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  Subjects -> MEDICAL SCIENCES (Total: 7249 journals)
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    - SPORTS MEDICINE (68 journals)
    - SURGERY (347 journals)
    - UROLOGY, NEPHROLOGY AND ANDROLOGY (132 journals)

MEDICAL SCIENCES (1802 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: 39)
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: 6)
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: 5)
Advances in Medicine     Open Access   (Followers: 2)
Advances in Microbial Physiology     Full-text available via subscription   (Followers: 4)
Advances in Molecular Oncology     Open Access   (Followers: 1)
Advances in Molecular Toxicology     Full-text available via subscription   (Followers: 8)
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: 5)
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: 11)
American Journal of Biomedical Research     Open Access   (Followers: 2)
American Journal of Biomedicine     Full-text available via subscription   (Followers: 6)
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: 1)
American Journal of Medicine     Hybrid Journal   (Followers: 46)
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: 9)
American Medical Journal     Open Access   (Followers: 4)
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: 3)
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: 8)
Annals of Family Medicine     Open Access   (Followers: 13)
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: 5)
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: 18)
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 Medical Informatics     Open Access   (Followers: 11)
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 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)
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  
Bangladesh Medical Research Council Bulletin     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  
Biology of Sex Differences     Open Access   (Followers: 3)

        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  [1589 journals]
  • 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
       
  • Mouse models to evaluate the role of estrogen receptor α in skeletal
           maintenance and adaptation
    • Authors: Amanda M. Rooney; Marjolein C.H. der Meulen
      Abstract: Estrogen signaling and mechanical loading have individual and combined effects on skeletal maintenance and adaptation. Previous work investigating estrogen signaling both in vitro and in vivo using global estrogen receptor α (ERα) gene knockout mouse models has provided information regarding the role of ERα in regulating bone mass and adaptation to mechanical stimulation. However, these models have inherent limitations that confound interpretation of the data. Therefore, recent studies have focused on mice with targeted deletion of ERα from specific bone cells and their precursors. Cell stage, tissue type, and mouse sex all influence the effects of ERα gene deletion. Lack of ERα in osteoblast progenitor and precursor cells generally affects the periosteum of female and male mice. The absence of ERα in differentiated osteoblasts, osteocytes, and osteoclasts in mice generally resulted in reduced cancellous bone mass, with differing reports of the effect by animal sex and greater deficiencies in bone mass typically occurring in cancellous bone in female mice. Limited data exist for the role of bone cell–specific ERα in skeletal adaptation in vivo. Cell-specific ERα gene knockout mice provide an excellent platform for investigating the function of ERα in regulating skeletal phenotype and response to mechanical loading by sex and age.
      PubDate: 2017-11-17T06:55:27.257869-05:
      DOI: 10.1111/nyas.13523
       
  • 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
       
  • Lambert–Eaton myasthenic syndrome: mouse passive-transfer model
           illuminates disease pathology and facilitates testing therapeutic leads
    • Authors: Stephen D. Meriney; Tyler B. Tarr, Kristine S. Ojala, Man Wu, Yizhi Li, David Lacomis, Adolfo Garcia-Ocaña, Mary Liang, Guillermo Valdomir, Peter Wipf
      Abstract: Lambert–Eaton myasthenic syndrome (LEMS) is an autoimmune disorder caused by antibodies directed against the voltage-gated calcium channels that provide the calcium ion flux that triggers acetylcholine release at the neuromuscular junction. To study the pathophysiology of LEMS and test candidate therapeutic strategies, a passive-transfer animal model has been developed in mice, which can be created by daily intraperitoneal injections of LEMS patient serum or IgG into mice for 2–4 weeks. Results from studies of the mouse neuromuscular junction have revealed that each synapse has hundreds of transmitter release sites but that the probability for release at each one is likely to be low. LEMS further reduces this low probability such that transmission is no longer effective at triggering a muscle contraction. The LEMS-mediated attack reduces the number of presynaptic calcium channels, disorganizes transmitter release sites, and results in the homeostatic upregulation of other calcium channel types. Symptomatic treatment is focused on increasing the probability of release from dysfunctional release sites. Current treatment uses the potassium channel blocker 3,4-diaminopyridine (DAP) to broaden the presynaptic action potential, providing more time for calcium channels to open. Current research is focused on testing new calcium channel gating modifiers that work synergistically with DAP.
      PubDate: 2017-11-10T07:46:27.047924-05:
      DOI: 10.1111/nyas.13512
       
  • Exosomes: biology, therapeutic potential, and emerging role in
           musculoskeletal repair and regeneration
    • Authors: Neil J. Cobelli; Daniel J. Leong, Hui B. Sun
      Abstract: Exosomes are nanovesicles secreted from cells that play key roles in intercellular communication. They carry unique content derived from parental cells and are capable of transferring this cargo between cells. The role and function of exosomes largely depends on the origin and functional status of the parental cells. Emerging evidence indicates that exosomes are associated with biological processes and pathogenesis of certain diseases. These nanovesicles offer great potential as biomarkers, enabling the monitoring and diagnosis of various diseases in a noninvasive manner. Furthermore, as an efficient vehicle of biomolecular intercellular transfer, exosomes are under intensive investigation for their potential for drug delivery and carriers for gene therapy. Here, we first summarize the basic biology and function of exosomes, followed by a discussion of their clinical potential, including the use of exosomes for disease diagnosis, treatment, and drug delivery. The review will highlight the potential of exosomes derived from stem cells in regenerative medicine, with a focus on musculoskeletal tissues. We conclude by sharing our views on the challenges, opportunities, and future directions for the use of exosomes as a therapeutic treatment for the repair and regeneration of musculoskeletal tissues.
      PubDate: 2017-11-10T07:46:08.857522-05:
      DOI: 10.1111/nyas.13469
       
