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1
Hermanussen, M., Karin Geiger-Benoit, and W. G. Sippell. "Catch-up growth following transfer from three times weekly im to daily sc administration of hGH in GH deficient patients, monitored by knemometry." Acta Endocrinologica 109, no. 2 (1985): 163–68. http://dx.doi.org/10.1530/acta.0.1090163.
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Abstract. A novel and non-invasive technique of growth measurement is introduced. By this method the length of the human lower leg is measured with an accuracy of 0.1 mm. Thus, growth velocities can be estimated within a few weeks. In the present study the immediate changes of growth velocity are demonstrated, following the transfer of growth hormone administration from three times weekly im to daily sc in 9 growth hormone deficient children, age 7.4 to 20.5 years. The first observation period (3 times weekly im administration) ranged from 32 to 72 days, the second observation period (daily sc administration) ranged from 160 to 267 days). During the study, the total weekly dosage of growth hormone remained unchanged (12 IU/m2/week). In all 9 patients growth velocity increased significantly after the transfer of application. Mean growth velocity of the lower leg rose from 0.04 mm/day up to 0.065 mm/day. Mean growth velocity of total body height rose form 4.8 cm/year up to 6.9 cm/year. In addition, differential lower leg growth rates of 3 to 4 week periods were established in all 9 patients, revealing a significant catch-up growth spurt immediately following the transfer of application. During this spurt mean lower leg growth velocity rose form 0.04 mm/day up to 0.091 mm/day. This marked increase of lower leg growth rates lasted for only a few weeks and was followed by a period of decreased growth velocity. On the long run, growth velocity shifted upward in a wave-like pattern, stabilizing on a significantly higher level than before the transfer of application.
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PARTSCH, C. J., M. HERMANUSSEN, and W. G. SIPPELL. "Treatment of Silver-Russell type dwarfism with human growth hormone: Effects on serum somatomedin-C levels and on longitudinal growth studied by knemometry." Acta Endocrinologica 113, no. 4_Suppl (1986): S139—S146. http://dx.doi.org/10.1530/acta.0.112s139.
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Abstract. Two patients, aged 5 and 12 years, with Silver-Russell type dwarfism are presented. As shown by standard tests and examination of the spontaneous nocturnal hGH secretion, there was only mild regulative hGH deficiency. HGH treatment was started with daily subcutaneous injections at age 5.5 years (height 90.3 cm, −6.1 SDS, bone age 2.75 years) and 12.6 years (height 125.7 cm, −3.7 SDS, bone age 8.75 years), respectively. Treatment was monitored by serial somatomedin-C (SM-C) determinations and by knemometry (lower leg measurement). SM-C values increased in both patients by 10.5 and 4.8 fold, respectively, and remained above the prepubertal range (>2.5 U/ml) during the treatment periods of 1.5 years. Pretreatment knemometric growth rate was high (after a somatomedin generation test) in patient 1 (0.7 mm/week) and low in patient 2 (0.31 mm/week). It remained at the same level in patient 1 (0.67 mm/week) and increased markedly in patient 2 (0.46 mm/week). During a treatment interruption, in both patients, knemometric growth rates fell to 0.33 and 0.30 mm/week, respectively. After resumption of treatment, now with biosynthetic hGH, growth rates increased again in patients 1 and 2 to 0.64 and 0.48 mm/week, respectively. This lower leg growth pattern was parallelled by similar changes in total body growth velocity. Even after the relatively short treatment period of 14 to 16 months, a slight net gain in statural height could be observed, as standard deviation scores for bone age increased.
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Huang, Peigen, Ayman Allam, Alphonse Taghian, Jill Freeman, Michael Duffy, and Herman D. Suit. "Growth and metastatic behavior of five human glioblastomas compared with nine other histological types of human tumor xenografts in SCID mice." Journal of Neurosurgery 83, no. 2 (1995): 308–15. http://dx.doi.org/10.3171/jns.1995.83.2.0308.
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✓ The growth and metastatic behavior of five human glioblastoma multiforme xenografts and nine human xenografts of various histological types were compared in severe combined immunodeficient (SCID) mice. The results demonstrate that the metastatic behavior of the human glioblastoma multiforme xenografts did not differ significantly from a variety of other histological xenografts when evaluated at the same transplantation site in the SCID model. These results are consistent with the hypothesis that the site of glioblastoma multiforme growth influences the extraneural metastatic spread of this disease and lead the authors to suggest that the clinical rarity of distant metastasis is not a fundamental property of these cells. A total of 340 male 7- to 8-week-old SCID mice received subcutaneous transplantation of tumor fragments (21–25 mice per tumor type). The tumor-bearing leg was amputated when the tumor reached a volume of 500 mm3; mice were observed for up to 5 months. There was a trend for a lower take rate, longer latent period, longer volume doubling time (VDT) and growth time (GT) in glioblastoma multiforme as opposed to carcinoma and soft tissue sarcoma xenografts. The highest local recurrence rates (78% and 68%) were observed in two glioblastomas multiforme. Both the glioblastoma multiforme and the other histological xenografts exhibited a widely varying metastatic rate: no correlation was demonstrated between VDT, GT, local control/recurrence, and distant metastasis. These findings show SCID mice to be an attractive model for further biological and preclinical studies of human glioblastoma multiforme.
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Fulford, A. J. C., S. E. Moore, S. E. Arifeen, et al. "Disproportionate early fetal growth predicts postnatal thymic size in humans." Journal of Developmental Origins of Health and Disease 4, no. 3 (2013): 223–31. http://dx.doi.org/10.1017/s2040174413000044.
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Prenatal events can affect neonatal thymus size and adult immune function. The causal insults are unknown, although fetal nutrient restriction is suspected. We used ultrasound at three time points during pregnancy (14, 19 and 30 weeks) to measure the growth of six fetal dimensions in rural Bangladeshi women participating in the Maternal and Infant Nutrition Interventions, Matlab study. Postnatal ultrasound was used to calculate thymic index (TI) at birth, 2, 6 and 12 m. Of the 3267 women recruited, 2861 participated by providing data at least at one fetal biometry and one TI time point. Patterns of fetal growth were summarized using principal components calculated from fetal dimensionz-scores. Random effects regression, controlling for infant size and season of measurement were used to relate these patterns to TI. We found that smaller leg length relative to head circumference, characteristic of head-sparing growth restriction, was predictive of lower TI. This association was significant at all time points but strongest in earlier pregnancy. Each standard deviation increase in leg–head proportion was associated with an increase in TI of ∼5%. We conclude that growth patterns typical of poor fetal nutrition are associated with poor thymic development. The greater strength of this association in the first trimester is consistent with a period of vulnerability during the early ontogeny of the thymus and suggests that preventative intervention would need to be given in early pregnancy.
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Yoshikawa, Kozo, Mitsuo Shimada, Jun Higashijima, et al. "Impact of blue 465nm LED on suppression of cancer growth." Journal of Clinical Oncology 34, no. 4_suppl (2016): 767. http://dx.doi.org/10.1200/jco.2016.34.4_suppl.767.
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767 Background: Recent studies demonstrate the efficacy of irradiation from light emitting diodes (LED) for wound healing and anti-inflammation and anti-cancertherapies. In this study, the blue LED (465nm) suppressed the tumor growth in various cancers. Methods: < Experiment 1, Effect of blue LED on colon cancer > Human colon cancer cells (HT29 or HCT116) were seeded onto laboratory dishes that were put on LED irradiation equipment with a blue LED (465 nm). Irradiation at 15 or 30 mW was performed 10 min/day, each day for 5 days. Cell counting kit8 was then used to measure cell viability. Apoptosis and expression of several mRNAs (caspase, MAPK and autophagy pathway) in HT29 cultures irradiated with 465 nm LED were evaluated via AnnexinV/PI and RT-PCR, respectively. < Experiment 2, Effect of blue LED on pancreas cancer > Human colon cancer cells (SUIT2) were examined by same way and additionally cell cycle was checked. < Experiment 3, Effect of LED on CSCs > Cancer sphere were seeded onto laboratory dishes that were then put on LED irradiation equipment with a 465 nm-LED. Stemness gene and cell surface markers of CSCs expressions were analyzed by RT-PCR. Results: < Experiment 1 > Viability of HT29 and HCT116 cells was lower in blue LED irradiated cultures than in control cultures. Moreover, the expression of FAS, caspase3, capase8, and JUK were significantly higher in 465 nm-LED irradiated cultures than in control cultures, and expression of ERK1/2 and LC3 was lower in blue LED-irradiated cells. < Experiment 2 > Viability of SUIT2 cells was lower in blue LED irradiated cultures than in control cultures. And the CCND1 mRNA expression was significantly lower in blue LED group (p < 0.05). The cells of phase G2/M was decreased. < Experiment 3 > Cell viability of cancer sphere were significantly decreased by LED irradiation(p < 0.05). And, stemness gene and cell surface markers of CSCs expressions were significantly decreased by LED irradiation (p < 0.05) Conclusions: Blue LED irradiation inhibited tumor growth in various cancer cell lines.
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Kuhlenhoelter, Alisha M., Kyoungrae Kim, Dustin Neff, et al. "Heat therapy promotes the expression of angiogenic regulators in human skeletal muscle." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 311, no. 2 (2016): R377—R391. http://dx.doi.org/10.1152/ajpregu.00134.2016.
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Heat therapy has been shown to promote capillary growth in skeletal muscle and in the heart in several animal models, but the effects of this therapy on angiogenic signaling in humans are unknown. We evaluated the acute effect of lower body heating (LBH) and unilateral thigh heating (TH) on the expression of angiogenic regulators and heat shock proteins (HSPs) in healthy young individuals. Exposure to LBH ( n = 18) increased core temperature (Tc) from 36.9 ± 0.1 to 37.4 ± 0.1°C ( P < 0.01) and average leg skin temperature (Tleg) from 33.1 ± 0.1 to 39.6 ± 0.1°C ( P < 0.01), but did not alter the levels of circulating angiogenic cytokines and bone marrow-derived proangiogenic cells (CD34+CD133+). In skeletal muscle, the change in mRNA expression from baseline of vascular endothelial growth factor (VEGF), angiopoietin 2 (ANGPT2), chemokines CCL2 and CX3CL1, platelet factor-4 (PF4), and several members of the HSP family was higher 30 min after the intervention in the individuals exposed to LBH ( n = 11) compared with the control group ( n = 12). LBH also reduced the expression of transcription factor FOXO1 ( P = 0.03). Exposure to TH ( n = 14) increased Tlegfrom 32.8 ± 0.2 to 40.3 ± 0.1°C ( P < 0.05) but Tcremained unaltered (36.8 ± 0.1°C at baseline and 36.9 ± 0.1°C at 90 min). This intervention upregulated the expression of VEGF, ANGPT1, ANGPT2, CCL2, and HSPs in skeletal muscle but did not affect the levels of CX3CL1, FOXO-1, and PF4. These findings suggest that both LBH and TH increase the expression of factors associated with capillary growth in human skeletal muscle.
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Davison, Raziel J., and Michael D. Gurven. "Human uniqueness? Life history diversity among small-scale societies and chimpanzees." PLOS ONE 16, no. 2 (2021): e0239170. http://dx.doi.org/10.1371/journal.pone.0239170.
