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1.
Biotechnol Bioeng ; 2019 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-31709510

RESUMO

A continuous viral inactivation (CVI) chamber has been designed to operate with acceptable residence time distribution (RTD) characteristics. However, altering the CVI's geometry and operation to accommodate the scale was not obvious. In this work, we elucidate the influence of Dean vortices and leverage the transition into the weak turbulent regime to establish relationships between input variables and process outputs. This study was targeted to understand and quantify the impact of viscosity, Dean number, internal diameter, and path length on the RTD. When the Dean number exceeds 70, radial mixing generated by the Dean vortices began to consistently alter the axial dispersive effects experienced by the pulse injection. Increasing to a Dean number of >100, the axial dispersive effects were dominated by the Dean vortices which allowed the calculation of the minimum and maximum residence time to be generated. This work provides a method to calculate operational solutions for a tubular incubation reactor in terms of path length, internal diameter, flow rate, and target minimum and maximum residence time specifications that assures both viral residence times while also establishing criteria to maximize product quality during continuous operation.

2.
J Leukoc Biol ; 2019 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-31682279

RESUMO

Discussion on exhaustion/senescence marker profiles on human T cells in BRGSF-A2 humanized mice and how they resemble those in human samples; describes how this model fits into the humanized-mouse research field.

3.
J Surg Orthop Adv ; 28(3): 215-223, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31675299

RESUMO

Significant debate persists about posterior cruciate-retaining (CR) versus posterior cruciate-substituting (PS) implant design for total knee arthroplasty (TKA). This study sought to test the hypothesis that CR TKA will facilitate improved early functional outcomes in gait compared with PS TKA. Patients were randomized to either the CR or PS implant. Various patient-reported and surgeon-reported outcomes as well as gait analyses were obtained pre- and postoperatively. Patients undergoing PS TKA had higher University of California, Los Angeles activity scores at 12 months. No significant difference in spatiotemporal, kinematic, or kinetic parameters between groups was detected, but there was a trend toward quadriceps overuse gait pattern in the CR group. Patients undergoing TKA with a PS implant were more willing to engage in regular higher level physical activity. The CR implant may be a risk factor for quadriceps overuse gait pattern, while the PS implant may be protective against quadriceps overuse. (Journal of Surgical Orthopaedic Advances 28(3):215-223, 2019).


Assuntos
Artroplastia do Joelho , Prótese do Joelho , Ligamento Cruzado Posterior , Artroplastia do Joelho/métodos , Fenômenos Biomecânicos , Marcha , Humanos , Articulação do Joelho , Estudos Prospectivos , Amplitude de Movimento Articular
4.
J Card Surg ; 2019 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-31705822

RESUMO

BACKGROUND: Congenital heart disease (CHD) continues to be among the most common birth defects, affecting an estimated 40 000 births annually in the United States. The most common complication of CHD is heart failure. With improved medical management and surgical outcomes, survival for complex congenital heart defects has dramatically improved, but consequentially there are more adults with CHD than children with CHD. Due to longer-term sequelae of CHD, surgical and medical treatment previously thought to be curative is now realized at best to be palliative, and there is a considerable burden of CHD-related heart failure. Stem cell therapy as an adjunct to current surgical and medical strategies is being explored in an effort to ameliorate CHD-related heart failure. This review aims to explore the current literature with regard to stem cell therapy for CHD as well as ongoing trials. METHODS: A MEDLINE (Ovid), MEDLINE (Pubmed), and clinicaltrials.gov search were performed using the medical subject headings congenital heart defects combined with hematopoietic stem cells, stem cell transplantation, mesenchymal stem cells (MSC), cell- or tissue-based therapy, or MSC transplantation. Articles must have been published after 2010. RESULTS: Twenty three articles and 9 ongoing trials met all inclusion criteria. CONCLUSIONS: Areas of interest include myocardiocyte regeneration, tissue graft development to minimize reoperations, and methods of stem cell delivery. While several small trials are showing promise, it is too soon to make definitive statements about the future of stem cell therapies in this field.

5.
Eur Radiol ; 2019 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-31728683

RESUMO

The original version of this article, published on 24 July 2014, unfortunately contained a mistake. In section "Discussion," a sentence was worded incorrectly.