  • Circulating microRNAs as potential biomarkers in myasthenia gravis
           patients
    • Authors: Anna Rostedt Punga; Tanel Punga
      Abstract: MicroRNAs (miRNAs) are small noncoding RNA molecules that bind to specific mRNA targets and regulate a wide range of important biological processes within cells. Circulating miRNAs are released into the extracellular space and can be measured in most biofluids, including blood serum and plasma. Recently, circulating miRNAs have emerged as easily accessible markers in various body fluids with different profiles and quantities specific for different human disorders, including autoimmune diseases. In myasthenia gravis (MG), diagnostic tests such as titers of serum autoantibodies specific for either the acetylcholine receptor (AChR+) or muscle-specific tyrosine kinase (MuSK+) do not necessarily reflect disease progression, and there is a great need for reliable objective biomarkers to monitor the disease course and therapeutic response. Recent studies in AChR+ MG revealed elevated levels of the immuno-miRNAs miR-150-5p and miR-21-5p. Of particular importance, levels of miR-150-5p were lower in immunosuppressed patients and in patients with clinical improvement following thymectomy. In MuSK+ MG, another profile of circulating miRNAs was found, including upregulation of the let-7 family of miRNAs. Here, we summarize the potential role of circulating miRNAs as biomarkers in general and in MG, and highlight important considerations for the analysis of circulating miRNA.
      PubDate: 2017-11-10T07:45:56.782179-05:
      DOI: 10.1111/nyas.13510
       
  • Thymus involvement in early-onset myasthenia gravis
    • Authors: Mélanie A. Cron; Solène Maillard, José Villegas, Frédérique Truffault, Muriel Sudres, Nadine Dragin, Sonia Berrih-Aknin, Rozen Panse
      Abstract: It has long been established that the thymus plays a central role in autoimmune myasthenia gravis (MG) because of either thymoma or thymic hyperplasia of lymphoproliferative origin. In this review, we discuss thymic changes associated with thymic hyperplasia and their implications in the development of an autoimmune response against the acetylcholine receptor (AChR).The hyperplastic MG thymus displays all the characteristics of tertiary lymphoid organs (TLOs): neoangiogenic processes with high endothelial venule and lymphatic vessel development, chemokine overexpression favoring peripheral cell recruitment, and ectopic germinal center development. As thymic epithelial cells or myoid cells express AChR, a specific antigen presentation can easily occur within the thymus in the presence of recruited peripheral cells, such as B cells and T follicular helper cells. How the thymus turns into a TLO is not known, but local inflammation seems mandatory. Interferon (IFN)-β is overexpressed in MG thymus and could orchestrate thymic changes associated with MG. Knowledge about how IFN-β is induced in MG thymus and why its expression is sustained even long after disease onset would be of interest in the future to better understand the etiological and physiopathological mechanisms involved in autoimmune MG.
      PubDate: 2017-11-10T07:45:52.11519-05:0
      DOI: 10.1111/nyas.13519
       
  • Evolutionary dynamics of interactions between plants and their enemies:
           comparison of herbivorous insects and pathogens
    • Authors: Kerry Wininger; Nathan Rank
      Abstract: Plants colonized land over 400 million years ago. Shortly thereafter, organisms began to consume terrestrial plant tissue as a nutritional resource. Most plant enemies are plant pathogens or herbivores, and they impose natural selection for plants to evolve defenses. These traits generate selection pressures on enemies. Coevolution between terrestrial plants and their enemies is an important element of the evolutionary history of both groups. However, coevolutionary studies of plant–pathogen interactions have tended to focus on different research topics than plant–herbivore interactions. Specifically, studies of plant–pathogen interactions often adopt a “gene-for-gene” conceptual framework. In contrast, studies of plants and herbivores often investigate escalation or elaboration of plant defense and herbivore adaptations to overcome it. The main exceptions to the general pattern are studies that focus on small, sessile herbivores that share many features with plant pathogens, studies that incorporate both herbivores and pathogens into a single investigation, and studies that test aspects of Thompson's geographic mosaic theory for coevolution. We discuss the implications of these findings for future research.
      PubDate: 2017-11-10T07:45:35.795927-05:
      DOI: 10.1111/nyas.13541
       
  • The mouse passive-transfer model of MuSK myasthenia gravis: disrupted MuSK
           signaling causes synapse failure
    • Authors: Nazanin Ghazanfari; Sofie Trajanovska, Marco Morsch, Simon X. Liang, Stephen W. Reddel, William D. Phillips
      Abstract: While the majority of myasthenia gravis patients express antibodies targeting the acetylcholine receptor, the second most common cohort instead displays autoantibodies against muscle-specific kinase (MuSK). MuSK is a transmembrane tyrosine kinase found in the postsynaptic membrane of the neuromuscular junction. During development, MuSK serves as a signaling hub, coordinating the alignment of the pre- and postsynaptic components of the synapse. Adult mice that received repeated daily injections of IgG from anti-MuSK+ myasthenia gravis patients developed muscle weakness, associated with neuromuscular transmission failure. MuSK autoantibodies are predominantly of the IgG4 type. They suppress the kinase activity of MuSK and the phosphorylation of target proteins in the postsynaptic membrane. Loss of postsynaptic acetylcholine receptors is the primary cause of neuromuscular transmission failure. MuSK autoantibodies also disrupt the capacity of the motor nerve terminal to adaptively increase acetylcholine release in response to the reduced postsynaptic responsiveness to acetylcholine. The passive IgG transfer model of MuSK myasthenia gravis has been used to test candidate treatments. Pyridostigmine, a first-line cholinesterase inhibitor drug, exacerbated the disease process, while 3,4-diaminopyridine and albuterol were found to be beneficial in this mouse model.
      PubDate: 2017-11-10T07:45:29.887844-05:
      DOI: 10.1111/nyas.13513
       
  • The Association of British Neurologists' myasthenia gravis guidelines
    • Authors: Jon Sussman; Maria E. Farrugia, Paul Maddison, Marguerite Hill, M. Isabel Leite, David Hilton-Jones
      Abstract: Myasthenia gravis (MG) is an autoimmune disease of the neuromuscular junction for which many therapies were developed before the era of evidence-based medicine. Despite the basic principles of treatment being well known, patients continue to receive suboptimal treatment. A myasthenia gravis guidelines group was therefore established under the aegis of the Association of British Neurologists. These guidelines attempt to steer a path between evidence-based practice where available and established best practice where evidence is unavailable. It is not possible to consider all the potential decisions in managing MG without resorting to opinion rather than evidence. Where there is insufficient evidence or a choice of options, the guidelines invite the clinician to seek the opinion of a myasthenia expert. The guidelines support clinicians in using the right treatments in the right order and in optimizing the use of well-known therapeutic agents. Clinical practice can be audited against these guidelines.
      PubDate: 2017-11-09T15:00:05.149348-05:
      DOI: 10.1111/nyas.13503
       
