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Material properties of soft-tissue samples are often derived through uniaxial tensile testing. For engineering materials, testing parameters (e.g., sample geometries and clamping conditions) are described by international standards; for biological tissues, such standards do not exist. To investigate what testing parameters have been reported for tensile testing of human soft-tissue samples, a systematic review of the literature was performed using PRISMA guidelines. Soft tissues are described as anisotropic and/or hyperelastic. Thus, we explored how the retrieved parameters compared against standards for engineering materials of similar characteristics. All research articles published in English, with an Abstract, and before 1 January 2023 were retrieved from databases of PubMed, Web of Science, and BASE. After screening of articles based on search terms and exclusion criteria, a total 1,096 articles were assessed for eligibility, from which 361 studies were retrieved and included in this review. We found that a non-tapered shape is most common (209 of 361), followed by a tapered sample shape (92 of 361). However, clamping conditions varied and were underreported (156 of 361). As a preliminary attempt to explore how the retrieved parameters might influence the stress distribution under tensile loading, a pilot study was performed using finite element analysis (FEA) and constitutive modeling for a clamped sample of little or no fiber dispersion. The preliminary FE simulation results might suggest the hypothesis that different sample geometries could have a profound influence on the stress-distribution under tensile loading. However, no conclusions can be drawn from these simulations, and future studies should involve exploring different sample geometries under different computational models and sample parameters (such as fiber dispersion and clamping effects). Taken together, reporting and choice of testing parameters remain as challenges, and as such, recommendations towards standard reporting of uniaxial tensile testing parameters for human soft tissues are proposed.
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BACKGROUND: Overall life expectancy continues to rise, approaching 80 years of age in several developed countries. However, healthy life expectancy lags far behind, which has, in turn, contributed to increasing costs in healthcare. One way to improve health and attenuate the socio-economic impact of an aging population is to increase overall fitness through physical activity. Telomere attrition or shortening is a well-known molecular marker in aging. As such, several studies have focused on whether exercise influences health and aging through telomere biology. This systematic review examines the recent literature on the effect of physical activity on telomere length (TL) and/or telomerase activity as molecular markers of aging. METHODS: A focused search was performed in the databases PubMed and Web of Science for retrieving relevant articles over the past ten years. The search contained the following keywords: exercise, sport, physical activity, fitness, sedentary, physical inactivity, telomere, telomere length, t/s ratio, and telomerase. PRISMA guidelines for systematic reviews were observed. RESULTS: A total of 43 articles were identified and categorized into randomized controlled trials (RCT), observational or interventional studies. RCTs (n = 8) showed inconsistent findings of increased TL length with physical activity in, e.g. obese, post-menopausal women. In comparison with a predominantly sedentary lifestyle, observational studies (n = 27) showed significantly longer TL with exercise of moderate to vigorous intensity; however, there was no consensus on the duration and type of physical activity and training modality. Interventional studies (n = 8) also showed similar findings of significantly longer TL prior to exercise intervention; however, these studies had smaller numbers of enrolled participants (mostly of high-performance athletes), and the physical activities covered a range of exercise intensities and duration. Amongst the selected studies, aerobic training of moderate to vigorous intensity is most prevalent. For telomere biology analysis, TL was determined mainly from leukocytes using qPCR. In some cases, especially in RCT and interventional studies, different sample types such as saliva, sperm, and muscle biopsies were analyzed; different leukocyte cell types and potential genetic markers in regulating telomere biology were also investigated. CONCLUSIONS: Taken together, physical activity with regular aerobic training of moderate to vigorous intensity appears to help preserve TL. However, the optimal intensity, duration of physical activity, as well as type of exercise still need to be further elucidated. Along with TL or telomerase activity, participants' fitness level, the type of physical activity, and training modality should be assessed at different time points in future studies, with the plan for long-term follow-up. Reducing the amount of sedentary behavior may have a positive effect of preserving and increasing TL. Further molecular characterization of telomere biology in different cell types and tissues is required in order to draw definitive causal conclusions on how physical activity affects TL and aging.
