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  Subjects -> MEDICAL SCIENCES (Total: 7328 journals)
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MEDICAL SCIENCES (1833 journals)                  1 2 3 4 5 6 7 8 | Last

Showing 1 - 200 of 3562 Journals sorted alphabetically
16 de Abril     Open Access  
AADE in Practice     Hybrid Journal   (Followers: 4)
ABCS Health Sciences     Open Access   (Followers: 1)
Abia State University Medical Students' Association Journal     Full-text available via subscription  
ACIMED     Open Access   (Followers: 1)
ACS Medicinal Chemistry Letters     Full-text available via subscription   (Followers: 40)
Acta Bio Medica     Full-text available via subscription   (Followers: 2)
Acta Bioethica     Open Access   (Followers: 1)
Acta Bioquimica Clinica Latinoamericana     Open Access   (Followers: 1)
Acta Facultatis Medicae Naissensis     Open Access  
Acta Informatica Medica     Open Access   (Followers: 1)
Acta Medica Bulgarica     Open Access  
Acta Medica Colombiana     Open Access   (Followers: 1)
Acta Médica Costarricense     Open Access   (Followers: 2)
Acta Medica Indonesiana     Open Access  
Acta medica Lituanica     Open Access  
Acta Medica Marisiensis     Open Access  
Acta Medica Martiniana     Open Access  
Acta Medica Nagasakiensia     Open Access  
Acta Medica Peruana     Open Access   (Followers: 2)
Acta Médica Portuguesa     Open Access  
Acta Medica Saliniana     Open Access  
Acta Scientiarum. Health Sciences     Open Access  
Acupuncture & Electro-Therapeutics Research     Full-text available via subscription   (Followers: 2)
Addiction Science & Clinical Practice     Open Access   (Followers: 7)
Addictive Behaviors Reports     Open Access   (Followers: 7)
Advanced Health Care Technologies     Open Access   (Followers: 4)
Advanced Science, Engineering and Medicine     Partially Free   (Followers: 7)
Advances in Bioscience and Clinical Medicine     Open Access   (Followers: 5)
Advances in Clinical Chemistry     Full-text available via subscription   (Followers: 29)
Advances in Life Course Research     Hybrid Journal   (Followers: 8)
Advances in Lipobiology     Full-text available via subscription   (Followers: 2)
Advances in Medical Education and Practice     Open Access   (Followers: 26)
Advances in Medical Sciences     Hybrid Journal   (Followers: 6)
Advances in Medicinal Chemistry     Full-text available via subscription   (Followers: 6)
Advances in Medicine     Open Access   (Followers: 2)
Advances in Microbial Physiology     Full-text available via subscription   (Followers: 5)
Advances in Molecular Oncology     Open Access   (Followers: 2)
Advances in Molecular Toxicology     Full-text available via subscription   (Followers: 9)
Advances in Parkinson's Disease     Open Access  
Advances in Phytomedicine     Full-text available via subscription  
Advances in Preventive Medicine     Open Access   (Followers: 6)
Advances in Protein Chemistry and Structural Biology     Full-text available via subscription   (Followers: 20)
Advances in Therapy     Hybrid Journal   (Followers: 5)
Advances in Veterinary Science and Comparative Medicine     Full-text available via subscription   (Followers: 13)
Advances in Virus Research     Full-text available via subscription   (Followers: 6)
Advances in Wound Care     Hybrid Journal   (Followers: 10)
African Health Sciences     Open Access   (Followers: 2)
African Journal of Biomedical Research     Open Access  
African Journal of Clinical and Experimental Microbiology     Open Access   (Followers: 1)
African Journal of Laboratory Medicine     Open Access   (Followers: 2)
African Journal of Medical and Health Sciences     Open Access   (Followers: 2)
African Journal of Trauma     Open Access  
Afrimedic Journal     Open Access   (Followers: 2)
Aggiornamenti CIO     Hybrid Journal   (Followers: 1)
AIDS Research and Human Retroviruses     Hybrid Journal   (Followers: 8)
AJOB Primary Research     Partially Free   (Followers: 3)
Aktuelle Ernährungsmedizin     Hybrid Journal   (Followers: 4)
Al-Azhar Assiut Medical Journal     Open Access  
Alexandria Journal of Medicine     Open Access   (Followers: 1)
Allgemeine Homöopathische Zeitung     Hybrid Journal   (Followers: 2)
Alpha Omegan     Full-text available via subscription  
ALTEX : Alternatives to Animal Experimentation     Open Access   (Followers: 3)
American Journal of Biomedical Engineering     Open Access   (Followers: 12)
American Journal of Biomedical Research     Open Access   (Followers: 2)
American Journal of Biomedicine     Full-text available via subscription   (Followers: 7)
American Journal of Chinese Medicine, The     Hybrid Journal   (Followers: 5)
American Journal of Clinical Medicine Research     Open Access   (Followers: 5)
American Journal of Family Therapy     Hybrid Journal   (Followers: 11)
American Journal of Law & Medicine     Full-text available via subscription   (Followers: 12)
American Journal of Lifestyle Medicine     Hybrid Journal   (Followers: 5)
American Journal of Managed Care     Full-text available via subscription   (Followers: 11)
American Journal of Medical Case Reports     Open Access   (Followers: 1)
American Journal of Medical Sciences and Medicine     Open Access   (Followers: 2)
American Journal of Medicine     Hybrid Journal   (Followers: 45)
American Journal of Medicine and Medical Sciences     Open Access   (Followers: 1)
American Journal of Medicine Studies     Open Access  
American Journal of Medicine Supplements     Full-text available via subscription   (Followers: 3)
American Journal of the Medical Sciences     Hybrid Journal   (Followers: 12)
American Journal on Addictions     Hybrid Journal   (Followers: 10)
American medical news     Free   (Followers: 3)
American Medical Writers Association Journal     Full-text available via subscription   (Followers: 2)
Amyloid: The Journal of Protein Folding Disorders     Hybrid Journal   (Followers: 4)
Anales de la Facultad de Medicina     Open Access  
Anales de la Facultad de Medicina, Universidad de la República, Uruguay     Open Access  
Anales del Sistema Sanitario de Navarra     Open Access   (Followers: 1)
Analgesia & Resuscitation : Current Research     Hybrid Journal   (Followers: 3)
Anatomical Science International     Hybrid Journal   (Followers: 2)
Anatomical Sciences Education     Hybrid Journal   (Followers: 1)
Anatomy Research International     Open Access   (Followers: 2)
Angewandte Schmerztherapie und Palliativmedizin     Hybrid Journal  
Angiogenesis     Hybrid Journal   (Followers: 3)
Annales de Pathologie     Full-text available via subscription  
Annales françaises d'Oto-rhino-laryngologie et de Pathologie Cervico-faciale     Full-text available via subscription   (Followers: 3)
Annals of African Medicine     Open Access   (Followers: 1)
Annals of Anatomy - Anatomischer Anzeiger     Hybrid Journal   (Followers: 2)
Annals of Bioanthropology     Open Access   (Followers: 4)
Annals of Biomedical Engineering     Hybrid Journal   (Followers: 18)
Annals of Biomedical Sciences     Full-text available via subscription   (Followers: 3)
Annals of Clinical Microbiology and Antimicrobials     Open Access   (Followers: 9)
Annals of Family Medicine     Open Access   (Followers: 12)
Annals of Fundeni Hospital     Open Access   (Followers: 1)
Annals of Ibadan Postgraduate Medicine     Open Access  
Annals of Medical and Health Sciences Research     Open Access   (Followers: 7)
Annals of Medicine     Hybrid Journal   (Followers: 12)
Annals of Medicine and Surgery     Open Access   (Followers: 7)
Annals of Microbiology     Hybrid Journal   (Followers: 10)
Annals of Nigerian Medicine     Open Access   (Followers: 1)
Annals of Saudi Medicine     Open Access  
Annals of the New York Academy of Sciences     Hybrid Journal   (Followers: 5)
Annals of The Royal College of Surgeons of England     Full-text available via subscription   (Followers: 3)
Annual Reports in Medicinal Chemistry     Full-text available via subscription   (Followers: 7)
Annual Reports on NMR Spectroscopy     Full-text available via subscription   (Followers: 4)
Annual Review of Medicine     Full-text available via subscription   (Followers: 17)
Anthropological Review     Open Access   (Followers: 24)
Anthropologie et santé     Open Access   (Followers: 5)
Antibiotics     Open Access   (Followers: 9)
Antibodies     Open Access   (Followers: 2)
Antibody Technology Journal     Open Access   (Followers: 1)
Anuradhapura Medical Journal     Open Access  
Anwer Khan Modern Medical College Journal     Open Access   (Followers: 2)
Apmis     Hybrid Journal   (Followers: 1)
Apparence(s)     Open Access   (Followers: 1)
Applied Clinical Informatics     Hybrid Journal   (Followers: 2)
Applied Clinical Research, Clinical Trials and Regulatory Affairs     Hybrid Journal  
Applied Medical Informatics     Open Access   (Followers: 10)
Arab Journal of Nephrology and Transplantation     Open Access   (Followers: 1)
Arak Medical University Journal     Open Access  
Archive of Clinical Medicine     Open Access   (Followers: 1)
Archive of Community Health     Open Access  
Archives of Biomedical Sciences     Open Access   (Followers: 7)
Archives of Medical and Biomedical Research     Open Access   (Followers: 3)
Archives of Medical Laboratory Sciences     Open Access   (Followers: 1)
Archives of Medicine and Health Sciences     Open Access   (Followers: 3)
Archives of Trauma Research     Open Access   (Followers: 2)
Archivos de Medicina (Manizales)     Open Access  
ArgoSpine News & Journal     Hybrid Journal  
Arquivos Brasileiros de Oftalmologia     Open Access  
Arquivos de Ciências da Saúde     Open Access  
Arquivos de Medicina     Open Access  
Ars Medica : Revista de Ciencias Médicas     Open Access  
ARS Medica Tomitana     Open Access   (Followers: 1)
Art Therapy: Journal of the American Art Therapy Association     Full-text available via subscription   (Followers: 10)
Arterial Hypertension     Open Access  
Artificial Intelligence in Medicine     Hybrid Journal   (Followers: 12)
Artificial Organs     Hybrid Journal   (Followers: 1)
Asia Pacific Family Medicine     Open Access  
Asia Pacific Journal of Clinical Nutrition     Full-text available via subscription   (Followers: 9)
Asia Pacific Journal of Clinical Trials : Nervous System Diseases     Open Access  
Asian Bioethics Review     Full-text available via subscription   (Followers: 2)
Asian Journal of Cell Biology     Open Access   (Followers: 6)
Asian Journal of Health     Open Access   (Followers: 3)
Asian Journal of Medical and Biological Research     Open Access   (Followers: 2)
Asian Journal of Medical and Pharmaceutical Researches     Open Access   (Followers: 1)
Asian Journal of Medical Sciences     Open Access   (Followers: 1)
Asian Journal of Scientific Research     Open Access   (Followers: 2)
Asian Journal of Transfusion Science     Open Access   (Followers: 2)
Asian Medicine     Hybrid Journal   (Followers: 4)
Asian Pacific Journal of Cancer Prevention     Open Access  
ASPIRATOR : Journal of Vector-borne Disease Studies     Open Access  
Astrocyte     Open Access  
Atención Familiar     Open Access  
Atención Primaria     Open Access   (Followers: 1)
Audiology - Communication Research     Open Access   (Followers: 8)
Auris Nasus Larynx     Full-text available via subscription  
Australian Coeliac     Full-text available via subscription   (Followers: 2)
Australian Family Physician     Full-text available via subscription   (Followers: 3)
Australian Journal of Medical Science     Full-text available via subscription   (Followers: 1)
Autopsy and Case Reports     Open Access  
Aviation, Space, and Environmental Medicine     Full-text available via subscription   (Followers: 10)
Avicenna     Open Access   (Followers: 2)
Avicenna Journal of Medicine     Open Access   (Followers: 1)
Bangabandhu Sheikh Mujib Medical University Journal     Open Access   (Followers: 1)
Bangladesh Journal of Anatomy     Open Access   (Followers: 1)
Bangladesh Journal of Bioethics     Open Access  
Bangladesh Journal of Medical Biochemistry     Open Access   (Followers: 3)
Bangladesh Journal of Medical Education     Open Access   (Followers: 2)
Bangladesh Journal of Medical Microbiology     Open Access   (Followers: 3)
Bangladesh Journal of Medical Physics     Open Access  
Bangladesh Journal of Medical Science     Open Access  
Bangladesh Journal of Medicine     Open Access   (Followers: 1)
Bangladesh Journal of Physiology and Pharmacology     Open Access  
Bangladesh Journal of Scientific Research     Open Access   (Followers: 2)
Bangladesh Medical Journal     Open Access  
Bangladesh Medical Journal Khulna     Open Access  
Basal Ganglia     Hybrid Journal  
Basic Sciences of Medicine     Open Access   (Followers: 2)
BBA Clinical     Open Access  
BC Medical Journal     Free  
Benha Medical Journal     Open Access  
Bijblijven     Hybrid Journal  
Bijzijn     Hybrid Journal   (Followers: 2)
Bijzijn XL     Hybrid Journal   (Followers: 1)
Bio-Algorithms and Med-Systems     Hybrid Journal   (Followers: 1)
BioDiscovery     Open Access   (Followers: 2)
Bioelectromagnetics     Hybrid Journal   (Followers: 1)
Bioengineering & Translational Medicine     Open Access  
Bioethics     Hybrid Journal   (Followers: 14)
Bioethics Research Notes     Full-text available via subscription   (Followers: 14)
Biologics in Therapy     Open Access  