  • Investigating metabolic regulation using targeted neuromodulation
    • Authors: Kavya Devarakonda; Sarah Stanley
      Abstract: The central nervous system (CNS) plays a vital role in regulating energy balance and metabolism. Over the last 50 years, studies in animal models have allowed us to identify critical CNS regions involved in these processes and even crucial cell populations. Now, techniques for genetically and anatomically targeted manipulation of specific neural populations using light (optogenetic), ligands (chemogenetic), or magnetic fields (radiogenetic/magnetogenetic) allow detailed investigation of circuits involved in metabolic regulation. In this review, we provide a brief overview of recent studies using light- and magnetic field–regulated neural activity to investigate the neural circuits contributing to metabolic control.
      PubDate: 2017-11-06T09:27:31.933063-05:
      DOI: 10.1111/nyas.13468
       
  • Recent developments on intramedullary nailing: a biomechanical perspective
    • Authors: Natacha Rosa; Miguel Marta, Mário Vaz, S.M.O. Tavares, Ricardo Simoes, Fernão D. Magalhães, Antonio Torres Marques
      Abstract: Combining contributions from engineering and medicine, we highlight the biomechanical turning points in the historical evolution of the intramedullary nailing stabilization technique and discuss the recent innovations concerning increase in bone–implant system stability. Following the earliest attempts, where stabilization of long bone fractures was purely based on intuition, intramedullary nailing evolved from allowing alignment and translational control through press-fit fixation to current clinical widespread acceptance marked by the mechanical linkage between nail and bone with interlocking screws that allow alignment, translation, rotation, and length control. In an attempt to achieve an optimum interfragmentary mechanical environment, recent improvements considered the impact of different biomaterials on bone–implant stiffness. Another strategy considered the increase in the structural stability through the reduction of the number of movements between the different components that constitute the bone–implant system. Intramedullary nail improvements will most likely benefit from merging mechanics and fracture-healing biology by combining surface engineering with sensor tools associated with the innovative progress in wireless technology and with bone-healing biological active agents. Future research should aim at better understanding the ideal mechanobiological environment for each stage of fracture healing in order to allow for intramedullary nail design that satisfies such requirements.
      PubDate: 2017-11-01T05:30:50.269201-05:
      DOI: 10.1111/nyas.13524
       
  • Sustaining attention to simple visual tasks: a central deficit in
           schizophrenia' A systematic review
    • Authors: Marc Hoonakker; Nadège Doignon-Camus, Anne Bonnefond
      Abstract: Impairments in sustained attention, that is, the ability to achieve and maintain the focus of cognitive activity on a given stimulation source or task, have been described as central to schizophrenia. Today, sustained attention deficit is still considered as a hallmark of schizophrenia. Nevertheless, current findings on this topic are not consistent. To clarify these findings, we attempt to put these results into perspective according to the type of assessment (i.e., overall and over time assessment), the participants’ characteristics (i.e., clinical and demographic characteristics), and the paradigms (i.e., traditionally formatted tasks, go/no-go tasks, and the sustained attention task) and measures used. Two types of assessment lead to opposite findings; they do not evaluate sustained attention the same way. Studies using overall assessments of sustained attention ability tend to reveal a deficit, whereas studies using over time assessments do not. Therefore, further research is needed to investigate the underlying cognitive control mechanisms of changes in sustained attention in schizophrenia.
      PubDate: 2017-11-01T05:30:43.199106-05:
      DOI: 10.1111/nyas.13514
       
  • Equivalence and regulatory approaches of nonbiological complex drug
           products across the United States, the European Union, and Turkey
    • Authors: Z. Gulsen Oner; Sarah L.J. Michel, James E. Polli
      Abstract: Regulatory agencies around the world may have different standards and approaches to evaluate and approve drug products and biological products. We describe the U.S. Food and Drug Administration's (FDA) Generic Drug User Fee Act program, as well as their approach to complex products. We discuss regulatory approaches for the development of nonbiological complex drug follow-ons and approval pathways in the United States. We compare FDA policies with other regulatory agencies (i.e., the European Medicines Agency and the Turkish Medicines and Medical Devices Agency). In particular, we describe the policies/pathways across these three agencies to assess equivalence of glatiramer acetate, enoxaparin sodium, and sodium ferric gluconate complex products. We also examine the Turkish market for these selected nonbiological complex drugs.
      PubDate: 2017-11-01T05:30:36.243586-05:
      DOI: 10.1111/nyas.13505
       
  • Biological plausibility of the gut–brain axis in autism
    • Authors: Alex Vasquez
      Abstract: Organic abnormalities with neuroinflammatory and psychiatric consequences involving abnormal kynurenine and purine metabolism, neurotransmitter and cytokine imbalances, and altered levels of nutrients and metabolites are noted in autism, and many of these abnormalities—specifically including increased intestinal permeability, microbial metabolites, and heightened serum levels of endotoxin—originate from the gut.
      PubDate: 2017-11-01T05:30:24.850287-05:
      DOI: 10.1111/nyas.13516
       
  • Freezing does not alter multiscale tendon mechanics and damage mechanisms
           in tension
    • Authors: Andrea H. Lee; Dawn M. Elliott
      Abstract: It is common in biomechanics to use previously frozen tissues, where it is assumed that the freeze–thaw process does not cause consequential mechanical or structural changes. We have recently quantified multiscale tendon mechanics and damage mechanisms using previously frozen tissue, where damage was defined as an irreversible change in the microstructure that alters the macroscopic mechanical parameters. Because freezing has been shown to alter tendon microstructures, the objective of this study was to determine if freezing alters tendon multiscale mechanics and damage mechanisms. Multiscale testing using a protocol that was designed to evaluate tendon damage (tensile stress–relaxation followed by unloaded recovery) was performed on fresh and previously frozen rat tail tendon fascicles. At both the fascicle and fibril levels, there was no difference between the fresh and frozen groups for any of the parameters, suggesting that there is no effect of freezing on tendon mechanics. After unloading, the microscale fibril strain fully recovered, and interfibrillar sliding only partially recovered, suggesting that the tendon damage is localized to the interfibrillar structures and that mechanisms of damage are the same in both fresh and previously frozen tendons.
      PubDate: 2017-10-25T10:26:24.544207-05:
      DOI: 10.1111/nyas.13460
       