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Many thanks to Dr. Mordaunt for his thoughtful Comment, which we were delighted to read with great interest[...].
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Mineração de Dados , Atenção à Saúde , Instalações de Saúde , OrganizaçõesRESUMO
Process mining can provide greater insight into medical treatment processes and organizational processes in healthcare. To enhance comparability between processes, the quality of the labelled-data is essential. A literature review of the clinical case studies by Rojas et al. in 2016 identified several common aspects for comparison, which include methodologies, algorithms or techniques, medical fields, and healthcare specialty. However, clinical aspects are not reported in a uniform way and do not follow a standard clinical coding scheme. Further, technical aspects such as details of the event log data are not always described. In this paper, we identified 38 clinically-relevant case studies of process mining in healthcare published from 2016 to 2018 that described the tools, algorithms and techniques utilized, and details on the event log data. We then correlated the clinical aspects of patient encounter environment, clinical specialty and medical diagnoses using the standard clinical coding schemes SNOMED CT and ICD-10. The potential outcomes of adopting a standard approach for describing event log data and classifying medical terminology using standard clinical coding schemes are further discussed. A checklist template for the reporting of case studies is provided in the Appendix A to the article.
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Atenção à Saúde , Medicina , Algoritmos , Codificação Clínica , HumanosRESUMO
BACKGROUND: Clinical research into the effects of hormonal supplementation has tended to focus on beneficial changes in anthropometric measures. There are fewer data on long-term safety with extended hormonal supplementation. METHODS: As part of a retrospective database survey, clinical outcomes were tabulated among patients who received at least 1 year of testosterone and/or growth hormone (GH) supplementation. In patients who were treated for at least 2 years, changes in markers of glucose and lipid metabolism were analyzed with and without concomitant use of oral hypoglycemics and statins. RESULTS: In 263 patients (mean age 56) treated for at least 2 years, the only statistically significant effect on markers of glucose metabolism was an increase in glycated hemoglobin (still within normal limits) in patients receiving GH alone or in combination with testosterone but without oral hypoglycemics; with or without hypoglycemics, insulin levels showed no significant change. The only significant effects on markers of lipid metabolism were decreases in total cholesterol and low-density lipoprotein (LDL) in patients receiving combined testosterone and GH without statins. Decreases in LDL were significant in both the statin and non-statin groups; decreases in triglycerides were significant only in the statin group. In 531 patients treated for at least 1 year (mean age 54), the overall incidence of adverse clinical outcomes (prostate disease, diabetes, cardiovascular disease, cancer) was 1.3%. CONCLUSIONS: In this retrospective survey, extended testosterone and/or GH supplementation did not adversely affect metabolic markers or clinical outcomes. KEYWORDS: Safety; Testosterone; Growth hormone; Supplementation.
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Osteoarthritis is associated with the irreversible degeneration of articular cartilage. Notably, in this condition, articular cartilage chondrocytes undergo phenotypic and gene expression changes that are reminiscent of their end-stage differentiation in the growth plate during skeletal development. Hedgehog (Hh) signaling regulates normal chondrocyte growth and differentiation; however, the role of Hh signaling in chondrocytes in osteoarthritis is unknown. Here we examine human osteoarthritic samples and mice in which osteoarthritis was surgically induced and find that Hh signaling is activated in osteoarthritis. Using several genetically modified mice, we found that higher levels of Hh signaling in chondrocytes cause a more severe osteoarthritic phenotype. Furthermore, we show in mice and in human cartilage explants that pharmacological or genetic inhibition of Hh signaling reduces the severity of osteoarthritis and that runt-related transcription factor-2 (RUNX2) potentially mediates this process by regulating a disintegrin and metalloproteinase with thrombospondin type 1 motif-5 (ADAMTS5) expression. Together, these findings raise the possibility that Hh blockade can be used as a therapeutic approach to inhibit articular cartilage degeneration.