        1 2 3 4 5 6 7 8 | Last

Journal Cover Annals of the New York Academy of Sciences
  [SJR: 2.389]   [H-I: 189]   [5 followers]  Follow
    
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 0077-8923 - ISSN (Online) 1749-6632
   Published by John Wiley and Sons Homepage  [1592 journals]
  • Factors associated with nutritional status and dietary practices of
           Bangladeshi adolescents in early pregnancy
    • Authors: Malay K. Mridha; Susana L. Matias, Charles D. Arnold, Kathryn G. Dewey
      Abstract: Bangladesh has a high prevalence of adolescent pregnancy, but little is known about the nutritional status and dietary practices of Bangladeshi adolescents in early pregnancy or associated factors. We used the baseline data of 1552 pregnant adolescents from a longitudinal, cluster-randomized effectiveness trial conducted in northwest Bangladesh. Forty-four percent of the adolescents were short for their age, 36% had low body mass index, 28% were anemic, 10% had iron deficiency, and 32% had vitamin A deficiency. The mean consumption of animal-source foods was 10.3 times/week. In multivariate analysis, socioeconomic status, education, and food security were generally positively associated with anthropometric indicators and dietary practices but not with iron or vitamin A status. Our findings confirm that there is a high burden of undernutrition among these Bangladeshi adolescents in early pregnancy. Understanding factors related to undernutrition can help to identify adolescent pregnant women at higher risk and provide appropriate counseling and care.
      PubDate: 2018-02-18T23:26:21.118608-05:
      DOI: 10.1111/nyas.13568
       
  • A public health approach for preventing neural tube defects: folic acid
           fortification and beyond
    • Authors: Greg S. Garrett; Lynn B. Bailey
      Abstract: In this paper we review the evidence basis for prevention of folic acid–sensitive neural tube defects (NTDs) through public health interventions in women of reproductive age (WRA), the proven vehicles for delivery of folic acid, and what is needed to effectively scale these, and provide a snapshot of potential innovations that require future research. Our primary focus is on the global situation affecting large-scale food fortification (LSFF) with folic acid, in particular the fortification of wheat flour and maize meal. Our overarching conclusion is that folic acid fortification is an evidence-based intervention that reduces the prevalence of NTDs, and that LSFF with folic acid is underutilized. Thus, food fortification with folic acid should be a component of most national public health strategies, in particular where folate status is insufficient and a fortifiable food vehicle, processed by a centralized industry, is consumed regularly by WRA. The evidence shows that there is still much work needed (1) to build the enabling environment and expand programs where there is currently no legislation, (2) to improve the low quality of delivery of existing programs, and (3) to measure and sustain programs by generating new coverage data and demonstrating evidence of impact in low- and middle-income countries.
      PubDate: 2018-02-16T02:10:34.175315-05:
      DOI: 10.1111/nyas.13579
       
  • Toward a multifactorial model of expertise: beyond born versus made
    • Authors: David Z. Hambrick; Alexander P. Burgoyne, Brooke N. Macnamara, Fredrik Ullén
      Abstract: The debate over the origins of individual differences in expertise has raged for over a century in psychology. The “nature” view holds that expertise reflects “innate talent”—that is, genetically determined abilities. The “nurture” view counters that, if talent even exists, its effects on ultimate performance are negligible. While no scientist takes seriously a strict nature-only view of expertise, the nurture view has gained tremendous popularity over the past several decades. This environmentalist view holds that individual differences in expertise reflect training history, with no important contribution to ultimate performance by innate ability (“talent”). Here, we argue that, despite its popularity, this view is inadequate to account for the evidence concerning the origins of expertise that has accumulated since the view was first proposed. More generally, we argue that the nature versus nurture debate in research on expertise is over—or certainly should be, as it has been in other areas of psychological research for decades. We describe a multifactorial model for research on the nature and nurture of expertise, which we believe will provide a progressive direction for future research on expertise.
      PubDate: 2018-02-15T07:36:35.723046-05:
      DOI: 10.1111/nyas.13586
       
  • The challenge of converting Gram-positive-only compounds into
           broad-spectrum antibiotics
    • Authors: Michelle F. Richter; Paul J. Hergenrother
      Abstract: Multidrug resistant Gram-negative bacterial infections are on the rise, and there is a lack of new classes of drugs to treat these pathogens. This drug shortage is largely due to the challenge of finding antibiotics that can permeate and persist inside Gram-negative species. Efforts to understand the molecular properties that enable certain compounds to accumulate in Gram-negative bacteria based on retrospective studies of known antibiotics have not been generally actionable in the development of new antibiotics. A recent assessment of the ability of>180 diverse small molecules to accumulate in Escherichia coli led to predictive guidelines for compound accumulation in E. coli. These “eNTRy rules” state that compounds are most likely to accumulate if they contain a nonsterically encumbered ionizable Nitrogen (primary amines are the best), have low Three-dimensionality (globularity ≤ 0.25), and are relatively Rigid (rotatable bonds ≤ 5). In this review, we look back through 50+ years of antibacterial research and 1000s of derivatives and assess this historical data set through the lens of these predictive guidelines. The results are consistent with the eNTRy rules, suggesting that the eNTRy rules may provide an actionable and general roadmap for the conversion of Gram-positive-only compounds into broad-spectrum antibiotics.
      PubDate: 2018-02-15T07:36:08.486966-05:
      DOI: 10.1111/nyas.13598
       
  • Biogeographic constraints to marine conservation in a changing climate
    • Authors: Alexa Fredston-Hermann; Steven D. Gaines, Benjamin S. Halpern
      Abstract: The siting of protected areas to achieve management and conservation objectives draws heavily on biogeographic concepts of the spatial distribution and connectivity of species. However, the marine protected area (MPA) literature rarely acknowledges how biogeographic theories underpin MPA and MPA network design. We review which theories from biogeography have been incorporated into marine spatial planning and which relevant concepts have yet to be translated to inform the next generation of design principles. This biogeographic perspective will only become more relevant as climate change amplifies these spatial and temporal dynamics, and as species begin to shift in and out of existing MPAs. The scale of climate velocities predicted for the 21st century dwarfs all but the largest MPAs currently in place, raising the possibility that in coming decades many MPAs will no longer contain the species or assemblages they were established to protect. We present a number of design elements that could improve the success of MPAs and MPA networks in light of biogeographic processes and climate change. Biogeographically informed MPA networks of the future may resemble the habitat corridors currently being considered for many terrestrial regions.
      PubDate: 2018-02-07T01:15:35.283225-05:
      DOI: 10.1111/nyas.13597
       
  • Disease prevention and delayed aging by dietary sulfur amino acid
           restriction: translational implications
    • Authors: Zhen Dong; Raghu Sinha, John P. Richie
      Abstract: Sulfur amino acids (SAAs) play numerous critical roles in metabolism and overall health maintenance. Preclinical studies have demonstrated that SAA-restricted diets have many beneficial effects, including extending life span and preventing the development of a variety of diseases. Dietary sulfur amino acid restriction (SAAR) is characterized by chronic restrictions of methionine and cysteine but not calories and is associated with reductions in body weight, adiposity and oxidative stress, and metabolic changes in adipose tissue and liver resulting in enhanced insulin sensitivity and energy expenditure. SAAR-induced changes in blood biomarkers include reductions in insulin, insulin-like growth factor-1, glucose, and leptin and increases in adiponectin and fibroblast growth factor 21. On the basis of these preclinical data, SAAR may also have similar benefits in humans. While little is known of the translational significance of SAAR, its potential feasibility in humans is supported by findings of its effectiveness in rodents, even when initiated in adult animals. To date, there have been no controlled feeding studies of SAAR in humans; however, there have been numerous relevant epidemiologic and disease-based clinical investigations reported. Here, we summarize observations from these clinical investigations to provide insight into the potential effectiveness of SAAR for humans.
      PubDate: 2018-02-05T02:40:27.523937-05:
      DOI: 10.1111/nyas.13584
       
  • Serological and experimental studies in different forms of myasthenia
           gravis
    • Authors: Angela Vincent; Saif Huda, Michelangelo Cao, Hakan Cetin, Inga Koneczny, Pedro Rodriguez-Cruz, Leslie Jacobson, Stuart Viegas, Saiju Jacob, Mark Woodhall, Akiko Nagaishi, Angelina Maniaol, Valentina Damato, M. Isabel Leite, Judith Cossins, Richard Webster, Jacqueline Palace, David Beeson
      Abstract: Antibodies to the acetylcholine receptor (AChR) have been recognized for over 40 years and have been important in the diagnosis of myasthenia gravis (MG), and its recognition in patients of different ages and thymic pathologies. The 10–20% of patients who do not have AChR antibodies are now known to comprise different subgroups, the most commonly reported of which is patients with antibodies to muscle-specific kinase (MuSK). The use of cell-based assays has extended the repertoire of antibody tests to clustered AChRs, low-density lipoprotein receptor–related protein 4, and agrin. Autoantibodies against intracellular targets, namely cortactin, titin, and ryanodine receptor (the latter two being associated with the presence of thymoma), may also be helpful as biomarkers in some patients. IgG4 MuSK antibodies are clearly pathogenic, but the coexisting IgG1, IgG2, and IgG3 antibodies, collectively, have effects that question the dominance of IgG4 as the sole pathologic factor in MuSK MG. After a brief historical review, we define the different subgroups and summarize the antibody characteristics. Experiments to demonstrate the in vitro and in vivo pathogenic roles of MuSK antibodies are discussed.
      PubDate: 2018-01-29T11:20:54.49726-05:0
      DOI: 10.1111/nyas.13592
       