  • The molecular cross talk of the dystrophin–glycoprotein complex
    • Authors: Marta Gawor; Tomasz J. Prószyński
      Abstract: The proper function of skeletal muscles relies on their ability to process signals derived from motor neurons, transmit stimuli along the muscle fibers, contract, and regenerate efficiently after injury. The dystrophin–glycoprotein complex (DGC; also called the dystrophin-associated protein complex) plays a central role in all of these processes. It acts as a transmembrane platform that anchors the extracellular matrix (ECM) to the intracellular cytoskeleton and makes muscle fibers more resistant to injury. The DGC also contributes to the transmission of contraction-evoked force from the sarcomere to the ECM. The dysfunction of DGC-associated proteins can lead to myopathies, including Duchenne's muscular dystrophy, manifested by progressive muscle damage and impairments in regeneration. The DGC also plays a pivotal role in the organization of neuromuscular junctions (NMJs), where it stabilizes postsynaptic machinery, including receptors for the neurotransmitter acetylcholine (AChRs). Here, we focus on the role of the DGC complex in NMJ and skeletal muscle physiology and discuss the novel components that are associated with the complex.
      PubDate: 2017-10-25T10:26:12.740152-05:
      DOI: 10.1111/nyas.13500
       
  • Neuromuscular synapse electrophysiology in myasthenia gravis animal models
    • Authors: Jaap J. Plomp; Maartje G.M. Huijbers, Jan J.G.M. Verschuuren
      Abstract: The neuromuscular junction (NMJ) forms the synaptic connection between a motor neuron and a skeletal muscle fiber. In order to achieve a sustained muscle contraction, this synapse has to reliably transmit motor neuronal action potentials onto the muscle fiber. To guarantee successful transmission even during intense activation of the NMJ, a safety factor of neuromuscular transmission exists. In the neuromuscular disorder myasthenia gravis (MG), autoantibodies are directed against acetylcholine receptors or, in the rarer variants, against other postsynaptic NMJ proteins. This causes loss of functional acetylcholine receptors, which compromises the safety factor of neuromuscular transmission, leading to the typical fatigable muscle weakness of MG. With intracellular microelectrode measurement of (miniature) endplate potentials at NMJs in ex vivo nerve–muscle preparations from MG animal models, these functional synaptic defects have been determined in much detail. Here, we describe the electrophysiological events at the normal NMJ and the pathoelectrophysiology at NMJs of animal models for MG.
      PubDate: 2017-10-25T10:26:04.763093-05:
      DOI: 10.1111/nyas.13507
       
  • Diagnostic utility of cortactin antibodies in myasthenia gravis
    • Authors: Isabel Illa; Elena Cortés-Vicente, María Ángeles Martínez, Eduard Gallardo
      Abstract: Patients with myasthenia gravis (MG) without antibodies to the acetylcholine receptor (AChR) or muscle-specific tyrosine kinase (MuSK) have been classified as having double-seronegative myasthenia gravis (dSNMG). We used the sera from six dSNMG patients with positive immunohistochemistry assays in a protein array to screen reactivity with 9000 human proteins. We identified cortactin, an intracellular protein that interacts with agrin/MuSK favoring AChR aggregation, as a new antigen in dSNMG. We then designed an in-house enzyme-linked immunosorbent assay as a screening assay and confirmed these results by western blot. We found that 19.7% of dSNMG patients had anti-cortactin antibodies. In contrast, patients with AChR+ MG or other autoimmune disorders and healthy controls were positive at significantly lower rates. Five percent of healthy controls were positive. In a recent study, we screened sera from 250 patients (AChR+ MG, MuSK+ MG, dSNMG) and 29 healthy controls. Cortactin antibodies were identified in 23.7% of dSNMG and 9.5% AChR+ MG patients (P = 0.02). None of the MuSK+ MG patients, patients with other autoimmune disorders, or healthy controls had antibodies against cortactin. Patients with dSNMG cortactin+ MG were negative for anti-striated muscle and anti-LRP4 antibodies. Patients with dSNMG cortactin+ MG presented ocular or mild generalized MG without bulbar symptoms. We conclude that cortactin autoantibodies are biomarkers of MG that, when present, suggest that the disease will be mild.
      PubDate: 2017-10-25T10:25:58.312979-05:
      DOI: 10.1111/nyas.13502
       
  • 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
       
  • Learning from the past: reflections on recently completed myasthenia
           gravis trials
    • Authors: Michael Benatar; James F. Howard, Richard Barohn, Gil I. Wolfe, Gary Cutter
      Abstract: Recently competed clinical trials of therapeutics for myasthenia gravis have varied widely in design, but also perhaps in less explicit ways. We explore ways in which these design characteristics may have influenced recruitment and results, as well as the implications for forthcoming studies. Trial eligibility criteria may inadvertently select for incident versus prevalent cases or patients with relatively mild versus more severe disease. Trial enrichment with patients who have relatively mild disease may limit the sensitivity of the trial to detect a therapeutic effect. Enrichment for patients with more severe disease may introduce confounds caused by regression toward the mean. Overly narrow eligibility may limit the generalizability of results. An exclusive focus on incident cases may hamper recruitment, as may many other factors, such as access to the experimental therapeutic treatment outside of the trial or following completion of the double-blind treatment period. We illustrate how other design characteristics (e.g., treatment duration, strategy for steroid tapering, selection of the primary outcome, and principal analytic approach) may affect the sensitivity of a trial to demonstrate therapeutic effects. Finally, we consider the importance of placebo effects, being careful to differentiate these from therapeutic effects observed in the placebo group, and discuss how the use of combined outcome measures may minimize placebo effects.
      PubDate: 2017-10-24T10:15:55.528092-05:
      DOI: 10.1111/nyas.13501
       
  • A diagnosis and treatment gap for thiamine deficiency disorders in
           sub-Saharan Africa'
    • Authors: Bola Adamolekun; Laurent Hiffler
      Abstract: Staple diets that are deficient in thiamine can result in low body thiamine levels, which may be subclinical or may manifest as a thiamine-deficiency syndrome. In many communities in the developing countries of Africa, the staple diets of polished rice or processed cassava are deficient in thiamine, and thus the communities are at high risk for marginal or frank thiamine deficiency unless their diets are supplemented by other sources of thiamine, such as protein meals and vegetables. African communities with large numbers of individuals in low socioeconomic strata are more likely to subsist on a monotonous diet of rice or cassava with minimal or no protein supplementation and are therefore particularly at risk of thiamine-deficiency disorders. Indeed, there is evidence of widespread biochemical thiamine deficiency from community-based studies in Africa. The protean manifestations of thiamine deficiency disorders in the developing countries of Africa are presented in this paper. We present evidence supporting the contention that there is a diagnosis and treatment gap for thiamine-deficiency disorders in Africa. We discuss research and clinical options for bridging the putative diagnosis and treatment gap for thiamine-deficiency disorders in the developing countries of Africa.
      PubDate: 2017-10-24T10:15:27.60406-05:0
      DOI: 10.1111/nyas.13509
       
