Publications by authors named "Jose Maldonado"

170 Publications

Endothelial Senescence and Chronic Fatigue Syndrome, a COVID-19 Based Hypothesis.

Front Cell Neurosci 2021 25;15:673217. Epub 2021 Jun 25.

International Agency for Research on Cancer (IARC), Lyon, France.

Myalgic encephalomyelitis/chronic fatigue syndrome is a serious illness of unknown etiology, characterized by debilitating exhaustion, memory impairment, pain and sleep abnormalities. Viral infections are believed to initiate the pathogenesis of this syndrome although the definite proof remains elusive. With the unfolding of COVID-19 pandemic, the interest in this condition has resurfaced as excessive tiredness, a major complaint of patients infected with the SARS-CoV-2 virus, often lingers for a long time, resulting in disability, and poor life quality. In a previous article, we hypothesized that COVID-19-upregulated angiotensin II triggered premature endothelial cell senescence, disrupting the intestinal and blood brain barriers. Here, we hypothesize further that post-viral sequelae, including myalgic encephalomyelitis/chronic fatigue syndrome, are promoted by the gut microbes or toxin translocation from the gastrointestinal tract into other tissues, including the brain. This model is supported by the SARS-CoV-2 interaction with host proteins and bacterial lipopolysaccharide. Conversely, targeting microbial translocation and cellular senescence may ameliorate the symptoms of this disabling illness.
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http://dx.doi.org/10.3389/fncel.2021.673217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8267916PMC
June 2021

Up-Regulation of Specific Bioactive Lipids in Celiac Disease.

Nutrients 2021 Jun 30;13(7). Epub 2021 Jun 30.

Biomedical Research Centre (CIBM), Department of Physiology and "José MataixVerdú", Institute of Nutrition and Food Technology (INYTA), University of Granada, 18071 Granada, Spain.

Celiac disease (CD) is an autoimmune enteropathy linked to alterations of metabolism. Currently, limited untargeted metabolomic studies evaluating differences in the plasma metabolome of CD subjects have been documented. We engage in a metabolomic study that analyzes plasma metabolome in 17 children with CD treated with a gluten-free diet and 17 healthy control siblings in order to recognize potential changes in metabolic networks. Our data demonstrates the persistence of metabolic defects in CD subjects in spite of the dietary treatment, affecting a minor but significant fraction (around 4%, 209 out of 4893 molecular features) of the analyzed plasma metabolome. The affected molecular species are mainly, but not exclusively, lipid species with a particular affectation of steroids and derivatives (indicating an adrenal gland affectation), glycerophospholipids (to highlight phosphatidic acid), glycerolipids (with a special affectation of diacylglycerols), and fatty acyls (eicosanoids). Our findings are suggestive of an activation of the diacylglycerol-phosphatidic acid signaling pathway in CD that may potentially have detrimental effects via activation of several targets including protein kinases such as mTOR, which could be the basis of the morbidity and mortality connected with untreated CD. However, more studies are necessary to validate this idea regarding CD.
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http://dx.doi.org/10.3390/nu13072271DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8308317PMC
June 2021

Delineation of an insula-BNST circuit engaged by struggling behavior that regulates avoidance in mice.

Nat Commun 2021 06 11;12(1):3561. Epub 2021 Jun 11.

Vanderbilt Center for Addiction Research, Vanderbilt University School of Medicine, Nashville, TN, USA.

Active responses to stressors involve motor planning, execution, and feedback. Here we identify an insular cortex to BNST (insula) circuit recruited during restraint stress-induced active struggling that modulates affective behavior. We demonstrate that activity in this circuit tightly follows struggling behavioral events and that the size of the fluorescent sensor transient reports the duration of the struggle event, an effect that fades with repeated exposure to the homotypic stressor. Struggle events are associated with enhanced glutamatergic- and decreased GABAergic signaling in the insular cortex, indicating the involvement of a larger circuit. We delineate the afferent network for this pathway, identifying substantial input from motor- and premotor cortex, somatosensory cortex, and the amygdala. To begin to dissect these incoming signals, we examine the motor cortex input, and show that the cells projecting from motor regions to insular cortex are engaged shortly before struggle event onset. This study thus demonstrates a role for the insula pathway in monitoring struggling activity and regulating affective behavior.
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http://dx.doi.org/10.1038/s41467-021-23674-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8196075PMC
June 2021

The Use of Physostigmine in the Diagnosis and Treatment of Anticholinergic Toxicity After Olanzapine Overdose: Literature Review and Case Report.

J Acad Consult Liaison Psychiatry 2021 May-Jun;62(3):285-297. Epub 2021 Jan 14.

Department of Psychiatry & Behavioral Sciences, Stanford University 401 Quarry Road, Stanford, CA. Electronic address:

Background: Second-generation antipsychotic agents are commonly used by clinicians for the treatment of various psychiatric and medical conditions. Despite their presumed safety, an overdose with olanzapine may lead to the development of anticholinergic toxicity. The anticholinergic toxidrome is characterized by both central and peripheral physical findings. Central anticholinergic syndrome, a term used to describe the symptoms that arise from reduced cholinergic activity in the central nervous system, is characterized primarily by signs and symptoms consistent with hyperactive delirium. Signs of peripheral anticholinergia include mydriasis and blurred vision, tremors, ataxia, fever/hyperthermia, flushed and dry skin, dry oral mucosa, decreased bowel sounds, constipation, and urinary retention, among other symptoms. In extreme cases, central anticholinergic syndrome can be associated with seizures, coma, respiratory failure, and cardiovascular collapse.

Objective: To provide scientific evidence regarding the efficacy and safety of physostigmine use in cases of anticholinergic toxicity.

Methods: We conducted a comprehensive review of the published literature on the symptoms, diagnosis, and treatment of anticholinergic toxicity.