  • Cardioprotective effects of dietary rapamycin on adult female
           C57BLKS/J-Leprdb mice
    • Authors: Peter C. Reifsnyder; Sergey Ryzhov, Kevin Flurkey, Rea P. Anunciado-Koza, Ian Mills, David E. Harrison, Robert A. Koza
      Abstract: Rapamycin (RAPA), an inhibitor of mTORC signaling, has been shown to extend life span in mice and other organisms. Recently, animal and human studies have suggested that inhibition of mTORC signaling can alleviate or prevent the development of cardiomyopathy. In view of this, we used a murine model of type 2 diabetes (T2D), BKS-Leprdb, to determine whether RAPA treatment can mitigate the development of T2D-induced cardiomyopathy in adult mice. Female BKS-Leprdb mice fed diet supplemented with RAPA from 11 to 27 weeks of age showed reduced weight gain and significant reductions of fat and lean mass compared with untreated mice. No differences in plasma glucose or insulin levels were observed between groups; however, RAPA-treated mice were more insulin sensitive (P < 0.01) than untreated mice. Urine albumin/creatinine ratio was lower in RAPA-treated mice, suggesting reduced diabetic nephropathy and improved kidney function. Echocardiography showed significantly reduced left ventricular wall thickness in mice treated with RAPA compared with untreated mice (P = 0.02) that was consistent with reduced heart weight/tibia length ratios, reduced myocyte size and cardiac fibrosis measured by histomorphology, and reduced mRNA expression of Col1a1, a marker for cardiomyopathy. Our results suggest that inhibition of mTORC signaling is a plausible strategy for ameliorating complications of obesity and T2D, including cardiomyopathy.
      PubDate: 2018-01-29T08:25:31.584067-05:
      DOI: 10.1111/nyas.13557
       
  • Therapeutic applications of betulinic acid nanoformulations
    • Authors: Ankit Saneja; Divya Arora, Robin Kumar, Ravindra Dhar Dubey, Amulya K. Panda, Prem N. Gupta
      Abstract: Betulinic acid (BA), a naturally occurring plant-derived pentacyclic triterpenoid, has gained attention in recent years owing to its broad-spectrum biological and medicinal properties. Despite the pharmacological activity of BA, it has been associated with some drawbacks, such as poor aqueous solubility and short half-life in vivo, which limit therapeutic application. To solve these problems, much work in recent years has focused on enhancing BA's aqueous solubility, half-life, and efficacy by using nanoscale drug delivery systems. Several different kinds of nanoscale delivery systems—including polymeric nanoparticles, magnetic nanoparticles, liposomes, polymeric conjugates, nanoemulsions, cyclodextrin complexes, and carbon nanotubes—have been developed for the delivery of BA. Here, we focus on the recent developments of novel nanoformulations used to deliver BA in order to improve its efficacy.
      PubDate: 2018-01-29T03:30:55.589172-05:
      DOI: 10.1111/nyas.13570
       
  • Sulfur amino acid restriction–induced changes in redox-sensitive
           proteins are associated with slow protein synthesis rates
    • Authors: Sailendra N. Nichenametla; Dwight A.L. Mattocks, Virginia L. Malloy, John T. Pinto
      Abstract: The mechanisms underlying life span extension by sulfur amino acid restriction (SAAR) are unclear. Cysteine and methionine are essential for the biosynthesis of proteins and glutathione (GSH), a major redox buffer in the endoplasmic reticulum (ER). We hypothesized that SAAR alters protein synthesis by modulating the redox milieu. Male F344-rats were fed control (CD: 0.86% methionine without cysteine) and SAAR diets (0.17% methionine without cysteine) for 12 weeks. Growth rates, food intake, cysteine and GSH levels, proteins associated with redox status and translation, and fractional protein synthesis rates (FSRs) were determined in liver. Despite a 40% higher food intake, growth rates for SAAR rats were 27% of those fed CD. Hepatic free cysteine in SAAR rats was 55% compared with CD rats. SAAR altered tissue distribution of GSH, as hepatic and erythrocytic levels were 56% and 196% of those in CD rats. Lower GSH levels did not induce ER stress (i.e., unchanged expression of Xbp1s, Chop, and Grp78), but activated PERK and its substrates eIF2-α and NRF2. SAAR-induced changes in translation-initiation machinery (higher p-eIF2-α and 4E-BP1, and lower eIF4G-1) resulted in slower protein synthesis rates (53% of CD). Proteins involved in the antioxidant response (NRF2, KEAP1, GCLM, and NQO1) and protein folding (PDI and ERO1-α) were increased in SAAR. Lower FSR and efficient protein folding might be improving proteostasis in SAAR.
      PubDate: 2018-01-29T03:17:31.455436-05:
      DOI: 10.1111/nyas.13556
       
  • Framework for laboratory harmonization of folate measurements in low- and
           middle-income countries and regions
    • Authors: Christine M. Pfeiffer; Mindy Zhang, Shameem Jabbar
      Abstract: The measurement of serum and red blood cell folate, two commonly used biomarkers of folate status in populations, is complicated by analytical and data interpretation challenges. Folate results show poor comparability across laboratories, even using the same analytical technique. The folate microbiologic assay produces accurate results and requires simple instrumentation. Thus, it could be set up and maintained in low- and middle-income country laboratories. However, the assay has to be harmonized through the use of common critical reagents (e.g., microorganism and folate calibrator) in order to produce comparable results across laboratories and over time, so that the same cutoff values can be applied across surveys. There is a limited need for blood folate measurements in a country owing to the periodic nature of surveys. Having a network of regional resource laboratories proficient in conducting the folate microbiologic assay and willing and able to perform service work for other countries will be the most efficient way to create an infrastructure wherein qualified laboratories produce reliable blood folate data. Continuous participation of these laboratories in a certification program can verify and document their proficiency. If the resource laboratories conduct the work on a fee-for-service basis, they could become self-sustaining in the long run.
      PubDate: 2018-01-29T03:15:45.918064-05:
      DOI: 10.1111/nyas.13532
       
  • Acetylcholine receptor–specific immunosuppressive therapy of
           experimental autoimmune myasthenia gravis and myasthenia gravis
    • Authors: Jie Luo; Jon Lindstrom
      Abstract: Experimental autoimmune myasthenia gravis (EAMG) and myasthenia gravis (MG) are caused by autoantibodies to the extracellular domain of muscle nicotinic acetylcholine receptors (AChRs). Autoantibodies to the cytoplasmic domain of AChRs do not cause EAMG because they cannot bind AChRs in vivo. The ideal MG therapy would quickly and permanently suppress only the pathological autoimmune response to AChRs. We have developed a specific immunosuppressive therapy for EAMG that involves immunizing rats with bacterially expressed cytoplasmic domains of human muscle AChRs. Therapy prevents onset of chronic EAMG, rapidly suppresses ongoing EAMG, and is potent, robust, long lasting, and safe, because the therapeutic antigen cannot induce EAMG. The therapy was developed using incomplete Freund's adjuvant, but is likely to work equally well with alum adjuvants routinely used for human immunizations. Therapeutic mechanisms may involve a combination of antibody-mediated feedback suppression and regulatory T and/or B lymphocytes.
      PubDate: 2018-01-29T03:15:36.14-05:00
      DOI: 10.1111/nyas.13550
       
  • Should vitamin B12 status be considered in assessing risk of neural tube
           defects'
    • Authors: Anne M. Molloy
      Abstract: There is a strong biological premise for including vitamin B12 with folic acid in strategies to prevent neural tube defects (NTDs), due to the closely interlinked metabolism of these two vitamins. For example, reduction of B12 deficiency among women of reproductive age could enhance the capacity of folic acid to prevent NTDs by optimizing the cellular uptake and utilization of natural folate cofactors. Vitamin B12 might also have an independent role in NTD prevention, such that adding it in fortification programs might be more effective than fortifying with folic acid alone. Globally, there is ample evidence of widespread vitamin B12 deficiency in low- and middle-income countries, but there is also considerable divergence of vitamin B12 status across regions, likely due to genetic as well as nutritional factors. Here, I consider the evidence that low vitamin B12 status may be an independent factor associated with risk of NTDs, and whether a fortification strategy to improve B12 status would help reduce the prevalence of NTDs. I seek to identify knowledge gaps in this respect and specify research goals that would address these gaps.
      PubDate: 2018-01-29T03:15:30.2625-05:00
      DOI: 10.1111/nyas.13574
       
  • Distinct patterns of gene expression in human cardiac fibroblasts exposed
           to rapamycin treatment or methionine restriction
    • Authors: Ashley Azar; Ibiyonu Lawrence, Sebastian Jofre, Joshua Mell, Christian Sell
      Abstract: Both methionine restriction and rapamycin treatment are robust longevity-enhancing regimens for which the mechanisms remain unclear. Cellular senescence is a major contributor to the aging process, and we find that both the methionine and rapamycin regimens delay or prevent activation of the senescence program in human cells. Using a transcriptome-wide analysis, we examined the impact of methionine restriction and rapamycin treatment on senescence-associated gene expression in human cardiac fibroblasts. Our findings have been integrated into gene expression data sets from human lung and skin fibroblasts during senescence. The data demonstrate both common and tissue-specific aspects to the senescent phenotype in these cell types. For example, cardiac fibroblasts express brain naturetic peptide, a clinically relevant marker for cardiac failure, whereas senescent cells from all three tissues express at least one of the insulin-like growth factor (IGF)-binding proteins. The IGF-binding proteins are tissue-specific mediators of IGF-1, a growth factor required for proliferation of all tissues. These data suggest that senescent cells serve tissue-specific roles. Moreover, the prolongevity regimens produce distinct patterns of gene expression.
      PubDate: 2018-01-28T01:11:59.325995-05:
      DOI: 10.1111/nyas.13566
       
  • A presynaptic congenital myasthenic syndrome attributed to a homozygous
           sequence variant in LAMA5
    • Authors: Ricardo A. Maselli; Juan Arredondo, Jessica Vázquez, Jessica X. Chong, Michael J. Bamshad, Deborah A. Nickerson, Marian Lara, Fiona Ng, Victoria Lee Lo, Peter Pytel, Craig M. McDonald
      Abstract: We report a severe defect of neuromuscular transmission in a consanguineous patient with a homozygous variant in the laminin α5 subunit gene (LAMA5). The variant c.8046C> T (p.Arg2659Trp) is rare and has a predicted deleterious effect. The affected individual, who also carries a rare homozygous sequence variant in LAMA1, had normal cognitive function, but magnetic resonance brain imaging showed mild volume loss and periventricular T2 prolongation. Repetitive nerve stimulation at 2 Hz showed 50% decrement of compound muscle action potential amplitudes but 250% facilitation immediately after exercise, similar to that seen in Lambert–Eaton myasthenic syndrome. Endplate studies demonstrated a profound reduction of the endplate potential quantal content but normal amplitudes of miniature endplate potentials. Electron microscopy showed endplates with increased postsynaptic folding that were denuded or only partially occupied by small nerve terminals. Expression studies revealed that p.Arg2659Trp caused decreased binding of laminin α5 to SV2A and impaired laminin-521 cell adhesion and cell projection support in primary neuronal cultures. In summary, this report describing severe neuromuscular transmission failure in a patient with a LAMA5 mutation expands the list of phenotypes associated with defects in genes encoding α-laminins.
      PubDate: 2018-01-28T01:11:39.539047-05:
      DOI: 10.1111/nyas.13585
       