  • Osteocalcin and osteopontin influence bone morphology and mechanical
           properties
    • Authors: Stacyann Bailey; Gerard Karsenty, Caren Gundberg, Deepak Vashishth
      Abstract: Osteocalcin (OC) and osteopontin (OPN) are major non-collagenous proteins (NCPs) involved in bone matrix organization and deposition. In spite of this, it is currently unknown whether OC and OPN alter bone morphology and consequently affect bone fracture resistance. The goal of this study is to establish the role of OC and OPN in the determination of cortical bone size, shape, and mechanical properties. Our results show that Oc–/– and Opn–/– mice were no different from each other or wild type (WT) with respect to bone morphology (P> 0.1). Bones from mice lacking both NCPs (Oc–/–Opn–/–) were shorter, with thicker cortices and larger cortical areas, compared with the WT, Oc–/–, and Opn–/– groups (P < 0.05), suggesting a synergistic role for NCPs in the determination of bone morphology. Maximum bending load was significantly different among the groups (P = 0.024), while tissue mineral density and measures of stiffness and strength were not different (P> 0.1). We conclude that the removal of both OC and OPN from bone matrix induces morphological adaptation at the structural level to maintain bone strength.
      PubDate: 2017-10-16T22:55:51.703568-05:
      DOI: 10.1111/nyas.13470
       
  • Nutrient sensing in pancreatic islets: lessons from congenital
           hyperinsulinism and monogenic diabetes
    • Authors: Ming Lu; Changhong Li
      Abstract: Pancreatic beta cells sense changes in nutrients during the cycles of fasting and feeding and release insulin accordingly to maintain glucose homeostasis. Abnormal beta cell nutrient sensing resulting from gene mutations leads to hypoglycemia or diabetes. Glucokinase (GCK) plays a key role in beta cell glucose sensing. As one form of congenital hyperinsulinism (CHI), activating mutations of GCK result in a decreased threshold for glucose-stimulated insulin secretion and hypoglycemia. In contrast, inactivating mutations of GCK result in diabetes, including a mild form (MODY2) and a severe form (permanent neonatal diabetes mellitus (PNDM)). Mutations of beta cell ion channels involved in insulin secretion regulation also alter glucose sensing. Activating or inactivating mutations of ATP-dependent potassium (KATP) channel genes result in severe but completely opposite clinical phenotypes, including PNDM and CHI. Mutations of the other ion channels, including voltage-gated potassium channels (Kv7.1) and voltage-gated calcium channels, also lead to abnormal glucose sensing and CHI. Furthermore, amino acids can stimulate insulin secretion in a glucose-independent manner in some forms of CHI, including activating mutations of the glutamate dehydrogenase gene, HDAH deficiency, and inactivating mutations of KATP channel genes. These genetic defects have provided insight into a better understanding of the complicated nature of beta cell fuel-sensing mechanisms.
      PubDate: 2017-10-16T22:55:46.198406-05:
      DOI: 10.1111/nyas.13448
       
  • 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
       
  • Disordered eating and obesity: associations between binge-eating disorder,
           night-eating syndrome, and weight-related comorbidities
    • Authors: Courtney McCuen-Wurst; Madelyn Ruggieri, Kelly C. Allison
      Abstract: Binge-eating disorder (BED) and night-eating syndrome (NES) are two forms of disordered eating associated with overweight and obesity. While these disorders also occur in nonobese persons, they seem to be associated with weight gain over time and higher risk of diabetes and other metabolic dysfunction. BED and NES are also associated with higher risk of psychopathology, including mood, anxiety, and sleep problems, than those of similar weight status without disordered eating. Treatments are available, including cognitive behavior therapy (CBT), interpersonal psychotherapy, lisdexamfetamine, and selective serotonin reuptake inhibitors (SSRIs) for BED; and CBT, SSRIs, progressive muscle relaxation, and bright light therapy for NES.
      PubDate: 2017-10-16T10:56:29.777838-05:
      DOI: 10.1111/nyas.13467
       
  • Complexity of intravenous iron nanoparticle formulations: implications for
           bioequivalence evaluation
    • Authors: Amy Barton Pai
      Abstract: Intravenous iron formulations are a class of complex drugs that are commonly used to treat a wide variety of disease states associated with iron deficiency and anemia. Venofer® (iron–sucrose) is one of the most frequently used formulations, with more than 90% of dialysis patients in the United States receiving this formulation. Emerging data from global markets outside the United States, where many iron–sucrose similars or copies are available, have shown that these formulations may have safety and efficacy profiles that differ from the reference listed drug. This may be attributable to uncharacterized differences in physicochemical characteristics and/or differences in labile iron release. As bioequivalence evaluation guidance evolves, clinicians should be educated on these potential clinical issues before a switch to the generic formulation is made in the clinical setting.
      PubDate: 2017-10-13T03:05:28.666509-05:
      DOI: 10.1111/nyas.13461
       
  • Postaxial limb hypoplasia (PALH): the classification, clinical features,
           and related developmental biology
    • Authors: Zeng Zhang; Dan Yi, Rong Xie, John L. Hamilton, Qing-Lin Kang, Di Chen
      Abstract: Postaxial limb hypoplasia (PALH) is a group of nonhereditary diseases with congenital lower limb deficiency affecting the fibular ray, including fibular hemimelia, proximal femoral focal deficiency, and tarsal coalition. The etiology and the developmental biology of the anomaly are still not fully understood. Here, we review the previous classification systems, present the clinical features, and discuss the developmental biology of PALH.
      PubDate: 2017-10-09T02:30:35.993047-05:
      DOI: 10.1111/nyas.13440
       