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Background Humans life histories have been described as “slow”, patterned by slow growth, delayed maturity, and long life span. While it is known that human life history diverged from that of a recent common chimpanzee-human ancestor some ~4–8 mya, it is unclear how selection pressures led to these distinct traits. To provide insight, we compare wild chimpanzees and human subsistence societies in order to identify the age-specific vital rates that best explain fitness variation, selection pressures and species divergence. Methods We employ Life Table Response Experiments to quantify vital rate contributions to population growth rate differences. Although widespread in ecology, these methods have not been applied to human populations or to inform differences between humans and chimpanzees. We also estimate correlations between vital rate elasticities and life history traits to investigate differences in selection pressures and test several predictions based on life history theory. Results Chimpanzees’ earlier maturity and higher adult mortality drive species differences in population growth, whereas infant mortality and fertility variation explain differences between human populations. Human fitness is decoupled from longevity by postreproductive survival, while chimpanzees forfeit higher potential lifetime fertility due to adult mortality attrition. Infant survival is often lower among humans, but lost fitness is recouped via short birth spacing and high peak fertility, thereby reducing selection on infant survival. Lastly, longevity and delayed maturity reduce selection on child survival, but among humans, recruitment selection is unexpectedly highest in longer-lived populations, which are also faster-growing due to high fertility. Conclusion Humans differ from chimpanzees more because of delayed maturity and lower adult mortality than from differences in juvenile mortality or fertility. In both species, high child mortality reflects bet-hedging costs of quality/quantity tradeoffs borne by offspring, with high and variable child mortality likely regulating human population growth over evolutionary history. Positive correlations between survival and fertility among human subsistence populations leads to selection pressures in human subsistence societies that differ from those in modern populations undergoing demographic transition.
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Churchley, Emmanuel G., Vernon G. Coffey, David J. Pedersen, et al. "Influence of preexercise muscle glycogen content on transcriptional activity of metabolic and myogenic genes in well-trained humans." Journal of Applied Physiology 102, no. 4 (2007): 1604–11. http://dx.doi.org/10.1152/japplphysiol.01260.2006.
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To determine whether preexercise muscle glycogen content influences the transcription of several early-response genes involved in the regulation of muscle growth, seven male strength-trained subjects performed one-legged cycling exercise to exhaustion to lower muscle glycogen levels (Low) in one leg compared with the leg with normal muscle glycogen (Norm) and then the following day completed a unilateral bout of resistance training (RT). Muscle biopsies from both legs were taken at rest, immediately after RT, and after 3 h of recovery. Resting glycogen content was higher in the control leg (Norm leg) than in the Low leg (435 ± 87 vs. 193 ± 29 mmol/kg dry wt; P < 0.01). RT decreased glycogen content in both legs ( P < 0.05), but postexercise values remained significantly higher in the Norm than the Low leg (312 ± 129 vs. 102 ± 34 mmol/kg dry wt; P < 0.01). GLUT4 (3-fold; P < 0.01) and glycogenin mRNA abundance (2.5-fold; not significant) were elevated at rest in the Norm leg, but such differences were abolished after exercise. Preexercise mRNA abundance of atrogenes was also higher in the Norm compared with the Low leg [atrogin: ∼14-fold, P < 0.01; RING (really interesting novel gene) finger: ∼3-fold, P < 0.05] but decreased for atrogin in Norm following RT ( P < 0.05). There were no differences in the mRNA abundance of myogenic regulatory factors and IGF-I in the Norm compared with the Low leg. Our results demonstrate that 1) low muscle glycogen content has variable effects on the basal transcription of select metabolic and myogenic genes at rest, and 2) any differences in basal transcription are completely abolished after a single bout of heavy resistance training. We conclude that commencing resistance exercise with low muscle glycogen does not enhance the activity of genes implicated in promoting hypertrophy.
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Liang, Xiaoniu, Xiantao Li, Ding Ding, et al. "Short Sitting Height and Low Relative Sitting Height Are Associated with Severe Cognitive Impairment among Older Women in an Urban Community in China." Neuroepidemiology 45, no. 4 (2015): 257–63. http://dx.doi.org/10.1159/000439569.
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Background: Anthropometric indexes are powerful indicators of the environment and the plasticity of the human body. This study aimed at exploring the anthropometric indexes that are associated with late-life cognition impairment among the elderly Chinese in the Shanghai Aging Study. Methods: The height, weight, and sitting height of 3,741 participants were measured. Participants were diagnosed with ‘dementia', ‘mild cognitive impairment', or ‘cognitive normal' by neurologists using DSM-IV and Petersen criteria. Logistic regression was used to evaluate the association between height, sitting height, leg length or relative sitting height and cognitive function. Results: Participants with dementia had the shortest body height (mean 157.2 cm, SD 9.1), the shortest sitting height (mean 81.8 cm, SD 5.6), and the lowest relative sitting height (mean 52.0 cm, SD 1.9). After adjustment for age, gender, education, lifestyles, medical history, apolipoprotein genotype and weight, shorter sitting height (OR 1.08, 95% CI 1.01-1.16 per cm), longer leg length (OR 0.93, 95% CI 0.88-0.99 per cm), and lower relative sitting height (OR 1.17, 95% CI 1.04-1.31 per 1%) were found to be significantly associated with dementia in older women. Conclusions: The potential risks for late-life severe cognitive impairment may be related to health problems in childhood and slow growth during puberty in women.
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Holz, C., J. Benning, M. Schaudt, et al. "Novel bioactive from Lactobacillus brevis DSM17250 to stimulate the growth of Staphylococcus epidermidis: a pilot study." Beneficial Microbes 8, no. 1 (2017): 121–31. http://dx.doi.org/10.3920/bm2016.0073.
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Commensal skin microbiota plays an important role in both influencing the immune response of the skin and acting as a barrier against colonisation of potentially pathogenic microorganisms and overgrowth of opportunistic pathogens. Staphylococcus epidermidis is a key constituent of the normal microbiota on human skin. It balances the inflammatory response after skin injury and produces antimicrobial molecules that selectively inhibit skin pathogens. Here we describe Lactobacillus brevis DSM17250 that was identified among hundreds of Lactobacillus strains to exhibit an anti-inflammatory effect in human keratinocytes in vitro and specific stimulatory impact on the growth of S. epidermidis. The aqueous cell-free extract of L. brevis DSM17250 was used in an ointment formulation and tested in a randomized placebo-controlled double blinded human pilot study. Healthy volunteers with diagnosed dry skin were treated for four weeks. The study data shows that L. brevis DSM17250 extract induces re-colonisation of the skin by protective commensal microorganisms as judged from selective bacterial cultivation of surface-associated skin microorganism of the lower leg. Furthermore, the 4 week administration of the L. brevis DSM17250 extract significantly improved the transepidermal water loss value (TEWL), reduced the xerosis cutis symptoms and stinging. The data shows that daily application of L. brevis DSM17250 extract in a topical product significantly improves the microbial skin microbiota by promoting the growth of species which possess beneficial regulatory and protective properties such as S. epidermidis. Restoring the natural skin microbiota leads to significantly improved skin barrier function (as transepidermal water loss) and decrease of xeroderma (xerosis cutis) symptoms (as measured by dry skin area and severity index, DASI). We propose that improving and stabilizing the natural skin microbiota by specifically stimulating the growth of S. epidermidis is an important and novel concept to manage skin diseases associated with microbiota dysbiosis.
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Stamos, Peter A., and Michael A. Berthaume. "The effects of femoral metaphyseal morphology on growth plate biomechanics in juvenile chimpanzees and humans." Interface Focus 11, no. 5 (2021): 20200092. http://dx.doi.org/10.1098/rsfs.2020.0092.
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The distal femoral metaphyseal surface presents dramatically different morphologies in juvenile extant hominoids—humans have relatively flat metaphyseal surfaces when compared with the more complex metaphyseal surfaces of apes. It has long been speculated that these different morphologies reflect different biomechanical demands placed on the growth plate during locomotor behaviour, with the more complex metaphyseal surfaces of apes acting to protect the growth plate during flexed-knee behaviours like squatting and climbing. To test this hypothesis, we built subject-specific parametric finite-element models from the surface scans of the femora of five Pan and six Homo juveniles. We then simulated the loading conditions of either a straight-leg or flexed-knee gait and measured the resulting stresses at the growth plate. When subjected to the simulated flexed-knee loading conditions, both the maximum and mean von Mises stresses were significantly lower in the Pan models than in the Homo models. Further, during these loading conditions, von Mises stresses were strongly negatively correlated with ariaDNE, a measure of complexity of the metaphyseal surface. These results indicate that metaphyseal surface morphology has a robust effect on growth plate mechanics.
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Raffetto, Joseph D., Daniela Ligi, Rosanna Maniscalco, Raouf A. Khalil, and Ferdinando Mannello. "Why Venous Leg Ulcers Have Difficulty Healing: Overview on Pathophysiology, Clinical Consequences, and Treatment." Journal of Clinical Medicine 10, no. 1 (2020): 29. http://dx.doi.org/10.3390/jcm10010029.
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Venous leg ulcers (VLUs) are one of the most common ulcers of the lower extremity. VLU affects many individuals worldwide, could pose a significant socioeconomic burden to the healthcare system, and has major psychological and physical impacts on the affected individual. VLU often occurs in association with post-thrombotic syndrome, advanced chronic venous disease, varicose veins, and venous hypertension. Several demographic, genetic, and environmental factors could trigger chronic venous disease with venous dilation, incompetent valves, venous reflux, and venous hypertension. Endothelial cell injury and changes in the glycocalyx, venous shear-stress, and adhesion molecules could be initiating events in VLU. Increased endothelial cell permeability and leukocyte infiltration, and increases in inflammatory cytokines, matrix metalloproteinases (MMPs), reactive oxygen and nitrogen species, iron deposition, and tissue metabolites also contribute to the pathogenesis of VLU. Treatment of VLU includes compression therapy and endovenous ablation to occlude the axial reflux. Other interventional approaches such as subfascial endoscopic perforator surgery and iliac venous stent have shown mixed results. With good wound care and compression therapy, VLU usually heals within 6 months. VLU healing involves orchestrated processes including hemostasis, inflammation, proliferation, and remodeling and the contribution of different cells including leukocytes, platelets, fibroblasts, vascular smooth muscle cells, endothelial cells, and keratinocytes as well as the release of various biomolecules including transforming growth factor-β, cytokines, chemokines, MMPs, tissue inhibitors of MMPs (TIMPs), elastase, urokinase plasminogen activator, fibrin, collagen, and albumin. Alterations in any of these physiological wound closure processes could delay VLU healing. Also, these histological and soluble biomarkers can be used for VLU diagnosis and assessment of its progression, responsiveness to healing, and prognosis. If not treated adequately, VLU could progress to non-healed or granulating VLU, causing physical immobility, reduced quality of life, cellulitis, severe infections, osteomyelitis, and neoplastic transformation. Recalcitrant VLU shows prolonged healing time with advanced age, obesity, nutritional deficiencies, colder temperature, preexisting venous disease, deep venous thrombosis, and larger wound area. VLU also has a high, 50–70% recurrence rate, likely due to noncompliance with compression therapy, failure of surgical procedures, incorrect ulcer diagnosis, progression of venous disease, and poorly understood pathophysiology. Understanding the molecular pathways underlying VLU has led to new lines of therapy with significant promise including biologics such as bilayer living skin construct, fibroblast derivatives, and extracellular matrices and non-biologic products such as poly-N-acetyl glucosamine, human placental membranes amnion/chorion allografts, ACT1 peptide inhibitor of connexin 43, sulodexide, growth factors, silver dressings, MMP inhibitors, and modulators of reactive oxygen and nitrogen species, the immune response and tissue metabolites. Preventive measures including compression therapy and venotonics could also reduce the risk of progression to chronic venous insufficiency and VLU in susceptible individuals.
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Trenouth, M. J. "Changes in the Jaw Relationships during Human Foetal Cranio-facial Growth." British Journal of Orthodontics 12, no. 1 (1985): 33–39. http://dx.doi.org/10.1179/bjo.12.1.33.
