Related Articles

Early-onset epileptic encephalopathy and severe developmental delay in an association with de novo double mutations in NF1 and MAGEL2.

Epilepsia Open. 2018 Mar;3(1):81-85

Authors: Akamine S, Sagata N, Sakai Y, Kato TA, Nakahara T, Matsushita Y, Togao O, Hiwatashi A, Sanefuji M, Ishizaki Y, Torisu H, Saitsu H, Matsumoto N, Hara T, Sawa A, Kano S, Furue M, Kanba S, Shaw CA, Ohga S

Abstract
Advance in the exome-wide sequencing analysis contributes to identifying hundreds of genes that are associated with early-onset epileptic encephalopathy and neurodevelopmental disorders. On the basis of massive sequencing data, functional interactions among different genes are suggested to explain the common molecular pathway underlying the pathogenic process of these disorders. However, the relevance of such interactions with the phenotypic severity or variety in an affected individual remains elusive. In this report, we present a 45-year-old woman with neurofibromatosis type 1 (NF1), infantile-onset epileptic encephalopathy, and severe developmental delay. Whole-exome sequencing identified de novo pathogenic mutations in NF1 and the Schaaf-Yang syndrome-associated gene, MAGEL2. Literature-curated interaction data predicted that NF1 and MAGEL2 proteins were closely connected in this network via their common interacting proteins. Direct conversion of fibroblasts into neurons in vitro showed that neuronal cells from 9 patients with NF1 expressed significantly lower levels of MAGEL2 (54%, p = 0.0047) than those from healthy individuals. These data provide the first evidence that pathogenic mutations of NF1 deregulate the expression of other neurodevelopmental disease-associated genes. De novo mutations in multiple genes may lead to severe developmental phenotypes through their cumulative effects or synergistic interactions.

PMID: 29588991 [PubMed]

Primaquine Pharmacokinetics in Lactating Women and Breastfed Infant Exposures.

Clin Infect Dis. 2018 Mar 24;:

Authors: Ellen Gilder M, Hanpithakphong W, Hoglund RM, Tarning J, Htun Win H, Hilda N, Chu CS, Bancone G, Carrara VI, Singhasivanon P, White NJ, Nosten F, McGready R

Abstract
Background: Primaquine is the only drug providing radical cure of Plasmodium vivax malaria. It is not recommended for breastfeeding women as it causes hemolysis in glucose-6-phosphate dehydrogenase (G6PD) deficient individuals, and breast milk excretion and thus infant exposure are not known.
Methods: Healthy G6PD normal breastfeeding women with previous P.vivax infection and their healthy G6PD normal infants between 28 days and 2 years old were enrolled. Mothers took primaquine 0.5 mg/kg/day for 14 days. Primaquine and carboxyprimaquine concentrations were measured in maternal venous plasma, capillary plasma, and breast milk samples and infant capillary plasma samples taken on days 0, 3, 7, and 13.
Results: In 20 mother-baby pairs primaquine concentrations were below measurement thresholds in all but one infant capillary plasma sample (that contained primaquine 2.6 ng/mL) and carboxyprimaquine was likewise unmeasurable in the majority of infant samples (maximum value 25.8 ng/mL). The estimated primaquine dose received by infants, based on measured breast milk levels, was 2.98 µg/kg/day (i.e. ~0.6% of a hypothetical infant daily dose of 0.5 mg/kg). There was no evidence of drug-related hemolysis in the infants. Maternal levels were comparable to non-lactating patients, and adverse events in mothers were mild.
Conclusions: The concentrations of primaquine in breast milk are very low and therefore very unlikely to cause adverse effects in the breast-feeding infant. Primaquine should not be withheld from mothers breastfeeding infants or young children. More information is needed in neonates.

PMID: 29590311 [PubMed - as supplied by publisher]

Liver and statins: a critical appraisal of the evidence.