6.
Nat Commun ; 10(1): 4955, 2019 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-31672989

RESUMO

Systemic sclerosis (SSc) is an autoimmune disease that shows one of the highest mortality rates among rheumatic diseases. We perform a large genome-wide association study (GWAS), and meta-analysis with previous GWASs, in 26,679 individuals and identify 27 independent genome-wide associated signals, including 13 new risk loci. The novel associations nearly double the number of genome-wide hits reported for SSc thus far. We define 95% credible sets of less than 5 likely causal variants in 12 loci. Additionally, we identify specific SSc subtype-associated signals. Functional analysis of high-priority variants shows the potential function of SSc signals, with the identification of 43 robust target genes through HiChIP. Our results point towards molecular pathways potentially involved in vasculopathy and fibrosis, two main hallmarks in SSc, and highlight the spectrum of critical cell types for the disease. This work supports a better understanding of the genetic basis of SSc and provides directions for future functional experiments.

7.
J Biopharm Stat ; : 1-18, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31730441

RESUMO

Evaluating the association between diseases and the longitudinal pattern of pharmacological therapy has become increasingly important. However, in many longitudinal studies, self-reported medication usage data collected at patients' follow-up visits could be missing for various reasons. These pieces of missing or inaccurate/untenable information complicate determining the trajectory of medication use and its complete effects for patients. Although longitudinal models can deal with specific types of missing data, inappropriate handling of this issue can lead to a biased estimation of regression parameters especially when missing data mechanisms are complex and depend upon multiple sources of variation. We propose a latent class-based multiple imputation (MI) approach using a Bayesian quantile regression (BQR) that incorporates cluster of unobserved heterogeneity for medication usage data with intermittent missing values. Findings from our simulation study indicate that the proposed method performs better than traditional MI methods under certain scenarios of data distribution. We also demonstrate applications of the proposed method to data from the Prospective Study of Outcomes in Ankylosing Spondylitis (AS) cohort when assessing an association between longitudinal nonsteroidal anti-inflammatory drugs (NSAIDs) usage and radiographic damage in AS, while the longitudinal NSAID index data are intermittently missing.

8.
Mol Biol Evol ; 2019 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-31693153

RESUMO

Lateral gene transfer (LGT) is a very common process in bacterial and archaeal evolution, playing an important role in the adaptation to new environments. In eukaryotes, its role and frequency remain highly debated, although recent research supports that gene transfer from bacteria to diverse eukaryotes may be much more common than previously appreciated. However, most of this research focused on animals and the true phylogenetic and functional impact of bacterial genes in less-studied microbial eukaryotic groups remains largely unknown. Here, we have analyzed transcriptome data from the deep-branching stramenopile Opalinidae, common members of frog gut microbiomes and distantly related to the well-known genus Blastocystis. Phylogenetic analyses suggest the early acquisition of several bacterial genes in a common ancestor of both lineages. Those LGTs most likely facilitated the adaptation of the free-living ancestor of the Opalinidae-Blastocystis symbiotic group to new niches in the oxygen-depleted animal gut environment.

9.
Trends Ecol Evol ; 2019 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-31606140

RESUMO

For 15 years, the eukaryote Tree of Life (eToL) has been divided into five to eight major groupings, known as 'supergroups'. However, the tree has been profoundly rearranged during this time. The new eToL results from the widespread application of phylogenomics and numerous discoveries of major lineages of eukaryotes, mostly free-living heterotrophic protists. The evidence that supports the tree has transitioned from a synthesis of molecular phylogenetics and biological characters to purely molecular phylogenetics. Most current supergroups lack defining morphological or cell-biological characteristics, making the supergroup label even more arbitrary than before. Going forward, the combination of traditional culturing with maturing culture-free approaches and phylogenomics should accelerate the process of completing and resolving the eToL at its deepest levels.

