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1.
J Genet Couns ; 2019 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-31478310

RESUMO

BACKGROUND: Despite growing evidence of diagnostic yield and clinical utility of whole exome sequencing (WES) in patients with undiagnosed diseases, there remain significant cost and reimbursement barriers limiting access to such testing. The diagnostic yield and resulting clinical actions of WES for patients who previously faced insurance coverage barriers have not yet been explored. METHODS: We performed a retrospective descriptive analysis of clinical WES outcomes for patients facing insurance coverage barriers prior to clinical WES and who subsequently enrolled in the Undiagnosed Diseases Network (UDN). Clinical WES was completed as a result of participation in the UDN. Payer type, molecular diagnostic yield, and resulting clinical actions were evaluated. RESULTS: Sixty-six patients in the UDN faced insurance coverage barriers to WES at the time of enrollment (67% public payer, 26% private payer). Forty-two of 66 (64%) received insurance denial for clinician-ordered WES, 19/66 (29%) had health insurance through a payer known not to cover WES, and 5/66 (8%) had previous payer denial of other genetic tests. Clinical WES results yielded a molecular diagnosis in 23 of 66 patients (35% [78% pediatric, 65% neurologic indication]). Molecular diagnosis resulted in clinical actions in 14 of 23 patients (61%). CONCLUSIONS: These data demonstrate that a substantial proportion of patients who encountered insurance coverage barriers to WES had a clinically actionable molecular diagnosis, supporting the notion that WES has value as a covered benefit for patients who remain undiagnosed despite objective clinical findings.

2.
Comput Biol Med ; 111: 103337, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31279981

RESUMO

Planning and practice of surgical procedures can be improved through the use of modelling. This study provides an insight into the biopsy needle (i.e. hollow cannula) and needle-tissue interactions using a modelling approach, thus enabling the optimization of needle-tip designs not only for training but also for the planning of surgical procedures. Simulations of needle insertion into agar gel were performed using a Coupled Eulerian-Lagrangian (CEL) based finite element (FE) analysis, adapted for large deformation and tissue fracture. The experimental work covers needle insertion into 3% agar gel using a needle with a beveled tip of various angles, to assess the validity of the simulation. The simulated needle deflection and insertion force for two needles (i.e. Needle 1 with 18° bevel angle and Needle 2 with 27° bevel angle) were compared with corresponding experimental results. The contact stress (i.e. contact pressure) on the needles from the agar gel during the insertion of the needles were also studied. Observations indicate that varying the needle bevel angle from 27° to 18° results in a decrease of the peak force (i.e. puncture force) and an increase in needle deflection. Quantitatively, the percentage errors between the experimental data and the FE model for the total insertion force along the z-direction (i.e. Z Force) for Needle 1 and 2 were 4% and 4.8% (p > 0.05), respectively. Similarly, needle deflection percentage errors along the x-z plane were 5.7% and 10% respectively. Therefore, the forces and needle deflection values predicted by the simulation are a close approximation of the experimental model, validating the Coupled Eulerian-Lagrangian based FE model. Thus, providing an experimentally validated model for biopsy and cytology needle design in silico that has the potential to replace the current build and break approach of needle design used by manufacturers.

3.
Hum Genomics ; 13(1): 24, 2019 05 29.
Artigo em Inglês | MEDLINE | ID: mdl-31142362

RESUMO

The HUGO Committee on Ethics, Law and Society (CELS) undertook a Working Group exploration of the key ethical issues arising from genome sequencing in 2013. The Imagined Futures paper the group subsequently published proposed points to consider when applying genomic bioinformatics to data repositories used in genomic medicine and research ( http://www.hugo-international.org/Resources/Documents/CELS_Article-ImaginedFutures_2014.pdf ). Given the ever-increasing power to sequence the human genome rapidly and inexpensively-as well as trends toward "Big Data" and "Open Science"-we take this opportunity to update and refine the key findings of that paper.