Curr Med Chem. 2018 Mar 26;:

Authors: Licata A, Giammanco A, Minissale MG, Pagano S, Petta S, Averna M

Abstract
Adverse drug reactions (ADRs) represent an important cause of morbidity and mortality worldwide. Statins are a class of drugs whose main adverse effects are drug-induced liver injury (DILI) and myopathy. Some of these may be predictable, due to their pharmacokinetic and pharmacodynamic properties, while others, unfortunately, are idiosyncratic. Genetic factors may also influence patient susceptibility to DILI and myopathy in the case of statins. This review will first discuss the role of statins in cardiovascular disease treatment and prevention and the underlying mechanisms of action. Furthermore, to explore the susceptibility of statin-induced adverse events such as myopathy and hepatotoxicity, it will then focus on the recent Genome-Wide Association Studies (GWAS) concerning the transporter genes, Cytochrome P450 (CYP), organic anion-transporting polypeptide (OATP) and ABCB1 and ABCC1, which seem to play a role in the development of clinically relevant adverse events. Finally, we appraise the evidence for and against the use of statins in metabolic syndrome and in HCV-infected patients, in terms of their safety and efficacy in cardiovascular events.

PMID: 29589533 [PubMed - as supplied by publisher]

Related Articles

Potentially inappropriate medication in the elderly: a systematic review of validated explicit criteria.

Eur J Clin Pharmacol. 2018 Mar 27;:

Authors: Motter FR, Fritzen JS, Hilmer SN, Paniz ÉV, Paniz VMV

Abstract
PURPOSE: Potentially inappropriate medication (PIM) use causes preventable adverse drug reactions in older patients. Several assessment tools have been published to identify and avoid PIM use. In this systematic literature review, we aim to provide summaries and comparisons of validated PIMs lists published between 1991 and 2017 internationally.
METHODS: In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Statement (PRISMA), we performed a systematic review of articles describing the development and validation of criteria for identification of PIMs among older people published between January 1991 and April 2017. The searches were conducted on PUBMED, AgeLine, Academic Search, Academic Search Premier, and CINAHL. We identified the most common medications/classes described as PIM. We also identified the drug-disease interactions and drug-drug interactions reported among criteria.
RESULTS: From 2933 articles screened, 36 met our inclusion criteria. The majority used the Delphi method to validate their criteria. We identified 907 different medications/classes, 536 different drug disease interactions involving 84 diseases/conditions, and 159 drug-drug interactions. Benzodiazepines and nonsteroidal anti-inflammatory drugs were the medications most commonly reported as potentially inappropriate for older people.
CONCLUSION: Although approaches aimed at detecting inappropriate prescribing have intensified in recent years, we observed limited overlap between different PIM lists. Additionally, some PIM lists did not provide special considerations of use and alternative therapies to avoid PIMs. These facts may compromise the use of PIM lists in clinical practice. Future PIM lists should integrate information about alternative therapies and special considerations of use in order to help clinicians in the drug prescription.

PMID: 29589066 [PubMed - as supplied by publisher]

Related Articles

Severe immune thrombocytopaenia in a patient taking benznidazole for chronic Chagas disease.

BMJ Case Rep. 2018 Mar 27;2018:

Authors: Crespillo-Andújar C, Calbacho Robles M, Norman FF, Pérez-Molina JA

Abstract
Chagas disease is a parasitic disease that mostly affects Latin American countries, but it has currently become a worldwide epidemic due to migration. Both drugs marketed for its treatment (benznidazole and nifurtimox) are associated with a high rate of adverse reactions. Benznidazole is preferred initially because of its more favourable toxicity profile and perceived greater efficacy. Hypersensitivity dermatological reactions, gastrointestinal and neurological disturbances represent the most common drug-related adverse events. General symptoms such as fever, arthralgia, myalgia or bone marrow depression (leucopaenia) are seen less frequently. We describe the case of a 33-year-old woman with chronic Chagas disease who presented with acute gingival bleeding and severe thrombocytopaenia, probably related to benznidazole treatment. Temporal association with drug initiation and recovery after treatment withdrawal were demonstrated. Clinicians should be aware of the possible association between immune thrombocytopaenia and benznidazole, even though the pathogenesis remains unclear at present.

