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2.
J Recept Signal Transduct Res ; : 1-9, 2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31509043

RESUMO

Cardiotonic steroids (CTS) are steroidal drugs, processed from the seeds and dried leaves of the genus Digitalis as well as from the skin and parotid gland of amphibians. The most commonly known CTS are ouabain, digoxin, digoxigenin and bufalin. CTS can be used for safer medication of congestive heart failure and other related conditions due to promising pharmacological and medicinal properties. Ouabain isolated from plants is widely utilized in in vitro studies to specifically block the sodium potassium (Na+/K+-ATPase) pump. For checking, whether ouabain derivatives are robust inhibitors of Na+/K+-ATPase pump, molecular docking simulation was performed between ouabain and its derivatives using YASARA software. The docking energy falls within the range of 8.470 kcal/mol to 7.234 kcal/mol, in which digoxigenin was found to be the potential ligand with the best docking energy of 8.470 kcal/mol. Furthermore, pharmacophore modeling was applied to decipher the electronic features of CTS. Molecular dynamics simulation was also employed to determine the conformational properties of Na+/K+-ATPase-ouabain and Na+/K+-ATPase-digoxigenin complexes with the plausible structural integrity through conformational ensembles for 100 ns which promoted digoxigenin as the most promising CTS for treating conditions of congestive heart failure patients.

3.
Childs Nerv Syst ; 2019 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-31444559

RESUMO

PURPOSE: This study reviews paediatric patients with raised intracranial pressure as a result of venous sinus thrombosis secondary to otogenic mastoiditis, requiring admission to the paediatric neuroscience centre at the University Hospital Wales, Cardiff. The consensus regarding the management of otogenic hydrocephalus in the published literature is inconsistent, with a trend towards conservative over surgical management. We reviewed our management of this condition over a 9-year period especially with regard to ventriculo-peritoneal (VP) shunting. METHODS: Analysis of a prospectively collected database of paediatric surgical patients was analysed and patients diagnosed with otogenic hydrocephalus from November 2010 to August 2018 were identified. Our data was compared with the published literature on this condition. RESULTS: Eleven children, 7 males and 4 females, were diagnosed with otogenic hydrocephalus over the 9-year period. Five (45.5%) required VP shunt insertion to manage their intracranial pressure and protect their vision. The remaining six patients (54.5%) were managed medically. CONCLUSIONS: When children with mastoiditis and venous sinus thrombosis progress to having symptoms or signs of raised intracranial pressure, they should ideally be managed within a neuroscience centre. Of those children, almost half will need permanent cerebrospinal fluid diversion to protect their sight.

4.
BMJ Open ; 9(8): e029541, 2019 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-31383705

RESUMO

INTRODUCTION: Recent advances in genomic technology have allowed better delineation of renal conditions, the identification of new kidney disease genes and subsequent targets for therapy. To date, however, the utility of genomic testing in a clinically ascertained, prospectively recruited kidney disease cohort remains unknown. The aim of this study is to explore the clinical utility and cost-effectiveness of genomic testing within a national cohort of patients with suspected genetic kidney disease who attend multidisciplinary renal genetics clinics. METHODS AND ANALYSIS: This is a prospective observational cohort study performed at 16 centres throughout Australia. Patients will be included if they are referred to one of the multidisciplinary renal genetics clinics and are deemed likely to have a genetic basis to their kidney disease by the multidisciplinary renal genetics team. The expected cohort consists of 360 adult and paediatric patients recruited by December 2018 with ongoing validation cohort of 140 patients who will be recruited until June 2020. The primary outcome will be the proportion of patients who receive a molecular diagnosis via genomic testing (diagnostic rate) compared with usual care. Secondary outcomes will include change in clinical diagnosis following genomic testing, change in clinical management following genomic testing and the cost-effectiveness of genomic testing compared with usual care. ETHICS AND DISSEMINATION: The project has received ethics approval from the Melbourne Health Human Research Ethics Committee as part of the Australian Genomics Health Alliance protocol: HREC/16/MH/251. All participants will provide written informed consent for data collection and to undergo clinically relevant genetic/genomic testing. The results of this study will be published in peer-reviewed journals and will also be presented at national and international conferences.