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Previous investigations into pre-natal cranio-facial growth have either been purely descriptive or have involved the use of cephalometric points, lines and angles. Neither methods have given an entirely clear picture of the changes taking place during the foetal period. The present investigation measured changes in shape, position and orientation of the jaws by using image outlines and their centroids (centres of area) in combination with the analytic method of morphanalysis. The image outlines of the foetuses were related to each other via a rectangular co-ordinate reference grid so that the exact sites where growth changes occurred could be plotted and isolated. It was found that the jaw relationships were constantly changing during the foetal period. Brain growth appeared to predominate which flattened out the cranial base and determined the definitive position of the naso-maxillary segment to which the musculature of the lower face in turn adjusted mandibular growth. The jaw relationships changed in the direction Class Ill to Class 11 mainly as a result of forward growth of the naso-maxillary segment, the mandible showing a lag followed by a catch-up regaining its original position. The two jaws exhibited different growth patterns which suggested differences in the underlying mechanisms responsible for their growth. This is almost certainly an important factor in the aetiology of malocclusion resulting from malrelationships of the basal bones and soft tissues.
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Matthews, Marc R., Emily Helmick, Christopher Mellon, et al. "552 Limb Salvage: Amputations Prevented with Dehydrated Human Amnion/Chorion Membrane Allografts (dHACM) Used in Combination with Decellularized Human Collagen Matrix (dHCM)." Journal of Burn Care & Research 42, Supplement_1 (2021): S124—S125. http://dx.doi.org/10.1093/jbcr/irab032.202.
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Abstract Introduction Burn and traumatic limb injuries with exposed bone/tendon typically require surgical flaps or amputations for healing. Some burn patients are not candidates for these invasive techniques. Placental amniotic membrane has been used as a wound dressing for more than 100 years and may offer an alternative to flaps and/or amputations. Processed dehydrated human amnion/chorion membrane (dHACM), from human placental tissue, contains type 1 human collagen as well as non-viable cells and 285 identified regulatory proteins including growth factors, chemokines, cytokines, metalloproteinases, and other tissue growth and inflammatory mediators. dHACM has been successfully used as a dressing for wound ulcers, burns, donor sites, & surgical debridement. This study reports the use of dHCAM as a limb salvage tool in four patients with severe injuries. Methods This is a retrospective case series of patients suffering severe lower extremity injury with bone/tendon exposure that had applied dHACM/dHCM over or packed (depending on wound depth), then covered with 3% bismuth tribromophenate petrolatum dressing & glycerol/ hydroxyethylcellulose lubricant. Negative pressure wound therapy (NPWT) was initiated; wound re-evaluation occurred in seven days. dHACM/dHCM was reapplied if required (bone still exposed). Results There were 3 males and 1 female with three burns and one NSTI. The mean±sd (median) age was 58±23 (61) years; % total burn surface area 3±3 (2); length of hospital stay 48±30 (40) days; number of tangential excisions & debridements 6.5±1 (6.5); days from admission to product application 49±47 (34) and discharge 24±19 (19) days; negative pressure wound therapy (NPWT) 53±6 (56) days. All four patients continued treatment upon discharge with clinic visits and home NPWT. All recovered with good results and no complications. Treatment may be continued with NPWT therapy at home or in a skilled nursing facility. Patients healed after two to three dHACM/dHCM applications and did not require leg or foot amputations. Conclusions In select limb salvage cases, dHACM/HCM may be a promising alternative to extremity amputations, tissue transfer flaps or other techniques for secondary intention healing of wounds with bone/tendon exposure.
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Shlomai, Gadi, Zara Zelenko, Irini Markella Antoniou, et al. "OP449 inhibits breast cancer growth without adverse metabolic effects." Endocrine-Related Cancer 24, no. 10 (2017): 519–29. http://dx.doi.org/10.1530/erc-17-0077.
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Hyperinsulinemia is associated with a decrease in breast cancer recurrence-free survival and overall survival. Inhibition of insulin receptor signaling is associated with glycemic dysregulation. SET is a direct modulator of PP2A, which negatively regulates the PI3K/AKT/mTOR pathway. OP449, a SET inhibitor, decreases AKT/mTOR activation. The effects of OP449 treatment on breast cancer growth in the setting of pre-diabetes, and its metabolic implications are currently unknown. We found that the volumes and weights of human MDA-MB-231 breast cancer xenografts were greater in hyperinsulinemic mice compared with controls (P < 0.05), and IR phosphorylation was 4.5-fold higher in these mice (P < 0.05). Human and murine breast cancer tumors treated with OP449 were 47% and 39% smaller than controls (P < 0.05, for both, respectively). AKT and S6RP phosphorylation were 82% and 34% lower in OP449-treated tumors compared with controls (P < 0.05, P = 0.06, respectively). AKT and S6RP phosphorylation in response to insulin was 30% and 12% lower in cells, pre-treated with OP449, compared with control cells (P < 0.01, P < 0.05, respectively). However, even with decreased AKT/mTOR activation, body weights and composition, blood glucose and plasma insulin, glucose tolerance, serum triglyceride and cholesterol levels were similar between OP449-treated mice and controls. Xenografts and liver tissue from OP449-treated mice showed a 64% and 70% reduction in STAT5 activation, compared with controls (P < 0.01 and P = 0.06, respectively). Our data support an anti-neoplastic effect of OP449 on human breast cancer cells in vitro and in xenografts in the setting of hyperinsulinemia. OP449 led to the inhibition of AKT/mTOR signaling, albeit, not leading to metabolic derangements.
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Földvári, Péter, Bas van Leeuwen, and Dmitry Didenko. "Capital formation and economic growth under central planning and transition: A theoretical and empirical analysis, ca. 1920–2008." Acta Oeconomica 65, no. 1 (2015): 27–50. http://dx.doi.org/10.1556/aoecon.65.2015.1.2.
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According to the consensus view, it was primarily physical capital accumulation that drove economic growth during the early years of state socialism. Growth models incorporating both human and physical capital accumulation led to the conclusion that a high physical/human capital ratio can cause a lower economic growth in the long run, hence offering an explanation for the failure of socialist economies. In this paper, we show theoretically and empirically that according to the logic of the socialist planner, it was optimal to achieve a higher physical to human capital ratio in socialist countries than in the West. Using a VAR analysis, we find empirical confirmation that within the Material Product System of national accounting, the relative dominance of investment in physical capital accumulation relative to human capital was indeed more efficient than under the system of national accounts.
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Tzounis, Xenofon, Jelena Vulevic, Gunter G. C. Kuhnle, et al. "Flavanol monomer-induced changes to the human faecal microflora." British Journal of Nutrition 99, no. 4 (2007): 782–92. http://dx.doi.org/10.1017/s0007114507853384.
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We have investigated the bacterial-dependent metabolism of ( − )-epicatechin and (+)-catechin using a pH-controlled, stirred, batch-culture fermentation system reflective of the distal region of the human large intestine. Incubation of ( − )-epicatechin or (+)-catechin (150 mg/l or 1000 mg/l) with faecal bacteria, led to the generation of 5-(3′,4′-dihydroxyphenyl)-γ-valerolactone, 5-phenyl-γ-valerolactone and phenylpropionic acid. However, the formation of these metabolites from (+)-catechin required its initial conversion to (+)-epicatechin. The metabolism of both flavanols occurred in the presence of favourable carbon sources, notably sucrose and the prebiotic fructo-oligosaccharides, indicating that bacterial utilisation of flavanols also occurs when preferential energy sources are available. (+)-Catechin incubation affected the growth of select microflora, resulting in a statistically significant increase in the growth of theClostridium coccoides–Eubacterium rectalegroup,Bifidobacteriumspp. andEscherichia coli, as well as a significant inhibitory effect on the growth of theC. histolyticumgroup. In contrast, the effect of ( − )-epicatechin was less profound, only significantly increasing the growth of theC. coccoides–Eubacterium rectalegroup. These potential prebiotic effects for both (+)-catechin and ( − )-epicatechin were most notable at the lower concentration of 150 mg/l. As both ( − )-epicatechin and (+)-catechin were converted to the same metabolites, the more dramatic change in the growth of distinct microfloral populations produced by (+)-catechin incubation may be linked to the bacterial conversion of (+)-catechin to (+)-epicatechin. Together these data suggest that the consumption of flavanol-rich foods may support gut health through their ability to exert prebiotic actions.
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Smith, G. D. P., M. Alam, L. P. Watson, and C. J. Mathias. "Effect of the Somatostatin Analogue, Octreotide, on Exercise-Induced Hypotension in Human Subjects with Chronic Sympathetic Failure." Clinical Science 89, no. 4 (1995): 367–73. http://dx.doi.org/10.1042/cs0890367.
Full textAbstract:
1. In autonomic failure, supine exercise lowers blood pressure and worsens postural hypotension. The somatostatin analogue, octreotide, reduces postprandial and postural hypotension, but its effects on exercise-induced hypotension and on postural hypotension post-exercise are unknown. 2. Eighteen subjects with chronic sympathetic denervation were studied; 12 had pure autonomic failure and six had additional neurological features of the Shy—Drager syndrome. Haemodynamic, hormonal and biochemical changes were measured before, during and after incremental supine leg exercise on two occasions: on no treatment and after subcutaneous octreotide. Exercise was performed 120 min after octreotide in eight subjects and 60 min after octreotide in ten subjects. 3. Octreotide did not improve exercise-induced hypotension; the blood pressure fall was greater during exercise, but the blood pressure level was no different than without treatment. Heart rate, stroke distance, cardiac index and systemic vascular resistance were similar at rest and changed to the same degree with exercise on and off octreotide. After octreotide, resting levels of serum growth hormone, plasma noradrenaline, adrenaline and renin were unchanged, but glucose was higher and insulin was lower. There was no change in biochemical and hormone levels during exercise either off or on octreotide. 4. After octreotide, although the rate of blood pressure recovery was similar post-exercise, the levels of blood pressure were higher than in the non-treatment phase and postural hypotension was improved before and after exercise. 5. In conclusion, in primary autonomic failure, octreotide did not improve exercise-induced hypotension in the supine position, suggesting that octreotide-sensitive vasodilatory peptides do not contribute to the blood pressure fall. With octreotide, supine blood pressure levels were higher post-exercise and postural hypotension was improved both before and after exercise.
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Katayama, N., M. Nishikawa, F. Komada, N. Minami, and S. Shirakawa. "A role for calmodulin in the growth of human hematopoietic progenitor cells." Blood 75, no. 7 (1990): 1446–54. http://dx.doi.org/10.1182/blood.v75.7.1446.1446.
Full textAbstract:
Abstract A possible role for calmodulin in the colony growth of human hematopoietic progenitor cells was investigated using pharmacologic approaches. We obtained evidence for a dose-dependent inhibition of colony formation of myeloid progenitor cells (CFU-C) stimulated by interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF), or granulocyte CSF (G-CSF) by three calmodulin antagonists, N- (6-aminohexyl)-5-chloro-1-naphthalenesulfonamide hydrochloride (W-7), N- (4-aminobutyl)-5-chloro-2-naphthalenesulfonamide hydrochloride (W-13), and trifluoperazine. Chlorine-deficient analogs of W-7 and W-13, with a lower affinity for calmodulin, did not inhibit the growth of CFU-C colonies. W-7, W-13, and trifluoperazine inhibited the colony formation of immature erythroid progenitor cells (BFU-E) stimulated by IL-3 plus erythropoietin (Ep) or GM-CSF plus Ep, in a dose-dependent manner, while they did not affect the colony formation of mature erythroid progenitor cells (CFU-E) induced by Ep. W-7, W-13, and trifluoperazine also led to a dose-dependent inhibition of GM-CSF-induced colony formation of KG-1 cells. Calmodulin-dependent kinase activity derived from the KG-1 cells was inhibited by these three calmodulin antagonists in a dose-dependent manner. These data suggest that calmodulin may play an important regulatory role via a common process in the growth of hematopoietic progenitor cells stimulated by IL-3, GM-CSF, and G-CSF. Mechanisms related to the growth signal of Ep apparently are not associated with calmodulin-mediated systems.