4.
Am J Med Genet A ; 179(6): 958-965, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30903737

RESUMO

The Undiagnosed Diseases Network (UDN) aims to achieve a unifying etiologic diagnosis for patients with mysterious conditions. Although the UDN has focused on the identification of genetic determinants, environmental etiologies may be causative or modifying agents that interact with predisposing genes. We developed and implemented a screening questionnaire to assess environmental exposures in UDN patients. We hypothesized that patients with potentially adverse environmental exposures would be less likely to have a genetic basis for their undiagnosed disease. Among seven postnatal environmental exposure categories assessed in 269 UDN participants, patients with a confirmed or strong candidate genetic diagnosis were significantly less likely to report exposures to metals, dust, or chemicals (p < 0.05). A composite variable of the seven exposure categories was substantially more common (40%) in patients without a genetic diagnosis than in those with a genetic diagnosis (18.4%) (p = 0.004). In multivariable analysis adjusting for age and sex, the composite variable of any positive environmental exposure was associated with a reduced odds of finding a genetic diagnosis (OR 0.41, 95% CI 0.18-0.96, p = 0.04). These results were generally robust to exclusion of patients with early life disease onset. Our results suggest a possible approach to increase the yield of genetic etiologies for adult undiagnosed diseases by first focusing on patients without significant environmental exposures. Still, there is ample reason to expect cases in which specific environmental exposures impact the risk of clinically evident genetic disease. Our findings emphasize the importance of systematic investigations of potential environmental risk factors for undiagnosed diseases.

5.
J Control Release ; 296: 202-224, 2019 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-30664977

RESUMO

Treating diseases of the central nervous system (CNS) is complicated by the presence of the blood-brain barrier (BBB), a semipermeable boundary layer protecting the CNS from toxins and homeostatic disruptions. However, this layer also excludes almost 100% of therapeutics, impeding the treatment of CNS diseases. The advent of nanoparticles, in particular metallic-based nanoparticles, presents the potential to overcome this barrier and transport drugs into the CNS. Recent interest in metallic-based nanoparticles has generated an immense array of information pertaining to nanoparticles of different materials, sizes, morphologies, and surface properties. Nanoparticles with different physico-chemical properties lead to distinct nanoparticle-host interactions; yet, comprehensive characterization is often not completed. Similarly, in vivo testing has involved a mixed evaluation of parameters, including: BBB permeability, integrity, biodistribution, and toxicity. The methods applied to assess these parameters are inconsistent; this complicates the comparison of different nanoparticle-host system responses. A systematic review was conducted to investigate the methods by which metallic-based nanoparticles are characterized and assessed in vivo. The introduction of a standardized approach to nanoparticle characterization and in vivo testing is crucial if research is to transition to a clinical setting. The approach suggested, herein, is based on equipment and techniques that are accessible and informative to facilitate the routine incorporation of this standardized, informative approach into different research settings. Thorough characterization could lead to improved interpretation of in vivo responses, which could clarify nanoparticle properties that result in favorable in vivo outcomes whilst exposing nanoparticle-specific weaknesses. Only then will researchers successfully identify nanoparticles capable of delivering life-saving therapeutics across the blood-brain barrier.

