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31.
Voutetakis A Zheng C Mineshiba F Cotrim AP Goldsmith CM Schmidt M Afione S Roescher N Metzger M Eckhaus MA Chiorini JA Dunbar CE Donahue RE Baum BJ 《Human gene therapy》2007,18(2):142-150
Salivary glands (SGs) are promising gene transfer targets with potential clinical applicability. Previous experiments in rodents using recombinant serotype 2 adeno-associated viral (rAAV2) vectors have demonstrated relatively stable transgene-encoded protein levels after SG gene transfer. In the present study, we examine direct SG administration of rAAV2 vectors encoding rhesus macaque erythropoietin (RhEPO) to the parotid glands of nonhuman primates using two different doses (n = 3 per group; 1 x 10(10) or 3 x 10(11) particles/gland, respectively). Gene transfer had no negative effects on general macaque physiology (e.g., weight, complete blood count, and serum chemistry). Macaques were euthanized 6 months after vector administration and complete necropsy and pathology assessments were performed, revealing no vector-related pathological lesions in any of the examined organs. In the high-dose group, RhEPO expression increased quickly (i.e., by week 1) and levels remained relatively stable both in serum and saliva until the end of the study. Serum-to-saliva ratios of RhEPO revealed secretion of the transgene product into the bloodstream, but not to the extent previously observed in mice. Furthermore, the kinetic results were not predicted by those observed in murine SGs. With respect to viral biodistribution, at necropsy vector was found overwhelmingly in the targeted parotid gland ( approximately 100 times more than levels in other tissues, most of which were similar to tissue levels in nontreated animals). We conclude that administration of modest doses of rAAV2 vectors to SGs for therapeutic purposes can be accomplished without significant or permanent injury to the targeted gland or to distant organs of nonhuman primates. 相似文献
32.
Nienke P. Dosa John T. Foley Michael Eckrich Denise Woodall-Ruff Gregory S. Liptak 《Disability and rehabilitation》2013,35(11):914-920
Purpose. Identify risk factors for obesity across the lifespan for individuals with spina bifida.Methods. Cross sectional chart review study of 203 patients aged 6–58 years. Obesity was based on body mass index. Rates were calculated for children aged 6–11 years; adolescents aged 12–19 years and adults aged > 20 years. Chi-square analyses were used to determine differences in obesity rates among subgroups. An ordered logistic regression model was developed for the three age groups to estimate the probability of a change in BMI classification from normal weight to overweight or overweight to obese, controlling for sex, functional motor level, shunt status and insurance status.Results. Obesity rates for children, adolescents and adults were 18, 8 and 37%, respectively. Obesity rates were higher among adults (χ2 = 27, p < 0.01) and for individuals who were publicly insured (χ2 = 7.2, p < 0.03). The ordered regression model for children demonstrated no independent association between sex, shunt status, functional motor level or insurance status and change in BMI category. For adolescents, lower functional motor level (i.e. sacral) increased the risk of becoming obese (Odds Ratio: 2.13; 95% CI: 1.12–4.06; p < 0.02). Among adults, female sex increased risk (OR = 2.28; 95% CI: 1.03–5.04; p < 0.04).Conclusions. Obesity rates for children and adolescents with spina bifida are similar to the general population; however, obesity rates are higher among adults, particularly women. Risk factors are similar to those observed in the general population. 相似文献
33.
Nienke van Egmond Dennis Janssen Gerjon Hannink Nico Verdonschot Albert van Kampen 《Journal of orthopaedic science》2018,23(1):105-111
Background
The purpose of this study was to compare the mechanical stability of a relatively thin locking plate (FlexitSystem implant) with a relatively firm locking plate (TomoFix implant), both used for opening wedge high tibial osteotomy.Methods
Seven fresh frozen paired human cadaveric tibiae were used. The opening wedge high tibial osteotomies in the left tibiae were fixated with the FlexitSystem implant and in the right tibiae with the TomoFix implant. The tibiae were CT-scanned to determine the bone mineral density. Axial loading was applied in a cyclic fashion for 50,000 cycles. We compared throughout the loading history the relative motions between the proximal and distal tibia using roentgen stereophotogrammetry analysis at set intervals. Also the strength of the reconstructions was compared using a displacement-controlled compressive test until failure.Results
One pair (with the lowest bone mineral density) failed during the preparation of the osteotomy. The FlexitSystem implant displayed a similar stability compared to the TomoFix implant, with low translations (mean 2.16 ± 1.02 mm vs. 4.29 ± 5.66 mm) and rotations (mean 3.17 ± 2.04° vs. 4.30 ± 6.78°), which was not significant different. Although on average the FlexitSystem reconstructions were slightly stronger than the Tomofix reconstructions (mean 4867 ± 944 N vs. 4628 ± 1987 N), no significant (p = 0.71) differences between the two implants were found.Conclusion
From a biomechanical point of view, the FlexitSystem implant is a suitable alternative to the TomoFix implant for a high tibial open wedge osteotomy. 相似文献34.
