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PubMed2003

In frame fibrillin-1 gene deletion in autosomal dominant Weill-Marchesani syndrome.

Weill-Marchesani syndrome (WMS) is a connective tissue disorder characterised by short stature, brachydactyly, joint stiffness, and characteristic eye anomalies including microspherophakia, ectopia of the lenses, severe myopia, and glaucoma. Both autosomal recessive (AR) and autosomal dominant (AD) modes of inheritance have been described and a gene for AR WMS has recently been mapped to chromosome 19p13.3-p13.2. Here, we report on the exclusion of chromosome 19p13.3-p13.2 in a large AD WMS family and show that, despite clinical homogeneity, AD and AR WMS are genetically heterogeneous entities. Because two AD WMS families were consistent with linkage to chromosome 15q21.1, the fibrillin-1 gene was sequenced and a 24 nt in frame deletion within a latent transforming growth factor-beta1 binding protein (LTBP) motif of the fibrillin-1 gene was found in a AD WMS family (exon 41, 5074_5097del). This in frame deletion cosegregated with the disease and was not found in 186 controls. This study strongly suggests that AD WMS and Marfan syndrome are allelic conditions at the fibrillin-1 locus and adds to the remarkable clinical heterogeneity of type I fibrillinopathies.

Abnormalities, Multiple↗
PubMed1987

Biochemistry of hyaluronan.

Hyaluronan (hyaluronic acid) is a linear polysaccharide formed from disaccharide units containing N-acetylglucosamine and glucuronic acid. It is ubiquitously distributed in the organism but is found in the highest concentrations in soft connective tissues. The molecular weight of hyaluronan is usually in the order of 10(6) to 10(7). Due to hydrogen bonding, the chain is rather stiff and the molecule behaves in solution as an extended, randomly kinked coil. Molecules of hyaluronan start to entangle already at concentrations of less than 1 g/l and form a continuous polymer network. Some of the functions of the polysaccharide have been connected with the unique physical chemical characteristics of the network such as its rheological properties, flow resistance, osmotic pressure, exclusion properties and filter effect. Hyaluronan is synthesized in the cell membrane by adding monosaccharides to the reducing end of the chain. The precursors are UDP-glucuronic acid and UDP-N-acetylglucosamine. The polysaccharide grows out from the cell surface and it can be shown that fibroblasts, for example, surround themselves with a coat of hyaluronan. The rate of biosynthesis is regulated by various factors, such as growth factors, hormones, inflammatory mediators, etc. The responsible enzyme, hyaluronan synthase, is a phosphoprotein and the regulation of the synthetic rate is apparently via phosphorylation. The hyaluronan is at least partly carried by lymph flow from the tissues. Part of the material is taken up and degraded in the lymph nodes. Another part is carried to the general circulation and taken up in the endothelial cells in the liver sinusoids. These cells have specific receptors for hyaluronan, which also recognize chondroitin sulphate. The uptake in the liver of high-molecular weight hyaluronan is very efficient and its normal half-life in serum is only in the order of 2 to 5 min. The polysaccharide is rapidly degraded in the lysosomes to low-molecular weight products, lactate and acetate. The total turnover of hyaluronan in serum is in the order of 10-100 mg/24 h. The normal concentration of hyaluronan in serum is less than 100 micrograms/l with a mean of 30-40 micrograms/l. High serum levels have been noted in liver cirrhosis (impaired uptake in the liver) and rheumatoid arthritis (increased synthesis in the tissues). Hyaluronan has been shown to interact specifically with certain proteins and cell surfaces. It binds to proteoglycans in cartilage and other tissues and fills an important structural role in the organization of the extra-cellular matrix.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed2006

A structural model for the flexural mechanics of nonwoven tissue engineering scaffolds.