6.
Cell Host Microbe ; 26(2): 283-295.e8, 2019 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-31415755

RESUMO

Despite substantial interest in the species diversity of the human microbiome and its role in disease, the scale of its genetic diversity, which is fundamental to deciphering human-microbe interactions, has not been quantified. Here, we conducted a cross-study meta-analysis of metagenomes from two human body niches, the mouth and gut, covering 3,655 samples from 13 studies. We found staggering genetic heterogeneity in the dataset, identifying a total of 45,666,334 non-redundant genes (23,961,508 oral and 22,254,436 gut) at the 95% identity level. Fifty percent of all genes were "singletons," or unique to a single metagenomic sample. Singletons were enriched for different functions (compared with non-singletons) and arose from sub-population-specific microbial strains. Overall, these results provide potential bases for the unexplained heterogeneity observed in microbiome-derived human phenotypes. One the basis of these data, we built a resource, which can be accessed at https://microbial-genes.bio.

7.
Nat Rev Drug Discov ; 18(9): 669-688, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31363227

RESUMO

Metabolic programming is emerging as a critical mechanism to alter immune cell activation, differentiation and function. Targeting metabolism does not completely suppress or activate the immune system but selectively regulates immune responses. The different metabolic requirements of the diverse cells that constitute an immune response provide a unique opportunity to separate effector functions from regulatory functions. Likewise, cells can be metabolically reprogrammed to promote either their short-term effector functions or long-term memory capacity. Studies in the growing field of immunometabolism support a paradigm of 'cellular selectivity based on demand', in which generic inhibitors of ubiquitous metabolic processes selectively affect cells with the greatest metabolic demand and have few effects on other cells of the body. Targeting metabolism, rather than particular cell types or cytokines, in metabolically demanding processes such as autoimmunity, graft rejection, cancer and uncontrolled inflammation could lead to successful strategies in controlling the pathogenesis of these complex disorders.

8.
Am J Hum Genet ; 105(2): 413-424, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31327508

RESUMO

WD40 repeat-containing proteins form a large family of proteins present in all eukaryotes. Here, we identified five pediatric probands with de novo variants in WDR37, which encodes a member of the WD40 repeat protein family. Two probands shared one variant and the others have variants in nearby amino acids outside the WD40 repeats. The probands exhibited shared phenotypes of epilepsy, colobomas, facial dysmorphology reminiscent of CHARGE syndrome, developmental delay and intellectual disability, and cerebellar hypoplasia. The WDR37 protein is highly conserved in vertebrate and invertebrate model organisms and is currently not associated with a human disease. We generated a null allele of the single Drosophila ortholog to gain functional insights and replaced the coding region of the fly gene CG12333/wdr37 with GAL4. These flies are homozygous viable but display severe bang sensitivity, a phenotype associated with seizures in flies. Additionally, the mutant flies fall when climbing the walls of the vials, suggesting a defect in grip strength, and repeat the cycle of climbing and falling. Similar to wall clinging defect, mutant males often lose grip of the female abdomen during copulation. These phenotypes are rescued by using the GAL4 in the CG12333/wdr37 locus to drive the UAS-human reference WDR37 cDNA. The two variants found in three human subjects failed to rescue these phenotypes, suggesting that these alleles severely affect the function of this protein. Taken together, our data suggest that variants in WDR37 underlie a novel syndromic neurological disorder.

9.
Clin Genet ; 96(4): 366-370, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31309540

RESUMO

The canonical wingless (Wnt) and fibroblast growth factor (FGF) signaling pathways involving CTNNB1 and TBX4, respectively, are crucial for the regulation of human development. Perturbations of these pathways and disruptions from biological homeostasis have been associated with abnormal morphogenesis of multiple organs, including the lung. The aim of this study was to identify the underlying genetic cause of abnormal lung growth, pulmonary hypertension (PAH), severe microcephaly, and muscle spasticity in a full-term newborn, who died at 4 months of age due to progressively worsening PAH and respiratory failure. Family trio exome sequencing showed a de novo heterozygous nonsense c.1603C>T (p.Arg535*) variant in CTNNB1 and a paternally inherited heterozygous missense c.1198G>A (p.Glu400Lys) variant in TBX4, both predicted to be likely deleterious. We expand the phenotypic spectrum associated with CTNNB1 and TBX4 variants and indicate that they could act synergistically to produce a distinct more severe phenotype. Our findings further support a recently proposed complex compound inheritance model in lethal lung developmental diseases and the contention that dual molecular diagnoses can parsimoniously explain blended phenotypes.