PMID: 29588298 [PubMed - in process]

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Notice NOT-OD-18-162 from the NIH Guide for Grants and Contracts

Funding Opportunity PAR-18-732 from the NIH Guide for Grants and Contracts. The purpose of this FOA is to stimulate research on interventions to reduce HIV/AIDS-associated stigma and its impact on the prevention and treatment of HIV/AIDS and on the quality of life of People Living with HIV/AIDS (PLWH). Specifically, this initiative will support research on a) novel stigma reduction interventions that link to increase in care-seeking behavior and/or decrease in transmission; b) reducing the impact of stigma on adolescent and/or youth health; c) strategies to cope with the complex burden of stigmatization due to HIV and one or more comorbidities/coinfections; d) reducing effects of stigma on and/or by family members or caregivers of PLWH; and e) innovative and improved stigma measurement in the context of implementation of an intervention. The overall goals are to understand how to reduce stigma as a factor in HIV transmission, to eliminate or mitigate the aspects of stigma that limit beneficial health outcomes for the infected and at-risk individuals and communities, and to initiate exploratory studies to determine the feasibility of stigma interventions related to HIV prevention, treatment and/or care in Low and Middle-Income Countries (LMICs).

Funding Opportunity PAR-18-727 from the NIH Guide for Grants and Contracts. The purpose of this Funding Opportunity Announcement (FOA) is to promote research on food specific molecular signatures and biomarkers of dietary consumption and to promote collaborative interactions among NIH and USDA supported nutrition researchers.

Funding Opportunity RFA-DA-19-006 from the NIH Guide for Grants and Contracts. The NIH Research Education Program (R25) supports research education activities in the mission areas of the NIH. The over-arching goal of this NIDA R25 program is to support educational activities that complement and/or enhance the training of a workforce to meet the nations biomedical, behavioral and clinical research needs in the use of ABCD data. To accomplish the stated over-arching goal, this FOA will support creative educational activities with a primary focus on Courses for Skills Development and Research Experience involving cooperative and competitive use of ABCD datas

Funding Opportunity PA-18-729 from the NIH Guide for Grants and Contracts. IC reissue of FOA in response to the new clinical trial requirements. This funding opportunity announcement (FOA) calls for research on the health of transgender and gender nonconforming people of all ages, including both youth and adults who are questioning their gender identity and those individuals who are making or who have made a transition from being identified as one gender to the other. This group encompasses individuals whose gender identity differs from the sex on their original birth certificate or whose gender expression varies significantly from what is traditionally associated with or typical for that sex.

Funding Opportunity PA-18-728 from the NIH Guide for Grants and Contracts. IC reissue of FOA in response to the new clinical trial requirements. This funding opportunity announcement (FOA) calls for research on the health of transgender and gender nonconforming people of all ages, including both youth and adults who are questioning their gender identity and those individuals who are making or who have made a transition from being identified as one gender to the other. This group encompasses individuals whose gender identity differs from the sex on their original birth certificate or whose gender expression varies significantly from what is traditionally associated with or typical for that sex.

Funding Opportunity PA-18-718 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) will support high risk and high reward basic and translational studies aimed at understanding the etiology, and the cellular and molecular mechanisms, including the environmental, genetic, epigenetic, biologic, and immunologic factors causing and/or associated with Hidradenitis Suppurativa. The purpose is to accelerate discovery in this field of research and to apply new knowledge to improve patients condition and ultimately better control disease. This FOA intends to support a broad range of mechanistic studies using animal and human models, with an emphasis on multidisciplinary collaboration for rapid bench-to-bedside exchange of information and therapy development. This FOA is not intended to support applications proposing epidemiology studies and/or clinical trials.