Results: Currently the recommended treatment for olanzapine overdose, as is the case of most severe anticholinergic toxicity cases, involves supportive care, along with cardiac, neurological, and respiratory status monitoring. In addition, we detail the symptoms characteristic of anticholinergic toxicity, using the case of a patient experiencing central anticholinergic syndrome after an overdose with olanzapine.

Conclusion: Physostigmine, a tertiary acetylcholinesterase inhibitor, can be used to assist in the both the diagnosis and management of severe anticholinergic toxicity associated with an olanzapine overdose, which might be applicable to the antimuscarinic toxidrome associated with the ingestion of agents with significant anticholinergic activity.
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http://dx.doi.org/10.1016/j.jaclp.2020.12.013DOI Listing
January 2021

Influence of Mediterranean Diet Adherence and Physical Activity on Bone Health in Celiac Children on a Gluten-Free Diet.

Nutrients 2021 May 13;13(5). Epub 2021 May 13.

Department of Physiology, Faculty of Pharmacy, University of Granada, 18071 Granada, Spain.

We aimed to assess the influence of the Mediterranean Diet adherence and physical activity (PA) on body composition, with a particular focus on bone health, in young patients with celiac disease (CD). The CD group ( = 59) included children with CD with a long (>18 months, = 41) or recent (<18 months, = 18) adherence to a gluten-free diet (GFD). The non-celiac group ( = 40) included non-celiac children. After adjusting for potential confounders, the CD group showed lower body weight ( = 0.034), lean mass ( = 0.003), bone mineral content ( = 0.006), and bone Z-score ( = 0.036) than non-celiac children, even when the model was further adjusted for adherence to a GFD for at least 18 months. Among CD children, spending greater time in vigorous physical activity was associated with higher lean mass ( = 0.020) and bone mineral density with evidence of statistical significance ( = 0.078) regardless of the time they followed a GFD. In addition, a greater Mediterranean Diet adherence was associated with a higher bone Z-score ( = 0.020). Moreover, lean mass was strongly associated with bone mineral density and independently explained 12% of its variability ( < 0.001). These findings suggest the importance of correctly monitoring lifestyle in children with CD regarding dietary habits and PA levels to improve lean mass and, consequently, bone quality in this population.
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http://dx.doi.org/10.3390/nu13051636DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8152289PMC
May 2021

Social distancing and testing as optimal strategies against the spread of COVID-19 in the Rio Grande Valley of Texas.

Infect Dis Model 2021 24;6:729-742. Epub 2021 Apr 24.

School of Mathematical & Statistical Sciences, University of Texas Rio Grande Valley, Edinburg, TX, 78539, USA.

At the beginning of August 2020, the Rio Grande Valley (RGV) of Texas experienced a rapid increase of coronavirus disease 2019 (abbreviated as COVID-19) cases and deaths. This study aims to determine the optimal levels of effective social distancing and testing to slow the virus spread at the outset of the pandemic. We use an age-stratified eight compartment epidemiological model to depict COVID-19 transmission in the community and within households. With a simulated 120-day outbreak period data we obtain a post 180-days period optimal control strategy solution. Our results show that easing social distancing between adults by the end of the 180-day period requires very strict testing a month later and then daily testing rates of 5% followed by isolation of positive cases. Relaxing social distancing rates in adults from 50% to 25% requires both children and seniors to maintain social distancing rates of 50% for nearly the entire period while maintaining maximum testing rates of children and seniors for 150 of the 180 days considered in this model. Children have higher contact rates which leads to transmission based on our model, emphasizing the need for caution when considering school reopenings.
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http://dx.doi.org/10.1016/j.idm.2021.04.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8065238PMC
April 2021

[Vulnerabilities of Brazil's domestic pharmaceutical and biotech industry in the context of the COVID-19 pandemic].

Cad Saude Publica 2021 16;37(4):e00254720. Epub 2021 Apr 16.

Escola Nacional de Saúde Pública Sergio Arouca, Fundação Oswaldo Cruz, Rio de Janeiro, Brasil.

During a pandemic, economic, technological, and health systems' vulnerability become even more evident. A key challenge in Brazil is to control the trade deficit and difficulty in access to medicines and health products, even their development. Brazil's heavy external dependency on health inputs and products is one of the negative factors in confronting the global health emergency caused by SARS-CoV-2. The article aimed to discuss the vulnerabilities of the domestic chemical and biotechnological subsystem in the face of the current pandemic, with a focus on the pharmaceutical and biotech industry and the linkage between the fields of health and political economics. A qualitative study was performed with a literature review and analysis of secondary data as the methodological procedures. The results revealed low investment in public health, low innovation capacity, the pharmaceutical industry's profile, external dependency, currency exchange policy, patents, and other factors, demonstrating the major vulnerability in innovation and technology in the domestic pharmaceutical and biotech industry and the essential nature of linkage between various fields, especially health and the economy, for the incorporation of a systemic vision that creates the conditions to reduce vulnerabilities in the response to the pandemic and promote a development project for the country.
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http://dx.doi.org/10.1590/0102-311X00254720DOI Listing
April 2021

The melanocortin-3 receptor is a pharmacological target for the regulation of anorexia.

Sci Transl Med 2021 04;13(590)

Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA.