  • IgG4-mediated autoimmune diseases: a niche of antibody-mediated disorders
    • Authors: Maartje G. Huijbers; Jaap J. Plomp, Silvère M. der Maarel, Jan J. Verschuuren
      Abstract: Immunoglobulin 4 (IgG4) is one of four human IgG subclasses and has several unique functional characteristics. It exhibits low affinity for complement and for most Fc receptors. It furthermore has generally high affinity for its antigen, with binding occurring in a monovalent fashion, as IgG4 can exchange Fab-arms with other IgG4 molecules. Because of these characteristics, IgG4 is believed to block its targets and prevent inflammation, which, depending on the setting, can have a protective or pathogenic effect. One example of IgG4 pathogenicity is muscle-specific kinase (MuSK) myasthenia gravis (MG), in which patients develop IgG4 MuSK autoantibodies, resulting in muscle weakness. As a consequence of the distinct IgG4 characteristics, the pathomechanism of MuSK MG is very different from IgG1-and IgG3-mediated autoimmune diseases, such as acetylcholine receptor MG. In recent years, new autoantibodies in a spectrum of autoimmune diseases have been discovered. Interestingly, some were found to be predominantly IgG4. These IgG4-mediated autoimmune diseases share many pathomechanistic aspects with MuSK MG, suggesting that IgG4-mediated autoimmunity forms a separate niche among the antibody-mediated disorders. In this review, we summarize the group of IgG4-mediated autoimmune diseases, discuss the role of IgG4 in MuSK MG, and highlight interesting future research questions for IgG4-mediated autoimmunity.
      PubDate: 2018-01-28T01:11:07.761815-05:
      DOI: 10.1111/nyas.13561
       
  • Pathophysiological mechanisms of autoimmunity
    • Authors: Muriel Sudres; Julien Verdier, Frédérique Truffault, Rozen Panse, Sonia Berrih-Aknin
      Abstract: Autoimmune diseases (AIDs) are chronic disorders characterized by inflammatory reactions against self-antigens that can be either systemic or organ specific. AIDs can differ in their epidemiologic features and clinical presentations, yet all share a remarkable complexity. AIDs result from an interplay of genetic and epigenetic factors with environmental components that are associated with imbalances in the immune system. Many of the pathogenic mechanisms of AIDs are also implicated in myasthenia gravis (MG), an AID in which inflammation of the thymus leads to a neuromuscular disorder. Our goal here is to highlight the similarities and differences between MG and other AIDs by reviewing the common transcriptome signatures and the development of germinal centers and by discussing some unresolved questions about autoimmune mechanisms. This review will propose hypotheses to explain the origin of regulatory T (Treg) cell defects and the causes of chronicity and specificity of AIDs.
      PubDate: 2018-01-28T01:11:01.68599-05:0
      DOI: 10.1111/nyas.13560
       
  • Comparative effectiveness clinical trials to advance treatment of
           myasthenia gravis
    • Authors: Jeffrey T. Guptill; Shruti Raja, Donald B. Sanders, Pushpa Narayanaswami
      Abstract: Myasthenia gravis (MG) presents many challenges for establishing treatment efficacy through clinical trials. Among these are the rarity and heterogeneity of the disease, spontaneous fluctuations, prolonged latency to effect for many immunosuppressive drugs, and the uncertain generalizability of results from randomized controlled trials (RCTs). Prospective observational study designs may overcome some of these limitations, but attention is required to ensure that internal validity is not compromised. Observational comparative effectiveness research (CER) utilizes data obtained during routine clinical care to evaluate the effectiveness of interventions in real-life practice conditions, thereby improving generalizability to the clinic. Compared with RCTs, observational CER studies may be less resource intensive and costly. Recent advances that have improved the feasibility of CER studies for MG are (1) the development of MG common data elements, (2) the publication of international consensus guidance for MG treatment, and (3) the development of a web-based REDCap database that can be shared and adapted to standardize data collection. This infrastructure could be used for multisite comparisons of commonly used therapies and provides longitudinal information on patient- and clinician-centered MG outcome measures. A challenge is to design studies that address the potential limitations of observational trials, such as confounding and selection and information bias.
      PubDate: 2018-01-28T01:10:56.108361-05:
      DOI: 10.1111/nyas.13582
       
  • Agrin and LRP4 antibodies as new biomarkers of myasthenia gravis
    • Authors: Min Yan; Guang-Lin Xing, Wen-Cheng Xiong, Lin Mei
      Abstract: Myasthenia gravis (MG) is a common disorder that affects the neuromuscular junction. It is caused by antibodies against acetylcholine receptor and muscle-specific tyrosine kinase; however, some MG patients do not have antibodies against either of the proteins. Recent studies have revealed antibodies against agrin and its receptor LRP4—both critical for neuromuscular junction formation and maintenance—in MG patients from various populations. Results from experimental autoimmune MG animal models indicate that anti-LRP4 antibodies are causal to MG. Clinical studies have begun to reveal the significance of the new biomarkers. With their identification, MG appears to be a complex disease entity that can be classified into different subtypes with different etiology, each with unique symptoms. Future systematic studies of large cohorts of well-diagnosed MG patients are needed to determine whether each subtype of patients would respond to different therapeutic strategies. Results should contribute to the goal of precision medicine for MG patients. Anti-agrin and anti-LRP4 antibodies are also detectable in some patients with amyotrophic lateral sclerosis or Lou Gehrig's disease; however, whether they are a cause or response to the disorder remains unclear.
      PubDate: 2018-01-28T01:10:45.5205-05:00
      DOI: 10.1111/nyas.13573
       
  • Misfolded proinsulin in the endoplasmic reticulum during development of
           beta cell failure in diabetes
    • Authors: Anoop Arunagiri; Leena Haataja, Corey N. Cunningham, Neha Shrestha, Billy Tsai, Ling Qi, Ming Liu, Peter Arvan
      Abstract: The endoplasmic reticulum (ER) is broadly distributed throughout the cytoplasm of pancreatic beta cells, and this is where all proinsulin is initially made. Healthy beta cells can synthesize 6000 proinsulin molecules per second. Ordinarily, nascent proinsulin entering the ER rapidly folds via the formation of three evolutionarily conserved disulfide bonds (B7–A7, B19–A20, and A6–A11). A modest amount of proinsulin misfolding, including both intramolecular disulfide mispairing and intermolecular disulfide-linked protein complexes, is a natural by-product of proinsulin biosynthesis, as is the case for many proteins. The steady-state level of misfolded proinsulin—a potential ER stressor—is linked to (1) production rate, (2) ER environment, (3) presence or absence of naturally occurring (mutational) defects in proinsulin, and (4) clearance of misfolded proinsulin molecules. Accumulation of misfolded proinsulin beyond a certain threshold begins to interfere with the normal intracellular transport of bystander proinsulin, leading to diminished insulin production and hyperglycemia, as well as exacerbating ER stress. This is most obvious in mutant INS gene–induced Diabetes of Youth (MIDY; an autosomal dominant disease) but also likely to occur in type 2 diabetes owing to dysregulation in proinsulin synthesis, ER folding environment, or clearance.
      PubDate: 2018-01-28T01:10:35.54424-05:0
      DOI: 10.1111/nyas.13531
       
  • Rationale for the clinical guidelines for myasthenia gravis in Japan
    • Authors: Hiroyuki Murai; Kimiaki Utsugisawa, Yuriko Nagane, Shigeaki Suzuki, Tomihiro Imai, Masakatsu Motomura
      Abstract: According to the 2014 Japanese clinical guidelines for myasthenia gravis, the most important priority in treatment is maintaining patients’ health-related quality of life. Therefore, the initial treatment goal is defined as maintaining a postintervention status of minimal manifestations or better (according to the Myasthenia Gravis Foundation of America classification) with an oral prednisolone dose of 5 mg/day or less. Every effort should be made to attain this level as rapidly as possible. To achieve this goal, the guidelines recommend minimizing the oral prednisolone dose, starting calcineurin inhibitors early in the course of treatment, using intravenous methylprednisolone infusion judiciously (often combined with plasma exchange/plasmapheresis or intravenous immunoglobulin), and effectively treating patients with an early, fast-acting treatment strategy. The early, fast-acting treatment strategy enables more frequent and earlier attainment of the initial goal than other strategies. Thymectomy is considered an option for treating nonthymomatous early-onset myasthenia gravis in patients with antiacetylcholine receptor antibodies and thymic hyperplasia in the early stages of the disease.
      PubDate: 2018-01-28T01:10:25.270665-05:
      DOI: 10.1111/nyas.13544
       
  • Western lifestyle and immunopathology of multiple sclerosis
    • Authors: Olga Matveeva; Jeroen F.J. Bogie, Jerome J.A. Hendriks, Ralf A. Linker, Aiden Haghikia, Markus Kleinewietfeld
      Abstract: There is increasing evidence for a sudden and unprecedented rise in the incidence of multiple sclerosis (MS) in Westernized countries over the past decades, emphasizing the role of environmental factors. Among many candidates, rapid changes in dietary habits seem to play a role in the pathogenesis of MS. Here, we summarize and discuss the available evidence for the role of dietary nutrients, such as table salt, fatty acids, and flavonoids, in the development and pathogenesis of MS. We also discuss new and emerging risk factors accompanying Western lifestyle, such as shift work, sleep, and circadian disruption.
      PubDate: 2018-01-27T23:20:38.066781-05:
      DOI: 10.1111/nyas.13583
       
  • Clinical trials for myasthenia gravis: a historical perspective
    • Authors: Henry J. Kaminski; Eman Alnosair, Rami M. Algahtani
      Abstract: Symposia dedicated to myasthenia gravis and related disorders date back to 1947 and serve as markers of the progress for the field. We provide a brief historical review of therapy development through the lens of the publications that arose from the close to quinquennial meetings that have been supported nearly since their inception by the Myasthenia Gravis Foundation of America and the New York Academy of Sciences. One can appreciate great advances, false starts, and dead ends that are found in all fields of medicine. We tally up the score card for MG and find points scored, but the win is not yet close.
      PubDate: 2018-01-27T23:20:29.370273-05:
      DOI: 10.1111/nyas.13545
       