6.
N Engl J Med ; 379(22): 2131-2139, 2018 11 29.
Artigo em Inglês | MEDLINE | ID: mdl-30304647

RESUMO

BACKGROUND: Many patients remain without a diagnosis despite extensive medical evaluation. The Undiagnosed Diseases Network (UDN) was established to apply a multidisciplinary model in the evaluation of the most challenging cases and to identify the biologic characteristics of newly discovered diseases. The UDN, which is funded by the National Institutes of Health, was formed in 2014 as a network of seven clinical sites, two sequencing cores, and a coordinating center. Later, a central biorepository, a metabolomics core, and a model organisms screening center were added. METHODS: We evaluated patients who were referred to the UDN over a period of 20 months. The patients were required to have an undiagnosed condition despite thorough evaluation by a health care provider. We determined the rate of diagnosis among patients who subsequently had a complete evaluation, and we observed the effect of diagnosis on medical care. RESULTS: A total of 1519 patients (53% female) were referred to the UDN, of whom 601 (40%) were accepted for evaluation. Of the accepted patients, 192 (32%) had previously undergone exome sequencing. Symptoms were neurologic in 40% of the applicants, musculoskeletal in 10%, immunologic in 7%, gastrointestinal in 7%, and rheumatologic in 6%. Of the 382 patients who had a complete evaluation, 132 received a diagnosis, yielding a rate of diagnosis of 35%. A total of 15 diagnoses (11%) were made by clinical review alone, and 98 (74%) were made by exome or genome sequencing. Of the diagnoses, 21% led to recommendations regarding changes in therapy, 37% led to changes in diagnostic testing, and 36% led to variant-specific genetic counseling. We defined 31 new syndromes. CONCLUSIONS: The UDN established a diagnosis in 132 of the 382 patients who had a complete evaluation, yielding a rate of diagnosis of 35%. (Funded by the National Institutes of Health Common Fund.).

7.
J Endourol ; 2018 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-30221548

RESUMO

PURPOSE: To investigate the principles that govern ureteral stent failure by digitally and mechanically characterizing their luminal reduction in response to various extrinsic compression forces. To explore the relationship between ureteral stent "material area," "luminal area," and "cross-sectional area (CSA)" for resisting extrinsic compression forces. MATERIALS AND METHODS: We mechanically investigated 4.8F (n = 9), 6F (n = 9), and 7F (n = 9) ureteral stents to determine parameters that contribute to resisting radial compression forces. Digitalized images of luminal reduction values under incrementally increased reductions of stent outer diameters were obtained (0%, 25%, 50%, and 60% of original outer diameter). Forces (Newton [N]) and percentage luminal reduction that resulted in complete ureteral stent obstruction were determined. RESULTS: Uniaxial incremental compression in the radial direction demonstrated complete luminal reduction (95%-100%) when 58% to 62% of the outer stent diameter was compressed. The 6F ureteral stents demonstrated the greatest resistance to extrinsic compression and the greatest "material area" relative to "CSA" (mm2). The force (N) required for 50% compression of outer stent diameter was 10.44, 28.13, and 25.39 N for 4.8F, 6F, and 7F ureteral stents, respectively. The "material area"/"CSA" at 50% compression of the outer stent diameter was 76%, 86%, and 78% for 4.8F, 6F, and 7F ureteral stents, respectively. CONCLUSIONS: Maintenance of intraluminal stent diameter in the presence of extrinsic compressive forces is primarily dependent on the stent's ratio of "material area" to "CSA." Urologists should be aware of these findings to decrease the risk of ureteral stent failure when treating extrinsic ureteral obstruction.

8.
Acta Biomater ; 80: 237-246, 2018 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-30208332

RESUMO

The meninges are pivotal in protecting the brain against traumatic brain injury (TBI), an ongoing issue in most mainstream sports. Improved understanding of TBI biomechanics and pathophysiology is desirable to improve preventative measures, such as protective helmets, and advance our TBI diagnostic/prognostic capabilities. This study mechanically characterised the porcine meninges by performing uniaxial tensile testing on the dura mater (DM) tissue adjacent to the frontal, parietal, temporal, and occipital lobes of the cerebellum and superior sagittal sinus region of the DM. Mechanical characterisation revealed a significantly higher elastic modulus for the superior sagittal sinus region when compared to other regions in the DM. The superior sagittal sinus and parietal regions of the DM also displayed local mechanical anisotropy. Further, fatigue was noted in the DM following ten preconditioning cycles, which could have important implications in the context of repetitive TBI. To further understand differences in regional mechanical properties, regional variations in protein content (collagen I, collagen III, fibronectin and elastin) were examined by immunoblot analysis. The superior sagittal sinus was found to have significantly higher collagen I, elastin, and fibronectin content. The frontal region was also identified to have significantly higher collagen I and fibronectin content while the temporal region had increased elastin and fibronectin content. Regional differences in the mechanical and biochemical properties along with regional tissue thickness differences within the DM reveal that the tissue is a non-homogeneous structure. In particular, the potentially influential role of the superior sagittal sinus in TBI biomechanics warrants further investigation. STATEMENT OF SIGNIFICANCE: This study addresses the lack of regional mechanical analysis of the cortical meninges, particularly the dura mater (DM), with accompanying biochemical analysis. To mechanically characterise the stiffness of the DM by region, uniaxial tensile testing was carried out on the DM tissue adjacent to the frontal, parietal, temporal and occipital lobes along with the DM tissue associated with the superior sagittal sinus. To the best of the authors' knowledge, the work presented here identifies, for the first time, the heterogeneous nature of the DM's mechanical stiffness by region. In particular, this study identifies the significant difference in the stiffness of the DM tissue associated with the superior sagittal sinus when compared to the other DM regions. Constitutive modelling was carried out on the regional mechanical testing data for implementation in Finite Element models with improved biofidelity. This work also presents the first biochemical analysis of the collagen I and III, elastin, and fibronectin content within DM tissue by region, providing useful insights into the accompanying macro-scale biomechanical data.