The development of methods to predict the strength and stiffness of biomaterials used in tissue engineering is critical for load-bearing applications in which the essential functional requirements are primarily mechanical. We previously quantified changes in the effective stiffness (E) of needled nonwoven polyglycolic acid (PGA) and poly-L-lactic acid (PLLA) scaffolds due to tissue formation and scaffold degradation under three-point bending. Toward predicting these changes, we present a structural model for E of a needled nonwoven scaffold in flexure. The model accounted for the number and orientation of fibers within a representative volume element of the scaffold demarcated by the needling process. The spring-like effective stiffness of the curved fibers was calculated using the sinusoidal fiber shapes. Structural and mechanical properties of PGA and PLLA fibers and PGA, PLLA, and 50:50 PGA/PLLA scaffolds were measured and compared with model predictions. To verify the general predictive capability, the predicted dependence of E on fiber diameter was compared with experimental measurements. Needled nonwoven scaffolds were found to exhibit distinct preferred (PD) and cross-preferred (XD) fiber directions, with an E ratio (PD/XD) of approximately 3:1. The good agreement between the predicted and experimental dependence of E on fiber diameter (R2 = 0.987) suggests that the structural model can be used to design scaffolds with E values more similar to native soft tissues. A comparison with previous results for cell-seeded scaffolds (Engelmayr, G. C., Jr., et al., 2005, Biomaterials, 26(2), pp. 175-187) suggests, for the first time, that the primary mechanical effect of collagen deposition is an increase in the number of fiber-fiber bond points yielding effectively stiffer scaffold fibers. This finding indicated that the effects of tissue deposition on needled nonwoven scaffold mechanics do not follow a rule-of-mixtures behavior. These important results underscore the need for structural approaches in modeling the effects of engineered tissue formation on nonwoven scaffolds, and their potential utility in scaffold design.

Biocompatible Materials↗
PubMed2006

The effects of leflunomide on clinical parameters and serum levels of IL-6, IL-10, MMP-1 and MMP-3 in patients with resistant rheumatoid arthritis.

OBJECTIVE: The purpose of this open pilot study was to assess possible mechanisms of the effects of leflunomide by studying the influence of the drug on the serum levels of MMP-1, MMP-3, IL-10, IL-6 and their possible correlation with clinical disease parameters. PATIENTS AND METHODS: Thirty patients with long standing active rheumatoid arthritis were enrolled in this study. All patients failed at least 5 DMARDs in the past and were on stable treatment for at least 3 months before starting the protocol. The patients received a loading dose of 100 mg for 3 days followed by 20 mg/day thereafter and followed up monthly for 6 months. Disease activity was assessed at baseline, 2 weeks, and every month of therapy thereafter using the following variables: tender joint count, swollen joint count, morning stiffness duration, pain, tiredness, physician's and patient's global assessment, using VAS, ESR and CRP. Clinical effects of the treatment regimen were calculated using the American College of Rheumatology (ACR) criteria for clinical response. Adverse events were recorded. Serum levels of MMP-1, MMP-3, IL-10 and IL-6 were measured before and 3 months after starting the protocol. RESULTS: Except for tiredness, a statistically significant improvement in all clinical and laboratory parameters of disease activity was reached after 3 months. At this time point the ACR-20 response rate was 46.2%. The levels of MMP-1, MMP-3, IL-6 and IL-10 decreased significantly after 3 months. A statistically significant correlation between serum levels of MMP-1, IL-10 and IL-6 and clinical and laboratory parameters was also shown. After 6 months, 16 out of 30 patients withdrew from the study [adverse events (35.4%), lack of efficacy (9.7%), and low compliance (6.4%)]. CONCLUSIONS: Leflunomide was clinically efficacious in this group of long standing resistant RA in an open study "real life" design. These results comply with those reported in previous clinical trials. Serum MMP-1, MMP-3, IL-10 and IL-6 levels decreased significantly. Despite high withdrawal rate, no serious adverse effects were recorded.

Adult↗
PubMed2004

The degree of mineralization is a determinant of bone strength: a study on human calcanei.