Ablation of hypothalamic AgRP (Agouti-related protein) neurons is known to lead to fatal anorexia, whereas their activation stimulates voracious feeding and suppresses other motivational states including fear and anxiety. Despite the critical role of AgRP neurons in bidirectionally controlling feeding, there are currently no therapeutics available specifically targeting this circuitry. The melanocortin-3 receptor (MC3R) is expressed in multiple brain regions and exhibits sexual dimorphism of expression in some of those regions in both mice and humans. MC3R deletion produced multiple forms of sexually dimorphic anorexia that resembled aspects of human anorexia nervosa. However, there was no sexual dimorphism in the expression of MC3R in AgRP neurons, 97% of which expressed MC3R. Chemogenetic manipulation of arcuate MC3R neurons and pharmacologic manipulation of MC3R each exerted potent bidirectional regulation over feeding behavior in male and female mice, whereas global ablation of MC3R-expressing cells produced fatal anorexia. Pharmacological effects of MC3R compounds on feeding were dependent on intact AgRP circuitry in the mice. Thus, the dominant effect of MC3R appears to be the regulation of the AgRP circuitry in both male and female mice, with sexually dimorphic sites playing specialized and subordinate roles in feeding behavior. Therefore, MC3R is a potential therapeutic target for disorders characterized by anorexia, as well as a potential target for weight loss therapeutics.
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http://dx.doi.org/10.1126/scitranslmed.abd6434DOI Listing
April 2021

Clinical Profile and Length of Hospital Stay in a Sample of Psychogeriatric Patients Referred to Consultation Liaison Psychiatric Unit.

Medicina (Kaunas) 2021 Mar 11;57(3). Epub 2021 Mar 11.

Department of Psychiatry, Hospital Clinic i Provincial of Barcelona, University of Barcelona, Casanova Street, 143, 08036 Barcelona, Spain.

: There has been a recent increase in older patients admitted to general hospitals. A significant percentage of hospitalized older patients are ≥75 years old, which differ from the patients aged 65 to 74 years old in terms of functional status at patient discharge. This study aims to compare sociodemographic, clinical features, and factors associated with length of hospital stay in youngest-old and oldest-old populations of inpatients referred to the consultation liaison psychiatry unit. : This is an observational, cross-sectional, retrospective, and comparative study. We obtained data from a sample of 1017 patients (≥65 years) admitted to a general hospital and referred from different services (medicine, surgery, etc.) to the consultation liaison psychiatry unit. The sample was divided into two groups of patients: youngest-old (65-74 years) and oldest-old (≥75 years). Psychiatric evaluations were performed while the patients were on wards at the hospital. Psychopharmacs were started as needed. A comparative analysis was carried out and predictive factors related to length of hospital stay were calculated. : The reference rate to consultation liaison psychiatry unit was 1.45% of the total older patients hospitalized. Our study demonstrates differences between the groups of older people: the oldest-old group were mainly female ( < 0.001), had more previous psychiatric diagnoses ( < 0.001), physical disabilities ( = 0.02), and neurocognitive disorders ( < 0.001), they used more antipsychotics ( < 0.001), and more frequently had a discharge disposition to a nursing home ( = 0.036). The presence of physical disability ( = 0.07, < 0.001) and logtime to referral to consultation liaison psychiatry unit ( = 0.58, < 0.001) were associated with increased length of hospital stay. : Youngest-old and oldest-old people should be considered as two different types of patients when we consider clinical features. The time to referral to consultation liaison psychiatry unit seems to be a relevant factor associated with length of hospital stay.
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http://dx.doi.org/10.3390/medicina57030256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7998973PMC
March 2021

SARS-CoV-2 infection of the oral cavity and saliva.

Nat Med 2021 05 25;27(5):892-903. Epub 2021 Mar 25.

Marsico Lung Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

Despite signs of infection-including taste loss, dry mouth and mucosal lesions such as ulcerations, enanthema and macules-the involvement of the oral cavity in coronavirus disease 2019 (COVID-19) is poorly understood. To address this, we generated and analyzed two single-cell RNA sequencing datasets of the human minor salivary glands and gingiva (9 samples, 13,824 cells), identifying 50 cell clusters. Using integrated cell normalization and annotation, we classified 34 unique cell subpopulations between glands and gingiva. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral entry factors such as ACE2 and TMPRSS members were broadly enriched in epithelial cells of the glands and oral mucosae. Using orthogonal RNA and protein expression assessments, we confirmed SARS-CoV-2 infection in the glands and mucosae. Saliva from SARS-CoV-2-infected individuals harbored epithelial cells exhibiting ACE2 and TMPRSS expression and sustained SARS-CoV-2 infection. Acellular and cellular salivary fractions from asymptomatic individuals were found to transmit SARS-CoV-2 ex vivo. Matched nasopharyngeal and saliva samples displayed distinct viral shedding dynamics, and salivary viral burden correlated with COVID-19 symptoms, including taste loss. Upon recovery, this asymptomatic cohort exhibited sustained salivary IgG antibodies against SARS-CoV-2. Collectively, these data show that the oral cavity is an important site for SARS-CoV-2 infection and implicate saliva as a potential route of SARS-CoV-2 transmission.
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http://dx.doi.org/10.1038/s41591-021-01296-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8240394PMC
May 2021

The Psychosocial Assessment of Transplant Candidates: Internal Consistency, Interrater Reliability, and Content Validity of the Thai Version of the Stanford Integrated Psychosocial Assessment for Transplantation (SIPAT-Thai Version).

Transplant Proc 2021 Apr 16;53(3):779-785. Epub 2021 Mar 16.

Department of Psychiatry & Behavioral Sciences, Stanford University School of Medicine, Stanford, California.

Background: Standardized pretransplant psychosocial assessment is critically needed in Thailand to optimize medical and psychosocial outcomes after transplantation. The Stanford Integrated Psychosocial Assessment for Transplantation (SIPAT) is a comprehensive and evidence-based tool that has demonstrated excellent reliability and predictive value in many psychosocial transplant studies. We translated the SIPAT into Thai and explored the validity and reliability of the SIPAT-Thai version among Thai transplant recipients.

Methods: We translated the original SIPAT into Thai following the World Health Organization's standard forward-backward translation procedure and then cross-sectionally assessed its validity and reliability in 110 Thai solid organ transplant candidates. The correlation between background data, total, and sectional scoring results of SIPAT-Thai were also analyzed.