Thom T. J. Veeger Nienke M. van de Velde Kevin R. Keene Erik H. Niks Melissa T. Hooijmans Andrew G. Webb Jurriaan H. de Groot Hermien E. Kan 《NMR in biomedicine》2022,35(7):e4691
In Becker muscular dystrophy (BMD), muscle weakness progresses relatively slowly, with a highly variable rate among patients. This complicates clinical trials, as clinically relevant changes are difficult to capture within the typical duration of a trial. Therefore, predictors for disease progression are needed. We assessed if temporal increase of fat fraction (FF) in BMD follows a sigmoidal trajectory and whether fat fraction at baseline (FFbase) could therefore predict FF increase after 2 years (ΔFF). Thereafter, for two different MR-based parameters, we tested the additional predictive value to FFbase. We used 3-T Dixon data from the upper and lower leg, and multiecho spin-echo MRI and 7-T 31P MRS datasets from the lower leg, acquired in 24 BMD patients (age: 41.4 [SD 12.8] years). We assessed the pattern of increase in FF using mixed-effects modelling. Subsequently, we tested if indicators of muscle damage like standard deviation in water T2 (stdT2) and the phosphodiester (PDE) over ATP ratio at baseline had additional value to FFbase for predicting ∆FF. The association between FFbase and ΔFF was described by the derivative of a sigmoid function and resulted in a peak ΔFF around 0.45 FFbase (fourth-order polynomial term: t = 3.7, p < .001). StdT2 and PDE/ATP were not significantly associated with ∆FF if FFbase was included in the model. The relationship between FFbase and ∆FF suggests a sigmoidal trajectory of the increase in FF over time in BMD, similar to that described for Duchenne muscular dystrophy. Our results can be used to identify muscles (or patients) that are in the fast progressing stage of the disease, thereby facilitating the conduct of clinical trials. 相似文献
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39.
Nijhuis MM Pasterkamp G Sluis NI de Kleijn DP Laman JD Ulfman LH 《Journal of vascular research》2007,44(3):214-222
The Toll-like receptor (TLR) 2/nucleotide-binding oligomerization domain ligand peptidoglycan (PG) has been shown to be present in macrophage-rich regions within atherosclerotic lesions, and stimulation of TLR2 promotes atherosclerotic plaque and intima formation in in vivo mouse models. We determined the effect of a PG preparation and Pam(3)Cys-SK(4), a synthetic TLR2 activator, on (1) adhesion molecule expression by flow cytometry; (2) monocyte adhesion under flow conditions, and (3) monocyte migration. The total adhesion (rolling and firm adhesion) of the PG-preparation-stimulated monocytes to L cells, constitutively expressing ICAM-1 (intercellular adhesion molecule-1) and E-selectin, was decreased. This was most likely due to the L-selectin shedding, since monocyte incubation with a blocking L-selectin antibody resulted in a comparable number of adherent monocytes as PG-stimulated cells. The PG preparation induced an increased percentage of firmly adherent, polarized cells and a beta(2)-integrin-dependent binding to ICAM-1-coated beads. Interestingly, the PG preparation induced a priming of the monocytes for increased migration towards the chemoattractant C5a which was TLR2 and beta(2)-integrin dependent. Pam(3)Cys-SK(4) gave comparable results to the PG preparation in all assays tested. This study demonstrates that PG activation of monocytes results in an increase in adhesive and migratory capacities of these cells. This might be a mechanism by which PG promotes atherosclerotic disease in vivo. 相似文献
40.
van der Werf N Kroese FG Rozing J Hillebrands JL 《Diabetes/metabolism research and reviews》2007,23(3):169-183
During the last decades, the incidence of type 1 diabetes (T1D) has increased significantly, reaching percentages of 3% annually worldwide. This increase suggests that besides genetical factors environmental perturbations (including viral infections) are also involved in the pathogenesis of T1D. T1D has been associated with viral infections including enteroviruses, rubella, mumps, rotavirus, parvovirus and cytomegalovirus (CMV). Although correlations between clinical presentation with T1D and the occurrence of a viral infection that precedes the development of overt disease have been recognized, causalities between viruses and the diabetogenic process are still elusive and difficult to prove in humans. The use of experimental animal models is therefore indispensable, and indeed more insight in the mechanism by which viruses can modulate diabetogenesis has been provided by studies in rodent models for T1D such as the biobreeding (BB) rat, nonobese diabetic (NOD) mouse or specific transgenic mouse strains. Data from experimental animals as well as in vitro studies indicate that various viruses are clearly able to modulate the development of T1D via different mechanisms, including direct beta-cell lysis, bystander activation of autoreactive T cells, loss of regulatory T cells and molecular mimicry. Data obtained in rodents and in vitro systems have improved our insight in the possible role of viral infections in the pathogenesis of human T1D. Future studies will hopefully reveal which human viruses are causally involved in the induction of T1D and this knowledge may provide directions on how to deal with viral infections in diabetes-susceptible individuals in order to delay or even prevent the diabetogenic process. 相似文献