Strength of bones depends on bone matrix volume (BMV), bone microarchitecture, and also on the degree of mineralization of bone (DMB). We have recently shown in osteoporotic patients treated with alendronate that fracture risk decreased and bone mineral density increased with a parallel increase of the DMB due to prolonged secondary mineralization but without modifications of BMV or bone microarchitecture. DMB and strength were both measured at the tissue level in calcaneus bone samples taken at autopsy from 20 subjects (aged 78 +/- 8 years, 8 women, 12 men) who died suddenly without apparent bone disease. DMB parameters measured on microradiographs (mean DMB, distribution of DMB, most frequent maximum DMB value, and width at half maximum, an index reflecting the homogeneity of DMB) were compared with those reported in iliac cancellous bone samples of 43 human bones. Histomorphometric measurements of microarchitectural parameters (TbTh, TbN, and TbSp) were also measured. Compression tests were performed on contiguous samples of the same calcaneus on a universal screw-driven machine (Schenck RSA 250). A 5000-N load cell (TME, F 501 TC) measured the compressive load. The displacement was measured directly on the sample using a specific displacement transducer developed by the < > The apparent Young's modulus (E), the maximal strength (sigma(max)), and the work (W) until failure were measured. In human cancellous bone tissue, mean DMB (+/- SD) was higher in calcaneus (1.135 +/- 0.147 g/cm(3)) than in iliac crest (1.098 +/- 0.077 g/cm(3)). The mean most frequent maximum DMB values (mean DMB freq. max.) were 1.118 +/- 0.175 g/cm(3) in calcaneus and 1.108 +/- 0.095 g/cm(3) in iliac samples, and DMB was more heterogeneous in calcaneus than in iliac samples (mean width at half maximum were 0.270 +/- 0.127 versus 0.227 +/- 0.056 g/cm(3), respectively). Compression tests revealed significant positive linear correlations between DMB and both elastic modulus (r(2) = 0.69) and maximal strength (r(2) = 0.69). Correlations with DMB persisted (P < 0.003) even after adjustment for both calcified bone volume, for the Young's modulus (E), the maximal strength (sigma(max)) (r(2) = 0.44 and 0.41, respectively), and microarchitectural parameters (0.50 < r(2) < 0.56, P < 0.001). The same results were obtained with the work to fracture (W) (0.23 < r(2) < 0.46, P < 0.045). We conclude that the more the cancellous tissue was mineralized, the higher was its stiffness and compressive strength. This may explain the increase in bone strength when DMB is modified in a physiological range without necessary changes of BMV and bone microarchitecture. The impact of such modifications on fracture risk and the therapeutic implications of these data remain to be analyzed.

Aged↗
PubMed2003

Bone augmentation by means of a stiff occlusive titanium barrier.

It has already been shown that occlusive titanium barriers have osteoconductive properties. These barriers, however, cover only a limited surface area and have only been used in animal experiments. The aim of this study was to evaluate bone neogenesis under a pre-shaped titanium barrier placed over the top of the rabbit skull and the top of highly resorbed edentulous upper-jaw bone in patients. Computed tomography (CT) scans made it possible to pre-shape the titanium barrier according to individual bone shape in human experiments. On the rabbit skull, tissue augmentation of up to 6 mm 1 year after barrier placement was observed, while the original thickness of skull bone was on average between 1.5 and 2.5 mm. The bone, which remained histologically immature for 1 year, grew systematically along the titanium surface, illustrating its osteoconductivity. Even after removal of the barrier, on average, 75.3 and 59.4% of the newly created tissue volume was maintained after 3 and 9 months, respectively. Clinical observations on 10 consecutive patients showed that, in those (5/10) in which the barrier remained unexposed for several months, an increase of the jawbone height and width of up to 16 mm could be observed when the barrier was removed after 12-18 months. As in the rabbits at barrier removal, the bone demonstrated a limited degree of mineralization as ascertained from biopsies. This newly formed osteoid tissue allowed the insertion of 33 screw-shaped titanium implants which in most cases (30/33) successfully osseointegrated to support a fixed prosthesis. The surrounding marginal bone level remained stable even up to 5 years after implant placement. Both animal and clinical data demonstrate that guided bone neogenesis under a subperiosteally placed titanium barrier can reach large volumes.