10.
Clin Cancer Res ; 2019 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-31320596

RESUMO

Purpose: Recommended phase II dose (RP2D) determination for combination therapy regimens is a constrained optimization problem of maximizing antitumor activity within the constraint of clinical tolerability to provide a wide therapeutic index. A methodology for addressing this problem was developed and tested using clinical and preclinical data from combinations of the investigational drugs TAK-117, a PI3Kα inhibitor, and TAK-228, a TORC1/2 dual inhibitor.Patients and Methods: Utilizing free fraction-corrected average concentrations, [Formula: see text]and [Formula: see text], which are the primary pharmacokinetic predictors of single-agent preclinical antitumor activity, a preclinical exposure-efficacy surface was characterized, allowing for nonlinear interactions between growth rate inhibition of the agents on a MDA-MB-361 cell line xenograft model. Logistic regression was used to generate an exposure-effect surface for [Formula: see text]and [Formula: see text] versus clinical toxicity outcomes [experiencing a dose-limiting toxicity (DLT)] in single-agent and combination dose-escalation studies. A maximum tolerated exposure curve was defined at which DLT probability was 25%; predicted antitumor activity along this curve was used to determine optimal RP2D.Results: The toxicity constraint curve determined from early clinical data predicted that any clinically tolerable combination was unlikely to result in greater antitumor activity than either single-agent TAK-117 or TAK-228 administered at their respective MTDs. Similar results were obtained with 10 other cell lines, with one agent or the other predicted to outperform the combination.Conclusions: This methodology represents a general, principled way of evaluating and selecting optimal RP2D combinations in oncology. The methodology will be retested upon availability of clinical data from TAK-117/TAK-228 combination phase II studies.

11.
Eur J Hum Genet ; 27(10): 1493-1501, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31148592

RESUMO

We investigated the attitudes of intensive care physicians and genetics professionals towards rapid genomic testing in neonatal and paediatric intensive care units (NICU/PICU). A mixed-methods study (surveys and interviews) was conducted at 13 Australian hospitals and three laboratories involved in multi-center implementation of rapid genomic testing. We investigated experience and confidence with genomic tests among intensivists; perceived usefulness of genomic diagnostic results; preferences for service delivery models; and implementation readiness among genetic services. The overall survey response rate was 59%, 47% for intensivists (80/170), and 75% (91/121) for genetics professionals. Intensivists reported moderate confidence with microarray tests and lower confidence with genomic tests. The majority of intensivists (77%), clinical geneticists (87%) and genetic counsellors (82%) favoured a clinical genetics-led service delivery model of genomic testing. Perceived clinical utility of genomic results was lower in the intensivist group compared to the genetics professionals group (20 v 50%, p < 0.001). Interviews (n = 6 intensivists; n = 11 genetic counselors) demonstrated support for implementation, with concerns relating to implementation environment and organizational readiness. Overall, our findings support initial implementation of genomic testing in NICU/PICU as part of an interdisciplinary service delivery model that promotes gradual adoption of genomics by the intensive care workforce while ensuring safety, sustainability, and efficiency.

12.
Aust J Gen Pract ; 48(6): 395-401, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31220878

RESUMO

BACKGROUND AND OBJECTIVES: Empirical treatment of sore throat with antibiotics has historically been aimed at preventing complications of group A ß-haemolytic streptococcus infection. Threats posed by multi-resistant organisms mean that antimicrobial stewardship is important. The aim of this study was to investigate antibiotic prescribing for tonsillopharyngitis in relation to components of the Modified Centor Criteria (MCC) documented in consultation records. METHOD: Analysis of two rural Australian general practices was performed using clinic management software. A keyword search for 'tonsillopharyngitis/tonsillitis/pharyngitis' identified consultations. RESULTS: Antibiotic prescribing was frequent and congruent with existing studies; however, documented evidence of history and examination covering MCC components was associated with lower antibiotic prescribing (77.7% versus 85.5%, P <0.001; odds ratio: 2.4; 95% confidence interval: 1.8, 3.3, P <0.0001). DISCUSSION: We believe this is the first study that assesses the correlation between documentation and prescribing. Adopting and documenting MCC may improve appropriate prescription and patient safety and significantly reduce antibiotic prescription rates.

