CJ, Reinhardt, MJ, Dogan, AS, Alexander, M, et al
Synapse (New York, N.Y.). 2009;(4):339-58
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Abstract
(S)-5-[(123)I]iodo-3-(2-azetidinylmethoxy)pyridine (5-[(123)I]IA), a novel potent radioligand for high-affinity alpha4beta2* neuronal nicotinic acetylcholine receptors (nAChRs), provides a means to evaluate the density and the distribution of nAChRs in the living human brain. We sought in healthy adult smokers and nonsmokers to (1) evaluate the safety, tolerability, and efficacy of 5-[(123)I]IA in an open nonblind trial and (2) to estimate the density and the distribution of alpha(4)beta(2)* nAChRs in the brain. Single photon emission computed tomography (SPECT) was performed for 5 h after the i.v. administration of approximately 0.001 microg/kg ( approximately 10 mCi) 5-[(123)I]IA. Blood pressure, heart rate, and neurobehavioral status were monitored before, during, and after the administration of 5-[(123)I]IA to 12 healthy adults (8 men and 4 women) (6 smokers and 6 nonsmokers) ranging in age from 19 to 46 years (mean = 28.25, standard deviation = 8.20). High plasma-nicotine level was significantly associated with low 5-[(123)I]IA binding in: (1) the caudate head, the cerebellum, the cortex, and the putamen, utilizing both the Sign and Mann-Whitney U-tests; (2) the fusiform gyrus, the hippocampus, the parahippocampus, and the pons utilizing the Mann-Whitney U-test; and (3) the thalamus utilizing the Sign test. We conclude that 5-[(123)I]IA is a safe, well-tolerated, and effective pharmacologic agent for human subjects to estimate high-affinity alpha4/beta2 nAChRs in the living human brain.