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With the advent of injectable insulin in the 1920s, physicians were finally given the ability to treat the symptoms of diabetes mellitus (DM). Despite this success, the lack of rapid-acting insulin and self-blood glucose monitoring meant that the available insulin therapy could do little to maintain glucose at physiological concentrations. The effects of large glycemic excursions were readily seen as diabetic women had extensive obstetric complications as a result of their poorly controlled diabetes. Until the 1980s, physicians actively counseled diabetic women to avoid pregnancy (1). Since that time, advancements in insulin therapies and diagnostic tests have allowed for near-normal glucose concentrations throughout pregnancy and produced dramatic improvements in the outcome of diabetic pregnancies. Despite these improvements, there is still a threefold increase in congenital anomalies in pregnancies complicated by diabetes in comparison to the background population (2). Through better use of current therapies, this unnecessarily high number of complications can be lowered.

The composition of cartilage is known to change during fetal and postnatal development. The objectives of this study were to characterize the compressive biomechanical properties of the 1 mm thick articular layer of cartilage of the distal femur from third-trimester bovine fetuses, from 1 to 3 week old bovine calf and from young adult bovine knees, and to correlate these properties with tissue components. The confined compression modulus increased 180% from the fetus to the calf and adult. The hydraulic permeability at 45% offset compression (relative to the free-swelling thickness) decreased by 70% from fetus to adult. These development-associated changes in biomechanical properties were primarily associated with a marked (approximately 2-3-fold) increase during development in collagen content and no detectable change in glycosaminoglycan (GAG) content. A role for collagen in the compressive properties of cartilage and the gradual increase in collagen during development suggest that collagen metabolism is critical for cartilage tissue engineering and repair therapies.

Compression tests have often been performed to assess the biomechanical properties of full-thickness articular cartilage. We tested whether the apparent homogeneous strain-dependent properties, deduced from such tests, reflect both strain- and depth-dependent material properties. Full-thickness bovine articular cartilage was tested by oscillatory confined compression superimposed on a static offset up to 45%. and the data fit to estimate modulus, permeability, and electrokinetic coefficient assuming homogeneity. Additional tests on partial-thickness cartilage were then performed to assess depth- and strain-dependent properties in an inhomogeneous model, assuming three discrete layers (i = 1 starting from the articular surface, to i = 3 up to the subchondral bone). Estimates of the zero-strain equilibrium confined compression modulus (H(A0)), the zero-strain permeability (kp0) and deformation dependence constant (M), and the deformation-dependent electrokinetic coefficient (ke) differed among individual layers of cartilage and full-thickness cartilage. HiA0 increased from layer 1 to 3 (0.27 to 0.71 MPa), and bracketed the apparent homogeneous value (0.47 MPa). ki(p0) decreased from layer 1 to 3 (4.6 x 10(-15) to 0.50 x 10(-15) m2/Pa s) and was less than the homogeneous value (7.3 x 10(-15) m2/Pa s), while Mi increased from layer 1 to 3 (5.5 to 7.4) and became similar to the homogeneous value (8.4). The amplitude of ki(e) increased markedly with compressive strain, as did the homogeneous value: at low strain, it was lowest near the articular surface and increased to a peak in the middle-deep region. These results help to interpret the biomechanical assessment of full-thickness articular cartilage.