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Proteínas Hedgehog/antagonistas & inibidores , Osteoartrite/metabolismo , Transdução de Sinais , Proteínas ADAM/metabolismo , Proteína ADAMTS5 , Animais , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Proteínas Hedgehog/metabolismo , Humanos , Camundongos , Osteoartrite/patologia , Índice de Gravidade de DoençaRESUMO
Rebaudioside A is a natural sweetener from Stevia rebaudiana in which four beta-D-glucopyranose units are attached to the aglycone steviol. Its (1)H and (13)C NMR spectra in pyridine-d(5) were assigned using 1D and 2D methods. Constrained molecular dynamics of solvated rebaudioside using NMR constraints derived from ROESY cross peaks yielded the orientation of the beta-D-glucopyranose units. Hydrogen bonding was examined using the temperature coefficients of the hydroxyl chemical shifts, ROESY and long-range COSY spectra, and proton-proton coupling constants.
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Diterpenos do Tipo Caurano/química , Espectroscopia de Ressonância Magnética/métodos , Configuração de Carboidratos , Ligação de Hidrogênio , Simulação de Dinâmica Molecular , Soluções , EdulcorantesRESUMO
Trichothecene mycotoxins, toxic natural products of fungi from the family Hypocreaceae, are potent inhibitors of protein synthesis. The application of 3D QSAR to these toxins explored the structural basis for their biological activities. A CoMFA (Q(2)=0.619, R(2)=0.921) model was developed for a set of 15 toxins with the trichothecene nucleus; CoMFA (Q(2)=0.518, R(2)=0.855) and CoMSIA (Q(2)=0.695, R(2)=0.960) models were developed for 31 toxins with the nucleus and a macrolide ring. The results show the role of electrostatics and steric factors in the activity of the toxins and indicate that the conformation of the macrolide ring influences the toxicity of the macrolide toxins.
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Hypocreales/química , Micotoxinas/química , Micotoxinas/farmacologia , Tricotecenos/química , Tricotecenos/farmacologia , Modelos Moleculares , Conformação Molecular , Relação Quantitativa Estrutura-Atividade , Ribossomos/química , Ribossomos/metabolismo , Eletricidade EstáticaRESUMO
BACKGROUND: Age-related declines in testosterone and growth hormone (GH) are associated with increased adiposity and decreases in lean mass and bone mineral density (BMD). A long-term retrospective study examined the effects of testosterone and/or GH supplementation on body composition and quality of life (QoL). METHODS: A database survey assessed the records of 91 men and 97 women (ages 25-82) in treatment groups based on their hormonal status: dehydroepiandrosterone but no hormonal supplementation (control); testosterone only (Tes); GH only (GH); and testosterone plus GH (Tes+GH). Pre-and post-treatment assessments recorded changes in fat and lean mass, BMD, and QoL. RESULTS: After an average of 3 years of treatment, weight decreased in women in the control and Tes+GH groups but remained stable in men in all groups. Tes and Tes+GH produced statistically significant increases in lean mass, reductions in fat mass, and improvements in BMD in both sexes; GH produced similar changes in women. QoL and mood improved in all groups. Treatments were generally safe and well tolerated. CONCLUSIONS: In this retrospective survey, treatment with testosterone and/or GH was associated with favorable effects in men and women across a wide age range.