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Katayama, N., M. Nishikawa, F. Komada, N. Minami, and S. Shirakawa. "A role for calmodulin in the growth of human hematopoietic progenitor cells." Blood 75, no. 7 (1990): 1446–54. http://dx.doi.org/10.1182/blood.v75.7.1446.bloodjournal7571446.
Full textAbstract:
A possible role for calmodulin in the colony growth of human hematopoietic progenitor cells was investigated using pharmacologic approaches. We obtained evidence for a dose-dependent inhibition of colony formation of myeloid progenitor cells (CFU-C) stimulated by interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF), or granulocyte CSF (G-CSF) by three calmodulin antagonists, N- (6-aminohexyl)-5-chloro-1-naphthalenesulfonamide hydrochloride (W-7), N- (4-aminobutyl)-5-chloro-2-naphthalenesulfonamide hydrochloride (W-13), and trifluoperazine. Chlorine-deficient analogs of W-7 and W-13, with a lower affinity for calmodulin, did not inhibit the growth of CFU-C colonies. W-7, W-13, and trifluoperazine inhibited the colony formation of immature erythroid progenitor cells (BFU-E) stimulated by IL-3 plus erythropoietin (Ep) or GM-CSF plus Ep, in a dose-dependent manner, while they did not affect the colony formation of mature erythroid progenitor cells (CFU-E) induced by Ep. W-7, W-13, and trifluoperazine also led to a dose-dependent inhibition of GM-CSF-induced colony formation of KG-1 cells. Calmodulin-dependent kinase activity derived from the KG-1 cells was inhibited by these three calmodulin antagonists in a dose-dependent manner. These data suggest that calmodulin may play an important regulatory role via a common process in the growth of hematopoietic progenitor cells stimulated by IL-3, GM-CSF, and G-CSF. Mechanisms related to the growth signal of Ep apparently are not associated with calmodulin-mediated systems.
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Beaulieu, Mélanie L., Madeleine G. DeClercq, Nathan T. Rietberg, et al. "The Anterior Cruciate Ligament Can Become Hypertrophied in Response to Mechanical Loading: A Magnetic Resonance Imaging Study in Elite Athletes." American Journal of Sports Medicine 49, no. 9 (2021): 2371–78. http://dx.doi.org/10.1177/03635465211012354.
Full textAbstract:
Background: Evidence, mainly from animal models, suggests that exercise during periods of pubertal growth can produce a hypertrophied anterior cruciate ligament (ACL) and improve its mechanical properties. In humans, the only evidence of ACL hypertrophy comes from a small cross-sectional study of elite weight lifters and control participants; that study had methodological weaknesses and, thus, more evidence is needed. Purpose: To investigate bilateral differences in the ACL cross-sectional area (CSA) for evidence of unilateral hypertrophy in athletes who have habitually loaded 1 leg more than the other. Study Design: Cross-sectional study; Level of evidence, 3. Methods: We recruited 52 figure skaters and springboard divers (46 female and 6 male; mean age, 20.2 ± 2.7 years) because the former always land/jump on the same leg while the latter always drive the same leg into the board during their hurdle approach. Sport training for all participants began before puberty and continued throughout as well as after. Using oblique axial– and oblique sagittal–plane magnetic resonance imaging, we measured the ACL CSA and the anteroposterior diameter of the patellar tendon, respectively. In addition, isometric and isokinetic knee extensor and flexor peak torques were acquired using a dynamometer. Bilateral differences in the ACL CSA, patellar tendon diameter, and knee muscle strength were evaluated via 2-sided paired-samples t tests. Correlations between the bilateral difference in the ACL CSA and age of training onset as well as between the bilateral difference in the ACL CSA and years of training were also examined. Results: A significantly larger ACL CSA (mean difference, 4.9% ± 14.0%; P = .041), as well as patellar tendon diameter (mean difference, 4.7% ± 9.4%; P = .002), was found in the landing/drive leg than in the contralateral leg. The bilateral difference in the ACL CSA, however, was not associated with the age of training onset or years of training. Last, the isometric knee flexor peak torque was significantly greater in the landing/drive leg than the contralateral leg (mean difference, 14.5% ± 33.8%; P = .019). Conclusion: Athletes who habitually loaded 1 leg more than the other before, during, and after puberty exhibited significant unilateral ACL hypertrophy. This study suggests that the ACL may be able to be “trained” in athletes. If done correctly, it could help lower the risk for ACL injuries.
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Miyaji, Katsuya, Eiichi Tani, Atsuhisa Nakano, Hideyasu Ikemoto, and Keizo Kaba. "Inhibition by 5′-methylthioadenosine of cell growth and tyrosine kinase activity stimulated by fibroblast growth factor receptor in human gliomas." Journal of Neurosurgery 83, no. 4 (1995): 690–97. http://dx.doi.org/10.3171/jns.1995.83.4.0690.
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✓ Stimulation of three human glioma cell lines with basic fibroblast growth factor (bFGF) led to the enhancement of cell growth and the rapid tyrosine phosphorylation of cellular proteins, including major substrates of 90 kD. A methyltransferase inhibitor, 5′-methylthioadenosine (MTA), inhibited dose dependently the bFGF-stimulated cell growth and protein tyrosine phosphorylation in glioma cells by blocking both receptor autophosphorylation and substrate phosphorylation, as shown by immunoblotting with antiphosphotyrosine antibodies and cross-linking bFGF to receptors. The antiproliferative activity of MTA correlated quantitatively with its potency as an inhibitor of bFGF-stimulated protein tyrosine kinase activity. The methyltransferase inhibitor MTA had no effect on either epidermal growth factor— or platelet-derived growth factor—stimulated protein tyrosine phosphorylation in glioma cells, but inhibited specifically bFGF-stimulated protein tyrosine kinase activity. The concentration of MTA required for inhibition of protein methylation correlated well with the concentration required for inhibition of bFGF-stimulated cell growth and protein tyrosine phosphorylation. Because MTA had no effect on numbers and dissociation constants of high- and low-affinity bFGF receptors, the inhibition of bFGF-stimulated bFGF receptor tyrosine kinase activity is not likely to be the result of a reduction in bFGF receptor and bFGF binding capacity. In fact, MTA delayed and reduced the internalization and nuclear translocation of bFGF, and the internalized bFGF was submitted to a limited proteolysis that converted it to lower molecular peptides whose presence remained for at least 22 hours. The effect of MTA on bFGF-stimulated tyrosine phosphorylation was immediate and readily reversible.
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Fawcett, J. P., V. Ravindran, P. C. H. Morel, et al. "Influence of salbutamol administered as the single active enantiomer (R-salbutamol) on the growth performance and carcass characteristics of broiler chickens." Animal Science 78, no. 1 (2004): 23–30. http://dx.doi.org/10.1017/s1357729800053807.
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AbstractSalbutamol (albuterol) is a β-adrenergic agonist marketed as a racemic (50: 50) mixture of R- and S-enantiomers (rac-salbutamol). Since only R-salbutamol is pharmacologically active and S-salbutamol has a longer half-life in humans, we examined R-salbutamol as a performance enhancer and repartitioning agent in domestic chickens. The effects of feeding diets containing R-salbutamol (5, 10 and 15 mg/kg diet) and rac-salbutamol (10 mg/kg diet) from day 21 to 42 post hatching on growth performance, carcass characteristics and tissue concentrations of R- and S-salbutamol in male and female broilers were compared with a control diet. R-salbutamol in the diet lowered the weight gains in both sexes, but the magnitude of reduction was greater in males as indicated by a significant R-salbutamol ✕ gender interaction. R-salbutamol also lowered food intake and improved food conversion ratios in both sexes. The relative weights of breast muscle and leg muscle were significantly increased and the relative weight of the fat pad was significantly decreased in birds of both sexes given diets containing R-salbutamol. Carcass protein content increased and carcass fat content decreased but the differences were not statistically significant. A significant dose-response effect was observed for tissue concentrations of R-salbutamol in all tissues, except the fat. Performance and carcass parameters in chickens given the 5 mg/kg R-salbutamol diet were similar to those given the 10 mg/kg rac-salbutamol diet, but tissue concentrations of R-salbutamol were lower. Chickens given the 10 mg/ kg rac-salbutamol diet had higher tissue concentrations of salbutamol than chickens given the 10 mg/kg R-salbutamol diet and higher concentrations of S-salbutamol than R-salbutamol in liver and leg muscle. Overall, these results demonstrate that R-salbutamol is an effective repartitioning agent in broiler chickens.
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Sakai, Jun. "1723. Human Serum Albumin Regulates the Growth of Candida auris in vitro." Open Forum Infectious Diseases 6, Supplement_2 (2019): S631—S632. http://dx.doi.org/10.1093/ofid/ofz360.1586.
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Abstract Background Candida auris is commonly detected in human ear secretions. However, C. auris occasionally causes bloodstream infections even in immunocompetent patients resulting in poor prognosis. It was speculated that C. auris growth within the blood might be regulated by proteins in the bloodstream. Thus, in this study, the potential role of blood proteins in the regulation of C. auris growth was investigated. Methods Five Candida species (C. albicans, C. auris, C. glabrata, C. parapsilosis, and C. tropicalis) were incubated overnight. Colony suspensions for each species were prepared and adjusted to OD 1.0 at absorbance 0.1. Then, human serum albumin (HSA) and bovine serum albumin (BSA) were diluted (2.5 g/dL–0.002 g/dL) and mixed with the suspensions. Mixed samples were adjusted to 100 μL and incubated on MHA plates at 35°C for 2 days. Then, 50 μL of the combined sample was extracted and streaked onto Yeast extract-Peptone-Dextrose (YPD) agar. The remaining 50 μL sample was analyzed using an XTT assay. Further testing was then conducted on the effects of a specific blood protein albumin on Candida. Thereby, C. albicans and C. auris were cultured following the procedure above and stained with Annexin V and PI. Results The growth of C. auris mixed with a high albumin concentration (2.5~0.15 g/dL) was regulated compared with that of other Candida species (P < 0.01) (Figures 1 and 2); however, the growth of C. auris mixed with a lower albumin concentration was similar to that of other species. The wash-out study showed that C. auris growth and survival in the high albumin concentration was not different than that of other species. Conclusion HSA and BSA regulated C. auris growth which led to increased necrosis of C. auris. Conversely, growth of the other Candida species was not regulated. Therefore, albumin might be involved in the growth and necrosis of C. auris. As the highest concentration at which albumin regulated C. auris growth was similar to that found in human serum, it is possible that serum albumin might help prevent C. auris from entering the bloodstream via the ear or skin. Disclosures All authors: No reported disclosures.
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Silva, Marta, Luis Filipe Martins, and Helena Lopes. "Asymmetric Labor Market Reforms: Effects on Wage Growth and Conversion Probability of Fixed-Term Contracts." ILR Review 71, no. 3 (2017): 760–88. http://dx.doi.org/10.1177/0019793917737506.
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The authors investigate the impact of a change in employment protection laws in Portugal that increased the maximum legal duration of fixed-term contracts. They find that this reform led to a reduction in the probability that a worker on a fixed-term contract would be converted to a permanent contract. In addition, those workers who had their contracts converted experienced a significantly higher hourly wage growth at the time of conversion and faced a lower reduction in wage growth during the years in which the changed legislation was in force. Consequently, the implementation of this law led to a 27% increase in the wage-growth differential between the two contracts. The findings are based on an endogenous regime-switching model using rich administrative linked employer–employee data.