  • Rituximab in myasthenia gravis: a “to be or not to be”
           inhibitor of T cell function
    • Authors: Mariapaola Marino; Emanuela Bartoccioni, Paolo Emilio Alboini, Amelia Evoli
      Abstract: In recent years, rituximab (RTX), a monoclonal antibody that binds the B lymphocyte membrane protein CD20, has been increasingly used for the treatment of autoimmune diseases, with the rationale of destroying pathogenic B lymphocytes and decreasing autoantibody formation. Surprisingly, RTX has also proven effective in predominantly T cell–mediated diseases, raising the question whether additional mechanisms may play roles in determining the therapeutic response. Here, we review the current literature on the effects of RTX in autoimmune diseases, with special emphasis on myasthenia gravis (MG). To elicit a complete and effective immune response, B and T lymphocytes cooperate in a loop in which they affect each other. Disruption of this cross talk has profound effects on the immune system. RTX is likely to affect the whole spectrum of B cell function, including antigen presentation, cytokine production, and T cell stimulation. In addition, as a small subset of T lymphocytes expresses CD20, its direct targeting by RTX may contribute to the therapeutic effect. Owing to its distinctive immune characteristics, MG proved to be a useful model to investigate the multifaceted implications of B cell depletion.
      PubDate: 2018-01-25T08:05:26.40464-05:0
      DOI: 10.1111/nyas.13562
       
  • An imbalance between regulatory T cells and T helper 17 cells in
           acetylcholine receptor–positive myasthenia gravis patients
    • Authors: Jose Adolfo Villegas; Jérôme Wassenhove, Rozen Le Panse, Sonia Berrih-Aknin, Nadine Dragin
      Abstract: A chronic autoimmune disease, myasthenia gravis (MG) is characterized in 85% of patients by antibodies directed against the acetylcholine receptor (AChR) located at the neuromuscular junction. The functional and effective balance between regulatory T cells (Treg cells) and effector T cells (Teff cells) is lost in the hyperplastic thymus of MG patients with antibodies specific for the AChR (AChR+ MG patients). The objective of this review is to describe how Treg cells and inflammatory T cells participate in this imbalance and contribute to induce a chronic inflammatory state in the MG thymus. We discuss the origins and characteristics of Treg cells and their reported dysfunctions in AChR+ MG patients. We also review the inflammatory condition observed in MG thymus, including overexpression of interleukin (IL)-1β, IL-6, and IL-23, cytokines that promote the differentiation of T helper 17 (TH17) cells and the expression of IL-17. We summarize the preclinical models used to determine the implication of expression of cytokines, such as IL-6, IL-12 (IL-23 subunit), IL-17, and interferon γ to the development of experimental autoimmune MG. Finally, we suggest that biological agents, such as humanized monoclonal antibodies that target the IL-23/TH17 pathway, should be investigated in the context of MG, as they have proven efficiency in other autoimmune diseases.
      PubDate: 2018-01-24T08:55:30.490209-05:
      DOI: 10.1111/nyas.13591
       
  • Gene regulatory mechanisms underlying sex differences in brain development
           and psychiatric disease
    • Authors: Devanand S. Manoli; Jessica Tollkuhn
      Abstract: The sexual differentiation of the mammalian nervous requires the precise coordination of the temporal and spatial regulation of gene expression in diverse cell types. Sex hormones act at multiple developmental time points to specify sex-typical differentiation during embryonic and early development and to coordinate subsequent responses to gonadal hormones later in life by establishing sex-typical patterns of epigenetic modifications across the genome. Thus, mutations associated with neuropsychiatric conditions may result in sexually dimorphic symptoms by acting on different neural substrates or chromatin landscapes in males and females. Finally, as stress hormone signaling may directly alter the molecular machinery that interacts with sex hormone receptors to regulate gene expression, the contribution of chronic stress to the pathogenesis or presentation of mental illness may be additionally different between the sexes. Here, we review the mechanisms that contribute to sexual differentiation in the mammalian nervous system and consider some of the implications of these processes for sex differences in neuropsychiatric conditions.
      PubDate: 2018-01-24T07:32:16.079274-05:
      DOI: 10.1111/nyas.13564
       
  • Quantitative genetic methods depending on the nature of the phenotypic
           trait
    • Authors: Pierre Villemereuil
      Abstract: A consequence of the assumptions of the infinitesimal model, one of the most important theoretical foundations of quantitative genetics, is that phenotypic traits are predicted to be most often normally distributed (so-called Gaussian traits). But phenotypic traits, especially those interesting for evolutionary biology, might be shaped according to very diverse distributions. Here, I show how quantitative genetics tools have been extended to account for a wider diversity of phenotypic traits using first the threshold model and then more recently using generalized linear mixed models. I explore the assumptions behind these models and how they can be used to study the genetics of non-Gaussian complex traits. I also comment on three recent methodological advances in quantitative genetics that widen our ability to study new kinds of traits: the use of “modular” hierarchical modeling (e.g., to study survival in the context of capture–recapture approaches for wild populations); the use of aster models to study a set of traits with conditional relationships (e.g., life-history traits); and, finally, the study of high-dimensional traits, such as gene expression.
      PubDate: 2018-01-24T07:32:06.920379-05:
      DOI: 10.1111/nyas.13571
       
  • Oral bisphosphonate use and age-related macular degeneration:
           retrospective cohort and nested case–control study
    • Authors: Cesar Garriga; Michael Pazianas, Samuel Hawley, Antonella Delmestri, Daniel Prieto-Alhambra, Cyrus Cooper, Andrew Judge
      Abstract: Our objective here was to determine whether oral bisphosphonate (BP) use is associated with the incidence of age-related macular degeneration (AMD). We performed a population-based study using electronic health records from UK primary care (Clinical Practice Research Datalink). A cohort of 13,974 hip fracture patients (1999–2013) was used to conduct (1) a propensity score–matched cohort analysis and (2) a nested case–control analysis. Hip fracture patients were aged ≥50 years without AMD diagnosis before hip fracture date or in the first year of follow-up. Among 6208 matched patients and during 22,142 person-years of follow-up, 57 (1.8%) and 42 (1.4%) AMD cases occurred in BP users and non-BP users, respectively. The survival analysis model did not provide significant evidence of a higher risk of AMD in BP users (subhazard ratio: 1.60; 95% confidence interval (CI): 0.95–2.72; P = 0.08), although there was a significant increased risk among BP users with high medication possession ratio (MPR) (top quartile) relative to non-BP users (odds ratio: 5.08, 95% CI: 3.11–8.30; P < 0.001, respectively). Overall, oral BP use was not associated with an increased risk of AMD in this cohort of hip fracture patients, although the risk increased significantly with higher MPR. More data are needed to confirm these findings.
      PubDate: 2018-01-24T07:31:58.075355-05:
      DOI: 10.1111/nyas.13589
       
  • Myasthenic syndromes due to defects in COL13A1 and in the N-linked
           glycosylation pathway
    • Authors: David Beeson; Judith Cossins, Pedro Rodriguez-Cruz, Susan Maxwell, Wei-Wei Liu, Jacqueline Palace
      Abstract: The congenital myasthenic syndromes (CMS) are hereditary disorders of neuromuscular transmission. The number of cases recognized, at around 1:100,000 in the United Kingdom, is increasing with improved diagnosis. The advent of next-generation sequencing has facilitated the discovery of many genes that harbor CMS-associated mutations. An emerging group of CMS, characterized by a limb-girdle pattern of muscle weakness, is caused by mutations in genes that encode proteins involved in the initial steps of the N-linked glycosylation pathway, which is surprising, since this pathway is found in all mammalian cells. However, mutations in these genes may also give rise to multisystem disorders (congenital disorders of glycosylation) or muscle disorders where the myasthenic symptoms constitute only one component within a wider phenotypic spectrum. We also report a CMS due to mutations in COL13A1, which encodes an extracellular matrix protein that is concentrated at the neuromuscular junction and highlights a role for these extracellular matrix proteins in maintaining synaptic stability that is independent of the AGRN/MuSK clustering pathway. Knowledge about the neuromuscular synapse and the different proteins involved in maintaining its structure as well as function enables us to tailor treatments to the underlying pathogenic mechanisms.
      PubDate: 2018-01-24T07:31:45.82948-05:0
      DOI: 10.1111/nyas.13576
       
  • Revisiting the genomic hypomethylation hypothesis of aging
    • Authors: Archana Unnikrishnan; Niran Hadad, Dustin R. Masser, Jordan Jackson, Willard M. Freeman, Arlan Richardson
      Abstract: The genomic hypomethylation hypothesis of aging proposes that an overall decrease in global DNA methylation occurs with age, and it has been argued that the decrease in global DNA methylation could be an important factor in aging, resulting in the relaxation of gene expression regulation and abnormal gene expression. Since it was initially observed that DNA methylation decreased with age in 1974, 16 articles have been published describing the effect of age on global DNA methylation in various tissues from rodents and humans. We critically reviewed the publications on the effect of age on DNA methylation and the expression of the enzymes involved in DNA methylation to evaluate the validity of the hypomethylation hypothesis of aging. On the basis of the current scientific literature, we conclude that a decrease in the global methylation of the genome occurs in most if not all tissues/cells as an animal ages. However, age-related changes in DNA methylation in specific regions or at specific sites in the genome occur even though the global DNA methylation does not change.
      PubDate: 2018-01-24T07:31:39.639131-05:
      DOI: 10.1111/nyas.13533
       
  • Toll-like receptors 7 and 9 in myasthenia gravis thymus: amplifiers of
           autoimmunity'
    • Authors: Paola Cavalcante; Claudia Barzago, Fulvio Baggi, Carlo Antozzi, Lorenzo Maggi, Renato Mantegazza, Pia Bernasconi
      Abstract: Pathogen infections and dysregulated Toll-like receptor (TLR)–mediated innate immune responses are suspected to play key roles in autoimmunity. Among TLRs, TLR7 and TLR9 have been implicated in several autoimmune conditions, mainly because of their ability to promote abnormal B cell activation and survival. Recently, we provided evidence of Epstein–Barr virus (EBV) persistence and reactivation in the thymus of myasthenia gravis (MG) patients, suggesting an involvement of EBV in the intrathymic pathogenesis of the disease. Considerable data highlight the existence of pathogenic crosstalk among EBV, TLR7, and TLR9: EBV elicits TLR7/9 signaling, which in turn can enhance B cell dysfunction and autoimmunity. In this article, after a brief summary of data demonstrating TLR activation in MG thymus, we provide an overview on the contribution of TLR7 and TLR9 to autoimmune diseases and discuss our recent findings indicating a pivotal role for these two receptors, along with EBV, in driving, perpetuating, and/or amplifying intrathymic B cell dysregulation and autoimmune responses in MG. Development of therapeutic approaches targeting TLR7 and TLR9 signaling could be a novel strategy for treating the chronic inflammatory autoimmune process in myasthenia gravis.
      PubDate: 2018-01-24T07:31:33.347302-05:
      DOI: 10.1111/nyas.13534
       