10.
Artif Intell Med ; 100: 101709, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31607341

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease characterized by an unpredictable progressive decline in lung function. Natural history of IPF is unknown and the prediction of disease progression at the time of diagnosis is notoriously difficult. High resolution computed tomography (HRCT) has been used for the diagnosis of IPF, but not generally for monitoring purpose. The objective of this work is to develop a novel predictive model for the radiological progression pattern at voxel-wise level using only baseline HRCT scans. Mainly, there are two challenges: (a) obtaining a data set of features for region of interest (ROI) on baseline HRCT scans and their follow-up status; and (b) simultaneously selecting important features from high-dimensional space, and optimizing the prediction performance. We resolved the first challenge by implementing a study design and having an expert radiologist contour ROIs at baseline scans, depending on its progression status in follow-up visits. For the second challenge, we integrated the feature selection with prediction by developing an algorithm using a wrapper method that combines quantum particle swarm optimization to select a small number of features with random forest to classify early patterns of progression. We applied our proposed algorithm to analyze anonymized HRCT images from 50 IPF subjects from a multi-center clinical trial. We showed that it yields a parsimonious model with 81.8% sensitivity, 82.2% specificity and an overall accuracy rate of 82.1% at the ROI level. These results are superior to other popular feature selections and classification methods, in that our method produces higher accuracy in prediction of progression and more balanced sensitivity and specificity with a smaller number of selected features. Our work is the first approach to show that it is possible to use only baseline HRCT scans to predict progressive ROIs at 6 months to 1year follow-ups using artificial intelligence.

11.
Ann Rheum Dis ; 2019 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-31662318

RESUMO

OBJECTIVES: Diverse evidence including clinical, genetic and microbiome studies support a major role of the gut microbiome in the common immune-mediated arthropathy, ankylosing spondylitis (AS). We set out to (1) further define the key microbial characteristics driving disease, and (2) examine the effects of tumour necrosis factor-inhibitor (TNFi) therapy upon the microbiome. METHODS: The stools from a case-control cohort of 250 Han-Chinese subjects underwent shotgun metagenomic sequencing. All subjects were genotyped using the Illumina CoreExome SNP microarray. RESULTS: Previous reports of gut dysbiosis in AS were reconfirmed and several notable bacterial species and functional categories were differentially abundant. TNFi therapy was correlated with a restoration the perturbed microbiome observed in untreated AS cases to that of healthy controls, including several important bacterial species that have been previously associated with AS and other related diseases. Enrichment of bacterial peptides homologous to HLA-B27-presented epitopes was observed in the stools of patients with AS, suggesting that either HLA-B27 fails to clear these or that they are involved in driving HLA-B27-associated immune reactions. TNFi therapy largely restored the perturbed microbiome observed in untreated AS cases to that of healthy controls, including several important bacterial species that have been previously associated with AS and other related diseases. TNFi therapy of patients with AS was also associated with a reduction of potentially arthritogenic bacterial peptides, relative to untreated patients. CONCLUSION: These findings emphasise the key role that the gut microbiome plays in driving the pathogenesis of AS and highlight potential therapeutic and/or preventative targets.

12.
Artigo em Inglês | MEDLINE | ID: mdl-31603229

RESUMO

Skeletal muscle wasting is a common complication of chronic kidney disease (CKD), characterized by the loss of muscle mass, strength and function, which significantly increases the risk of morbidity and mortality in this population. Numerous complications associated with declining renal function and lifestyle activate catabolic pathways and impair muscle regeneration, resulting in substantial protein wasting. Evidence suggests that increasing skeletal muscle mass improves outcomes in CKD, making this a clinically important research focus. Despite extensive research, the pathogenesis of skeletal muscle wasting is not completely understood. It is widely recognized that microRNAs (miRNAs), a family of short non-coding RNAs, are pivotal in the regulation of skeletal muscle homoeostasis, with significant roles in regulating muscle growth, regeneration and metabolism. The abnormal expression of miRNAs in skeletal muscle during disease has been well described in cellular and animal models of muscle atrophy, and in recent years, the involvement of miRNAs in the regulation of muscle atrophy in CKD has been demonstrated. As this exciting field evolves, there is emerging evidence for the involvement of miRNAs in a beneficial crosstalk system between skeletal muscle and other organs that may potentially limit the progression of CKD. In this article, we describe the pathophysiological mechanisms of muscle wasting and explore the contribution of miRNAs to the development of muscle wasting in CKD. We also discuss advances in our understanding of miRNAs in muscle-organ crosstalk and summarize miRNA-based therapeutics currently in clinical trials.