Results: The SIPAT-Thai demonstrated moderate to good reliability, which was represented by internal consistency with a Cronbach α of .751 and interrater reliability with a κ value at 0.767. The index of item-objective congruence value was 0.94, indicating good the content validity.

Conclusions: The SIPAT-Thai was systematically translated and shown to have acceptable validity and a moderate to good reliability index. The use of the SIPAT-Thai would provide a standardized, evidence-based, and a more systematic pretransplant psychosocial evaluation process for transplant candidates in Thailand.
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http://dx.doi.org/10.1016/j.transproceed.2021.02.013DOI Listing
April 2021

Modeling the effect of lockdown timing as a COVID-19 control measure in countries with differing social contacts.

Sci Rep 2021 02 8;11(1):3354. Epub 2021 Feb 8.

Department of Environmental and Occupational Health, Faculty of Public Health, Kuwait University, 13110, Safat, Kuwait.

The application, timing, and duration of lockdown strategies during a pandemic remain poorly quantified with regards to expected public health outcomes. Previous projection models have reached conflicting conclusions about the effect of complete lockdowns on COVID-19 outcomes. We developed a stochastic continuous-time Markov chain (CTMC) model with eight states including the environment (SEAMHQRD-V), and derived a formula for the basic reproduction number, R, for that model. Applying the [Formula: see text] formula as a function in previously-published social contact matrices from 152 countries, we produced the distribution and four categories of possible [Formula: see text] for the 152 countries and chose one country from each quarter as a representative for four social contact categories (Canada, China, Mexico, and Niger). The model was then used to predict the effects of lockdown timing in those four categories through the representative countries. The analysis for the effect of a lockdown was performed without the influence of the other control measures, like social distancing and mask wearing, to quantify its absolute effect. Hypothetical lockdown timing was shown to be the critical parameter in ameliorating pandemic peak incidence. More importantly, we found that well-timed lockdowns can split the peak of hospitalizations into two smaller distant peaks while extending the overall pandemic duration. The timing of lockdowns reveals that a "tunneling" effect on incidence can be achieved to bypass the peak and prevent pandemic caseloads from exceeding hospital capacity.
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http://dx.doi.org/10.1038/s41598-021-82873-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7870675PMC
February 2021

Sensitive extraction-free SARS-CoV-2 RNA virus detection using a novel RNA preparation method.

medRxiv 2021 Feb 1. Epub 2021 Feb 1.

Current conventional detection of SARS-CoV-2 involves collection of a patient sample with a nasopharyngeal swab, storage of the swab during transport in a viral transport medium, extraction of RNA, and quantitative reverse transcription PCR (RT-qPCR). We developed a simplified and novel preparation method using a Chelex resin that obviates RNA extraction during viral testing. Direct detection RT-qPCR and digital-droplet PCR was compared to the current conventional method with RNA extraction for simulated samples and patient specimens. The heat-treatment in the presence of Chelex markedly improved detection sensitivity as compared to heat alone, and lack of RNA extraction shortens the overall diagnostic workflow. Furthermore, the initial sample heating step inactivates SARS-CoV-2 infectivity, thus improving workflow safety. This fast RNA preparation and detection method is versatile for a variety of samples, safe for testing personnel, and suitable for standard clinical collection and testing on high throughput platforms.
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http://dx.doi.org/10.1101/2021.01.29.21250790DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7852279PMC
February 2021

Influence of Ultra-Processed Foods Consumption on Redox Status and Inflammatory Signaling in Young Celiac Patients.

Nutrients 2021 Jan 6;13(1). Epub 2021 Jan 6.

Department of Physiology, Faculty of Pharmacy, University of Granada, 18071 Granada, Spain.

The current study was designed to assess the influence of consumption of ultra-processed (UPF) on oxidative/antioxidant balance and evoked inflammatory signaling in young patients with celiac disease (CD). The study included 85 children. The celiac group ( = 53) included children with CD with a long (>18 months, = 17) or recent (<18 months, = 36) adherence to a gluten-free diet (GFD). The control group ( = 32) included healthy children with a significantly higher consumption of UPF compared to the control group, both expressed as kcal/day ( = 0.043) and as percentage of daily energy intake ( = 0.023). Among children with CD, the group with the lowest consumption of UPF (below the 50% of daily energy intake) had a greater Mediterranean diet (MD) adherence and higher moderate physical activity levels. In addition, CD children with the lowest consumption of UPF had healthier redox (lower soluble superoxide dismutase-1 and 15-F2t-isoprostanes) and inflammatory profiles (lower macrophage inflammatory protein-1α) compared to the group with the highest consumption of UPF (all, < 0.05) regardless of the time on a GFD. These findings highlight the importance of a correct monitoring of the GFD. An unbalanced GFD with high consumption of UPF and an unhealthy pattern with less physical activity and worse adherence to MD results in a worse inflammatory profile, which could act as a parallel pathway that could have important consequences on the pathophysiology of the disease.
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http://dx.doi.org/10.3390/nu13010156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7825019PMC
January 2021

COVID-19, ferrosenescence and neurodegeneration, a mini-review.

Prog Neuropsychopharmacol Biol Psychiatry 2021 07 26;109:110230. Epub 2020 Dec 26.

University of Texas, Rio Grande Valley, United States of America.