  • The role of autophagy in the regulation of yeast life span
    • Authors: Jessica K. Tyler; Jay E. Johnson
      Abstract: The goal of the aging field is to develop novel therapeutic interventions that extend human health span and reduce the burden of age-related disease. While organismal aging is a complex, multifactorial process, a popular theory is that cellular aging is a significant contributor to the progressive decline inherent to all multicellular organisms. To explore the molecular determinants that drive cellular aging, as well as how to retard them, researchers have utilized the highly genetically tractable budding yeast Saccharomyces cerevisiae. Indeed, every intervention known to extend both cellular and organismal health span was identified in yeast, underlining the power of this approach. Importantly, a growing body of work has implicated the process of autophagy as playing a critical role in the delay of aging. This review summarizes recent reports that have identified a role for autophagy, or autophagy factors in the extension of yeast life span. These studies demonstrate (1) that yeast remains an invaluable tool for the identification and characterization of conserved mechanisms that promote cellular longevity and are likely to be relevant to humans, and (2) that the process of autophagy has been implicated in nearly all known longevity-promoting manipulations and thus represents an ideal target for interventions aimed at improving human health span.
      PubDate: 2018-01-24T07:31:17.419265-05:
      DOI: 10.1111/nyas.13549
       
  • Estimates of global and regional prevalence of neural tube defects for
           2015: a systematic analysis
    • Authors: Hannah Blencowe; Vijaya Kancherla, Sowmiya Moorthie, Matthew W. Darlison, Bernadette Modell
      Abstract: Neural tube defects (NTDs) are associated with substantial mortality, morbidity, disability, and psychological and economic costs. Many are preventable with folic acid, and access to appropriate services for those affected can improve survival and quality of life. We used a compartmental model to estimate global and regional birth prevalence of NTDs (live births, stillbirths, and elective terminations of pregnancy) and subsequent under-5 mortality. Data were identified through web-based reviews of birth defect registry databases and systematic literature reviews. Meta-analyses were undertaken where appropriate. For 2015, our model estimated 260,100 (uncertainty interval (UI): 213,800–322,000) NTD-affected birth outcomes worldwide (prevalence 18.6 (15.3–23.0)/10,000 live births). Approximately 50% of cases were elective terminations of pregnancy for fetal anomalies (UI: 59,300 (47,900–74,500)) or stillbirths (57,800 (UI: 35,000–88,600)). Of NTD-affected live births, 117,900 (∼75%) (UI: 105,500–186,600) resulted in under-5 deaths. Our systematic review showed a paucity of high-quality data in the regions of the world with the highest burden. Despite knowledge about prevention, NTDs remain highly prevalent worldwide. Lack of surveillance and incomplete ascertainment of affected pregnancies make NTDs invisible to policy makers. Improved surveillance of all adverse outcomes is needed to improve the robustness of total NTD prevalence estimation, evaluate effectiveness of prevention through folic acid fortification, and improve outcomes through care and rehabilitation.
      PubDate: 2018-01-24T07:31:10.596014-05:
      DOI: 10.1111/nyas.13548
       
  • Genetic constraints on adaptation: a theoretical primer for the genomics
           era
    • Authors: Tim Connallon; Matthew D. Hall
      Abstract: Genetic constraints are features of inheritance systems that slow or prohibit adaptation. Several population genetic mechanisms of constraint have received sustained attention within the field since they were first articulated in the early 20th century. This attention is now reflected in a rich, and still growing, theoretical literature on the genetic limits to adaptive change. In turn, empirical research on constraints has seen a rapid expansion over the last two decades in response to changing interests of evolutionary biologists, along with new technologies, expanding data sets, and creative analytical approaches that blend mathematical modeling with genomics. Indeed, one of the most notable and exciting features of recent progress in genetic constraints is the close connection between theoretical and empirical research. In this review, we discuss five major population genetic contexts of genetic constraint: genetic dominance, pleiotropy, fitness trade-offs between types of individuals of a population, sign epistasis, and genetic linkage between loci. For each, we outline historical antecedents of the theory, specific contexts where constraints manifest, and their quantitative consequences for adaptation. From each of these theoretical foundations, we discuss recent empirical approaches for identifying and characterizing genetic constraints, each grounded and motivated by this theory, and outline promising areas for future work.
      PubDate: 2018-01-24T07:30:59.473881-05:
      DOI: 10.1111/nyas.13536
       
  • The investment case for folic acid fortification in developing countries
    • Authors: John Hoddinott
      Abstract: There is compelling evidence that neural tube defects can be prevented through mandatory folic acid fortification. Why, then, is an investment case needed' At the core of the answer to this question is the notion that governments and individuals have limited resources for which there are many competing claims. An investment case compares the costs and benefits of folic acid fortification relative to alternative life-saving investments and informs estimates of the financing required for implementation. Our best estimate is that the cost per death averted through mandatory folic acid fortification is $957 and the cost per disability-adjusted life year is $14.90. Both compare favorably to recommended life-saving interventions, such as the rotavirus vaccine and insecticide-treated bed nets. Thus, there is a strong economic argument for mandatory folic acid fortification. Further improvements to these estimates will require better data on the costs of implementing fortification and on the costs of improving compliance where regulations are already in place.
      PubDate: 2018-01-24T07:30:29.603497-05:
      DOI: 10.1111/nyas.13527
       
  • Lessons from animal nutritionists: dietary amino acid requirement studies
           and considerations for healthy aging studies
    • Authors: Anna K. Shoveller; Leslie M. McKnight, Katharine M. Wood, John P. Cant
      Abstract: Dietary restriction (DR) increases median life span and protects against age-related disease. Improved longevity can be achieved by restriction of dietary energy, protein, or amino acids (AAs), such as methionine (Met). Met requirements have been defined using methodologies that measure the dose response to Met when all other dietary variables are held constant and with outcomes focused on protein turnover. Here, we cover protein and sulfur AA requirements and discuss the terms “deficient,” “optimal,” and “excess” and how these need to be considered. We additionally discuss the effect of methyl-donating compounds on sulfur AA metabolism and outcomes. We will discuss how the mechanistic target of rapamycin complex 1 (mTORC1) signaling network regulates protein turnover, lipogenesis and cell growth, proliferation, differentiation, and metabolism in response to hormones, AAs, and cellular energy status. Inhibition of mTORC1 signaling with rapamycin or genetic mutation increases median life span in model organisms, and mTORC1 inhibition may be responsible for some of the life span–extending effects of DR. Finally, we discuss how the sulfur AAs may regulate aspects of reactive oxygen species (ROS) mitigation. Overall, we suggest that approaches evaluating AA intake need to consider whole-body protein synthesis and measures related to tissue-specific and whole-body metabolism that have been associated with longevity.
      PubDate: 2018-01-24T07:30:25.694635-05:
      DOI: 10.1111/nyas.13546
       
  • Understanding the determinants of hemoglobin and iron status:
           adolescent–adult women comparisons in SANHANES-1
    • Authors: Zandile J. Mchiza; Whadi-ah Parker, Ronel Sewpaul, Nophiwe Job, Lumbwe Chola, Chipo Mutyambizi, Moses Sithole, Andrew Stokes, Demetre Labadarios
      Abstract: The study compared hemoglobin (Hb) and serum ferritin levels between adolescent and adult women with different body mass indices, dietary intake, and sociodemography. A secondary analysis of data for 3177 South African women ⩾15 years of age who participated in the SANHANES-1 study was undertaken. Abnormal Hb (≤12 g/dL) and serum ferritin (
      PubDate: 2018-01-23T00:50:38.408-05:00
      DOI: 10.1111/nyas.13528
       
  • Understanding the determinants of adolescent nutrition in Bangladesh
    • Authors: Jef L. Leroy; Marie Ruel, Celeste Sununtnasuk, Akhter Ahmed
      Abstract: Evidence on the nutritional status and diets of adolescents in low- and middle-income countries is scant. We characterized the nutritional status (body mass index Z-scores (BMIZs)) and nutrient intakes of adolescent boys and girls in rural areas in Bangladesh using the 2011–2012 BIHS data, used regression models to identify the socioeconomic determinants of these outcomes, and household fixed effects models to assess whether the gap between boys and girls changed with women's education and empowerment and household wealth. The adolescents’ BMIZ and adequacy of their nutrient intakes were suboptimal. Gender differences varied by outcome and were not systematically in favor of boys. Household wealth was associated with higher BMIZ and probability of adequate energy and micronutrient intakes. Women's education and empowerment were mostly not associated with the study outcomes and did not modify gender differences. There is an urgent need to invest in improving the diets of adolescent boys and girls in Bangladesh. The limited role of women's education and empowerment in improving adolescent nutrition suggests that resources may be too constrained. It may also reflect deeply rooted beliefs about adolescent nutrition and differences between boys and girls that would need to be addressed to improve their nutrition.
      PubDate: 2018-01-22T08:46:18.624812-05:
      DOI: 10.1111/nyas.13530
       
  • The unfolding landscape of the congenital myasthenic syndromes
    • Authors: Andrew G. Engel; Xin-Ming Shen, Duygu Selcen
      Abstract: Congenital myasthenic syndromes (CMS) are heterogeneous disorders in which the safety margin of neuromuscular transmission is impaired by one or more specific mechanisms. Since the advent of next-generation sequencing methods, the discovery of novel CMS targets and phenotypes has proceeded at an accelerated rate. Here, we review the current classification of CMS and describe our findings in five of these targets identified and investigated in our laboratory in the past 5 years. Defects in LRP4 hinder synaptic development and maintenance; the defects in PREPL are predicted to diminish filling of the synaptic vesicle with acetylcholine; and defects in SNAP25, Munc13-1, and synaptotbrevin-1 impede synaptic vesicle exocytosis.
      PubDate: 2018-01-21T05:19:29.959063-05:
      DOI: 10.1111/nyas.13539
       
  • Passive transfer models of myasthenia gravis with muscle-specific kinase
           antibodies
    • Authors: Jan J.G.M. Verschuuren; Jaap J. Plomp, Steve J. Burden, Wei Zhang, Yvonne E. Fillié-Grijpma, Inge E. Stienstra-van Es, Erik H. Niks, Mario Losen, Silvère M. der Maarel, Maartje G. Huijbers
      Abstract: Myasthenia gravis (MG) with antibodies to muscle-specific kinase (MuSK) is characterized by fluctuating fatigable weakness. In MuSK MG, involvement of bulbar muscles, neck, and shoulder and respiratory weakness are more prominent than in acetylcholine receptor (AChR) MG. MuSK autoantibodies are mainly of the IgG4 subclass, and as such are unable to activate complement, have low affinity for Fc receptors, and are functionally monovalent. Therefore, the pathogenicity of IgG4 MuSK autoantibodies was initially questioned. A broad collection of in vitro active immunization and passive transfer models has been developed that have shed light on the pathogenicity of MuSK autoantibodies. Passive transfer studies with purified IgG4 from MuSK MG patients confirmed that IgG4 is sufficient to reproduce clear clinical, electrophysiological, and histological signs of myasthenia. In vitro experiments revealed that MuSK IgG4 autoantibodies preferably bind the first Ig-like domain of MuSK, correlate with disease severity, and interfere with the association between MuSK and low-density lipoprotein receptor–related protein 4 and collagen Q. Some patients have additional IgG1 MuSK autoantibodies, but their role in the disease is unclear. Altogether, this provides a rationale for epitope-specific or IgG4-specific treatment strategies for MuSK MG and emphasizes the importance of the development of different experimental models.
      PubDate: 2018-01-21T05:19:11.543002-05:
      DOI: 10.1111/nyas.13543
       