  • 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
       
  • A unique subphenotype of myasthenia gravis
    • Authors: Jeannine M. Heckmann; Melissa Nel
      Abstract: While extraocular muscles (EOMs) are affected early in generalized myasthenia gravis (MG), and their treatment responsiveness is similar to nonocular muscles, we have identified an ophthalmoplegic (OP) subphenotype that remains resistant to treatment. This subphenotype of ophthalmoplegic MG (OP-MG) most commonly affects acetylcholine receptor antibody-positive cases with juvenile-onset MG and African genetic ancestry. However, a few OP-MG cases have been found with MuSK antibodies and triple-seronegative MG. In a proportion of OP-MG cases, the EOM treatment resistance manifests from treatment initiation, while in others the EOMs may initially respond until a critical trigger, such as treatment interruption or crisis. The management of OP-MG is an unmet need. Managing the visual disability may require a surgical or nonsurgical solution. The ideal case selection for surgery and the timing of surgery should be carefully considered. The pathogenesis of OP-MG remains unknown. A genetic study, using extended whole-exome sequencing and an “extreme” phenotype sample of OP-MG versus control MG cases differing only by their EOM responsivity to therapy, discovered several potentially functional OP-MG risk variants. These variants implicate myogenesis and gangliosphingolipid biosynthesis pathways at the EOM endplates in OP-MG.
      PubDate: 2017-10-06T04:01:12.97326-05:0
      DOI: 10.1111/nyas.13471
       
  • Strategies to retain properties of bone marrow–derived mesenchymal
           stem cells ex vivo
    • Authors: Yaxian Zhou; Tsung-Lin Tsai, Wan-Ju Li
      Abstract: Mesenchymal stem cells (MSCs) have been extensively used for cell therapies and tissue engineering. The current MSC strategy requires a large quantity of cells for such applications, which can be achieved through cell expansion in culture. In the body, stem cell fate is largely determined by their microenvironment, known as the niche. The complex and dynamic stem cell niche provides physical, mechanical, and chemical cues to collaboratively regulate cell activities. It remains a great challenge to maintain the properties of MSCs in culture. Constructing a microenvironment as an engineered stem cell niche in culture to maintain MSC phenotypes, properties, and functions is a viable strategy to address the issue. Here, we review the current understanding of MSC behavior in the bone marrow niche, describe different strategies to engineer an in vitro microenvironment for maintaining MSC properties and functions, and discuss previous findings on environmental factors critical to the modulation of MSC activities in engineered microenvironments.
      PubDate: 2017-10-06T04:01:07.45875-05:0
      DOI: 10.1111/nyas.13451
       
  • 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
       
  • Homeostatic synaptic plasticity at the neuromuscular junction in
           myasthenia gravis
    • Authors: Xueyong Wang; Mark M. Rich
      Abstract: A number of studies in the past 20 years have shown that perturbation of activity of the nervous system leads to compensatory changes in synaptic strength that serve to return network activity to its original level. This response has been termed homeostatic synaptic plasticity. Despite the intense interest in homeostatic synaptic plasticity, little attention has been paid to its role in the prototypic synaptic disease, myasthenia gravis. In this review, we discuss mechanisms that have been shown to mediate homeostatic synaptic plasticity at the mammalian neuromuscular junction. A subset of these mechanisms have been shown to occur in myasthenia gravis. The homeostatic changes occurring in myasthenia gravis appear to involve the presynaptic nerve terminal and may even involve changes in the excitability of motor neurons within the spinal cord. The finding of presynaptic homeostatic synaptic plasticity in myasthenia gravis leads us to propose that changes in the motor unit in myasthenia gravis may be more widespread than previously appreciated.
      PubDate: 2017-10-05T11:50:22.429901-05:
      DOI: 10.1111/nyas.13472
       
  • 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
       
  • WHO standards for biotherapeutics, including biosimilars: an example of
           the evaluation of complex biological products
    • Authors: Ivana Knezevic; Elwyn Griffiths
      Abstract: The most advanced regulatory processes for complex biological products have been put in place in many countries to provide appropriate regulatory oversight of biotherapeutic products in general, and similar biotherapeutics in particular. This process is still ongoing and requires regular updates to national regulatory requirements in line with scientific developments and up-to-date standards. For this purpose, strong knowledge of and expertise in evaluating biotherapeutics in general and similar biotherapeutic products, also called biosimilars, in particular is essential. Here, we discuss the World Health Organization's international standard-setting role in the regulatory evaluation of recombinant DNA–derived biotherapeutic products, including biosimilars, and provide examples that may serve as models for moving forward with nonbiological complex medicinal products. A number of scientific challenges and regulatory considerations imposed by the advent of biosimilars are described, together with the lessons learned, to stimulate future discussions on this topic. In addition, the experiences of facilitating the implementation of guiding principles for evaluation of similar biotherapeutic products into regulatory and manufacturers’ practices in various countries over the past 10 years are briefly explained, with the aim of promoting further developments and regulatory convergence of complex biological and nonbiological products.
      PubDate: 2017-09-14T01:56:29.806087-05:
      DOI: 10.1111/nyas.13434
       
  • Mechanical signals protect stem cell lineage selection, preserving the
           bone and muscle phenotypes in obesity
    • Authors: Danielle M. Frechette; Divya Krishnamoorthy, Tee Pamon, M. Ete Chan, Vihitaben Patel, Clinton T. Rubin
      Abstract: The incidence of obesity is rapidly rising, increasing morbidity and mortality rates worldwide. Associated comorbidities include type 2 diabetes, heart disease, fatty liver disease, and cancer. The impact of excess fat on musculoskeletal health is still unclear, although it is associated with increased fracture risk and a decline in muscular function. The complexity of obesity makes understanding the etiology of bone and muscle abnormalities difficult. Exercise is an effective and commonly prescribed nonpharmacological treatment option, but it can be difficult or unsafe for the frail, elderly, and morbidly obese. Exercise alternatives, such as low-intensity vibration (LIV), have potential for improving musculoskeletal health, particularly in conditions with excess fat. LIV has been shown to influence bone marrow mesenchymal stem cell differentiation toward higher-order tissues (i.e., bone) and away from fat. While the exact mechanisms are not fully understood, recent studies utilizing LIV both at the bench and in the clinic have demonstrated some efficacy. Here, we discuss the current literature investigating the effects of obesity on bone, muscle, and bone marrow and how exercise and LIV can be used as effective treatments for combating the negative effects in the presence of excess fat.
      PubDate: 2017-09-11T01:10:25.426424-05:
      DOI: 10.1111/nyas.13442
       