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Tamir, Raz, Gal Eyal, Itay Cohen, and Yossi Loya. "Effects of Light Pollution on the Early Life Stages of the Most Abundant Northern Red Sea Coral." Microorganisms 8, no. 2 (2020): 193. http://dx.doi.org/10.3390/microorganisms8020193.
Full textAbstract:
The growth in human population along coastal areas is exposing marine environments to increasing anthropogenic light sources. Despite the potential effects of this modern phenomenon, very few studies have examined its implications for corals. Here, we present a long-term study of coral early life stages under light pollution conditions at night. Coral larvae were collected from Stylophora pistillata colonies, and then settled and grown under experimental conditions of two different common city lighting methods (fluorescent or LED). Effects of the artificial lighting on the coral settlement success, survivorship, growth rate, photosynthetic efficiency, and calcification rate were examined over a period of one year. The control exhibited ~30% higher settlement success compared to the two light treatments, while under the light treatments corals showed higher survivorship, growth, and calcification rates. In addition, an indication of damage to the photosynthetic system was found in the light-polluted corals, which was reflected in their photosynthesis efficiency parameters: i.e., lower maximum light utilization coefficient (α), lower maximum potential photosynthetic rate (Pmax), and lower photosynthetic maximal quantum yield (Fv/Fm). Our findings provide evidence of the potential adverse effects of artificial lighting methods on the natural environment of coral reefs. We conclude that the use of the LED lighting method has high interference potential for the early life stages of corals.
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Aysin, Ferhunde, Asli Yilmaz, and Mehmet Yilmaz. "Metallic Nanoparticle-Decorated Polydopamine Thin Films and Their Cell Proliferation Characteristics." Coatings 10, no. 9 (2020): 802. http://dx.doi.org/10.3390/coatings10090802.
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Plasmonic metal nanoparticle (NP)-decorated thin films of biobased and biocompatible polymers provide significant opportunities in various biomedical applications. Inspired from the adhesive proteins of the marine mussels, polydopamine (PDA) serves as a versatile, biocompatible, and simple thin-film material and enhances cell growth and proliferation. Herein, we report the fabrication of the gold NPs (AuNPs) or silver NPs (AgNPs)-deposited thin films of PDA and their employment in cell growth and proliferation. PDA thin film with its numerous functional groups enabled well-controlled adsorption of NPs. The number density of NPs was manipulated simply by tuning the deposition time. Cell viability test for human lung cancer (A549) and human colon cancer (CaCO2) cell lines indicated that a thin layer of PDA film remarkably enhanced the cell growth and proliferation. The lower number density of NPs for the 24 h of the culture time resulted in a higher proliferation rate. However, the increase in both the number density of NPs and culture time led to a decrease in cell growth.
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Ribo, Silvia, David Sánchez-Infantes, Laura Martinez-Guino, et al. "Increasing breast milk betaine modulates Akkermansia abundance in mammalian neonates and improves long-term metabolic health." Science Translational Medicine 13, no. 587 (2021): eabb0322. http://dx.doi.org/10.1126/scitranslmed.abb0322.
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Accelerated postnatal growth is a potentially modifiable risk factor for future obesity. To study how specific breast milk components contribute to early growth and obesity risk, we quantified one-carbon metabolism-related metabolites in human breast milk and found an inverse association between milk betaine content and infant growth. This association was replicated in an independent and geographically distinct cohort. To determine the potential role of milk betaine in modulating offspring obesity risk, we performed maternal betaine supplementation experiments in mice. Higher betaine intake during lactation increased milk betaine content in dams and led to lower adiposity and improved glucose homeostasis throughout adulthood in mouse offspring. These effects were accompanied by a transient increase in Akkermansia spp. abundance in the gut during early life and a long-lasting increase in intestinal goblet cell number. The link between breast milk betaine and Akkermansia abundance in the gut was also observed in humans, as infants exposed to higher milk betaine content during breastfeeding showed higher fecal Akkermansia muciniphila abundance. Furthermore, administration of A. muciniphila to mouse pups during the lactation period partially replicated the effects of maternal breast milk betaine, including increased intestinal goblet cell number, lower adiposity, and improved glucose homeostasis during adulthood. These data demonstrate a link between breast milk betaine content and long-term metabolic health of offspring.
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Kjær, Michael, Birgitte Hanel, Lars Worm, et al. "Cardiovascular and neuroendocrine responses to exercise in hypoxia during impaired neural feedback from muscle." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 277, no. 1 (1999): R76—R85. http://dx.doi.org/10.1152/ajpregu.1999.277.1.r76.
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Reflex mechanisms from contracting skeletal muscle have been shown to be important for cardiovascular, neuroendocrine, and extramuscular fuel-mobilization responses in exercise. Furthermore, because hypoxia results in exaggerated metabolic changes in contracting muscle, the present study evaluated whether enhancement of cardiovascular and neuroendocrine responses by hypoxia during exercise is influenced by neural feedback from contracting muscle. Seven healthy males cycled at 46% maximal O2 uptake for 20 min both during normoxia and at 11.5% O2, and both without and with epidural anesthesia (EA; 20 ml 0.25% bupivacain, resulting in cutaneous hypesthesia below T10-T12 and 25% reduction in maximal leg strength). Exercise to exhaustion was also performed at 7.8% O2. The exercise-induced increases in heart rate; cardiac output; leg blood flow; plasma concentrations of growth hormone, adrenocorticotropin, cortisol, and catecholamines; renin activity; glucose production and disappearance; norepinephrine spillover [2,190 ± 341 ng/min (exercise at 11.5% O2) vs. 988 ± 95 ng/min (exercise during normoxia)]; lactate release from and glucose uptake in the leg; and the decreases in plasma insulin and free fatty acids were exaggerated in hypoxia ( P < 0.05). In muscle, concentrations of lactate, creatine, and inosine 5′-monophosphate were higher, and those of phosphocreatine were lower after exercise in hypoxia compared with normoxia. The exercise-induced increase in mean arterial blood pressure was not affected by hypoxia, but it was reduced by EA [108 ± 4 mmHg (control) vs. 97 ± 4 mmHg (EA); P < 0.05], and the reduction was more pronounced during severe hypoxia compared with normoxia. Apart from this, time to exhaustion at extreme hypoxia, circulatory responses, concentrations of neuroendocrine hormones, and extramuscular substrate mobilization were not diminished by EA. In conclusion, in essence the hypoxia-induced enhancement of systemic adaptation to exercise is not mediated by neural feedback from working muscle in humans.
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Pham, Khoa, Micah J. Maxwell, Heather Sweeney, et al. "Novel Glutamine Antagonist JHU395 Suppresses MYC-Driven Medulloblastoma Growth and Induces Apoptosis." Journal of Neuropathology & Experimental Neurology 80, no. 4 (2021): 336–44. http://dx.doi.org/10.1093/jnen/nlab018.
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Abstract Medulloblastoma is the most common malignant pediatric brain tumor. Amplification of c-MYC is a hallmark of a subset of poor-prognosis medulloblastoma. MYC upregulates glutamine metabolism across many types of cancer. We modified the naturally occurring glutamine antagonist 6-diazo-5-oxo-l-norleucine (DON) by adding 2 promoeities to increase its lipophilicity and brain penetration creating the prodrug isopropyl 6-diazo-5-oxo-2-(((phenyl (pivaloyloxy) methoxy) - carbonyl) amino) hexanoate, termed JHU395. This prodrug was shown to have a 10-fold improved CSF-to-plasma ratio and brain-to-plasma ratio relative to DON. We hypothesized that JHU395 would have superior cell penetration compared with DON and would effectively and more potently kill MYC-expressing medulloblastoma. JHU395 treatment caused decreased growth and increased apoptosis in multiple human high-MYC medulloblastoma cell lines at lower concentrations than DON. Parenteral administration of JHU395 in Nu/Nu mice led to the accumulation of micromolar concentrations of DON in brain. Treatment of mice bearing orthotopic xenografts of human MYC-amplified medulloblastoma with JHU395 increased median survival from 26 to 45 days compared with vehicle control mice (p &lt; 0.001 by log-rank test). These data provide preclinical justification for the ongoing development and testing of brain-targeted DON prodrugs for use in medulloblastoma.
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Goff, D. J., and C. J. Tabin. "Analysis of Hoxd-13 and Hoxd-11 misexpression in chick limb buds reveals that Hox genes affect both bone condensation and growth." Development 124, no. 3 (1997): 627–36. http://dx.doi.org/10.1242/dev.124.3.627.
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Hox genes are important regulators of limb pattern in vertebrate development. Misexpression of Hox genes in chicks using retroviral vectors provides an opportunity to analyze gain-of-function phenotypes and to assess their modes of action. Here we report the misexpression phenotype for Hoxd-13 and compare it to the misexpression phenotype of Hoxd-11. Hoxd-13 misexpression in the hindlimb results in a shortening of the long bones, including the femur, the tibia, the fibula and the tarsometatarsals. Mutations in an alanine repeat region in the N-terminus of Hoxd-13 have recently been implicated in human synpolydactyly (Muragaki, Y., Mundlos, S., Upton, J. and Olsen, B. R. (1996) Science 272, 548–551). N-terminal truncations of Hoxd-13 which lack this repeat were constructed and were found to produce a similar, although slightly milder, misexpression phenotype than the full-length Hoxd-13. The stage of bone development regulated by Hox genes has not previously been examined. The changes in bone lengths caused by Hoxd-13 misexpression are late phenotypes that first become apparent during the growth phase of the bones. Analysis of tritiated thymidine uptake by the tibia and fibula demonstrates that Hox genes can pattern the limb skeleton by regulating the rates of cell division in the proliferative zone of growing cartilage. Hoxd-11, in contrast to Hoxd-13, acts both at the initial cartilage condensation phase in the foot and during the later growth phase in the lower leg. Ectopic Hoxd-13 appears to act in a dominant negative manner in regions where it is not normally expressed. We propose a model in which all Hox genes are growth promoters, regulating the expression of the same target genes, with some Hox genes being more effective promoters of growth than other Hox genes. According to this model, the overall rate of growth in a given region is the result of the combined action of all of the Hox genes expressed in that region competing for the same target genes.
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Boriani, Filippo, and Paolo Bogetti. "Lower Leg Perforators and Bone Growth." Plastic and Reconstructive Surgery 123, no. 3 (2009): 1134–35. http://dx.doi.org/10.1097/prs.0b013e31819a353c.
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Shelburne, Samuel A., Nnaja Okorafor, Izabela Sitkiewicz, et al. "Regulation of Polysaccharide Utilization Contributes to the Persistence of Group A Streptococcus in the Oropharynx." Infection and Immunity 75, no. 6 (2007): 2981–90. http://dx.doi.org/10.1128/iai.00081-07.
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ABSTRACT Group A Streptococcus (GAS) genes that encode proteins putatively involved in polysaccharide utilization show growth phase-dependent expression in human saliva. We sought to determine whether the putative polysaccharide transcriptional regulator MalR influences the expression of such genes and whether MalR helps GAS infect the oropharynx. Analysis of 32 strains of 17 distinct M protein serotypes revealed that MalR is highly conserved across GAS strains. malR transcripts were detectable in patients with GAS pharyngitis, and the levels increased significantly during growth in human saliva compared to the levels during growth in glucose-containing or nutrient-rich media. To determine if MalR influenced the expression of polysaccharide utilization genes, we compared the transcript levels of eight genes encoding putative polysaccharide utilization proteins in the parental serotype M1 strain MGAS5005 and its ΔmalR isogenic mutant derivative. The transcript levels of all eight genes were significantly increased in the ΔmalR strain compared to the parental strain, especially during growth in human saliva. Following experimental infection, the ΔmalR strain persistently colonized the oropharynx in significantly fewer mice than the parental strain colonized, and the numbers of ΔmalR strain CFU recovered were significantly lower than the numbers of the parental strain CFU recovered. These data led us to conclude that MalR influences the expression of genes putatively involved in polysaccharide utilization and that MalR contributes to the persistence of GAS in the oropharynx.