  • Acetylcholine receptor antibody–mediated animal models of myasthenia
           gravis and the role of complement
    • Authors: Linda L. Kusner; Manjistha Sengupta, Henry J. Kaminski
      Abstract: Because of the failure of many promising therapeutics identified in preclinical evaluation, funding sources have established guidelines for increased rigor in animal evaluations. The myasthenia gravis (MG) community of scientists has developed guidelines for preclinical assessment for potential MG treatments. Here, we provide a focused summary of these recommendations and the role of complement in disease development in experimental models of MG.
      PubDate: 2018-01-21T05:19:05.728337-05:
      DOI: 10.1111/nyas.13555
       
  • Gut microbiota and probiotics: novel immune system modulators in
           myasthenia gravis'
    • Authors: Elena Rinaldi; Alessandra Consonni, Elena Guidesi, Marina Elli, Renato Mantegazza, Fulvio Baggi
      Abstract: Gut microorganisms (microbiota) live in symbiosis with the host and influence human nutrition, metabolism, physiology, and immune development and function. The microbiota prevents pathogen infection to the host, and in turn the host provides a niche for survival. The alteration of gut bacteria composition (dysbiosis) could contribute to the development of immune-mediated diseases by influencing the immune system activation and driving the pro- and anti-inflammatory responses in order to promote or counteract immune reactions. Probiotics are nonpathogenic microorganisms able to interact with the gut microbiota and provide health benefits; their use has recently been exploited to dampen immunological response in several experimental models of autoimmune diseases. Here, we focus on the relationships among commensal bacteria, probiotics, and the gut, describing the main interactions occurring with the immune system and recent data supporting the clinical efficacy of probiotic administration in rheumatoid arthritis, multiple sclerosis, and myasthenia gravis (MG) animal models. The encouraging results suggest that selected strains of probiotics should be evaluated in clinical trials as adjuvant therapy to restore the disrupted tolerance in myasthenia gravis.
      PubDate: 2018-01-17T01:15:31.773349-05:
      DOI: 10.1111/nyas.13567
       
  • Issue Information
    • Pages: 1 - 3
      PubDate: 2018-02-05T10:58:44.492046-05:
      DOI: 10.1111/nyas.13476
       
  • Congenital myasthenic syndromes with acetylcholinesterase deficiency, the
           pathophysiological mechanisms
    • Authors: Claire Legay
      Pages: 104 - 110
      Abstract: The neuromuscular junction (NMJ) is a cholinergic synapse in vertebrates. This synapse connects motoneurons to muscles and is responsible for muscle contraction, a physiological process that is essential for survival. A key factor for the normal functioning of this synapse is the regulation of acetylcholine (ACh) levels in the synaptic cleft. This is ensured by acetylcholinesterase (AChE), which degrades ACh. A number of mutations in synaptic genes expressed in motoneurons or muscle cells have been identified and are causative for a class of neuromuscular diseases called congenital myasthenic syndromes (CMSs). One of these CMSs is due to deficiency in AChE, which is absent or diffuse in the synaptic cleft. Here, I focus on the origins of the syndrome. The role of ColQ, a collagen that anchors AChE in the synaptic cleft, is discussed in this context. Studies performed on patient biopsies, transgenic mice, and muscle cultures have provided a more comprehensive view of the connectome at the NMJ that should be useful for understanding the differences in the symptoms observed in specific CMSs due to mutated proteins in the synaptic cleft.
      PubDate: 2018-02-05T10:58:45.968473-05:
      DOI: 10.1111/nyas.13595
       
  • Efficient long-term depletion of CD20+ B cells by rituximab does not
           affect gut-resident plasma cells
    • Authors: Mathieu Uzzan; Huaibin M. Ko, Adam K. Rosenstein, Kamron Pourmand, Jean-Frederic Colombel, Saurabh Mehandru
      Abstract: The vast majority of antibody-producing B cells are located within the gastrointestinal tract and are key players in maintaining homeostasis. The failure of rituximab, a potent B cell–depleting agent, to ameliorate ulcerative colitis in a single clinical trial has dampened enthusiasm to study B cells in patients with inflammatory bowel disease (IBD). However, several lines of evidence suggest that intestinal B cells may be affected in IBD. Additionally, the pathophysiological mechanisms underlying rituximab's lack of efficacy in IBD remain unclear. Here, on the basis of detailed immunophenotyping of a patient who underwent a colonoscopy 6 months after the end of rituximab-based therapy, we observed that rituximab did not deplete colon-resident plasma cells (PCs) while ablating all CD20+ B cells in tissues and in the circulation. On the basis of these observations, we propose that one factor underlying the lack of efficacy of rituximab relates to the fact that it does not affect the entire B cell compartment in tissues, sparing the intestinal-resident PCs while effectively depleting CD20+ B cell populations. Thus, we contend that, despite the results of the Rituximab study, there is a need for more intensive B cell–oriented research in inflammatory disorders, including IBD.
      PubDate: 2017-12-31T22:26:01.27768-05:0
      DOI: 10.1111/nyas.13577
       
  • CYP21A2 genetic profile in 14 Egyptian children with suspected congenital
           adrenal hyperplasia: a diagnostic challenge
    • Authors: Fatma Elmougy; Sahar Sharaf, Mona Hafez, Ahmed Khattab, Hazem Abou-Yousef, Marwa Elsharkawy, Heba Baz, Sherif Ekladious, Balsam Sherif, Noha Musa, Yasmin Elshiwy, Alaa Afif, Mona Abdullatif, Ghada Thabet, Normeen Rady, Amany Ibrahim, Hend Soliman
      Abstract: CYP21A2 genotyping remains an important element in the diagnosis and management of congenital adrenal hyperplasia, and establishing accurate genotype–phenotype correlations has facillitated adequate genetic counseling and prenatal management for at-risk families. Despite extensive efforts to establish a clear genotype–phenotype correlation, some discordance remains. Establishing a diagnosis of congenital adrenal hyperplasia on the basis of biochemical and clinical data is occasionally challenging, and the identification of CYP21A2 mutations may help confirm the diagnosis. We review the diagnostic challenges despite an extensive genetic evaluation for 14 patients with a suspected clinical and biochemical diagnosis of congenital adrenal hyperplasia. Other diagnostic entities should be considered in the absence of convincing genetic data.
      PubDate: 2017-12-21T04:13:07.504032-05:
      DOI: 10.1111/nyas.13540
       
  • Evolution on the bright side of life: microorganisms and the evolution of
           mutualism
    • Authors: Kristina Linnea Hillesland
      Abstract: Mutualistic interactions, where two interacting species have a net beneficial effect on each other's fitness, play a crucial role in the survival and evolution of many species. Despite substantial empirical and theoretical work in past decades, the impact of these interactions on natural selection is not fully understood. In addition, mutualisms between microorganisms have been largely ignored, even though they are ecologically important and can be used as tools to bridge the gap between theory and empirical work. Here, I describe two problems with our current understanding of natural selection in mutualism and highlight the properties of microbial mutualisms that could help solve them. One problem is that bias and methodological problems have limited our understanding of the variety of mechanisms by which species may adapt to mutualism. Another problem is that it is rare for experiments testing coevolution in mutualism to address whether each species has adapted to evolutionary changes in its partner. These problems can be addressed with genome resequencing and time-shift experiments, techniques that are easier to perform in microorganisms. In addition, microbial mutualisms may inspire novel insights and hypotheses about natural selection in mutualism.
      PubDate: 2017-11-30T05:06:15.067569-05:
      DOI: 10.1111/nyas.13515
       
  • Safety of folic acid
    • Authors: Martha S. Field; Patrick J. Stover
      Abstract: There is a large body of literature demonstrating the efficacy of maternal folic acid intake in preventing birth defects, as well as investigations into potential adverse consequences of consuming folic acid above the upper intake level (UL). Recently, two authoritative bodies convened expert panels to assess risks from high intakes of folic acid: the U.S. National Toxicology Program and the UK Scientific Advisory Committee on Nutrition. Overall, the totality of the evidence examined by these panels, as well as studies published since the release of their reports, have not established risks for adverse consequences resulting from existing mandatory folic acid fortification programs that have been implemented in many countries. Current folic acid fortification programs have been shown to support public health in populations, and the exposure levels are informed by and adherent to the precautionary principle. Additional research is needed to assess the health effects of folic acid supplement use when the current upper limit for folic acid is exceeded.
      PubDate: 2017-11-20T10:20:49.927508-05:
      DOI: 10.1111/nyas.13499
       
  • Folate status in women of reproductive age as basis of neural tube defect
           risk assessment
    • Authors: Lynn B. Bailey; Dorothy B. Hausman
      Abstract: Reliable folate status data for women of reproductive age (WRA) to assess global risk for neural tube defects (NTDs) are needed. We focus on a recent recommendation by the World Health Organization that a specific “optimal” red blood cell (RBC) folate concentration be used as the sole indicator of NTD risk within a population and discuss how to best apply this guidance to reach the goal of assessing NTD risk globally. We also emphasize the importance of using the microbiologic assay (MBA) as the most reliable assay for obtaining comparable results for RBC folate concentration across time and countries, the need for harmonization of the MBA through use of consistent key reagents and procedures within laboratories, and the requirement to apply assay-matched cutoffs for folate deficiency and insufficiency. To estimate NTD risk globally, the ideal scenario would be to have country-specific population-based surveys of RBC folate in WRA determined utilizing a harmonized MBA, as was done in recent studies in Guatemala and Belize. We conclude with guidance on next steps to best navigate the road map toward the goal of generating reliable folate status data on which to assess NTD risk in WRA in low- and middle-income countries.
      PubDate: 2017-11-15T03:25:29.46023-05:0
      DOI: 10.1111/nyas.13511
       
  • The impact of sociodemography, diet, and body size on serum retinol in
           women 16–35 years of age: SANHANES-1
    • Authors: Whadi-ah Parker; Zandile J. Mchiza, Ronel Sewpaul, Nophiwe Job, Lumbwe Chola, Moses Sithole, Demetre Labadarios
      Abstract: To determine the current vitamin A status of a nationally representative sample of women aged 16–35 years, compare it with previous national data, and determine the impact of sociodemography, diet, and body size on vitamin A status, we performed secondary analysis of data on South African women who participated in the first South African National Health and Nutrition Examination Survey (SANHANES-1). Vitamin A status was assessed by serum retinol, and the findings are reported as means and prevalences with corresponding 95% confidence intervals. Overall, the age-standardized vitamin A deficiency prevalence was 11.7%, a decrease from previous national data, but serum retinol levels remained lower than in other developing countries. Overall, unweighted, multilevel, multivariate logistic regression showed that vitamin A deficiency was influenced by race only (odds ratio (OR) = 1.89, P = 0.031), while weighted multiple logistic regression for 16- to 18-year-olds showed that vitamin A deficiency was influenced by locality (OR = 9.83, P = 0.005) and household income (intermediate (OR = 0.2, P = 0.022) and upper (OR = 0.25, P = 0.049)). Despite the decreased prevalence, vitamin A deficiency remains a moderate public health problem in the country. Opportunities for targeted interventions have been identified.
      PubDate: 2017-11-10T07:46:54.417715-05:
      DOI: 10.1111/nyas.13504
       