Exacerbation of cognitive, motor and nonmotor symptoms have been described in critically ill COVID-19 patients, indicating that, like prior pandemics, neurodegenerative sequelae may mark the aftermath of this viral infection. Moreover, SARS-CoV-2, the causative agent of COVID-19 disease, was associated with hyperferritinemia and unfavorable prognosis in older individuals, suggesting virus-induced ferrosenescence. We have previously defined ferrosenescence as an iron-associated disruption of both the human genome and its repair mechanisms, leading to premature cellular senescence and neurodegeneration. As viruses replicate more efficiently in iron-rich senescent cells, they may have developed the ability to induce this phenotype in host tissues, predisposing to both immune dysfunction and neurodegenerative disorders. In this mini-review, we summarize what is known about the SARS-CoV-2-induced cellular senescence and iron dysmetabolism. We also take a closer look at immunotherapy with natural killer cells, angiotensin II receptor blockers ("sartans"), iron chelators and dipeptidyl peptidase 4 inhibitors ("gliptins") as adjunct treatments for both COVID-19 and its neurodegenerative complications.
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http://dx.doi.org/10.1016/j.pnpbp.2020.110230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7832711PMC
July 2021

Alterations in One-Carbon Metabolism in Celiac Disease.

Nutrients 2020 Dec 2;12(12). Epub 2020 Dec 2.

Biomedical Research Centre (CIBM), Department of Physiology and "José MataixVerdú" Institute of Nutrition and Food Technology (INYTA), University of Granada, 18071 Granada, Spain.

Celiac disease (CD) is an autoimmune enteropathy associated with alterations of metabolism. Metabolomics studies, although limited, showed changes in choline, choline-derived lipids, and methionine concentrations, which could be ascribed to alterations in one-carbon metabolism. To date, no targeted metabolomics analysis investigating differences in the plasma choline/methionine metabolome of CD subjects are reported. This work is a targeted metabolomic study that analyzes 37 metabolites of the one-carbon metabolism in 17 children with CD, treated with a gluten-free diet and 17 healthy control siblings, in order to establish the potential defects in this metabolic network. Our results demonstrate the persistence of defects in the transsulfuration pathway of CD subjects, despite dietary treatment, while choline metabolism, methionine cycle, and folate cycle seem to be reversed and preserved to healthy levels. These findings describe for the first time, a metabolic defect in one-carbon metabolism which could have profound implications in the physiopathology and treatment of CD.
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http://dx.doi.org/10.3390/nu12123723DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7761552PMC
December 2020

Integrated Single-Cell Atlases Reveal an Oral SARS-CoV-2 Infection and Transmission Axis.

medRxiv 2020 Oct 27. Epub 2020 Oct 27.

Despite signs of infection, the involvement of the oral cavity in COVID-19 is poorly understood. To address this, single-cell RNA sequencing data-sets were integrated from human minor salivary glands and gingiva to identify 11 epithelial, 7 mesenchymal, and 15 immune cell clusters. Analysis of SARS-CoV-2 viral entry factor expression showed enrichment in epithelia including the ducts and acini of the salivary glands and the suprabasal cells of the mucosae. COVID-19 autopsy tissues confirmed in vivo SARS-CoV-2 infection in the salivary glands and mucosa. Saliva from SARS-CoV-2-infected individuals harbored epithelial cells exhibiting expression and SARS-CoV-2 RNA. Matched nasopharyngeal and saliva samples found distinct viral shedding dynamics and viral burden in saliva correlated with COVID-19 symptoms including taste loss. Upon recovery, this cohort exhibited salivary antibodies against SARS-CoV-2 proteins. Collectively, the oral cavity represents a robust site for COVID-19 infection and implicates saliva in viral transmission.
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http://dx.doi.org/10.1101/2020.10.26.20219089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605572PMC
October 2020

Genetic disease and intellectual disability as contraindications to transplant listing in the United States: A survey of heart, kidney, liver, and lung transplant programs.

Pediatr Transplant 2020 11 30;24(7):e13837. Epub 2020 Sep 30.

Departments of Pediatrics and Medicine and Center for Biomedical Ethics, Stanford University, Stanford, California, USA.

Discrimination based on disability is prohibited in organ transplantation, yet studies suggest it continues in listing practices for intellectual disability and genetic diseases. It is not known if this differs between adult and pediatric programs, or by organ type. We performed an online, forced-choice survey of psychosocial listing criteria for adult and pediatric heart, kidney, liver, and lung transplant programs in the United States. Of 650 programs contacted, 343 (52.8%) submitted complete. A minority of programs had formal listing guidelines for any condition considered (Down Syndrome, Duchenne Muscular Dystrophy, Becker Muscular Dystrophy, DiGeorge Syndrome, and Wolf Hirschhorn Syndrome; and mild [IQ < 70] and severe [IQ < 35] intellectual disability), although a majority had encountered most. Pediatric programs were significantly (P < .02) more lenient in the level of contraindication to listing for all genetic conditions considered except Duchenne Muscular Dystrophy, and for mild and severe intellectual disability. Level of contraindication differed significantly by organ type (heart, lung, liver, and kidney) for Duchenne Muscular dystrophy (P = <.001), Becker Muscular Dystrophy (P < .001), DiGeorge Syndrome (P < .001), Wolf-Hirschhorn syndrome (P = .0012), and severe intellectual disability (P < .001). There is significant variation among transplant programs in availability of guidelines for as well as listing practices regarding genetic diseases and intellectual disability, differing by both adult vs pediatric program, and organ type. Programs with absolute contraindications to listing for specific genetic diseases or intellectual disability should reframe their approach, ensuring individualized assessments and avoiding elimination of patients based on membership in a particular group.
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http://dx.doi.org/10.1111/petr.13837DOI Listing
November 2020

Genetic polymorphisms associated with telomere length and risk of developing myeloproliferative neoplasms.

Blood Cancer J 2020 09 1;10(8):89. Epub 2020 Sep 1.

Department of Biology, University of Pisa, Pisa, Italy.