  • Endoluminal weight loss and metabolic therapies: current and future
           techniques
    • Authors: Christine Hill; Mouen A. Khashab, Anthony N. Kalloo, Vivek Kumbhari
      Abstract: Obesity is a public health epidemic associated with a number of comorbidities, most notably type 2 diabetes and hypertension, as well as elevated all-cause mortality. The treatment for obesity and its associated comorbidities has most recently expanded into the field of bariatric endoscopy. This field bridges a gap between lifestyle counseling with or without pharmaceutical treatment and the most effective treatment of obesity, bariatric surgery. Because of its minimally invasive nature, bariatric endoscopic therapy has the potential to appeal to the large sector of the obese population that resists surgery, as well as those early in the onset of obesity. To date, five endoscopic devices have been approved by the U.S. Food and Drug Administration for the treatment of obesity, and many more are in development, undergoing clinical trials, or being used around the world. Here, we present the current state of the field, highlight recent developments, and describe the clinical outcomes of these minimally invasive procedures in terms of weight loss, improvement in metabolic profile, and reduction in comorbidities.
      PubDate: 2017-09-08T05:25:38.629325-05:
      DOI: 10.1111/nyas.13441
       
  • Mechanisms of weight loss and improved metabolism following bariatric
           surgery
    • Authors: Christopher M. Mulla; Roeland J.W. Middelbeek, Mary-Elizabeth Patti
      Abstract: Bariatric surgery is increasingly recognized as one of the most effective interventions to help patients achieve significant and sustained weight loss, as well as improved metabolic and overall health. Unfortunately, the cellular and physiological mechanisms by which bariatric surgery achieves weight loss have not been fully elucidated, yet are critical to understanding the central role of the intestinal tract in whole-body metabolism and to developing novel strategies for the treatment of obesity. In this review, we provide an overview of potential mechanisms contributing to weight loss, including effects on regulation of energy balance and both central and peripheral nervous system regulation of appetite and metabolism. Moreover, we highlight the importance of the gastrointestinal tract, including alterations in bile acid physiology, secretion of intestinally derived hormones, and the microbiome, as a potent mediator of improved metabolism in postbariatric patients.
      PubDate: 2017-09-03T23:26:21.948511-05:
      DOI: 10.1111/nyas.13409
       
  • Insulin regulation of gluconeogenesis
    • Authors: Maximilian Hatting; Clint D.J. Tavares, Kfir Sharabi, Amy K. Rines, Pere Puigserver
      Abstract: The coordinated regulation between cellular glucose uptake and endogenous glucose production is indispensable for the maintenance of constant blood glucose concentrations. The liver contributes significantly to this process by altering the levels of hepatic glucose release, through controlling the processes of de novo glucose production (gluconeogenesis) and glycogen breakdown (glycogenolysis). Various nutritional and hormonal stimuli signal to alter hepatic gluconeogenic flux, and suppression of this metabolic pathway during the postprandial state can, to a significant extent, be attributed to insulin. Here, we review some of the molecular mechanisms through which insulin modulates hepatic gluconeogenesis, thus controlling glucose production by the liver to ultimately maintain normoglycemia. Various signaling pathways governed by insulin converge at the level of transcriptional regulation of the key hepatic gluconeogenic genes PCK1 and G6PC, highlighting this as one of the focal mechanisms through which gluconeogenesis is modulated. In individuals with compromised insulin signaling, such as insulin resistance in type 2 diabetes, insulin fails to suppress hepatic gluconeogenesis, even in the fed state; hence, an insight into these insulin-moderated pathways is critical for therapeutic purposes.
      PubDate: 2017-09-03T23:25:25.423126-05:
      DOI: 10.1111/nyas.13435
       
  • Mechanobiology of limb musculoskeletal development
    • Authors: Varun Arvind; Alice H. Huang
      Abstract: While there has been considerable progress in identifying molecular regulators of musculoskeletal development, the role of physical forces in regulating induction, differentiation, and patterning events is less well understood. Here, we highlight recent findings in this area, focusing primarily on model systems that test the mechanical regulation of skeletal and tendon development in the limb. We also discuss a few of the key signaling pathways and mechanisms that have been implicated in mechanotransduction and highlight current gaps in knowledge and opportunities for further research in the field.
      PubDate: 2017-08-22T22:11:32.56046-05:0
      DOI: 10.1111/nyas.13427
       
  • Looking beyond the intervertebral disc: the need for behavioral assays in
           models of discogenic pain
    • Authors: Grace E. Mosley; Thomas W. Evashwick-Rogler, Alon Lai, James C. Iatridis
      Abstract: Orthopedic research into chronic discogenic back pain has commonly focused on aging- and degeneration-related changes in intervertebral disc structure, biomechanics, and biology. However, the primary spine-related reason for physician office visits is pain. The ambiguous nature of the human condition of discogenic low back pain motivates the use of animal models to better understand the pathophysiology. Discogenic back pain models must consider both emergent behavioral changes following pain induction and changes in the nervous system that mediate such behavior. Looking beyond the intervertebral disc, we describe the different ways to classify pain in human patients and animal models. We describe several behavioral assays that can be used in rodent models to augment disc degeneration measurements and characterize different types of pain. We review rodent models of discogenic pain that employed behavioral pain assays and highlight a need to better integrate neuroscience and orthopedic science methods to extend current understanding of the complex and multifactorial pathophysiology of discogenic back pain.
      PubDate: 2017-08-10T16:50:32.853484-05:
      DOI: 10.1111/nyas.13429
       
  • 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
       
  • Deciphering adipose tissue heterogeneity
    • Authors: Matthew D. Lynes; Yu-Hua Tseng
      Abstract: Obesity is an excess accumulation of adipose tissue mass, and, together with its sequelae, in particular type II diabetes and metabolic syndrome, obesity presents a major health crisis. Although obesity is simply caused by increased adipose mass, the heterogeneity of adipose tissue in humans means that the response to increased energy balance is highly complex. Individual subjects with similar phenotypes may respond very differently to the same treatments; therefore, obesity may benefit from a personalized precision medicine approach. The variability in the development of obesity is indeed driven by differences in sex, genetics, and environment, but also by the various types of adipose tissue as well as the different cell types that compose it. By describing the distinct cell populations that reside in different fat depots, we can interpret the complex effect of these various players in the maintenance of whole-body energy homeostasis. To further understand adipose tissue, adipogenic differentiation and the transcriptional program of lipid accumulation must be investigated. As the cell- and depot-specific functions are described, they can be placed in the context of energy excess to understand how the heterogeneity of adipose tissue shapes individual metabolic status and condition.
      PubDate: 2017-08-01T16:26:02.143338-05:
      DOI: 10.1111/nyas.13398
       