13.
J Nucl Med ; 2019 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-31171595

RESUMO

Purpose: The aim of this study was development of an improved positron emission tomography (PET) radiotracer for measuring xC- activity with increased tumor uptake and reduced uptake in inflammatory cells compared to (S)-4-(3-18F-Fluoropropyl)-L-glutamic acid (18F-FSPG). Experimental design: A racemic glutamate derivative, 18F-hGTS13 was evaluated in cell culture and animal tumor models. 18F-hGTS13 was separated into C5-epimers and the corresponding 18F-hGTS13-isomer1 and 18F-hGTS13-isomer2 evaluated in H460 tumor bearing rats. Preliminary studies investigate the cellular uptake of 18F-hGTS13-isomer2 in multiple immune cell populations and states. Results: 18F-hGTS13 demonstrated excellent H460 tumor visualization with high tumor-to-background ratios, confirmed by ex vivo biodistribution studies. Tumor associated radioactivity of 18F-hGTS13 (7.5±0.9%ID/g, n = 3) was significantly higher than with 18F-FSPG (4.6±0.7%ID/g, n = 3, P = 0.01). 18F-hGTS13-isomer2 exhibited excellent H460 tumor visualization (6.3±1.1%ID/g, n-3), and significantly reduced uptake in multiple immune cell populations relative to 18F-FSPG. 18F-hGTS13-isomer2 exhibited increased liver uptake relative to 18F-FSPG (4.6±0.8%ID/g vs. 0.7±0.01%ID/g) limiting its application in hepatocellular carcinoma. Conclusion: 18F-hGTS13-isomer2 is a new PET radiotracer for molecular imaging of xC- activity which may provide information regarding tumor oxidation states. 18F-hGTS13-isomer2 has potential for clinical translation for imaging cancers of the thorax due to the low background signal in healthy tissue.

14.
Am J Epidemiol ; 2019 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-31172187

RESUMO

Family history is a strong risk factor for many common chronic diseases and summarizes shared environmental and genetic risk, but how this increased risk is mediated is unknown. We developed a "Family History-Wide Association Study" (FamWAS) to systematically and comprehensively test Clinical and Environmental Quantitative Traits (CEQTs) for their association with family history of disease. We implemented our method on 457 CEQTs for association with family history of diabetes, asthma, and coronary heart disease (CHD) in 42,940 adults spanning 8 waves of the 1999-2014 National Health and Nutrition Examination Survey (NHANES). We conducted pooled analyses of the 8 survey waves and analyzed trait associations using survey-weighted logistic regression. We identified 172 (37.6% of total), 32 (7.0%), and 78 (17.1%) CEQTs associated with family history of diabetes, asthma, and CHD, respectively, in sub-cohorts of individuals without the respective disease. 20 associated CEQTs were shared across family history of diabetes, asthma, and CHD, far more than expected by chance. FamWAS can examine traits not previously studied in association with family history and uncover trait overlap, highlighting a putative shared mechanism by which family history influences disease risk.

15.
Eur J Med Chem ; 177: 12-31, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31129451

RESUMO

Synthesis of novel and potent hit molecules has an eternal demand. It is our continuous study to search novel bioactive hit molecules and as a part of this, a series of novel N'-isonicotinoyl-2-methyl-4-(pyridin-2-yl)-4H-benzo[4,5]thiazolo[3,2-a]pyrimidine-3-carbohydrazide analogs (5a-5n) were synthesized with good yields by the conventional method. The various novel compounds have been characterized and identified by many analytical technique such as IR, 1H NMR, 13C NMR, mass spectral analysis, and elemental analysis. All the synthetic analogs (5a-5n) are evaluated for their in vitro antibacterial and anti-mycobacterial activities against different bacterial strains. Molecular docking and Molecular dynamics studies were helped in revealing the mode of action of these compounds through their interactions with the active site of the Mycobacterium tuberculosis enoyl reductase (InhA) enzyme. The calculated ADMET descriptors for the synthesized compounds validated good pharmacokinetic properties, confirming that these compounds could be used as templates for the development of new Anti-mycobacterial agents.