9.
Curr Stem Cell Res Ther ; 13(6): 458-465, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29697030

RESUMO

BACKGROUND: The urinary bladder and urethra comprise the lower urinary tracts. Pathological conditions that affect both structures necessitate reconstructive urological intervention with autologous tissue sources that cause neuromechanical and metabolic complications. Stem-cell therapies may offer an attractive alternative as they can replicate important host derived cellular functions such as mitosis, proliferation, differentiation and apoptosis. OBJECTIVE: To provide an overview on the application of stem cell therapies for regenerating the lower urinary tracts and to discuss factors that need to be addressed before stem-cells can be reliably introduced into clinical urological practice. RESULTS: Advantages of stem cells in reconstructive urology are their ability to self-renew and their durability. Mesenchymal stem cells (MSCs), embryonic stem cells (ESCs) and adult stem cells (ASCs) demonstrate excellent urological regenerative properties. Repairing defective lower urinary tract structures with various stem-cell derived therapies has been widely reported with encouraging results in vitro and in pre-clinical in vivo trials. Ethical considerations, cost, regulation, manufacturing and reimbursement need to be fully transparent before stem-cells are routinely applied to urological patients. International collaboration with consensus guidelines should be considered to facilitate standards that allow safe use of stem-cell therapies in urology. CONCLUSION: Stem cells therapies in urology are developing rapidly with many important achievements to date. Despite promising in vitro and pre-clinical data; implementation of stem cells into daily urological practice is not imminent. Further investigation is required to determine whether stem-cells will provide better clinical outcomes than current urological tissue replacement strategies.


Assuntos
Regeneração/fisiologia , Medicina Regenerativa , Transplante de Células-Tronco , Engenharia Tecidual , Bexiga Urinária/citologia , Humanos , Medicina Regenerativa/métodos , Engenharia Tecidual/métodos , Uretra/citologia , Bexiga Urinária/cirurgia
10.
J Trace Elem Med Biol ; 49: 210-221, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29325805

RESUMO

A local dyshomeostasis of zinc ions in the vicinity of amyloid aggregates has been proposed in Alzheimer's disease (AD) due to the sequestration of zinc in senile plaques. While an increase in zinc levels may promote the aggregation of amyloid beta (Aß), increased brain zinc might also be beneficial rescuing some pathological alterations caused by local zinc deficiency. For example, increased Aß degradation by metalloproteinases, and a reduction in inflammation can be hypothesized. In addition, zinc may allow a stabilization of the number of synapses in AD brains. Thus, to evaluate whether altering zinc-levels within the brain is a promising new target for the prevention and treatment of AD, we employed novel zinc loaded nanoparticles able to deliver zinc into the brain across the blood-brain barrier. We performed in vivo studies using wild type (WT) and APP23 mice to assess plaque load, inflammatory status and synapse loss. Furthermore, we performed behavioral analyses. After chronically injecting these nanoparticles for 14 days, our results show a significant reduction in plaque size and effects on the pro-inflammatory cytokines IL-6 and IL-18. On behavioral level we could not detect negative effects of increased brain zinc levels in APP23 mice and treatment with g7-NP-Zn normalized the observed hyperlocomotion of APP23 mice. Therefore, we conclude that a targeted increase in brain zinc levels may have beneficial effects in AD.


Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Nanopartículas/química , Polímeros/química , Zinco/metabolismo , Zinco/uso terapêutico , Doença de Alzheimer/tratamento farmacológico , Animais , Sistema Nervoso Central/efeitos dos fármacos , Sistema Nervoso Central/metabolismo , Modelos Animais de Doenças , Feminino , Masculino , Camundongos , Nanopartículas/uso terapêutico , Reação em Cadeia da Polimerase em Tempo Real , Zinco/administração & dosagem
11.
J Natl Cancer Inst ; 110(5): 534-538, 2018 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-29228263

RESUMO

To examine whether cancer survivors diagnosed before age 35 years are more likely to have offspring with chromosomal abnormalities than their siblings, chromosomal abnormalities were determined in a population-based cohort of 14 611 offspring (14 580 live-born children and 31 fetuses) of 8945 Danish cancer survivors and 40 859 offspring (40 794 live-born children and 65 fetuses) of 19 536 siblings. Chromosomal abnormalities include numeric and structural abnormalities. Odds ratios were estimated by multiple logistic regression models comparing the risk of chromosomal abnormalities among survivors' offspring with that in siblings' offspring. In a subgroup of survivors with gonadal radiation doses (mean = 0.95 Gy for males and 0.91 Gy for females), no indication of a dose response was found. Overall, no increased risk of chromosomal abnormalities among survivors' offspring was observed compared with their siblings' offspring (odds ratio = 0.99, 95% confidence interval = 0.67 to 1.44, two-sided P = .94), with similar risk between male and female survivors. Cancer survivors were not more likely than their siblings to have children with a chromosomal abnormality.

12.
Ann Biomed Eng ; 46(2): 365-374, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29181720

RESUMO

Glaucoma is a common optic neuropathy characterized by retinal ganglion cell death. Elevated intraocular pressure (IOP), a key risk factor for glaucoma, leads to significant biomechanical deformation of optic nerve head (ONH) cells and tissues. ONH astrocytes respond to this deformation by transforming to a reactive, proliferative phenotype, which has been implicated in the progression of glaucomatous vision loss. However, little is known about the mechanisms of this transformation. In this study, we developed a 3D collagen gel culture system to mimic features of ONH deformation due to elevated IOP. Compressive loading of astrocyte-seeded collagen gels led to cell alignment perpendicular to the direction of strain, and increased astrocyte activation, as assayed by GFAP, vimentin, and s100ß levels, as well as MMP activity. This proof-of-concept study shows that this system has potential for studying mechanisms of astrocyte mechanobiology as related to the pathogenesis of glaucoma. Further work is needed to establish the possible interplay of mechanical stimulation, matrix properties, and hypoxia on the observed response of astrocytes.

13.
Hum Genomics ; 11(1): 20, 2017 08 29.
Artigo em Inglês | MEDLINE | ID: mdl-28851444

RESUMO

This paper considers the tensions created in genomic research by public and private for-profit ideals. Our intent is to strengthen the public good at a time when doing science is strongly motivated by market possibilities and opportunities. Focusing on the emergence of gene editing, and in particular CRISPR, we consider how commercialisation encourages hype and hope-a sense that only promise and idealism can achieve progress. At this rate, genomic research reinforces structures that promote, above all else, private interests, but that may attenuate conditions for the public good of science. In the first part, we situate genomics using the aphorism that 'on the shoulders of giants we see farther'; these giants are infrastructures and research cultures rather than individual 'heroes' of science. In this respect, private initiatives are not the only pivot for successful discovery, and indeed, fascination in those could impinge upon the fundamental role of public-supported discovery. To redress these circumstances, we define the extent to which progress presupposes research strategies that are for the public good. In the second part, we use a 'falling giant' narrative to illustrate the risks of over-indulging for-profit initiatives. We therefore offer a counterpoint to commercialised science, using three identifiable 'giants'-scientists, publics and cultures-to illustrate how the public good contributes to genomic discovery.