  • How to select a nanosimilar
    • Authors: Alain Astier; Amy Barton Pai, Marco Bissig, Daan J.A. Crommelin, Beat Flühmann, Jean-Daniel Hecq, Josefien Knoeff, Hans-Peter Lipp, Alberto Morell-Baladrón, Stefan Mühlebach
      Abstract: Nanomedicines in the class of nonbiological complex drugs (NBCDs) are becoming increasingly available. Up to 23 nanomedicines have been approved, and approximately 50 are in clinical development. Meanwhile, the first nanosimilars have entered the market through the generic approval pathway, but clinical differences have been observed. Many healthcare professionals may be unaware of this issue and must be informed of these clinically relevant variances. This article provides a tool for rational decision making for the inclusion of nanomedicines into the hospital formulary, including defined criteria for evaluation of substitutability or interchangeability. The tool was generated by conducting a roundtable with an international panel of experts and follows the same thought process that was developed and published earlier for the selection of biologicals/biosimilars. In addition to the existing criteria for biosimilars, a set of seven criteria was identified that specifically apply to nanosimilars. These include (1) particle size and size distribution, (2) particle surface characteristics, (3) fraction of uncaptured bioactive moiety, (4) stability on storage, (5) bioactive moiety uptake and (6) distribution, and (7) stability for ready-to-use preparation. Pharmacists should utilize their pharmaceutical expertise to use the appropriate criteria to evaluate the comparability of the drug to decide on interchangeability or substitutability.
      PubDate: 2017-07-17T13:45:32.683436-05:
      DOI: 10.1111/nyas.13382
       
  • 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
       
  • Equivalence of complex drug products: advances in and challenges for
           current regulatory frameworks
    • Authors: Leonie Hussaarts; Stefan Mühlebach, Vinod P. Shah, Scott McNeil, Gerrit Borchard, Beat Flühmann, Vera Weinstein, Sesha Neervannan, Elwyn Griffiths, Wenlei Jiang, Elena Wolff-Holz, Daan J.A. Crommelin, Jon S.B. Vlieger
      Abstract: Biotechnology and nanotechnology provide a growing number of innovator-driven complex drug products and their copy versions. Biologics exemplify one category of complex drugs, but there are also nonbiological complex drug products, including many nanomedicines, such as iron–carbohydrate complexes, drug-carrying liposomes or emulsions, and glatiramoids. In this white paper, which stems from a 1-day conference at the New York Academy of Sciences, we discuss regulatory frameworks in use worldwide (e.g., the U.S. Food and Drug Administration, the European Medicines Agency, the World Health Organization) to approve these complex drug products and their follow-on versions. One of the key questions remains how to assess equivalence of these complex products. We identify a number of points for which consensus was found among the stakeholders who were present: scientists from innovator and generic/follow-on companies, academia, and regulatory bodies from different parts of the world. A number of topics requiring follow-up were identified: (1) assessment of critical attributes to establish equivalence for follow-on versions, (2) the need to publish scientific findings in the public domain to further progress in the field, (3) the necessity to develop worldwide consensus regarding nomenclature and labeling of these complex products, and (4) regulatory actions when substandard complex drug products are identified.
      PubDate: 2017-04-26T12:10:34.962138-05:
      DOI: 10.1111/nyas.13347
       
  • Issue Information
    • Pages: 1 - 3
      PubDate: 2017-11-23T03:11:50.663288-05:
      DOI: 10.1111/nyas.13251
       
  • Iron sucrose: assessing the similarity between the originator drug and its
           intended copies
    • Authors: Tiziana Di Francesco; Erik Philipp, Gerrit Borchard
      Pages: 63 - 74
      Abstract: Iron sucrose (IS) is a complex nanocolloidal intravenous suspension used in the treatment of iron-deficiency anemia. Follow-on IS products (iron sucrose similars (ISSs)) have obtained marketing authorization by the generic pathway, implying that identical copies of IS may be manufactured. However, recent prospective and retrospective clinical studies showed discrepancies in clinical outcomes, which might be related to differences in physicochemical properties. The aim of this work is to measure and compare the physicochemical properties of IS and three ISSs available in the market using innovative analytical procedures. The comprehensive elucidation of size, size distribution, morphology, and stability of these complex drugs revealed very significant differences between the products. This study serves to provide the basis to define critical quality attributes that may be linked to differences in clinical outcome and thus may contribute to an adequate regulatory approach for IS and its follow-on products.
      PubDate: 2017-11-23T03:11:52.364382-05:
      DOI: 10.1111/nyas.13517
       
  • Compositional differences between Copaxone and Glatopa are reflected in
           altered immunomodulation ex vivo in a mouse model
    • Authors: Iris Grossman; Sarah Kolitz, Arthur Komlosh, Benjamin Zeskind, Vera Weinstein, Daphna Laifenfeld, Adrian Gilbert, Oren Bar-Ilan, Kevin D. Fowler, Tal Hasson, Attila Konya, Kevin Wells-Knecht, Pippa Loupe, Sigal Melamed-Gal, Tatiana Molotsky, Revital Krispin, Galia Papir, Yousif Sahly, Michael R. Hayden
      Pages: 75 - 89
      Abstract: Copaxone (glatiramer acetate, GA), a structurally and compositionally complex polypeptide nonbiological drug, is an effective treatment for multiple sclerosis, with a well-established favorable safety profile. The short antigenic polypeptide sequences comprising therapeutically active epitopes in GA cannot be deciphered with state-of-the-art methods; and GA has no measurable pharmacokinetic profile and no validated pharmacodynamic markers. The study reported herein describes the use of orthogonal standard and high-resolution physicochemical and biological tests to characterize GA and a U.S. Food and Drug Administration–approved generic version of GA, Glatopa (USA-FoGA). While similarities were observed with low-resolution or destructive tests, differences between GA and USA-FoGA were measured with high-resolution methods applied to an intact mixture, including variations in surface charge and a unique, high-molecular-weight, hydrophobic polypeptide population observed only in some USA-FoGA lots. Consistent with published reports that modifications in physicochemical attributes alter immune-related processes, genome-wide expression profiles of ex vivo activated splenocytes from mice immunized with either GA or USA-FoGA showed that 7–11% of modulated genes were differentially expressed and enriched for immune-related pathways. Thus, differences between USA-FoGA and GA may include variations in antigenic epitopes that differentially activate immune responses. We propose that the assays reported herein should be considered during the regulatory assessment process for nonbiological complex drugs such as GA.
      PubDate: 2017-11-23T03:11:51.955328-05:
      DOI: 10.1111/nyas.13547
       
 
 
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