13.
Artigo em Inglês | MEDLINE | ID: mdl-31567897

RESUMO

INTRODUCTION: Historically, hip precautions have been prescribed after total hip arthroplasty (THA) to limit certain motions felt to place the arthroplasty construct in a position at increased risk for dislocation. This study aimed to determine whether relaxed hip precautions after primary THA done via a posterolateral approach resulted in a higher early dislocation rate compared with standard hip precautions. METHODS: The hip precaution protocol was changed from standard to relaxed at our institution for all patients with THA in December 2016. One cohort had THA in the 18 months before the protocol change and had standard hip precautions, and the second cohort had THA in the 18 months after the protocol change and had relaxed precautions. We determined the early dislocation rate (within 3 months postoperatively) for both cohorts and controlled for selected demographic and surgical details. RESULTS: The standard precaution group included 597 primary THAs and the relaxed precaution group included 692 hips. No notable differences were found between the groups in terms of age at surgery, body mass index, sex, laterality, or diagnosis. Early dislocation occurred in seven hips (1.2%) in the standard precaution cohort and in nine hips (1.4%) in the relaxed precaution cohort. This difference was not statistically significant (P = 0.77). DISCUSSION: The results of our study suggest that well-trained, high-volume surgeons may potentially relax hip precautions prescribed to the patients after primary THA done via a posterolateral approach without subjecting patients to a markedly higher incidence of dislocation. However, unlike previous studies, this study controlled for femoral head size, which is a well-known confounder for dislocation risk.

14.
PLoS One ; 14(10): e0222835, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31574098

RESUMO

BACKGROUND: Guyana expanded its HIV response in 2005 but the epidemiology of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections has not been characterized. METHODS: The 2011 Seroprevalence and Behavioral Epidemiology Risk Survey for HIV and STIs collected biologic specimens with demographic and behavioral data from a representative sample of Guyana military personnel. Diagnostics included commercial serum: HIV antibody; total antibody to hepatitis B core (anti-HBc); IgM anti-HBc; hepatitis B surface antigen (HBsAg); anti-HBs; antibody to HCV with confirmatory testing; and HBV DNA sequencing with S gene fragment phylogenetic analysis. Chi-square, p-values and prevalence ratios determined statistical significance. RESULTS: Among 480 participants providing serologic specimens, 176 (36.7%) tested anti-HBc-positive. Overall, 19 (4.0%) participants tested HBsAg-positive; 17 (89.5%) of the HBsAg-positive participants also had detectable anti-HBc, including 1 (5.3%) IgM anti-HBc-positive male. Four (6.8%) females with available HBV testing were HBsAg-positive, all aged 23-29 years. Sixteen (16, 84.2%) HBsAg-positive participants had sufficient specimen for DNA testing. All 16 had detectable HBV DNA, 4 with viral load >2x104IU/ml. Sequencing found: 12 genotype (gt) A1 with 99.9% genetic identity between 1 IgM anti-HBc-positive and 1 anti-HBc-negative; 2 gtD1; and 2 with insufficient specimen. No statistically significant associations between risk factors and HBV infection were identified. CONCLUSIONS: Integrated HIV surveillance identified likely recent adult HBV transmission, current HBV infection among females of reproductive age, moderate HBV infection prevalence (all gtA1 and D1), no HCV infections and low HIV frequency among Guyana military personnel. Integrated HIV surveillance helped characterize HBV and HCV epidemiology, including probable recent transmission, prompting targeted responses to control ongoing HBV transmission and examination of hepatitis B vaccine policies.

15.
Abdom Radiol (NY) ; 2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31650375

RESUMO

PURPOSE: Clear cell renal cell carcinoma (ccRCC) comprises nearly 90% of all diagnosed RCC subtypes and has the worst prognosis and highest metastatic potential. The strongest prognostic factors for patients with ccRCC include histological subtype and Fuhrman grade, which are incorporated into prognostic models. Since ccRCC is a highly vascularized tumor, there may be differences in enhancement patterns on multidetector CT (MDCT) due to the hemodynamics and microvessel density (MVD) of the lesions. This may provide a noninvasive method to characterize incidentally detected low- and high-grade ccRCCs on MDCT. The purpose of our study was to determine the correlation between MDCT enhancement parameters, ccRCC MVD, and Fuhrman grade to determine its utility and value in assessing tumor vascularity and grade in vivo. METHODS: In this retrospective, HIPAA-compliant, institutional review board-approved study with waiver of informed consent, 127 consecutive patients with 89 low-grade (LG), and 43 high-grade (HG) ccRCCs underwent preoperative four-phase MDCT. A 3D volume of interest (VOI) was obtained for every tumor and absolute enhancement and the wash-in/wash-out of enhancement for each phase was assessed. Immunohistochemistry on resected specimens was used to quantify MVD. Linear regression and Pearson correlation were used to investigate the strength of the association between 3D VOI enhancement and MVD. Stepwise logistic regression analysis determined independent predictors of HG ccRCC. Cut-off values and odds Ratio (OR) with 95% CIs were reported. The clinical, radiomic, and pathologic features with the highest performance in the stepwise logistic regression analysis were evaluated using receiver operator characteristics (ROC) and area under the curve (AUC). RESULTS: Absolute enhancement in the nephrographic phase < 52.1 Hounsfield Units (HU) (HR 0.979, 95% CI 0.964-0.994, p value = 0.006), lesion size > 4.3 cm (HR 1.450, 95% CI 1.211-1.738, p value < 0.001), and an intratumoral MVD < 15% (HR 0.932, 95% CI 0.867-1.002, p value = 0.058) were independent predictors of HG ccRCC with an AUC of 0.818 (95% CI 0.725-0.911). HG ccRCCs had a significant association between 3D VOI enhancement and MVD in each post-contrast phase (r2 = 0.238 to 0.455, p < 0.05). CONCLUSIONS: Absolute enhancement of the entire lesion obtained from a 3D VOI in the nephrographic phase on preoperative MDCT can provide quantitative data that are a significant, independent predictor of a high-grade clear cell RCC and can be used to assess tumor vascularity and grade in vivo.