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Levy, David Jessula, Amy Goundry, Raquel S. S. Laires, et al. "Role of the inhibitor of serine peptidase 2 (ISP2) of Trypanosoma brucei rhodesiense in parasite virulence and modulation of the inflammatory responses of the host." PLOS Neglected Tropical Diseases 15, no. 6 (2021): e0009526. http://dx.doi.org/10.1371/journal.pntd.0009526.
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Trypanosoma brucei rhodesiense is one of the causative agents of Human African Trypanosomiasis (HAT), known as sleeping sickness. The parasite invades the central nervous system and causes severe encephalitis that is fatal if left untreated. We have previously identified ecotin-like inhibitors of serine peptidases, named ISPs, in trypanosomatid parasitic protozoa. Here, we investigated the role of ISP2 in bloodstream form T. b. rhodesiense. We generated gene-deficient mutants lacking ISP2 (Δisp2), which displayed a growth profile in vitro similar to that of wild-type (WT) parasites. C57BL/6 mice infected with Δisp2 displayed lower blood parasitemia, a delayed hind leg pathological phenotype and survived longer. The immune response was examined at two time-points that corresponded with two peaks of parasitemia. At 4 days, the spleens of Δisp2-infected mice had a greater percentage of NOS2+ myeloid cells, IFN-γ+-NK cells and increased TNF-α compared to those infected with WT and parasites re-expressing ISP2 (Δisp2:ISP2). By 13 days the increased NOS2+ population was sustained in Δisp2-infected mice, along with increased percentages of monocyte-derived dendritic cells, as well as CD19+ B lymphocytes, and CD8+ and CD4+ T lymphocytes. Taken together, these findings indicate that ISP2 contributes to T. b. rhodesiense virulence in mice and attenuates the inflammatory response during early infection.
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Weber, C., S. Gokorsch, and P. Czermak. "Expansion and Chondrogenic Differentiation of Human Mesenchymal Stem Cells." International Journal of Artificial Organs 30, no. 7 (2007): 611–18. http://dx.doi.org/10.1177/039139880703000709.
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The potential of human mesenchymal stem cells (hMSC) to differentiate into various types of mesenchymal tissue, such as chondrocytes, makes them a potential cell source in cartilage tissue engineering. Because of the requirement of high cell amounts for the generation of cartilage implants or for the extensive experimental studies to investigate the culture parameters, the initial cells have to be expanded, which leads to high population doubling numbers. It is known that hMSC can differentiate into chondrocytes at least up to the 15th population doubling. To monitor the differentiation status, the protein MIA (melanoma inhibitory activity), which is only synthesized by malignant melanomas and chondrocytes, can be used. In this study the chondrogenic differentiation potential of hMSC beyond the 15th population doubling was investigated using MIA as a chondrocyte marker. A chondrogenic potential of hMSC at higher population doubling numbers may be of interest due to the requirement of less frequent isolations of cells. Therefore hMSC were cultured in a monolayer until the 37th population doubling. Cells of different passages were cultured as pellets for two weeks in transforming growth factor (TGF)-β3 containing differentiation medium. The MIA contents in medium on the last three cultivation days were measured for each case using an MIA-ELISA-kit. A significant difference between MIA content in medium of the pellet and non-stimulated monolayer reference cultures was detectable until the 32nd population doubling. In addition, the hMSC were seeded at lower densities to investigate whether the cells may be expanded faster and with less amount of work due to higher population doubling numbers per passage. The reduced inoculation density led to an increased growth rate. (Int J Artif Organs 2007; 30: 611–8)
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Shelburne, Samuel A., Paul Sumby, Izabela Sitkiewicz, et al. "Maltodextrin Utilization Plays a Key Role in the Ability of Group A Streptococcus To Colonize the Oropharynx." Infection and Immunity 74, no. 8 (2006): 4605–14. http://dx.doi.org/10.1128/iai.00477-06.
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ABSTRACT Analysis of multiple group A Streptococcus (GAS) genomes shows that genes encoding proteins involved in carbohydrate utilization comprise some 15% of the core GAS genome. Yet there is a limited understanding of how carbohydrate utilization contributes to GAS pathogenesis. Previous genome-wide GAS studies led us to a focused investigation of MalE, a putative maltodextrin-binding protein. Analysis of 28 strains of 22 distinct M protein serotypes showed that MalE is highly conserved among diverse GAS strains. malE transcript levels were significantly increased during growth in human saliva compared to growth in a chemically defined glucose-containing medium or a nutrient-rich medium. MalE was accessible to antibody binding, indicating that it is expressed on the GAS cell surface. Moreover, growth in human saliva appeared to increase MalE surface expression compared to growth in a nutrient-rich medium. Analysis of a ΔmalE isogenic mutant strain revealed decreased growth in human saliva compared to wild-type GAS. Radiolabeled carbohydrate binding assays showed that MalE was required for the binding of maltose but not glucose. The ΔmalE isogenic mutant strain colonized a lower percentage of GAS-challenged mice compared to wild-type and genetically complemented strains. Furthermore, decreased numbers of CFU were recovered from mice infected with the ΔmalE strain compared to those infected with wild-type GAS. These data demonstrate that maltodextrin acquisition is likely to be a key factor in the ability of GAS to successfully infect the oropharynx. Further investigation into carbohydrate transport and metabolism pathways may yield novel insights into GAS pathogenesis.
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Li, Peng, and Yaofu Ouyang. "THE DYNAMIC IMPACTS OF FINANCIAL DEVELOPMENT AND HUMAN CAPITAL ON CO2 EMISSION INTENSITY IN CHINA: AN ARDL APPROACH." Journal of Business Economics and Management 20, no. 5 (2019): 939–57. http://dx.doi.org/10.3846/jbem.2019.10509.
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This paper studies the dynamic impacts of financial development, human capital, and economic growth on CO2 emission intensity in China for the period 1978–2015, with a structural breakpoint in 1992, by employing an autoregressive distributed lag (ARDL) approach. The estimations show that there exists a long-run cointegration linkage among the variables, with three main findings. First, financial openness measured by net FDI inflows can significantly reduce CO2 emission intensity in both the short-term and the long-term, whereas the effects of both financial scale and financial efficiency are limited and insignificant. Second, there exists an inverted N-shaped relationship between human capital and CO2 emission intensity: improving human capital first decreases CO2 emission intensity (before 1992), then increases it in the short-run (after 1992), and, finally, lessens it in the long-run. Last, raising per capita income can also significantly lower CO2 emission intensity in the long-run. Accordingly, some policy implications are also discussed.
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Desai, Krisha, Radhika Aiyappa, Jyothi S. Prabhu, et al. "HR+HER2− breast cancers with growth factor receptor–mediated EMT have a poor prognosis and lapatinib downregulates EMT in MCF-7 cells." Tumor Biology 39, no. 3 (2017): 101042831769502. http://dx.doi.org/10.1177/1010428317695028.
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Despite an overall good prognosis, a significant proportion of patients with hormone receptor positive human epidermal growth factor receptor 2 negative breast cancers develop distant metastases. The metastatic potential of epithelial cells is known to be regulated by tumor–stromal interaction and mediated by epithelial-to-mesenchymal transition. Hormone receptor positive human epidermal growth factor receptor 2 negative tumors were used to estimate markers of epithelial-to-mesenchymal transition, and the luminal breast cancer cell line MCF-7 was used to examine the interactions between integrins and growth factor receptors in causation of epithelial-to-mesenchymal transition. A total of 140 primary tumors were sub-divided into groups enriched for the markers of epithelial-to-mesenchymal transition (snail family transcriptional repressor 2 and integrin β6) versus those with low levels. Within the epithelial-to-mesenchymal transition+ tumors, there was a positive correlation between the transcripts of integrin β6 and growth factor receptors—human epidermal growth factor receptor 2 and epidermal growth factor receptor. In tumors enriched for epithelial-to-mesenchymal transition markers, patients with tumors with the highest quartile of growth factor receptor transcripts had a shorter disease-free survival compared to patients with low growth factor receptor expression by Kaplan–Meier analysis (log rank, p = 0.03). Epithelial-to-mesenchymal transition was induced in MCF-7 cells by treatment with transforming growth factor beta 1 and confirmed by upregulation of SNAI1 and SNAI2 transcripts, increase of vimentin and integrin β6 protein, and repression of E-cadherin. Treatment of these cells with the dual-specificity tyrosine-kinase inhibitor lapatinib led to downregulation of epithelial-to-mesenchymal transition as indicated by lower levels of SNAI1 and SNAI2 transcripts, integrin αvβ6, and matrix metalloproteinase 9 protein. The results suggest that synergistic interactions between growth factor receptors and integrin β6 could mediate epithelial-to-mesenchymal transition and migration in a subset of luminal breast cancers and lapatinib might be effective in disrupting this interaction.
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Tu, Lin, Enhao Zhao, Wenyi Zhao, et al. "hsa-miR-376c-3p Regulates Gastric Tumor Growth BothIn VitroandIn Vivo." BioMed Research International 2016 (2016): 1–7. http://dx.doi.org/10.1155/2016/9604257.
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Background. In recent studies, aberrant expression of various microRNAs (miRNAs) is reported to be associated with gastric cancer metastasis.Method. Overexpression construct and inhibitor of hsa-miR-376c-3p were expressed in human gastric adenocarcinoma cell line SGC-7901. The expression level of tumor related genes was detected by qPCR, western blot, and immunostaining. Cell apoptosis was determined by flow cytometry. Xenograft of SGC-7901 cells was used to elucidate the function of hsa-miR-376c-3p in gastric tumor growthin vivo.Result. Expression of hsa-miR-376c-3p was detected in SGC-7901 cells. Downregulation of hsa-miR-376c-3p increased the expression level of BCL-2 and decreased the expression of smad4 and BAD. On the contrary, overexpression of hsa-miR-376c-3p increased the expression of BAD and smad4, while it led to the decreasing expression level of BCL-2. Overexpression of hsa-miR-376c-3p also promoted cell apoptosisin vitroand inhibited gastric tumor growthin vivo. Furthermore, the expression of BCL-2 was higher and expression of smad4 and BAD was lower in tumor tissue than the tissue adjacent to tumor from gastric cancer patients.Conclusion. This study demonstrated that hsa-miR-376c-3p plays an important role in the inhibition of gastric tumor growth and tumor related gene expression bothin vitroandin vivo.
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Khandanpour, Cyrus, James D. Phelan, Riyan Chen, et al. "Growth Factor Independent-1 (Gfi1) As a New Target for Human Leukemia Therapy." Blood 118, no. 21 (2011): 560. http://dx.doi.org/10.1182/blood.v118.21.560.560.