Assuntos
Antituberculosos/farmacologia , Benzotiazóis/farmacologia , Isoniazida/análogos & derivados , Isoniazida/farmacologia , Pirimidinas/farmacologia , Antituberculosos/síntese química , Antituberculosos/metabolismo , Antituberculosos/farmacocinética , Benzotiazóis/síntese química , Benzotiazóis/metabolismo , Benzotiazóis/farmacocinética , Coenzima A Ligases/química , Coenzima A Ligases/metabolismo , Isoniazida/metabolismo , Isoniazida/farmacocinética , Ligantes , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/enzimologia , Ligação Proteica , Pirimidinas/síntese química , Pirimidinas/metabolismo , Pirimidinas/farmacocinética
16.
Proc Natl Acad Sci U S A ; 116(23): 11402-11407, 2019 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-31123153

RESUMO

There is a growing need for monitoring or imaging gene therapy in the central nervous system (CNS). This can be achieved with a positron emission tomography (PET) reporter gene strategy. Here we report the development of a PET reporter gene system using the PKM2 gene with its associated radiotracer [18F]DASA-23. The PKM2 reporter gene was delivered to the brains of mice by adeno-associated virus (AAV9) via stereotactic injection. Serial PET imaging was carried out over 8 wk to assess PKM2 expression. After 8 wk, the brains were excised for further mRNA and protein analysis. PET imaging at 8 wk post-AAV delivery showed an increase in [18F]DASA-23 brain uptake in the transduced site of mice injected with the AAV mice over all controls. We believe PKM2 shows great promise as a PET reporter gene and to date is the only example that can be used in all areas of the CNS without breaking the blood-brain barrier, to monitor gene and cell therapy.

17.
Mol Imaging Biol ; 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30989436

RESUMO

PURPOSE: Pyruvate kinase M2 (PKM2) catalyzes the final step in glycolysis, the key process of tumor metabolism. PKM2 is found in high levels in glioblastoma (GBM) cells with marginal expression within healthy brain tissue, rendering it a key biomarker of GBM metabolic re-programming. Our group has reported the development of a novel radiotracer, 1-((2-fluoro- 6-[18F]fluorophenyl)sulfonyl)-4-((4-methoxyphenyl)sulfonyl)piperazine ([18F]DASA- 23), to non-invasively detect PKM2 levels with positron emission tomography (PET). PROCEDURE: U87 human GBM cells were treated with the IC50 concentration of various agents used in the treatment of GBM, including alkylating agents (temozolomide, carmustine, lomustine, procarbazine), inhibitor of topoisomerase I (irinotecan), vascular endothelial and epidermal growth factor receptor inhibitors (cediranib and erlotinib, respectively) anti-metabolite (5-fluorouracil), microtubule inhibitor (vincristine), and metabolic agents (dichloroacetate and IDH1 inhibitor ivosidenib). Following drug exposure for three or 6 days (n = 6 replicates per condition), the radiotracer uptake of [18F]DASA-23 and 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) was assessed. Changes in PKM2 protein levels were determined via Western blot and correlated to radiotracer uptake. RESULTS: Significant interactions were found between the treatment agent (n = 12 conditions total comprised 11 drugs and vehicle) and the duration of treatment (3- or 6-day exposure to each drug) on the cellular uptake of [18F]DASA-23 (p = 0.0001). The greatest change in the cellular uptake of [18F]DASA-23 was found after exposure to alkylating agents (p < 0. 0001) followed by irinotecan (p = 0. 0012), erlotinib (p = 0. 02), and 5-fluorouracil (p = 0. 005). Correlation of PKM2 protein levels and [18F]DASA-23 cellular uptake revealed a moderate correlation (r = 0.44, p = 0.15). CONCLUSIONS: These proof of principle studies emphasize the superiority of [18F]DASA-23 to [18F]FDG in detecting the glycolytic response of GBM to multiple classes of anti-neoplastic drugs in cell culture. A clinical trial evaluating the diagnostic utility of [18F]DASA-23 PET in GBM patients (NCT03539731) is ongoing.

18.
Nat Biotechnol ; 37(5): 531-539, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30886438

RESUMO

Endogenous biomarkers remain at the forefront of early disease detection efforts, but many lack the sensitivities and specificities necessary to influence disease management. Here, we describe a cell-based in vivo sensor for highly sensitive early cancer detection. We engineer macrophages to produce a synthetic reporter on adopting an M2 tumor-associated metabolic profile by coupling luciferase expression to activation of the arginase-1 promoter. After adoptive transfer in colorectal and breast mouse tumor models, the engineered macrophages migrated to the tumors and activated arginase-1 so that they could be detected by bioluminescence imaging and luciferase measured in the blood. The macrophage sensor detected tumors as small as 25-50 mm3 by blood luciferase measurements, even in the presence of concomitant inflammation, and was more sensitive than clinically used protein and nucleic acid cancer biomarkers. Macrophage sensors also effectively tracked the immunological response in muscle and lung models of inflammation, suggesting the potential utility of this approach in disease states other than cancer.