The repair of articular cartilage injuries remains a challenge, with many of the current therapeutic strategies based on the grafting or recruitment of chondrogenic tissues or cells. This 1-year study compared the repair of a 3.7-mm diameter by 3-mm deep osteochondral defect in the medial femoral condyle of 24 New Zealand White rabbits; the defect was obtained using an autogenic perichondrium cell polylactic acid composite graft with a contralateral control in which the osteochondral defect remained empty. To elucidate the effect of host immune responses on the repair process after perichondrium cell transplantation, the results of the autogenic perichondrium cell polylactic acid graft group were compared with those obtained in the authors' previous 1-year study of allogenic perichondrium cell polylactic acid composite grafts implanted in a similar model. One year after surgery, the repair site underwent gross inspection and histologic, histomorphometric, biochemical, and biomechanical analyses. The autogenic perichondrium cell polylactic acid graft group (92%) and the control group in which the osteochondral defect remained empty (88%) resulted in a high percentage of grossly acceptable repairs. The autogenic grafts appeared to augment the intrinsic healing capacity of the animals (as compared with the animals in the No Implant Group). The autogenic perichondrium cell polylactic and grafts improved the histologic appearance and percentage of Type II collagen of the cartilaginous repair tissue. Compared with allogenic grafts, the autogenic grafts had better reconstitution of the subchondral bone. However, the results of this experimental model suggest a suboptimal concentration of glycosaminoglycans in the neocartilage matrix, a depressed surface of the repair tissue, a histologic appearance that was not equivalent to that of normal articular cartilage, and reduced biomechanical properties for the repair tissue. The future application of growth factors to this model may yield a treatment that can be applied in the clinical arena.

The transplantation of chondrocytes has shown promise for augmenting the repair of defects in articular cartilage. This in vitro study examined the efficiency of the transplantation of bovine chondrocytes onto articular cartilage disks and the ability of the transplanted chondrocytes to subsequently synthesize and deposit proteoglycan. The radiolabeling of chondrocyte cultures with [3H]thymidine, followed by 4 days of chase incubation, resulted in the incorporation of 98% of the radiolabel into DNA (as assessed by susceptibility to DNase). At the end of the culture period, the [3H]DNA was stable, with a half-life of radioactivity loss into the medium of 73 days. With use of radiolabeled chondrocytes for quantitation, the efficiency of transplantation onto a cartilage substrate was 93 +/- 4% for seeding densities of as much as 650,000 cells per cm2 and a seeding duration of 1 hour. These findings were confirmed both by tracking cells stained with 5-chlormethylfluorescein diacetate and by quantitating DNA. During the 16 hours after seeding onto a cartilage substrate (in which the endogenous cells had been lysed by lyophilization), the transplanted cells synthesized sulfated proteoglycan in direct proportion to the number of cells seeded. Most (83%) of the newly synthesized proteoglycan was released into the medium rather than retained within the layer of transplanted cells and the recipient cartilage substrate. Comparative studies with lyophilized-rehydrated or live cartilage as the recipient substrate indicated a similar efficiency of chondrocyte seeding and proteoglycan synthesis by the seeded chondrocytes. The transplanted cells retained the chondrocyte phenotype, as judged by a high proportion of the [35S]macromolecules being in the form of aggrecan that was capable of aggregating with hyaluronan and link protein, as well as by immunostaining within and around the transplanted cells for type-II, but not type-I, collagen. These results indicate that the number of chondrocytes transplanted onto a cut cartilage surface greatly affects the level of matrix synthesis; this in turn may affect repair.

In vitro studies in our laboratory have shown that the biomechanical and biochemical characteristics of osteochondral grafts can be preserved for as long as 28 days under tissue culture conditions. This study represents an attempt to extend these results to an in vivo model. In adult mongrel dogs, either an autograft, a fresh allograft, or a stored allograft was placed in a standardized defect on the weight-bearing surface of the medial femoral condyle. The stored grafts were kept at 4 degrees C in tissue culture medium for 14 days prior to implantation. The animals were killed at 12 weeks. Cartilage from the contralateral knee served as a control. The modulus and permeability of the cartilage were assessed with confined compression creep tests. The collagen and glycosaminoglycan contents were measured, and the cartilage was analyzed histologically with hematoxylin and eosin and safranin O stains. Grossly, the cartilage appeared viable at harvest. The histologic results were similar in the treatment groups, with the same spectrum of mild degenerative changes being noted in each group. The glycosaminoglycan content was significantly less in the autograft group than in its control group and than in the fresh allograft group. The glycosaminoglycan content did not differ significantly between fresh and stored allografts. The collagen content, modulus, and permeability did not differ either between experimental and control groups or between graft types. Our results support the conclusion that osteochondral allografts can be stored for as many as 14 days without significantly affecting the results of the procedure.