16.
Heart ; 2019 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-31551292

RESUMO

In recent large-scale cardiovascular outcome trials, two new classes of glucose-lowering medications-sodium glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RAs)-demonstrated cardiovascular benefits in adults with type 2 diabetes mellitus (T2DM). These findings have prompted growing optimism among clinicians regarding the potential for these agents to reduce the burden of cardiovascular disease in people with T2DM. GLP-1RAs and SGLT2i are now advocated as second-line agents in European and US guidelines for management of both hyperglycaemia and for primary prevention of cardiovascular disease in people with T2DM. Given the high prevalence of T2DM in patients with cardiovascular disease, cardiologists will increasingly encounter these agents in routine clinical practice. In this review, we summarise evidence from cardiovascular outcome trials of GLP-1RAs and SGLT2i, give practical advice on prescribing and detail safety considerations associated with their use. We also highlight areas where further work is needed, giving details on active clinical trials. The review aims to familiarise cardiologists with these emerging treatments, which will be increasingly encountered in clinical practice, given the expanding representation of T2DM in patients with cardiovascular disease. Whether these drugs will be initiated by cardiologists remains to be determined.

17.
Artigo em Inglês | MEDLINE | ID: mdl-31545010

RESUMO

The aquatic bladderwort Utricularia gibba captures zooplankton in mechanically triggered underwater traps. With characteristic dimensions <1 mm, the trapping structures are among the smallest known that work by suction-a mechanism that would not be effective in the creeping-flow regime. To understand the adaptations that make suction feeding possible on this small scale, we have measured internal flow speeds during artificially triggered feeding strikes in the absence of prey. These data are compared with complementary analytical models of the suction event: an inviscid model of the jet development in time and a steady-state model incorporating friction. The initial dynamics are well described by a time-dependent Bernoulli equation in which the action of the trap door is represented by a step increase in driving pressure. According to this model, the observed maximum flow speed (5.2 m/s) depends only on the pressure difference, whereas the initial acceleration (3 × 104 m/s2 ) is determined by pressure difference and channel length. Because the terminal speed is achieved quickly (~0.2 ms) and the channel is short, the remainder of the suction event (~2.0 ms) is effectively an undeveloped viscous steady state. The steady-state model predicts that only 17% of power is lost to friction. The energy efficiency and steady-state fluid speed decrease rapidly with decreasing channel diameter, setting a lower limit on practical bladderwort size.

18.
Artigo em Inglês | MEDLINE | ID: mdl-31519782

RESUMO

Capture bioprocessing unit operations were shown previously to clear or kill several log10 of a model mycoplasma Acholeplasma laidlawii in lab-scale spike/removal studies. Here, we confirm this observation with two additional mollicute species relevant to biotechnology products for human use: Mycoplasma orale and Mycoplasma arginini. Clearance of M. orale and M. arginini from Protein A column purification was similar to that seen with A. laidlawii, though some between cycle carryover was evident, especially for M. orale. However, on-resin growth studies revealed that residual mycoplasma in a column slowly die off over time rather than expanding further for all three species. Solvent/detergent exposure completely inactivated M. arginini though detectable levels of M. orale remained. A small-scale model of a commercial low-pH hold step did inactivate live M. orale, but this inactivation required a lower pH set point and occurred with slower kinetics than previously seen with A. laidlawii. Additionally, UVc irradiation was shown to be effective for A. laidlawii and M. orale inactivation while virus-retentive filters for upstream and downstream processes, as expected, cleared A. laidlawii. These data argue that M. orale and M. arginini overall would be largely cleared by early bioprocessing steps as shown previously for A. laidlawii, and barrier technologies can effectively reduce risk from media components. For some unit operations, the other two species may be hardier, and require more stringent processing or equipment cleaning conditions to assure effective mycoplasma reduction. By exploring how some of the failure modes in commercial antibody manufacturing processes can still eliminate mycoplasma burden, we demonstrate that required best practices assure biotechnology products will be safe for patients.