  • Adolescent mothers’ anthropometrics and grandmothers’ schooling
           predict infant anthropometrics in Ethiopia, India, Peru, and Vietnam
    • Authors: Whitney Schott; Elisabetta Aurino, Mary E. Penny, Jere R. Behrman
      Abstract: We investigated intergenerational associations of adolescent mothers’ and grandmothers’ anthropometrics and schooling with adolescent mothers’ offspring's anthropometrics in Ethiopia, India, Peru, and Vietnam. We examined birthweight (n = 283), birthweight Z-score (BWZ), conditional growth in weight-for-age Z-score (cWAZ, residuals from a regression of WAZ at last survey round on BWZ, sex, and age), and height-for-age Z-score (HAZ) of children born to older cohort adolescent girls in the Young Lives study. Our key independent variables were adolescent mothers’ body size: HAZ and body-mass-index-for-age Z-score (BMIZ) at age 8, conditional HAZ (cHAZ, residuals from a regression of HAZ at the end of a growth period on prior HAZ, age, and sex), conditional BMIZ growth (cBMIZ, calculated analogously), and grandmaternal BMIZ, HAZ, and schooling. We adjusted for child, maternal, and household characteristics. Adolescent mothers’ cHAZ (ages 8–15) predicted birthweight (β = 130 g, 95% confidence interval (CI) 31–228), BWZ (β = 0.31, CI 0.09–0.53), and cWAZ (β = 0.28, CI 0.04–0.51). Adolescent mothers’ BMIZ at age 8 predicted birthweight (β = 79 g, CI 16–43) and BWZ (β = 0.22, CI 0.08–0.36). Adolescent mothers’ cBMIZ (ages 12–15) predicted child cWAZ and HAZ. Grandmothers’ schooling predicted grandchild birthweight (β = 22 g, CI 1–44) and BWZ (β = 0.05, CI 0.01–0.10).
      PubDate: 2017-10-24T10:25:08.121351-05:
      DOI: 10.1111/nyas.13455
       
  • Adolescent pregnancy and nutrition: a subgroup analysis from the
           Mamachiponde study in Malawi
    • Authors: Alyssa Friebert; Meghan Callaghan-Gillespie, Peggy C. Papathakis, Mark J. Manary
      Abstract: Young age at childbearing (≤19 years) is common and associated with poor birth outcomes. A trial among Malawian pregnant women with moderate malnutrition was used to determine outcomes of young adolescents (≤18 years), older adolescents (18–20 years), and adults (>20 years). Women received one of three supplementary foods that provided ∼900 kcal/day and 33–36 g protein/day and returned every 2 weeks. Newborn/maternal measurements were taken at delivery and after 6 and 12 weeks. Upon enrollment, adolescents had greater body mass index than adults (19.9 ± 1.3 versus 19.5 ± 1.4 kg/m2, P < 0.001). Young adolescents received more rations of food and enrolled and delivered with a lower fundal height than adults (21.7 ± 5.2 versus 23.0 ± 5.6, P = 0.00 enrollment; 30.2 ± 3.1 versus 31.0 ± 2.8, P < 0.001 delivery). Among newborns, length for age was lowest in young adolescents, greater in older adolescents, and greatest in adults (Z-scores –1.7 ± 1.2, –1.4 ± 1.2, and –1.1 ± 1.1, respectively; P < 0.001). These differences persisted in length for age at 6 and 12 weeks of age for infants. Adolescents enrolled earlier in pregnancy and appeared more nutritionally adequate than adults; adolescent outcomes were inferior to those of adults, suggesting that they were subject to more physiologic stressors and/or different nutritional needs.
      PubDate: 2017-10-16T22:55:30.528897-05:
      DOI: 10.1111/nyas.13465
       
  • Host–microbiota interplay in mediating immune disorders
    • Authors: Krysta M. Felix; Shekha Tahsin, Hsin-Jung Joyce Wu
      Abstract: To maintain health, the immune system must maintain a delicate balance between eliminating invading pathogens and avoiding immune disorders such as autoimmunity and allergies. The gut microbiota provide essential health benefits to the host, particularly by regulating immune homeostasis. Dysbiosis, an alteration and imbalance of the gut microbiota, is associated with the development of several autoimmune diseases in both mice and humans. In this review, we discuss recent advances in understanding how certain factors, such as age and gender, affect the gut microbiota, which in turn can influence the development of autoimmune diseases. The age factor in microbiota-dependent immune disorders indicates a window of opportunity for future diagnostic and therapeutic approaches. We also discuss unique commensal bacteria with strong immunomodulatory activity. Finally, we provide an overview of the potential molecular mechanisms whereby gut microbiota induce autoimmunity, as well as the evidence that gut microbiota trigger extraintestinal diseases by inducing the migration of gut-derived immune cells. Elucidating the interaction of gut microbiota and the host immune system will help us understand the pathogenesis of immune disorders, and provide us with new foundations to develop novel immuno- or microbe-targeted therapies.
      PubDate: 2017-10-06T07:00:42.101307-05:
      DOI: 10.1111/nyas.13508
       
  • Evolutionary ecology of telomeres: a review
    • Authors: Mats Olsson; Erik Wapstra, Christopher R. Friesen
      Abstract: Telomere-induced selection could take place if telomere-associated disease risk shortens reproductive life span and differently reduces relative fitness among individuals. Some of these diseases first appear before reproductive senescence and could thus influence ongoing selection. We ask whether we can estimate the components of the breeder's equation for telomeres, in which the response to selection (R, by definition “evolution”) is the product of ongoing selection (S) and heritability (h2). However, telomere inheritance is a conundrum: in quantitative genetics, traits can usually be allocated to categories with relatively high or low heritability, depending on their association with relative fitness. Telomere traits, however, show wide variation in heritability from zero to one, across taxa, gender, ethnicity, age, and disease status. In spite of this, there is divergence in telomere length among populations, supporting past and ongoing telomere evolution. Rates of telomere attrition and elongation vary among taxa with some, but not complete, taxonomic coherence. For example, telomerase is commonly referred to as “restricted to the germ line in mammals,” but inbred mice and beavers have telomerase upregulation in somatic tissue, as do many ectotherms. These observations provoke a simplistic understanding of telomere evolutionary biology—clearly much is yet to be discovered.
      PubDate: 2017-10-06T04:00:58.125129-05:
      DOI: 10.1111/nyas.13443
       
  • Birth weight and prepubertal body size predict menarcheal age in India,
           Peru, and Vietnam
    • Authors: Elisabetta Aurino; Whitney Schott, Mary E. Penny, Jere R. Behrman
      Abstract: Evidence on the associations of birth weight and prepubertal nutritional status with menarcheal age for low- and middle-income countries is limited. We investigated these relationships using the Young Lives younger cohort for 2001 Indian, Peruvian, and Vietnamese girls born in 2001–2002. Girls were followed at approximately ages 1, 5, 8, and 12 years. Weibull survival models estimated hazards of earlier menarche on the basis of birth weight Z-scores (BWZ), and age-8 BMI-for-age Z-scores (BMIZ) and height-for-age Z-scores (HAZ). Estimates controlled for potential individual-, mother-, and household-level confounders and for changes in anthropometry between 1 and 8 years. In adjusted models, BWZ predicted later age at menarche (hazard ratio (HR) = 0.90, 95% CI: 0.83–0.97). Conversely, HAZ (HR = 1.66, 95% CI 1.5–1.83) and BMIZ at 8 years (HR = 1.28, 95% CI: 1.18–1.38) predicted earlier menarche. Changes in HAZ and BMIZ between 1 and 8 years were not associated with earlier menarche. Associations were consistent across countries, though with variation in estimated magnitudes. Maternal height and age were associated with later menarche. This evidence points to consistently robust and opposite associations of birth weight versus prepubertal attained height and body mass index with menarcheal age in three diverse settings with regard to nutrition, ethnicity, and socioeconomic status.
      PubDate: 2017-09-28T01:50:24.257943-05:
      DOI: 10.1111/nyas.13445
       
  • Recent developments in understanding the role of the gut microbiota in
           brain health and disease
    • Authors: Eoin Sherwin; Timothy G. Dinan, John F. Cryan
      Abstract: There is a growing appreciation of the role of the gut microbiota in all aspects of health and disease, including brain health. Indeed, roles for the bacterial commensals in various psychiatric and neurological conditions, such as depression, autism, stroke, Parkinson's disease, and Alzheimer's disease, are emerging. Microbiota dysregulation has been documented in all of these conditions or in animal models thereof. Moreover, depletion or modulation of the gut microbiota can affect the severity of the central pathology or behavioral deficits observed in a variety of brain disorders. However, the mechanisms underlying such effects are only slowly being unraveled. Additionally, recent preclinical and clinical evidence suggest that targeting the microbiota through prebiotic, probiotic, or dietary interventions may be an effective “psychobiotic” strategy for treating symptoms in mood, neurodevelopmental disorders, and neurodegenerative diseases.
      PubDate: 2017-08-02T17:26:36.916386-05:
      DOI: 10.1111/nyas.13416
       
  • Mesenchymal stem cells and their immunosuppressive role in transplantation
           tolerance
    • Authors: Pamina Contreras-Kallens; Claudia Terraza, Karina Oyarce, Tania Gajardo, Mauricio Campos-Mora, María Teresa Barroilhet, Carla Álvarez, Ricardo Fuentes, Fernando Figueroa, Maroun Khoury, Karina Pino-Lagos
      Abstract: Since they were first described, mesenchymal stem cells (MSCs) have been shown to have important effector mechanisms and the potential for use in cell therapy. A great deal of research has been focused on unveiling how MSCs contribute to anti-inflammatory responses, including describing several cell populations involved and identifying soluble and other effector molecules. In this review, we discuss some of the contemporary evidence for use of MSCs in the field of immune tolerance, with a special emphasis on transplantation. Although considerable effort has been devoted to understanding the biological function of MSCs, additional resources are required to clarify the mechanisms of their induction of immune tolerance, which will undoubtedly lead to improved clinical outcomes for MSC-based therapies.
      PubDate: 2017-07-12T12:55:29.241734-05:
      DOI: 10.1111/nyas.13364
       
  • Genomics of antibiotic-resistance prediction in Pseudomonas aeruginosa
    • Authors: Julie Jeukens; Luca Freschi, Irena Kukavica-Ibrulj, Jean-Guillaume Emond-Rheault, Nicholas P. Tucker, Roger C. Levesque
      Abstract: Antibiotic resistance is a worldwide health issue spreading quickly among human and animal pathogens, as well as environmental bacteria. Misuse of antibiotics has an impact on the selection of resistant bacteria, thus contributing to an increase in the occurrence of resistant genotypes that emerge via spontaneous mutation or are acquired by horizontal gene transfer. There is a specific and urgent need not only to detect antimicrobial resistance but also to predict antibiotic resistance in silico. We now have the capability to sequence hundreds of bacterial genomes per week, including assembly and annotation. Novel and forthcoming bioinformatics tools can predict the resistome and the mobilome with a level of sophistication not previously possible. Coupled with bacterial strain collections and databases containing strain metadata, prediction of antibiotic resistance and the potential for virulence are moving rapidly toward a novel approach in molecular epidemiology. Here, we present a model system in antibiotic-resistance prediction, along with its promises and limitations. As it is commonly multidrug resistant, Pseudomonas aeruginosa causes infections that are often difficult to eradicate. We review novel approaches for genotype prediction of antibiotic resistance. We discuss the generation of microbial sequence data for real-time patient management and the prediction of antimicrobial resistance.
      PubDate: 2017-06-02T08:00:46.444097-05:
      DOI: 10.1111/nyas.13358
       
 
 
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