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BACKGROUND: Delayed fracture healing causes substantial disability and usually requires additional surgical treatments. Pharmacologic management to improve fracture repair would substantially improve patient outcome. The signaling pathways regulating bone healing are beginning to be unraveled, and they provide clues into pharmacologic management. The beta-catenin signaling pathway, which activates T cell factor (TCF)-dependent transcription, has emerged as a key regulator in embryonic skeletogenesis, positively regulating osteoblasts. However, its role in bone repair is unknown. The goal of this study was to explore the role of beta-catenin signaling in bone repair. METHODS AND FINDINGS: Western blot analysis showed significant up-regulation of beta-catenin during the bone healing process. Using a beta-Gal activity assay to observe activation during healing of tibia fractures in a transgenic mouse model expressing a TCF reporter, we found that beta-catenin-mediated, TCF-dependent transcription was activated in both bone and cartilage formation during fracture repair. Using reverse transcription-PCR, we observed that several WNT ligands were expressed during fracture repair. Treatment with DKK1 (an antagonist of WNT/beta-catenin pathway) inhibited beta-catenin signaling and the healing process, suggesting that WNT ligands regulate beta-catenin. Healing was significantly repressed in mice conditionally expressing either null or stabilized beta-catenin alleles induced by an adenovirus expressing Cre recombinase. Fracture repair was also inhibited in mice expressing osteoblast-specific beta-catenin null alleles. In stark contrast, there was dramatically enhanced bone healing in mice expressing an activated form of beta-catenin, whose expression was restricted to osteoblasts. Treating mice with lithium activated beta-catenin in the healing fracture, but healing was enhanced only when treatment was started subsequent to the fracture. CONCLUSIONS: These results demonstrate that beta-catenin functions differently at different stages of fracture repair. In early stages, precise regulation of beta-catenin is required for pluripotent mesenchymal cells to differentiate to either osteoblasts or chondrocytes. Once these undifferentiated cells have become committed to the osteoblast lineage, beta-catenin positively regulates osteoblasts. This is a different function for beta-catenin than has previously been reported during development. Activation of beta-catenin by lithium treatment has potential to improve fracture healing, but only when utilized in later phases of repair, after mesenchymal cells have become committed to the osteoblast lineage.
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Fraturas Ósseas/fisiopatologia , Transdução de Sinais/fisiologia , Cicatrização/fisiologia , beta Catenina/fisiologia , Adenoviridae/genética , Animais , Western Blotting , Fraturas Ósseas/genética , Fraturas Ósseas/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Integrases/genética , Integrases/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Lítio/farmacologia , Masculino , Camundongos , Camundongos Transgênicos , Modelos Animais , Osteoblastos/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Fatores de Tempo , Transfecção/métodos , Proteínas Wnt/genética , Proteínas Wnt/metabolismo , Proteínas Wnt/fisiologia , Cicatrização/efeitos dos fármacos , Cicatrização/genética , beta Catenina/genética , beta Catenina/metabolismoRESUMO
Endochondral ossification is recapitulated during bone morphogenetic protein (BMP)-induced ectopic bone formation. Although BMP and beta-catenin have been investigated in bone development and in mesenchymal cells, how they interact in this process is not clear. We implanted recombinant BMP-2 into the muscle of mice to investigate the effect of beta-catenin signaling on BMP-induced in vivo endochondral bone formation. BMP-2 induced expression of several Wnt ligands and their receptors and also activated beta-catenin-mediated T cell factor-dependent transcriptional activity. An adenovirus expressing Dickkopf-1 (Dkk-1, an inhibitor of canonical Wnt pathway) inhibited beta-catenin signaling and endochondral bone formation. Interestingly, Dkk-1 inhibited both chondrogenesis and osteogenesis. Likewise, mice expressing conditional beta-catenin null alleles also displayed an inhibition of BMP-induced chondrogenesis and osteogenesis. This is in contrast to studies of embryonic skeletogenesis, which demonstrate that beta-catenin is required for osteogenesis but is dispensable for chondrogenesis. These findings suggest that embryonic development pathways are not always recapitulated during post-natal regenerative processes, and the biochemical pathways utilized to regulate cell differentiation may be different. During in vivo ectopic bone formation, BMP-2 induces beta-catenin-mediated signaling through Wnt ligands, and beta-catenin is required for both chondrogenesis and osteogenesis.