Telomere length measured in leukocyte (LTL) has been found to be associated with the risk of developing several cancer types, including myeloproliferative neoplasms (MPNs). LTL is genetically determined by, at least, 11 SNPs previously shown to influence LTL. Their combination in a score has been used as a genetic instrument to measure LTL and evaluate the causative association between LTL and the risk of several cancer types. We tested, for the first time, the "teloscore" in 480 MPN patients and 909 healthy controls in a European multi-center case-control study. We found an increased risk to develop MPNs with longer genetically determined telomeres (OR = 1.82, 95% CI 1.24-2.68, P = 2.21 × 10, comparing the highest with the lowest quintile of the teloscore distribution). Analyzing the SNPs individually we confirm the association between TERT-rs2736100-C allele and increased risk of developing MPNs and we report a novel association of the OBFC1-rs9420907-C variant with higher MPN risk (OR= 1.43; 95% CI 1.15-1.77; P = 1.35 × 10). Consistently with the results obtained with the teloscore, both risk alleles are also associated with longer LTL. In conclusion, our results suggest that genetically determined longer telomeres could be a risk marker for MPN development.
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http://dx.doi.org/10.1038/s41408-020-00356-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7463014PMC
September 2020

CLIN-IK-LINKS: A platform for the design and execution of clinical data transformation and reasoning workflows.

Comput Methods Programs Biomed 2020 Dec 25;197:105616. Epub 2020 Jun 25.

Department of Computer Engineering and Science, Universitat Jaume I, Spain.

Background And Objective: Effective sharing and reuse of Electronic Health Records (EHR) requires technological solutions which deal with different representations and different models of data. This includes information models, domain models and, ideally, inference models, which enable clinical decision support based on a knowledge base and facts. Our goal is to develop a framework to support EHR interoperability based on transformation and reasoning services intended for clinical data and knowledge.

Methods: Our framework is based on workflows whose primary components are reusable mappings. Key features are an integrated representation, storage, and exploitation of different types of mappings for clinical data transformation purposes, as well as the support for the discovery of new workflows. The current framework supports mappings which take advantage of the best features of EHR standards and ontologies. Our proposal is based on our previous results and experience working with both technological infrastructures.

Results: We have implemented CLIN-IK-LINKS, a web-based platform that enables users to create, modify and delete mappings as well as to define and execute workflows. The platform has been applied in two use cases: semantic publishing of clinical laboratory test results; and implementation of two colorectal cancer screening protocols. Real data have been used in both use cases.

Conclusions: The CLIN-IK-LINKS platform allows the composition and execution of clinical data transformation workflows to convert EHR data into EHR and/or semantic web standards. Having proved its usefulness to implement clinical data transformation applications of interest, CLIN-IK-LINKS can be regarded as a valuable contribution to improve the semantic interoperability of EHR systems.
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http://dx.doi.org/10.1016/j.cmpb.2020.105616DOI Listing
December 2020

Healthcare telemonitoring and business dynamics: challenges and opportunities for SUS.

Rev Saude Publica 2020 26;54:65. Epub 2020 Jun 26.

Fundação Oswaldo Cruz. Escola Nacional de Saúde Pública Sérgio Arouca. Rio de Janeiro, RJ, Brasil.

Objective: To point out challenges and opportunities for the Brazilian Unified Health System (SUS) with the use of telemonitoring to face the increasing costs of non-communicable chronic diseases, based on its general panorama in Brazil, business dynamics and reapplication of data from American studies.

Methods: Quali-quantitative approach with exploratory research. The field work focused on the analysis of the national market from private companies, since no experiences or studies related to this theme were identified in the SUS. To analyze the panorama and market dynamics, we investigated the offer of this technology based on the products and services available and their demand by reference hospitals the ten largest private health plan companies. To support the central discussion, we analyzed the reduction of costs with hospital admissions by the SUS due to chronic non-communicable diseases sensitive to telemonitoring (HCDST), using data from Datasus and some American studies from the MEDLINE/PubMed database.

Results: Although in the embryonic phase, business agents search for new business opportunities, whereas public initiatives for the use of telemonitoring in collective health seem inexistent. The reapplication of U.S. data would reduce spending on HCDST and provide benefits, such as the reduction in emergency room care, acute hospitalizations, readmissions and home care time, among others, which point to even greater economic gains.

Conclusions: The development of a major project to reduce HCDST using this technology has the potential to advance in a comprehensive network of primary care, contribute to a greater dynamism of the national productive and innovative base and induce innovations along the chain of this emerging industry.
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http://dx.doi.org/10.11606/s1518-8787.2020054001996DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7304882PMC
July 2020

COVID-19-Associated Hyperactive Intensive Care Unit Delirium With Proposed Pathophysiology and Treatment: A Case Report.

Psychosomatics 2020 Sep - Oct;61(5):544-550. Epub 2020 May 19.

Department of Medicine - Pulmonary, Allergy & Critical Care Medicine, Stanford University Medical Center, Stanford, CA.

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http://dx.doi.org/10.1016/j.psym.2020.05.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236743PMC
October 2020

Transcriptome sequencing reveals signatures of positive selection in the Spot-Tailed Earless Lizard.

PLoS One 2020 15;15(6):e0234504. Epub 2020 Jun 15.

Department of Biology, Amphibian and Reptile Diversity Research Center, The University of Texas at Arlington, Arlington, TX, United States of America.

The continual loss of threatened biodiversity is occurring at an accelerated pace. High-throughput sequencing technologies are now providing opportunities to address this issue by aiding in the generation of molecular data for many understudied species of high conservation interest. Our overall goal of this study was to begin building the genomic resources to continue investigations and conservation of the Spot-Tailed Earless lizard. Here we leverage the power of high-throughput sequencing to generate the liver transcriptome for the Northern Spot-Tailed Earless Lizard (Holbrookia lacerata) and Southern Spot-Tailed Earless Lizard (Holbrookia subcaudalis), which have declined in abundance in the past decades, and their sister species, the Common Lesser Earless Lizard (Holbrookia maculata). Our efforts produced high quality and robust transcriptome assemblies validated by 1) quantifying the number of processed reads represented in the transcriptome assembly and 2) quantifying the number of highly conserved single-copy orthologs that are present in our transcript set using the BUSCO pipeline. We found 1,361 1-to-1 orthologs among the three Holbrookia species, Anolis carolinensis, and Sceloporus undulatus. We carried out dN/dS selection tests using a branch-sites model and identified a dozen genes that experienced positive selection in the Holbrookia lineage with functions in development, immunity, and metabolism. Our single-copy orthologous sequences additionally revealed significant pairwise sequence divergence (~.73%) between the Northern H. lacerata and Southern H. subcaudalis that further supports the recent elevation of the Southern Spot-Tailed Earless Lizard to full species.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0234504PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7295237PMC
August 2020

Phylogeography of montane dragons could shed light on the history of forests and diversification processes on Sumatra.