Funding Opportunity PA-18-719 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) will support basic and translational studies aimed at understanding the etiology, and the cellular and molecular mechanisms, including the environmental, genetic, epigenetic, biologic, and immunologic factors causing and/or associated with Hidradenitis Suppurativa. The purpose is to accelerate discovery in this field of research and to apply new knowledge to improve patients condition and ultimately better control disease. This FOA intends to support a broad range of mechanistic studies using animal and human models, with an emphasis on multidisciplinary collaboration for rapid bench-to-bedside exchange of information and therapy development. This FOA is not intended to support applications proposing epidemiology studies and/or clinical trials.

Funding Opportunity PAR-18-721 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) encourages applications for Countermeasures Against Chemical Threats (CounterACT) exploratory/developmental translational research (R21). The mission of the CounterACT program is to foster and support research and development of new and improved therapeutics to mitigate the health effects of chemical threats. Chemical threats are toxic chemicals that could be used in a terrorist attack or accidentally released from industrial production, storage or shipping. They include traditional chemical warfare agents, toxic industrial chemicals, pesticides, and pharmaceutical-based agents. The scope of the research includes basic toxicological research on the chemical threat for the purpose of target and therapeutic hit identification, hit validation, lead optimization, and demonstration of in vivo ADME/Tox and efficacy. Projects supported by this FOA are expected to generate preliminary data that would facilitate the development of competitive applications for more extensive support from the NIH CounterACT Cooperative Agreement programs or other related initiatives.

Funding Opportunity RFA-GM-18-003 from the NIH Guide for Grants and Contracts. The Coordination Center for the Models of Infectious Disease Agent Study (MIDAS) program will serve as a hub for collaboration, testing and dissemination of research products from the network of MIDAS investigators. The Coordination Center will also serve as the primary repository for MIDAS related datasets, models and software. The Coordination Center will maintain, promote and maximize utility and use of the shared MIDAS resources. In addition, the Program Director(s)/Principal Investigator(s) of the Coordination Center will proactively develop collaborative activities and training opportunities intended to enhance the utility of MIDAS resources and to improve the training experiences for members of the MIDAS network and their graduate students and postdoctoral researchers. Limited funding will also be provided to allow the Coordination Center to conduct impactful research on the evaluation and meta-analysis of existing modeling resources for the study of infectious disease spread and intervention.

Funding Opportunity PAR-18-726 from the NIH Guide for Grants and Contracts. The purpose of this Funding Opportunity Announcement (FOA) is to encourage institutions to propose creative and innovative institutional research career development programs which prepare clinically-trained vision scientists for independent research careers. This initiative is intended to expand and strengthen the community of investigators engaged in clinical research. Such an increase in the number of well-trained clinical researchers is necessary to achieve a pool of scientists with contemporary, multidisciplinary expertise able to leverage recent advances in ocular genetics, therapeutics, bioengineering, and bio-behavioral research in order to enhance patient treatment and to increase scientific momentum in these fields. This Funding Opportunity Announcement (FOA) allows appointment of Scholars (K12) proposing a separate ancillary study to an existing trial or proposing to gain research experience in a clinical trial led by another investigator, as part of their research and career development. Applications supported by this FOA that meet the NIH definition of a clinical trial (see NOT-OD-15-015) must also fulfill the NIH requirements for either a mechanistic or minimal risk trial. A mechanistic trial is designed to understand a biological or behavioral process, the pathophysiology of a disease, or the mechanism of action of an intervention. A minimal risk trial is one in which the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests. A proposed research career development program that includes a clinical trial that is not a mechanistic trial and/or involves a level of risk beyond that defined as minimal, will not be supported. Applicants are strongly advised to consult with NEI program staff prior to submitting an application with human subjects to determine the

Funding Opportunity RFA-FD-18-016 from the NIH Guide for Grants and Contracts. The FDA Center for Drug Evaluation and Research (CDER) is encouraging applications to explore the development of HL7 Fast Healthcare Interoperability Resources (FHIR) standards to address healthcare and clinical research information exchange.