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Osso e Ossos/metabolismo , Transdução de Sinais , beta Catenina/metabolismo , Alelos , Animais , Diferenciação Celular , Condrócitos/metabolismo , Humanos , Ligantes , Masculino , Camundongos , Camundongos Transgênicos , Osteoblastos/metabolismo , Proteínas Recombinantes/química , Transcrição GênicaRESUMO
Neuroendocrine abnormalities in anorexia nervosa (AN) include hypercortisolemia, hypogonadism, and hypoleptinemia, and neuroendocrine predictors of menstrual recovery are unclear. Preliminary data suggest that increases in fat mass may better predict menstrual recovery than leptin. High doses of cortisol decrease luteinizing hormone (LH) pulse frequency, and cortisol predicts regional fat distribution. We hypothesized that an increase in fat mass and decrease in cortisol would predict menstrual recovery in adolescents with AN. Thirty-three AN girls 12-18 y old and 33 controls were studied prospectively for 1 y. Body composition [dual energy x-ray absorptiometry (DXA)], leptin, and urinary cortisol (UFC) were measured at 0, 6, and 12 mo. Serum cortisol was measured overnight (every 30 min) in 18 AN subjects and 17 controls. AN subjects had higher UFC/cr x m2 and cortisol area under curve (AUC), and lower leptin levels than controls. Leptin increased significantly with recovery. When menses-recovered AN subjects were compared with AN subjects not recovering menses and controls, menses-recovered AN subjects had higher baseline cortisol levels and greater increases in leptin than controls and greater increases in fat mass than AN subjects not recovering menses and controls (adjusted for multiple comparisons). In a logistic regression model, increasing fat mass, but not leptin, predicted menstrual recovery. Baseline cortisol level strongly predicted increases in the percentage of body fat. We demonstrate that 1) high baseline cortisol level predicts increases in body fat and 2) increases in body fat predict menses recovery in AN.
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Tecido Adiposo/metabolismo , Anorexia Nervosa/fisiopatologia , Hidrocortisona , Menstruação/fisiologia , Adolescente , Composição Corporal , Índice de Massa Corporal , Criança , Feminino , Humanos , Hidrocortisona/sangue , Hidrocortisona/urina , Leptina/metabolismo , Estudos ProspectivosRESUMO
Chondrosarcoma is a malignant cartilage tumor that may arise from benign precursor lesions, such as enchondromas. Some cases of multiple enchondromas are caused by a mutation that results in constitutive activation of Hedgehog-mediated signaling. We found that chondrosarcomas expressed high levels of the Hedgehog target genes PTCH1 and GLI1. Treatment with parathyroid hormone-related protein down-regulated Indian Hedgehog (IHH) expression in normal growth plates but not in chondrosarcoma or enchondroma organ cultures. Treatment of the chondrosarcoma organ cultures with Hedgehog protein increased cell proliferation rate, whereas addition of chemical inhibitors of Hedgehog signaling decreased the proliferation rate. Chondrosarcoma xenografts from 12 different human tumors were established in NOD-SCID mice. Treatment with triparanol, an inhibitor of Hedgehog signaling, resulted in a 60% decrease in tumor volume, a 30% decrease in cellularity, and a 20% reduction in proliferation rate. These results show that Hedgehog signaling is active in chondrosarcoma and benign cartilage tumors and regulates tumor cell proliferation. Our data raise the intriguing possibility that Hedgehog blockade could serve as an effective treatment for chondrosarcoma, a tumor for which there are currently no universally effective nonsurgical management options.