Mol Phylogenet Evol 2020 08 17;149:106840. Epub 2020 Apr 17.

University of Texas at Arlington and Amphibian and Reptile Diversity Research Center, Department of Biology, 501 S. Nedderman Road, Arlington, TX 76010, USA.

Biogeographical evidence, both, for and against the "regional endemism paradigm" hypothesis has been uncovered across the Greater Sunda Region (Sundaland) of Southeast Asia. Additionally, there are competing hypotheses regarding how Pleistocene forests may have impacted biological patterns and processes in Sumatra. Using montane agamid lizards from Sumatra, we derived and analyzed a phylogenetic dataset, genetic divergence estimates, and contemporary distributional patterns among species. We tested whether (1) Sumatra's highland Draconinae diversification fits the regional endemism paradigm hypothesis and (2) Draconinae phylogeography provides biological evidence for Pleistocene forest extent at various points in history. Our results suggest in situ diversification was the main driver behind montane Draconinae lizard diversification in Sumatra, rejecting the "regional endemism paradigm". Contemporary distribution of endemic species and their genetic relationships may potentially provide biologicalevidence for determining more precise elevational lower limits of montane forests during the Pleistocene epoch. Our data suggests montane forests did not retreat more than 700-750 m during glacial maxima because lower retreating forests would have become interconnected, allowing for widespread dispersal, exchange of gene flow and sympatric distributions contemporarily. To the contrary, our divergence estimates show that cloud forest dragons have been isolated for millions of years, suggesting there may have been a continuous disconnect between some areas, predating the Pleistocene. There may also be other ecological and evolutionary factors that impacted Draconinae distributions, such as competition, making this an excellent system for testing questions regarding montane biogeography. Additionally, we provide the first phylogeny for a wide range of Sundaland agamid species and identify some biogeographic pressures that may have triggered montane Draconinae diversification in Sumatra.
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http://dx.doi.org/10.1016/j.ympev.2020.106840DOI Listing
August 2020

Differences in Brain Volume between Metabolically Healthy and Unhealthy Overweight and Obese Children: The Role of Fitness.

J Clin Med 2020 Apr 8;9(4). Epub 2020 Apr 8.

PROFITH "PROmoting FITness and Health through physical activity" research group, Department of Physical and Sports Education, Faculty of Sport Sciences, University of Granada, 18071 Granada, Spain.

The aim of this study was to examine whether metabolically healthy overweight/obese children have greater global and regional gray matter volumes than their metabolically unhealthy peers. We further examined the association between gray matter volume and academic achievement, along with the role of cardiorespiratory fitness in these associations. A total of 97 overweight/obese children (10.0 ± 1.2 years) participated. We classified children as metabolically healthy/unhealthy based on metabolic syndrome cut-offs. Global and regional brain volumes were assessed by magnetic resonance imaging. Academic achievement was assessed using the Woodcock-Muñoz standardized test. Cardiorespiratory fitness was assessed by the 20 m shuttle run test. Metabolically healthy overweight/obese (MHO) children had greater regional gray matter volume compared to those who were metabolically unhealthy (MUO) (all ≤ 0.001). A similar trend was observed for global gray matter volume ( = 0.06). Global gray matter volume was positively related to academic achievement ( = 0.237, = 0.036). However, all the associations were attenuated or disappeared after adjusting for cardiorespiratory fitness ( > 0.05). The findings of the present study support that metabolically healthy overweight/obese children have greater gray matter volume compared to those that are metabolically unhealthy, which is in turn related to better academic achievement. However, cardiorespiratory fitness seems to explain, at least partially, these findings.
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http://dx.doi.org/10.3390/jcm9041059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7231256PMC
April 2020

Is a Gluten-Free Diet Enough to Maintain Correct Micronutrients Status in Young Patients with Celiac Disease?

Nutrients 2020 Mar 21;12(3). Epub 2020 Mar 21.

Department of Pediatrics, University of Granada, 18071 Granada, Spain.

The current study assesses whether the use of a gluten-free diet (GFD) is sufficient for maintaining correct iron status in children with celiac disease (CD). The study included 101 children. The celiac group ( = 68) included children with CD, with long (> 6 months) ( = 47) or recent (< 6 months) ( = 21) adherence to a GFD. The control group ( = 43) included healthy children. Dietary assessment was performed by a food frequency questionnaire and a 3-day food record. Celiac children had lower iron intake than controls, especially at the beginning of GFD ( < 0.01). The group CD-GFD >6 months showed a higher intake of cobalamin, meat derivatives and fish compared to that of CD-GFD <6 months (all, < 0.05). The control group showed a higher consumption of folate, iron, magnesium, selenium and meat derivatives than that of children CD-GFD >6 months (all, < 0.05). Control children also showed a higher consumption of folate and iron compared to that of children CD-GFD <6 months (both, < 0.05). The diet of celiac children was nutritionally less balanced than that of the control. Participation of dietitians is necessary in the management of CD to guide the GFD as well as assess the inclusion of iron supplementation and other micronutrients that may be deficient.
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http://dx.doi.org/10.3390/nu12030844DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7146183PMC
March 2020

Tuberculosis recurrences and predictive factors in a vulnerable population in Catalonia.