Assuntos
Pesquisa Biomédica , Edição de Genes/ética , Genética Médica , Genômica/métodos , Opinião Pública , Comunicação , Humanos
14.
Am J Obstet Gynecol ; 217(3): 249-262, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28578176

RESUMO

Only through concerted and well-executed research endeavors can we gain the requisite knowledge to advance pregnancy care and have a positive impact on maternal and newborn health. Yet the heterogeneity inherent in individual studies limits our ability to compare and synthesize study results, thus impeding the capacity to draw meaningful conclusions that can be trusted to inform clinical care. The PhenX Toolkit (http://www.phenxtoolkit.org), supported since 2007 by the National Institutes of Health, is a web-based catalog of standardized protocols for measuring phenotypes and exposures relevant for clinical research. In 2016, a working group of pregnancy experts recommended 15 measures for the PhenX Toolkit that are highly relevant to pregnancy research. The working group followed the established PhenX consensus process to recommend protocols that are broadly validated, well established, nonproprietary, and have a relatively low burden for investigators and participants. The working group considered input from the pregnancy experts and the broader research community and included measures addressing the mode of conception, gestational age, fetal growth assessment, prenatal care, the mode of delivery, gestational diabetes, behavioral and mental health, and environmental exposure biomarkers. These pregnancy measures complement the existing measures for other established domains in the PhenX Toolkit, including reproductive health, anthropometrics, demographic characteristics, and alcohol, tobacco, and other substances. The preceding domains influence a woman's health during pregnancy. For each measure, the PhenX Toolkit includes data dictionaries and data collection worksheets that facilitate incorporation of the protocol into new or existing studies. The measures within the pregnancy domain offer a valuable resource to investigators and clinicians and are well poised to facilitate collaborative pregnancy research with the goal to improve patient care. To achieve this aim, investigators whose work includes the perinatal population are encouraged to utilize the PhenX Toolkit in the design and implementation of their studies, thus potentially reducing heterogeneity in data measures across studies. Such an effort will enhance the overall impact of individual studies, increasing the ability to draw more meaningful conclusions that can then be translated into clinical practice.


Assuntos
Bases de Dados Factuais/normas , Projetos de Pesquisa/normas , Software , Feminino , Humanos , Internet , Fenótipo , Gravidez , Pesquisa/normas
15.
Br Med Bull ; 122(1): 17-29, 2017 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-28334154

RESUMO

Background: The avalanche of commentaries on CRISPR-Cas9 technology, a bacterial immune system modified to recognize any short DNA sequence, cut it out, and insert a new one, has rekindled hopes for gene therapy and other applications and raised criticisms of engineering genes in future generations. Sources of data: This discussion draws on articles that emphasize ethics, identified partly through PubMed and Google, 2014-2016. Areas of agreement: CRISPR-Cas9 has taken the pace and prospects for genetic discovery and applications to a high level, stoking anticipation for somatic gene engineering to help patients. We support a moratorium on germ line manipulation. Areas of controversy: We place increased emphasis on the principle of solidarity and the public good. The genetic bases of some diseases are not thoroughly addressable with CRISPR-Cas9. We see no new ethical issues, compared with gene therapy and genetic engineering in general, apart from the explosive rate of findings. Other controversies include eugenics, patentability and unrealistic expectations of professionals and the public. Growing points: Biggest issues are the void of research on human germ cell biology, the appropriate routes for oversight and transparency, and the scientific and ethical areas of reproductive medicine. Areas timely for developing research: The principle of genomic solidarity and priority on public good should be a lens for bringing clarity to CRISPR debates. The valid claim of genetic exceptionalism supports restraint on experimentation in human germ cells, given the trans-generational dangers and the knowledge gap in germ cell biology.