The effects of basic fibroblast growth factor (bFGF) and insulin-like growth factor-I (IGF-I) on cell and matrix metabolism in calf and adult bovine cartilage explants were examined. In calf cartilage, bFGF elicited dose-dependent and bi-directional effects on mitotic activity and anabolic processes. Addition of bFGF at 3 ng/ml stimulated cell mitotic activity (total DNA) and synthesis of proteoglycan ([ 35 S]sulfate incorporation), protein [ 3 H]proline incorporation), and collagen (formation of [ 3 H]hydroxyproline), and resulted in a slight increase in proteoglycan deposition compared to basal medium. However, 30-300 ng/ml of bFGF inhibited mitotic activity and synthetic processes, accelerated [ 35 S]proteoglycan release compared to basal medium, and resulted in an inhibition of proteoglycan deposition during the culture period. In contrast, treatment of adult cartilage with 3-300 ng/ml of bFGF did not affect the DNA content but did stimulate synthetic processes in a dose-dependent manner. Basic FGF also had bidirectional effects on matrix catabolism in adult cartilage, with 3 ng/ml accelerating [ 35 S]proteoglycan release, but 30-300 ng/ml of bFGF resulting in release rates comparable to that in basal medium. Nonetheless, even with maximal bFGF stimulation, adult bovine cartilage suffered a net loss of proteoglycan during culture. Addition of 3-300 ng/ml of IGF-I to either calf or adult bovine cartilage stimulated synthetic processes and shifted the metabolic balance toward a net deposition of proteoglycan. Neither bFGF nor IGF-I altered the low basal rate of [ 3 H]hydroxyproline release from either calf or adult bovine cartilage. Thus, (i) the regulatory effects of bFGF and IGF-I on bovine articular cartilage appear age-dependent, and (ii) bFGF is capable of promoting either anabolic or catabolic processes, and may therefore serve a dual role in the regulation of cartilage metabolism.

This paper presents methods to concurrently exploit AND and OR parallelism in logic programs. The execution sequence of the system is driven by the demand to reduce complexity. The concept of environment copying is applied to achieve modularity when OR parallelism is exploited. As a result, multiple independent structures can be dynamically constructed according to the data dependency to solve various systolic algorithms.

Background HCMV phosphoprotein 65 (HCMVpp65) is a putative immunogen that acts as an accelerator, inducing autoantibody and exacerbating autoimmune response in susceptible animals. The immunity to pp65336-439 instigates autoimmunity, suggesting that pp65336-439 contains crucial B cell epitope(s) for the development of nephritis. This study narrowed down the target epitope to pp65422-439 for immunization of BALB/c mice and mapping of B cell epitope. Methods The target epitope pp65422-439 reactivity and B cell epitope mapping was examined in serum from pp65422-439-immunized mice and patients with systemic lupus erythematosus (SLE). Kidney tissue from immunized mice was examined for signs of immune complex nephritis. Results Anti-pp65422-439 antibody in serum either from patients with SLE or from pp65422-439-immunized mice exhibited cross-reactivity to several nuclear components such as double-stranded DNA (dsDNA). Moreover, the pp65422-439-immunized mice developed initial signs of glomerulonephritis such as deposition of immunoglobulin G/M (IgG/IgM) and third complement component (C3). With B cell epitope mapping by pp65422-439-derived decapeptides, one dominant epitope, pp65428-437, was identified in serum from pp65422-439-immunized mice and patients with SLE with anti-pp65422-439 antibody. Epitope spreading from pp65428-437 to pp65430-439 was found in pp65422-439-immunized mice in which we generated monoclonal antibodies to pp65425-434 and pp65430-439. However, dsDNA positive reactivity was exclusively observed in Crithidia luciliae stains with pp65430-439-reactive monoclonal antibody. Additionally, we observed the amelioration of autoimmunity following the elevation of IgM targeting pp65428-437. Conclusions Our data suggest that pp65428-437 may be an autoimmune or lupus-prone B cell epitope and may catalyze further epitope spreading for inducing autoantibodies in lupus-susceptible individuals. Electronic supplementary material The online version of this article (doi:10.1186/s13075-017-1268-2) contains supplementary material, which is available to authorized users.