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Abstract Abstract 560 More than 50% of patients diagnosed with B or T-cell leukemia and lymphoma will fail current treatment protocols. This highlights the urgent need for new and improved therapies. Since the transcription factor Growth factor independent-1 (Gfi1) plays an important role in lymphoid differentiation, we explored whether it might be a suitable target for therapy. Using mouse models in which T-cell leukemia can be induced by transgenic expression of mutated forms of Notch1, by injection of the carcinogen N-Ethyl–nitrosourea (ENU) or infection with a Murine Moloney Leukemia Virus, we found that Gfi1 knockout mice had a significantly lower incidence and a longer latency period of T-ALL. To verify whether targeting Gfi1 would be a novel approach to treat B- or T-cell lymphoma, we used Mx1Cre Gfi1fl/fl mice. In these mice, injection of polyinosinic-polycytidylic acid (pIpC) activates the Mx1 promoter driven Cre expression, which ultimately leads to the deletion of the floxed Gfi1 alleles. As controls, we used Gfi1fl/fl mice, which lack the Cre recombinase and thus still express Gfi1 after pIpC injection. To elicit a T- or B-cell lymphoma, we used ENU injection combined with expression of a mutated Notch1 transgene for T-ALL, or transgenic over-expression of c-Myc for B-cell leukemia (Eμ-Myc). Using in-vivo ultrasound supported imaging, we observed complete regression of tumour masses when Gfi1 was eliminated in Mx1Cre Gfi1fl/fl mice, curing the mice of the either the T or B-cell malignancies. Strikingly, this effect was observed in the absence of any other treatment regimen. To explore the mechanisms underlying this phenomenon, we explanted tumor samples from mice, in which Gfi1 expression was either maintained or deleted and performed gene expression arrays. A comparative analysis of the array data demonstrated that loss of Gfi1 affects pathways of key importance for leukemia such as metabolism, cell cycle progression, basal transcription and apoptosis but also the response to DNA damage. It has been shown previously for non hematological malignancies that oncogenic transformation in conjuction with dysregulated cell cycle induces DNA strand breaks (DSBs), which leads to an increased p53 dependent apoptotic response in tumours compared to non-transformed cells. This forces the tumor cells to counteract this effect – for instance by selection for the loss of p53. Consistent with this concept, we noted that leukemic cells from our tumor models displayed a greater amount of DSBs and also higher rates of spontaneous apoptosis than normal cells. Interestingly, the number of apoptotic cells was further increased in those tumors where Gfi1 had been deleted. We hypothesized that Gfi1 protects leukemia cells against DSB induced apoptosis. To test this hypothesis, we irradiated in Gfi1+/+ and Gfi1−/− thymocytes, which induces DSB in thymocytes. In line with our hypothesis we found that Gfi1−/− thymocytes showed increased rates of apoptosis compared to irradiated Gfi1+/+ thymocytes and that loss of Gfi1 led to an increased induction of pro-apoptotic genes such as Bax, Noxa and Puma after irradiation. Since Bax, Noxa and Puma are all p53 target genes, we investigated a possible link between Gfi1 and p53 and found that (I) Gfi1 binds to p53, (II) that Gfi1 inhibits the transcription of p53 target genes and (III) that Gfi1 occupies p53 target gene at the same sites as p53. In summary, Gfi1 antagonizes p53 function and loss of Gfi1 sensitizes cells to p53-mediated apoptosis. Next, we used different human T-ALL cell lines and treated these cells either with sh-RNA lentivirus or morpholinos to abrogate GFI1 expression. In all cases, down-regulation of GFI1 expression led to increased apoptosis and impeded growth of human leukemia cells. Finally, we transplanted leukemic cells of T-ALL patients into NOD-Scid, IL2Rnull (NSG) mice, waited for the leukemic cells to engraft, and then injected GFI1 specific- or control morpholinos. While mice treated with control morpholino died of leukemia, the animals treated with GFI1-specific morpholinos survived showing a significant reduction of human leukemic cells in the blood, bone marrow and spleen, even with samples from patients who did not respond to first line therapy. Since morpholinos have received approval for use in humans, our data suggest that targeting GFI1 in human T-ALL patients may be a promising therapeutic target and a feasible way to complement current T-ALL treatment regimens. Disclosures: No relevant conflicts of interest to declare.
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Bae, Dong-Hun, Patric J. Jansson, Michael L. Huang, et al. "The role of NDRG1 in the pathology and potential treatment of human cancers." Journal of Clinical Pathology 66, no. 11 (2013): 911–17. http://dx.doi.org/10.1136/jclinpath-2013-201692.
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N-myc downstream regulated gene 1 (NDRG1) has been well characterised to act as a metastatic suppressor in a number of human cancers. It has also been implicated to have a significant function in a number of physiological processes such as cellular differentiation and cell cycle. In this review, we discuss the role of NDRG1 in cancer pathology. NDRG1 was observed to be downregulated in the majority of cancers. Moreover, the expression of NDRG1 was found to be significantly lower in neoplastic tissues as compared with normal tissues. The most important function of NDRG1 in inhibiting tumour progression is associated with its ability to suppress metastasis. However, it has also been shown to have important effects on other stages of cancer progression (primary tumour growth and angiogenesis). Recently, novel iron chelators with selective antitumour activity (ie, Dp44mT, DpC) were shown to upregulate NDRG1 in cancer cells. Moreover, Dp44mT showed its antimetastatic potential only in cells expressing NDRG1, making this protein an important therapeutic target for cancer chemotherapy. This observation has led to increased interest in the examination of these novel anticancer agents.
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Golfman, Leonard S., Sankaranarayanan Kannan, Mandy A. Hall, and Patrick A. Zweidler-McKay. "Notch/HES1 Implicated As a Tumor Suppressor Mechanism in Human AML in Vivo." Blood 120, no. 21 (2012): 3524. http://dx.doi.org/10.1182/blood.v120.21.3524.3524.
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Abstract Abstract 3524 Background: Although Notch signaling contributes to T cell leukemogenesis, the role of Notch in human AML is unclear. We and others have found that activation of Notch signaling inhibits AML growth and survival, e.g. a tumor suppressor like effect. However it is not known what the consequences of activating or inhibiting Notch signaling are in human AML in vivo. Approach: To determine whether Notch signaling would have growth inhibiting effects in vivo, we stably-transduced ML1 human AML cells with the constitutively-active forms of Notch1 and Notch2 (ICN1, ICN2), the common Notch target gene Hairy/Enhancer of Split 1 (HES1) or the pan-Notch inhibitor dominant-negative Mastermind-like (dnMAML) and performed in vivo competitive proliferation assays. Briefly, following transduction, each vector type were sorted to 50% GFP+ (containing the gene of interest) and GFP- (untransduced control cells). Groups of NSG mice were injected with these 50:50 mixtures of ML1 cells, and peripheral blood levels of GFP- and GFP+ cells were measured with flow cytometry for anti-human CD45 and GFP. Results: Peripheral blood engraftment of human CD45+ ML1 cells by week 5 was similar (2–5%) for ICN1, ICN2 and HES1 injected mice, but was significantly higher (23%) in dnMAML injected mice (Panel A). Similar to in vitro competitive proliferation assays, ICN1, ICN2 and HES1 all led to decreased relative numbers of GFP%+ cells, with 1%, 4% and 16% respectively (Panel B). Importantly, dnMAML had little effect on AML proliferation in vitro, however led to dramatic increases in GFP% as well as early morbidity and mortality due to increased leukemia burden, with 93% GFP+ (Panel B), demonstrating a selective advantage for dnMAML-expressing ML1 in vivo. When GFP+ (transduced) ML1 peripheral engraftment was directly compared to GFP- (parental CD45+) engraftment, the GFP- control cells had similar engraftment rates (2–5%) across groups of mice, while the GFP+ engraftment rates were significantly lower in ICN1, ICN2, and HES1 groups, but significantly higher in the dnMAML group (Panel C), demonstrating enhanced engraftment/proliferation in dnMAML-expressing cells. Conclusions: This suggests a previously unreported concept, namely that endogenous Notch ligands can inhibit human AML growth in vivo. This data supports the hypothesis that Notch behaves as a tumor suppressor in AML, and suggests the potential use of Notch agonists in human AML. Disclosures: No relevant conflicts of interest to declare.
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Wang, Chenyuan, Ming Zhang, Huiyuan Guo, et al. "Human Milk Oligosaccharides Activate Epidermal Growth Factor Receptor and Protect Against Hypoxia-Induced Injuries in the Mouse Intestinal Epithelium and Caco2 Cells." Journal of Nutrition 150, no. 4 (2020): 756–62. http://dx.doi.org/10.1093/jn/nxz297.
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ABSTRACT Background Hypoxia-induced intestinal barrier injuries lead to necrotizing enterocolitis (NEC). Although NEC in preterm neonates is preventable by human milk oligosaccharides (HMOs), the underlying mechanism remains unknown. Objective To reveal the role and mechanism of HMOs in protecting against hypoxia-induced injuries in intestinal epithelium of neonatal mice and cultured Caco2 cells. Methods NEC was induced by hypoxia and cold stress. Seventy C57BL/C pups (7-d-old) were divided into 5 groups and fed maternal breast milk (BM), formula alone (FF), or the formula added with HMOs at 5 (LHMO), 10 (MHMO), or 20 mg/mL (HHMO) for 3 d. Ileal hypoxia inducible factor 1α (HIF1α) and cleaved Caspase 3 were determined, along with staining for Ki-67 protein to labeled proliferative cells. In vitro, adherent Caco2 cells (undifferentiated, passage 14) were treated with HMOs, galacto-oligosaccharides, fructo-oligosaccharides, or mixed oligosaccharides at 10 mg/mL for 1 d exposed to 1% O2. Cell proliferation and apoptosis, along with phosphorylated epidermal growth factor receptor (P-EGFR) and 38KD MAPK (P-P38), were assayed in differentiated or undifferentiated Caco2 cells. Results Compared with the FF-fed mice, those fed MHMO and HHMO had 52% lower (P &lt; 0.05) NEC scores, 60–80% greater (P &lt; 0.05) KI67-positive cell numbers, and 56–71% decreases (P &lt; 0.05) in ileal HIF1α and cleaved Caspase 3 (56–71%). Compared with those untreated, the HMO-treated Caco2 cells displayed 60% greater (P &lt; 0.05) proliferative activity and 19% lower (P &lt; 0.05) apoptotic cells after the hypoxia exposure. The HMO treatment led to 58% or 10-fold increases (P &lt; 0.05) of P-EGFR and 48–89% decreases (P &lt; 0.05) of P-P38 in either differentiated or undifferentiated Caco2 cells compared with the controls. Conclusion Supplementing HMOs at 10–20 mg/mL into the formula for neonatal mice or media for Caco2 cells conferred protection against the hypoxia-induced injuries. The protection in the Caco2 cells was associated with an activation of EGFR.
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RIBEIRO, V. B., and M. T. DESTRO. "Listeria monocytogenes Serotype 1/2b and 4b Isolates from Human Clinical Cases and Foods Show Differences in Tolerance to Refrigeration and Salt Stress." Journal of Food Protection 77, no. 9 (2014): 1519–26. http://dx.doi.org/10.4315/0362-028x.jfp-13-548.
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Control of Listeria monocytogenes in food processing facilities is a difficult issue because of the ability of this microorganism to form biofilms and adapt to adverse environmental conditions. Survival at high concentrations of sodium chloride and growth at refrigeration temperatures are two other important characteristics of L. monocytogenes isolates. The aim of this study was to compare the growth characteristics under stress conditions at different temperatures of L. monocytogenes serotypes responsible for the majority of clinical cases from different sources. Twenty-two L. monocytogenes isolates, 12 from clinical cases (8 serotype 4b and 4 serotype 1/2a) and 10 from food (6 serotype 4b and 4 serotype 1/2a), and an L. monocytogenes Scott A (serotype 4b) reference strain were analyzed for the ability to grow in brain heart infusion broth plus 1.9 M NaCl (11%) at 4, 10, and 25°C for 73, 42, and 15 days, respectively. The majority of L. monocytogenes strains was viable or even grew at 4°C and under the high osmotic conditions usually used to control pathogens in the food industry. At 10°C, most strains could adapt and grow; however, no significant difference (P &gt; 0.05) was found for lag-phase duration, maximum growth rate, and maximum cell density. At 25°C, all strains were able to grow, and populations increased by up 5 log CFU/ml. Clinical strains had a significantly longer lag phase and lower maximum cell density (P &lt; 0.05) than did food strains. Regarding virulence potential, no significant differences in hemolytic activity were found among serotypes; however, serotype 4b strains were more invasive in Caco-2 cells than were serotype 1/2a strains (P &lt; 0.05). The global tendency of decreasing NaCl concentrations in processed foods for health reasons may facilitate L. monocytogenes survival and growth in these products. Therefore, food companies must consider additional microbial growth barriers to assure product safety.