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Neoplasias Ósseas/metabolismo , Proliferação de Células , Condrossarcoma/metabolismo , Proteína Relacionada ao Hormônio Paratireóideo/metabolismo , Transdução de Sinais/fisiologia , Transativadores/metabolismo , Animais , Proliferação de Células/efeitos dos fármacos , Análise Mutacional de DNA , Proteínas Hedgehog , Humanos , Hipolipemiantes/farmacologia , Imuno-Histoquímica , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Proteínas Oncogênicas/biossíntese , Técnicas de Cultura de Órgãos , Proteína Relacionada ao Hormônio Paratireóideo/genética , Receptores Patched , Receptor Patched-1 , Polimorfismo Conformacional de Fita Simples , Receptores de Superfície Celular/biossíntese , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/efeitos dos fármacos , Transativadores/efeitos dos fármacos , Fatores de Transcrição/biossíntese , Triparanol/farmacologia , Regulação para Cima , Proteína GLI1 em Dedos de ZincoRESUMO
BACKGROUND: Peptide YY (PYY) is an intestinally derived anorexigen that acts via the Y2 receptor, and Y2 receptor deletion in rodents increases bone formation. Anorexia nervosa (AN) is associated with a deliberate reduction in food intake and low bone density, but endocrine modulators of food intake in AN are not known. In addition, known regulators of bone turnover, such as GH, cortisol, and estrogen, explain only a fraction of the variability in bone turnover marker levels. HYPOTHESES: We hypothesized that PYY may be elevated in AN compared with controls and may contribute to decreased food intake and bone formation. METHODS: Fasting PYY was examined in 23 AN girls and 21 healthy adolescents 12-18 yr old. We also examined GH, cortisol, ghrelin, and leptin (overnight frequent sampling) and fasting IGF-I, estradiol, total T3, and bone markers. Macronutrient intake and resting energy expenditure (REE) were measured. RESULTS: AN girls had higher PYY levels compared with controls (17.8 +/- 10.2 vs. 4.8 +/- 4.3 pg/ml; P < 0.0001). Predictors of log PYY were nutritional markers, including body mass index (r = -0.62; P < 0.0001), fat mass (r = -0.55; P = 0.0003), and REE (r = -0.51; P = 0.0006), and hormones, including GH (r = 0.38; P = 0.004) and T3 (r = -0.59; P = 0.0001). Body mass index, fat mass, REE, GH, and T3 explained 68% of the variability of log PYY. Log PYY predicted percentage of calories from fat (r = -0.56; P = 0.0002) and independently predicted osteocalcin (r = -0.45; P = 0.003), bone-specific alkaline phosphatase (r = -0.46; P = 0.003), N-telopeptide/creatinine (r = -0.55; P = 0.0003), and deoxypyridinoline/creatinine (r = -0.52; P = 0.001) on regression modeling. CONCLUSION: Elevated PYY may contribute to reduced intake and decreased bone turnover in AN.
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Anorexia Nervosa/sangue , Peptídeo YY/sangue , Adolescente , Índice de Massa Corporal , Peso Corporal , Osso e Ossos/fisiologia , Osso e Ossos/fisiopatologia , Estradiol/sangue , Feminino , Grelina , Hematócrito , Humanos , Hidrocortisona/sangue , Hormônios Peptídicos/sangue , Valores de Referência , Tri-Iodotironina/sangueRESUMO
The ultrastructure of fibrous long spacing (FLS) collagen fibrils has been investigated by performing both atomic force microscopy (AFM) and transmission electron microscopy (TEM) on exactly the same area of FLS collagen fibril samples. These FLS collagen fibrils were formed in vitro from type I collagen and alpha1-acid glycoprotein (AAG) solutions. On the basis of the correlated AFM and TEM images obtained before and after negative staining, the periodic dark bands observed in TEM images along the longitudinal axis of the FLS collagen fibril correspond directly to periodic protrusions seen by AFM. This observation is in agreement with the original surmise made by Gross, Highberger, and Schmitt (Gross J, Highberger JH, Schmitt FO, Proc Natl Acad Sci USA 1954;40:679-688) that the major repeating dark bands of FLS collagen fibrils observed under TEM are thick relative to the interband region. Although these results do not refute the idea of negative stain penetration into gap regions proposed by Hodge and Petruska (Petruska JA, Hodge AJ. Aspects of protein structure. Ramachandran GN, editor. New York: Academic Press; 1963. p. 289-300), there is no need to invoke the presence of gap regions to explain the periodic dark bands observed in TEM images of FLS collagen fibrils.