Assuntos
Sistemas CRISPR-Cas , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Edição de Genes/ética , Engenharia Genética/ética , Edição de Genes/métodos , Terapia Genética/ética , Humanos
16.
Am J Hum Genet ; 100(2): 185-192, 2017 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-28157539

RESUMO

Diagnosis at the edges of our knowledge calls upon clinicians to be data driven, cross-disciplinary, and collaborative in unprecedented ways. Exact disease recognition, an element of the concept of precision in medicine, requires new infrastructure that spans geography, institutional boundaries, and the divide between clinical care and research. The National Institutes of Health (NIH) Common Fund supports the Undiagnosed Diseases Network (UDN) as an exemplar of this model of precise diagnosis. Its goals are to forge a strategy to accelerate the diagnosis of rare or previously unrecognized diseases, to improve recommendations for clinical management, and to advance research, especially into disease mechanisms. The network will achieve these objectives by evaluating patients with undiagnosed diseases, fostering a breadth of expert collaborations, determining best practices for translating the strategy into medical centers nationwide, and sharing findings, data, specimens, and approaches with the scientific and medical communities. Building the UDN has already brought insights to human and medical geneticists. The initial focus has been on data sharing, establishing common protocols for institutional review boards and data sharing, creating protocols for referring and evaluating patients, and providing DNA sequencing, metabolomic analysis, and functional studies in model organisms. By extending this precision diagnostic model nationally, we strive to meld clinical and research objectives, improve patient outcomes, and contribute to medical science.


Assuntos
Doenças Raras/diagnóstico , Doenças Raras/genética , Genótipo , Técnicas de Genotipagem , Humanos , Disseminação de Informação/métodos , Metabolômica , National Institutes of Health (U.S.) , Fenótipo , Análise de Sequência de DNA , Estados Unidos
17.
Front Mol Neurosci ; 10: 456, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29386995

RESUMO

Neuronal metal ions such as zinc are essential for brain function. In particular synaptic processes are tightly related to metal and protein homeostasis, for example through extracellular metal-binding proteins. One such protein is neuronal S100B, a calcium and zinc binding damage-associated molecular pattern (DAMP), whose chronic upregulation is associated with aging, Alzheimer's disease (AD), motor neuron disease and traumatic brain injury (TBI). Despite gained insights on the structure of S100B, it remains unclear how its calcium and zinc binding properties regulate its function on cellular level. Here we report a novel role of S100B in trace metal homeostasis, in particular the regulation of zinc levels in the brain. Our results show that S100B at increased extracellular levels is not toxic, persists at high levels, and is taken up into neurons, as shown by cell culture and biochemical analysis. Combining protein bioimaging and zinc quantitation, along with a zinc-binding impaired S100B variant, we conclude that S100B effectively scavenges zinc ions through specific binding, resulting in a redistribution of the intracellular zinc pool. Our results indicate that scavenging of zinc by increased levels of S100B affects calcium levels in vitro. Thereby S100B is able to mediate the cross talk between calcium and zinc homeostasis. Further, we investigated a possible new neuro-protective role of S100B in excitotoxicity via its effects on calcium and zinc homeostasis. Exposure of cells to zinc-S100B but not the zinc-binding impaired S100B results in an inhibition of excitotoxicity. We conclude that in addition to its known functions, S100B acts as sensor and regulator of elevated zinc levels in the brain and this metal-buffering activity is tied to a neuroprotective role.

18.
J Biomech ; 49(15): 3697-3704, 2016 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-27776741

RESUMO

This study compares the mechanical properties of excised carotid and femoral human plaques and also develops a predictor of these properties based on plaque composition. Circumferential planar tension tests were performed on 24 carotid and 16 femoral plaque samples. Composition was characterised using Fourier Transform Infrared spectroscopy. Stretch at failure, strength, and stiffness are significantly higher in the carotid group (P=.012, P<.001 and P=.002, respectively). The ratio of calcified to lipid plaque content demonstrates the strongest correlation with the stretch at failure and strength (R2=.285, P<.001 and R2=.347, P<.001). No composition based parameter correlates significantly with stiffness. The significantly different mechanical properties of the two groups aids in explaining the varying endovascular treatment outcomes clinically observed in these vessels. Furthermore, determining the ratio of calcified to lipid plaque content may be useful in predicting individual plaque mechanical response to endovascular treatment.