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Chang, Yu-Tsen, Po-Chen Li, An-Chin Cheng, and Ming-Fen Lee. "Effect of MED28 on Glucose Transporters and Glycolysis in Human Colorectal Cancer Cells." Current Developments in Nutrition 4, Supplement_2 (2020): 1248. http://dx.doi.org/10.1093/cdn/nzaa058_006.
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Abstract Objectives MED28 exhibits several cellular roles, including a Mediator subunit for transcriptional activation as well as an interactor with merlin, NF2 tumor suppressor protein, and Grb2, a signaling adaptor. Our laboratory has previously reported that MED28 not only mediates cell growth but also appears to regulate glucose metabolism in human colorectal cancer cells. Therefore, the objective of the current study is to investigate the in vivo effect of MED28 on glucose metabolism and cell growth in colorectal cancer. Methods HCT116 colorectal cancer cells were transfected with MED28 siRNA or non-target siRNA for 72 h, and then undergone Western blotting or immunofluorescence analysis, by incubating with anti-c-Myc antibodies and DAPI for nuclear staining. We also established shMED28-transfected HCT116 cells and employed a NOD/SCID immunodeficient mouse xenograft model by subcutaneously implanting 1 × 107 stably transfected cells to the flanks of the animals to study the in vivo effect of MED28 expression on glucose metabolism. The animal study continued for 21 days, and the animal use protocol was approved by the Institutional Animal Care and Use Committee. The subcutaneous tumors were analyzed for the expression of MED28, glucose transporter 1 (GLUT1), and glycolysis-associated enzymes, including hexokinase 2 (HK2) and lactate dehydrogenase A (LDHA). Results The expression of c-Myc was decreased upon MED28 knockdown in HCT116 cells. Our in vivo data indicated smaller xenograft volumes and lower expression levels of MED28, GLUT1, HK2, and LDHA in tumors carrying shMED28-transfected HCT116 cells than those of control counterparts. Conclusions MED28 upregulates glucose transporters and glycolysis-associated enzymes as well as cell growth in NOD/SCID subcutaneous xenografts, suggesting nutrient-gene interactions between glucose metabolism and MED28 in human colorectal cancer cells. Funding Sources This work was supported by the grants MOST106–2320-B-039–062-MY3 and CMU108-SR-31 to M-F Lee, and MOST108–2813-C-039–058-B to Y-T Chang.
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Zhang, Ligen, Jiaqi Zhang, Enfa Yan, et al. "Dietary Supplemented Curcumin Improves Meat Quality and Antioxidant Status of Intrauterine Growth Retardation Growing Pigs via Nrf2 Signal Pathway." Animals 10, no. 3 (2020): 539. http://dx.doi.org/10.3390/ani10030539.
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Intrauterine growth retardation (IUGR) exhibits programming consequences and may induce oxidative stress in growing animals and humans. This study was conducted to investigate the hypothesis that dietary curcumin may protect growing pigs from IUGR-induced oxidative stress via the Nrf2 pathway. Twelve normal birth weight (NBW) and 24 IUGR female piglets were selected and fed control diets supplemented 0 (NBW), 0 (IUGR) and 200 (IUGR + Cur) mg/kg curcumin from 26 to 115 days of age (n = 12). Growth performance, meat quality, redox status and its related Nrf2 pathway were determined. Results showed that IUGR pigs exhibited decreased body weight on 0 d, 26 d and 56 d (p < 0.01) but had no difference on 115 d among NBW, IUGR and IUGR + Cur groups (p > 0.05). Compared with NBW and IUGR groups, a significant decrease in drip loss (24 h and 48 h) was observed in the IUGR + Cur group (p < 0.01). IUGR pigs had higher concentrations of malondialdehyde (MDA) (p < 0.01) and protein carbonyl (PC) (p = 0.03) and lower activities of glutathione peroxidase (p = 0.02), catalase (p < 0.01) and peroxidase (p = 0.02) in leg muscles than NBW pigs. Dietary-added 200 mg/kg curcumin decreased concentrations of MDA and PC and improved the activities of catalase, superoxide dismutase (SOD) and peroxidase as compared to the IUGR group (p < 0.05). Additionally, dietary curcumin enhanced protein (NQO1) and mRNA expression of genes (Nrf2, NQO1, gamma-glutamyltransferase 1 (GGT1), heme oxygenase-1 (HO-1), glutathione S-transferase (GST) and catalase (CAT)) as compared to the IUGR group (p < 0.05). These results suggest that dietary curcumin could serve as a potential additive to enhance redox status and improve meat quality of IUGR growing pigs via the Nrf2 signal pathway.
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Owczarek, Piotr, Magdalena Opała-Owczarek, Oimahmad Rahmonov, Abdurauf Razzokov, Zdzisław Jary, and Tadeusz Niedźwiedź. "Relationships between loess and the Silk Road reflected by environmental change and its implications for human societies in the area of ancient Panjikent, central Asia." Quaternary Research 89, no. 3 (2017): 691–701. http://dx.doi.org/10.1017/qua.2017.69.
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AbstractRich ancient societies of central Asia developed on the basis of trade between East and West; their existence was dependent on natural resources that favoured agriculture. The branches of the Silk Road in central Asia clearly coincide with loess areas, where many settlements were erected based on the presence of fertile loess soil and water. The aim of the study was to analyse the environmental factors that led to the growth and decline of one of the most important Silk Road “loess towns,” ancient Panjikent, as an example of human and climatic impacts on landscape changes. The town, established in the fifth century, quickly became one of the most important cities of Sogdiana. Local loess material was used for the production of the sun-dried bricks. Rapid population growth led to deforestation and consequently increased the intensity of erosion rates and reductions in cultivation area. A period of drought near the end of the first millennium AD influenced the final abandonment of the ancient town and its relocation to the lower terrace of the Zarafshan River. A decline in natural and agricultural resources and subsequently climatic forces caused a decline in the number of cities in semiarid regions of central Asia.
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Pedró-Rosa, Laura, Frederick S. Buckner, Ranae M. Ranade, et al. "Identification of Potent Inhibitors of the Trypanosoma brucei Methionyl-tRNA Synthetase via High-Throughput Orthogonal Screening." Journal of Biomolecular Screening 20, no. 1 (2014): 122–30. http://dx.doi.org/10.1177/1087057114548832.
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Improved therapies for the treatment of Trypanosoma brucei, the etiological agent of the neglected tropical disease human African trypanosomiasis, are urgently needed. We targeted T. brucei methionyl-tRNA synthetase (MetRS), an aminoacyl-tRNA synthase (aaRS), which is considered an important drug target due to its role in protein synthesis, cell survival, and its significant differences in structure from its mammalian ortholog. Previous work using RNA interference of MetRS demonstrated growth inhibition of T. brucei, further validating it as an attractive target. We report the development and implementation of two orthogonal high-throughput screening assays to identify inhibitors of T. brucei MetRS. First, a chemiluminescence assay was implemented in a 1536-well plate format and used to monitor adenosine triphosphate depletion during the aminoacylation reaction. Hit confirmation then used a counterscreen in which adenosine monophosphate production was assessed using fluorescence polarization technology. In addition, a miniaturized cell viability assay was used to triage cytotoxic compounds. Finally, lower throughput assays involving whole parasite growth inhibition of both human and parasite MetRS were used to analyze compound selectivity and efficacy. The outcome of this high-throughput screening campaign has led to the discovery of 19 potent and selective T. brucei MetRS inhibitors.
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Bartman, Melissa T., Zhanna Kaidarova, Dale Hirschkorn, et al. "Long-Term Increases in Lymphocytes and Platelets in Human T-Lymphotropic Virus Type II Infection." Blood 112, no. 11 (2008): 4900. http://dx.doi.org/10.1182/blood.v112.11.4900.4900.
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Abstract Human T-lymphotropic viruses types I and II (HTLV-I and HTLV-II) cause chronic infections of T-lymphocytes, leading to adult T-cell lymphoma (HTLV-I) and myelopathy (both types) in a minority of infected humans. However, their long-term effects on blood counts and hematopoiesis are not fully understood. We followed 151 HTLV-I and 387 HTLV-II seropositive former blood donors, and 799 HTLV seronegative donors from five US blood centers prospectively for a median of 14.0 years. Complete blood counts were performed every 2 years on fresh anticoagulated blood at licensed clinical laboratories near each center. Multivariable repeated measures analyses were conducted to evaluate the independent effect of HTLV infection and potential confounders on 9 hematologic measurements. HTLV-II subjects had significant (p&lt;0.05) increases in their adjusted lymphocyte counts (+126 cells/mm3; approx +7%), hemoglobin (+0.2 gm/dL) and mean corpuscular volume (MCV; 1.0 fL) compared to seronegative subjects. Both HTLV-I and -II subjects had higher adjusted platelet counts (+16,544 and +21,657 cells/mm3; p&lt;0.05) than seronegatives. Among all subjects, time led to decreases in platelet count (−6,750 to −6,600 cells) and lymphocyte counts (−67 to −66 cells), and to increases in MCV (+0.4 fL) and monocytes (+19 to +20 cells per uL; all per two-year interval). Women had lower hemoglobin but higher platelet and white blood cell (WBC) counts than men. Blacks had lower hemoglobin, MCV and neutrophil counts, but higher platelet and lymphocyte counts than whites. Heavy drinking was associated with higher MCV but lower WBC counts, whereas cigarette smoking was associated with higher WBC counts of all lineages. These results suggest that HTLV-I and -II infection can produce significant, independent and long term changes in lymphocytes, platelets and red blood cells. The finding of increased lymphocytes in HTLV-II infection is novel and may be related to viral transactivation or immune response. HTLV-I and –II associations with higher platelet counts suggest viral effects on hematopoietic growth factors or cytokines.
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Franco, Daniel, Mirian Pateiro, Diego Rois, Jose Antonio Vázquez, and José Manuel Lorenzo. "Effects of Caponization on Growth Performance, Carcass and Meat Quality of Mos Breed Capons Reared in Free-Range Production System." Annals of Animal Science 16, no. 3 (2016): 909–29. http://dx.doi.org/10.1515/aoas-2016-0009.
Full textAbstract:
AbstractThe effects of caponization on growth performance, carcass characteristics, meat quality and fatty acid profile of breast and drumstick of Mos and Sasso genotypes, reared in free-range production system were examined. A total of 47 birds of Mos breed (19 Castrated and 25 Entire) and 37 of Sasso X-44 (18 Castrated and 19 Entire) slaughtered at 32 weeks were used in this trial. The growth of broilers and the differences between genotypes and caponization effects were modelled by Weibull-growth equation. Capon’s growth was higher than that obtained by roosters and Sasso weight was greater than Mos results (P<0.05). For both genotypes the chemical composition of breast and drumstick cuts showed significantly higher values of intramuscular fat (P<0.0001) and lesser values of moisture (P<0.0001) in capons in comparison with intact ones. In Mos breed, capons exhibited significantly (P<0.0001) higher values of breast and drumstick luminosity and yellowness, as well as lower values of redness. Regarding Warner-Braztler test (WB), there were no significant differences (P>0.05) by caponization effect, but hardness measured using textural profile analysis was lesser in meat from capons. Finally castration of animals led to important modifications in the intramuscular fat because meat from capons showed significantly lower values for total saturated fatty acids (SFA) and higher polyunsaturated fatty acids (PUFA ). Nutritional indices were also more favorable in capon’s meat, so overall fatty acid profile of capons was desirable from the viewpoint of human nutrition.