Assuntos
Arginase/sangue , Detecção Precoce de Câncer , Macrófagos/imunologia , Neoplasias/sangue , Animais , Arginase/genética , Arginase/imunologia , Biomarcadores Tumorais/sangue , Engenharia Celular , Modelos Animais de Doenças , Regulação Neoplásica da Expressão Gênica , Humanos , Luciferases/sangue , Luciferases/genética , Luciferases/imunologia , Camundongos , Neoplasias/imunologia , Neoplasias/patologia
19.
BMJ Case Rep ; 12(2)2019 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-30819681

RESUMO

Spinal arachnoid cysts (SAC) are rare in isolation and the exact aetiology is still debated. Primary (congenital) cysts are caused by structural abnormalities in the arachnoid layer and largely affect the thoracic region. Secondary cysts are induced by a multitude of factors, infection, trauma or iatrogenic response, and can affect any level of the spinal cord. While subarachnoid haemorrhage (SAH) is a relatively common condition with significant repercussions, it is extremely uncommonly associated with SAC. When present, it may develop in the months and years after the original bleed, giving rise to new neurological symptoms. Prompt treatment is needed to halt or reverse the worsening of symptoms and questions are still being asked about how best to approach this condition. A 42-year-old man presented with chronic back pain, severe worsening ataxia and numbness below the umbilicus, 7 months after treatment for a World Federation of Neurosurgical Societies grade five (WFNS V) SAH. Imaging revealed a SAC extending from T12 to L4 and causing thecal compression. This was treated with a L3 laminectomy andmarsupialisation. An improvement in neurological function was observed at 6 months. Aetiology of the SAC and its association with SAH are discussed and a review of the relevant literature is provided.


Assuntos
Cistos Aracnóideos/complicações , Cistos Aracnóideos/diagnóstico por imagem , Paraparesia/etiologia , Doenças da Medula Espinal/complicações , Doenças da Medula Espinal/diagnóstico por imagem , Hemorragia Subaracnóidea/etiologia , Adulto , Cistos Aracnóideos/cirurgia , Dor nas Costas/etiologia , Humanos , Laminectomia , Imagem por Ressonância Magnética/métodos , Masculino , Medula Espinal/diagnóstico por imagem , Medula Espinal/cirurgia , Compressão da Medula Espinal/diagnóstico por imagem , Compressão da Medula Espinal/etiologia , Compressão da Medula Espinal/cirurgia , Doenças da Medula Espinal/cirurgia , Resultado do Tratamento
20.
Aging (Albany NY) ; 11(5): 1404-1426, 2019 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-30822279

RESUMO

Phenotypic biomarkers (e.g. cholesterol, weight, and glucose) are important to diagnose and treat diseases associated with aging. However, while many biomarkers are co-dependent (e.g. glycohemoglobin and glucose), it is generally unknown how age influences their co-dependence. In the following, we analyzed 50 biomarkers in 27,508 National Health and Nutrition Examination Survey (NHANES) participants (age range: 20 to 80, mean age: 46.3 years old, sexes: 48.9% males, 51.1% females, ethnicities: 46.0% Whites, 27.8% Hispanics, 20.0% non-Hispanic Blacks, 6.1% others) to investigate how the co-dependency structure of common biomarkers evolves with age and whether differences exist between sexes and ethnicities. First, we associated the change in correlations between biomarkers with chronological age. We identified six trends and replicated our top finding (height vs. systolic blood pressure) in participants of the UK Biobank (N=470,895). We found that, on average, correlations tend to decrease with age. Secondly, we examined how biomarkers predict other biomarkers in participants of different age groups. We found 17 (34%) biomarkers whose predictability decreases with age and 5 (10%) biomarkers whose predictability increases with age. A limitation of this study is that it cannot distinguish between biological changes related to aging and generational effects. Our results can be interactively explored here: http://apps.chiragjpgroup.org/Aging_Biomarkers_Co-Dependencies/.

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