Assuntos
Artérias Carótidas/fisiologia , Artéria Femoral/fisiologia , Placa Aterosclerótica/fisiopatologia , Idoso , Artérias Carótidas/patologia , Feminino , Artéria Femoral/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Placa Aterosclerótica/patologia , Espectroscopia de Infravermelho com Transformada de Fourier
19.
Genet Med ; 18(11): 1075-1084, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27171546

RESUMO

The introduction of diagnostic clinical genome and exome sequencing (CGES) is changing the scope of practice for clinical geneticists. Many large institutions are making a significant investment in infrastructure and technology, allowing clinicians to access CGES, especially as health-care coverage begins to extend to clinically indicated genomic sequencing-based tests. Translating and realizing the comprehensive clinical benefits of genomic medicine remain a key challenge for the current and future care of patients. With the increasing application of CGES, it is necessary for geneticists and other health-care providers to understand its benefits and limitations in order to interpret the clinical relevance of genomic variants identified in the context of health and disease. New, collaborative working relationships with specialists across diverse disciplines (e.g., clinicians, laboratorians, bioinformaticians) will undoubtedly be key attributes of the future practice of clinical genetics and may serve as an example for other specialties in medicine. These new skills and relationships will also inform the development of the future model of clinical genetics training curricula. To address the evolving role of the clinical geneticist in the rapidly changing climate of genomic medicine, two Clinical Genetics Think Tank meetings were held that brought together physicians, laboratorians, scientists, genetic counselors, trainees, and patients with experience in clinical genetics, genetic diagnostics, and genetics education. This article provides recommendations that will guide the integration of genomics into clinical practice.Genet Med 18 11, 1075-1084.


Assuntos
Aconselhamento Genético/tendências , Genética Médica/tendências , Genoma Humano/genética , Genômica , Exoma/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos
20.
Mol Genet Metab ; 117(4): 393-400, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26846157

RESUMO

INTRODUCTION: The inability of some seriously and chronically ill individuals to receive a definitive diagnosis represents an unmet medical need. In 2008, the NIH Undiagnosed Diseases Program (UDP) was established to provide answers to patients with mysterious conditions that long eluded diagnosis and to advance medical knowledge. Patients admitted to the NIH UDP undergo a five-day hospitalization, facilitating highly collaborative clinical evaluations and a detailed, standardized documentation of the individual's phenotype. Bedside and bench investigations are tightly coupled. Genetic studies include commercially available testing, single nucleotide polymorphism microarray analysis, and family exomic sequencing studies. Selected gene variants are evaluated by collaborators using informatics, in vitro cell studies, and functional assays in model systems (fly, zebrafish, worm, or mouse). INSIGHTS FROM THE UDP: In seven years, the UDP received 2954 complete applications and evaluated 863 individuals. Nine vignettes (two unpublished) illustrate the relevance of an undiagnosed diseases program to complex and common disorders, the coincidence of multiple rare single gene disorders in individual patients, newly recognized mechanisms of disease, and the application of precision medicine to patient care. CONCLUSIONS: The UDP provides examples of the benefits expected to accrue with the recent launch of a national Undiagnosed Diseases Network (UDN). The UDN should accelerate rare disease diagnosis and new disease discovery, enhance the likelihood of diagnosing known diseases in patients with uncommon phenotypes, improve management strategies, and advance medical research.


Assuntos
National Institutes of Health (U.S.) , Medicina de Precisão , Doenças Raras/diagnóstico , Pesquisa , Humanos , Medicina de Precisão/métodos , Doenças Raras/etiologia , Estados Unidos
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