19.
J Bone Miner Res ; 2019 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-31525280

RESUMO

Novel anabolic drug targets are needed to treat osteoporosis. Having established a large national cohort with unexplained high bone mass (HBM), we aimed to identify a novel monogenic cause of HBM and provide insight into a regulatory pathway potentially amenable to therapeutic intervention. We investigated a pedigree with unexplained HBM in whom previous sequencing had excluded known causes of monogenic HBM. Whole exome sequencing identified a rare (minor allele frequency 0.0023), highly evolutionarily conserved missense mutation in SMAD9 (c.65T>C, p.Leu22Pro) segregating with HBM in this autosomal dominant family. The same mutation was identified in another two unrelated individuals both with HBM. In silico protein modeling predicts the mutation severely disrupts the MH1 DNA-binding domain of SMAD9. Affected individuals have bone mineral density (BMD) Z-scores +3 to +5, mandible enlargement, a broad frame, torus palatinus/mandibularis, pes planus, increased shoe size, and a tendency to sink when swimming. Peripheral quantitative computed tomography (pQCT) measurement demonstrates increased trabecular volumetric BMD and increased cortical thickness conferring greater predicted bone strength; bone turnover markers are low/normal. Notably, fractures and nerve compression are not found. Both genome-wide and gene-based association testing involving estimated BMD measured at the heel in 362,924 white British subjects from the UK Biobank Study showed strong associations with SMAD9 (PGWAS = 6 × 10-16 ; PGENE = 8 × 10-17 ). Furthermore, we found Smad9 to be highly expressed in both murine cortical bone-derived osteocytes and skeletal elements of zebrafish larvae. Our findings support SMAD9 as a novel HBM gene and a potential novel osteoanabolic target for osteoporosis therapeutics. SMAD9 is thought to inhibit bone morphogenetic protein (BMP)-dependent target gene transcription to reduce osteoblast activity. Thus, we hypothesize SMAD9 c.65T>C is a loss-of-function mutation reducing BMP inhibition. Lowering SMAD9 as a potential novel anabolic mechanism for osteoporosis therapeutics warrants further investigation. © 2019 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.

20.
Artigo em Inglês | MEDLINE | ID: mdl-31529687

RESUMO

OBJECTIVE: Nonsteroidal anti-inflammatory drugs (NSAIDs) increase blood pressure and potentially cardiovascular burden, which may limit their use in ankylosing spondylitis (AS). Our objective was to determine the association of NSAID use with incident hypertension in a longitudinal AS cohort. METHODS: Adults with AS were enrolled in a prospective cohort study of patient outcomes and examined every 4-6 months. Hypertension was defined by patient-reported hypertension; anti-hypertensive medication use; or, on two consecutive visits, systolic blood pressure ≥140 mm Hg or diastolic ≥90 mm Hg. Continuous NSAID use was dichotomized based on the validated NSAID index. We assessed the association of NSAID use as a time-varying exposure with the incidence of hypertension using Cox proportional hazards models. RESULTS: Of the 1282 patients in the cohort, 628 patients without baseline hypertension had at least one year of follow up, and were included in the analysis. Of these, 72% were male, the mean age at baseline was 39 ± 13 years, and 200 used NSAIDs continuously. On follow-up, 129 developed incident hypertension. After controlling for other variables, continuous NSAID use was associated with a hazard ratio (HR) of 1.12 for incident hypertension (95% CI, 1.04-1.20), compared to non-continuous or no use. The association did not differ in subgroups defined by age, body mass index, biologic use, or disease activity. CONCLUSION: In our prospective, longitudinal AS cohort, continuous NSAID use was associated with a 12% increased risk for the development of incident hypertension, as compared to non-continuous or no NSAID use.

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