PLoS One 2020 15;15(1):e0227291. Epub 2020 Jan 15.

Epidemiology Service, Agència de Salut Pública de Barcelona (ASPB), Barcelona, Spain.

Background: Patients with a history of tuberculosis (TB) have a high probability of recurrence because long-term cure is not always maintained in successfully treated patients. The aim of this study was to identify the probability of TB recurrence and its predictive factors in a cohort of socially vulnerable patients who completed treatment in the TB referral center in Catalonia, which acts as the center for patients with social and health problems.

Methods: This retrospective open cohort study included all patients diagnosed with TB who were admitted and successfully treated in Serveis Clínics between 2000 and 2016 and who remained disease-free for a minimum of 1 year after treatment completion. We calculated the incidence density of TB recurrences per person-years of follow-up. We also estimated the cumulative incidence of TB recurrence at 1, 2, 5, and 10 years of follow-up. Bivariate analysis was conducted using Kaplan-Meier curves. Multivariate analysis was conducted using Cox regression. Hazard ratios (HR) were calculated with their 95% confidence intervals (95%CI).

Results: There were 839 patients and 24 recurrences (2.9%), representing 0.49 per 100 person-years. The probability of a recurrence was 0.63% at 1 year of follow-up, 1.35% at 2 years, and 3.69% at 5 years. The multivariate analysis showed that the predictive factors of recurrence were age older than 34 years (aHR = 3.90; CI = 1.06-14.34 at age 35-45 years and aHR = 3.88; CI = 1.02-14.80 at age >45 years) and resistance to at least one anti-TB drug (aHR = 2.91; CI = 1.11-7.65).

Conclusions: Attention should be paid to socially vulnerable persons older than 34 years with a previous episode of resistant TB. Surveillance resources should be directed toward adequately treated patients who nevertheless have a high risk of recurrence.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0227291PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6961944PMC
May 2020

The Psychosocial Assessment of Transplant Candidates: Inter-Rater Reliability and Predictive Value of the Italian Stanford Integrated Psychosocial Assessment for Transplantation (SIPAT).

Psychosomatics 2020 Mar - Apr;61(2):127-134. Epub 2019 Dec 4.

Department of Psychiatry & Behavioral Sciences, Stanford University School of Medicine, Stanford, CA.

Background: The Stanford Integrated Psychosocial Assessment for Transplantation (SIPAT) is a comprehensive instrument developed to accurately assess the main pretransplant psychosocial risk factors that may impact transplant outcomes.

Objective: As neither established assessment procedures nor standardized tools designed to perform pretransplant psychosocial evaluation are currently available in Italy, the present study was designed to develop and preliminarily validate the Italian version of the SIPAT.

Methods: First, our team developed the Italian version of the SIPAT, following standard forward-back translation procedures. Then, the Italian version of the SIPAT was retrospectively and blindly applied to 118 randomly selected transplant cases (40 heart, 40 lung, and 38 liver) by 2 independent examiners. Information about the patients' final transplant listing recommendation (i.e., listing vs. deferral) was independently collected from the respective transplant teams.

Results: The inter-rater reliability of the Italian version of the SIPAT scores was substantial (Cohen's kappa = 0.77; P < 0.001). Moreover, the predictive value of the SIPAT ratings on the final transplant listing recommendation (i.e., listing vs. deferral) for each examiner was significant (both P < 0.05).

Conclusion: Current findings suggest that SIPAT is a promising and reliable instrument in its Italian version. Given these excellent psychometric characteristics, the use of the SIPAT as part of the pretransplant psychosocial evaluation in Italian medical settings is highly encouraged.
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http://dx.doi.org/10.1016/j.psym.2019.11.008DOI Listing
February 2021

A Study of the Psychometric Properties of the "Stanford Proxy Test for Delirium" (S-PTD): A New Screening Tool for the Detection of Delirium.

Psychosomatics 2020 Mar - Apr;61(2):116-126. Epub 2019 Dec 4.

Consultation-Liaison Psychiatry Service, Department of Psychiatry & Behavioral Sciences, Stanford University School of Medicine, Stanford, CA.

Background: Delirium is a prevalent neuropsychiatric disorder associated with increased morbidity and mortality. Half the cases remain misdiagnosed.

Objective: Assess the effectiveness of the Stanford Proxy Test for Delirium (S-PTD) in detecting delirium in an inpatient setting.

Methods: This is a comparison study. Daily assessment with S-PTD, by the patient's nurse, and a neuropsychiatric assessment by a psychiatrist. Assessments were blinded. Inclusion criteria included 18 years or older. Exclusion criteria included patient's or surrogate's unwillingness to participate, inability to consent if a surrogate was not available, and inability to communicate in English or Spanish. A total of 309 patients were approached: 27 declined participation, 4 were excluded, and 278 subjects were followed up throughout their hospital stay. In the end, 78 were excluded for lack of neuropsychiatric assessment, S-PTD, or both. One was excluded for lack of demographic data. The sensitivity and specificity of the S-PTD in detecting delirium when compared with a neuropsychiatric assessment.

Results: Participants were on average 60.8 years old and 54.3% were male. Patients who developed delirium were, on average, older (15.12 y, confidence interval: 8.94-21.32). A total of 199 patients were analyzed; 43 patients (21.6%) met criteria for delirium. S-PTD detected 67 days with delirium (16.5%) of 405 hospital days, while neuropsychiatric evaluation identified 83 (20.5%). S-PTD had a sensitivity of 80.72% and a specificity of 90.37%.

Conclusion: S-PTD is an effective, comprehensive, and simple screening tool for delirium, which is robust despite fluctuating symptoms and lack of cooperation. The use of S-PTD may enhance early diagnosis of delirium.
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http://dx.doi.org/10.1016/j.psym.2019.11.009DOI Listing
February 2021
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