Adult↗
PubMed2005

Passive osmotic properties of in situ human articular chondrocytes within non-degenerate and degenerate cartilage.

Osteoarthritis is characterized by many factors, including proteoglycan loss, decreased collagen stiffness, and increased cartilage hydration. Chondrocyte swelling also occurs, and correlates with the degree of osteoarthritis, however, the cause is unknown but might be related to alterations to their passive osmotic properties. We have used two-photon confocal laser scanning microscopy to measure the passive osmotic characteristics of in situ chondrocytes within relatively non-degenerate and degenerate human tibial plateau cartilage, and in chondrocytes isolated from relatively non-degenerate cartilage. Explants with bone attached were taken from a total of 42 patients undergoing arthroplasty and graded macroscopically and microscopically into two groups, grade 0 + 1 and grade 2 + 3. There was a significant increase in cartilage hydration between these two groups (P < 0.05), however, there was no change when medium osmolarity was varied over approximately 0-480 mOsm. The passive osmotic behavior of in situ chondrocytes (at 4 degrees C) was identical over a range of culture medium osmolarities ( approximately 0-515 mOsm), however, the maximum swelling of cells within degenerate cartilage and isolated chondrocytes was greater compared to those in non-degenerate cartilage. The swelling in the majority of in situ chondrocytes was accounted for by the reduced interstitial osmolarity occurring with cartilage degeneration. There was, however, a small population of in situ chondrocytes whose volume was in excess (>/=2,500 microm(3)) of that predicted from the decreased interstitial osmotic pressure. These results show that for the majority of cells studied, the differences in passive chondrocyte volume between relatively non-degenerate, degenerate, and isolated cells were entirely accounted for by changes to the extracellular osmolarity (180-515 mOsm).

Cartilage, Articular↗
PubMed1998

Micro-compression: a novel technique for the nondestructive assessment of local bone failure.

Many bones within the axial and appendicular skeleton are subjected to repetitive, cyclic loading during the course of ordinary daily activities. If this repetitive loading is of sufficient magnitude or duration, fatigue failure of the bone tissue may result. In clinical orthopedics, trabecular fatigue fractures are observed as compressive stress fractures in the proximal femur, vertebrae, calcaneus and tibia, and are often preceded by buckling and bending of microstructural elements. However, the relative importance of bone density and architecture in the etiology of these fractures is poorly understood. The aim of the study was to investigate failure mechanisms of 3D trabecular bone using micro-computed tomography (microCT). Because of its nondestructive nature, microCT represents an ideal approach for performing not only static measurements of bone architecture but also dynamic measurements of failure initiation and propagation as well as damage accumulation. For the purpose of the study, a novel micro-compression device was devised to measure loaded trabecular bone specimens directly in a micro-tomographic system. The measurement window in the device was made of a radiolucent, highly stiff plastic to enable X-rays to penetrate the material. The micro-compressor has an outer diameter of 19 mm and a total length of 65 mm. The internal load chamber fits wet or dry bone specimens with maximal diameters of 9 mm and maximal lengths of 22 mm. For the actual measurement, first, the unloaded bone is measured in the microCT. Second, a load-displacement curve is recorded where the load is measured with an integrated mini-button load cell and the displacement is computed directly from the microCT scout-view. For each load case, a 3D snap-shot of the structure under load is taken providing 34 microm nominal resolution. Initial measurements included specimens from bovine tibiae and whale spine to investigate the influence of the structure type on the failure mechanism. In a rod-like type of architecture as seen in the whale spine, structural failure was described by an initial buckling and bending of structural elements followed by a collapse of the overloaded trabeculae. In the more plate-like bovine tibial architecture, buckling and bending could not be observed. Failure rather seemed to occur instantaneously. In conclusion, micro-compression in combination with 3D microCT allows visualization of failure initiation and propagation and monitoring of damage accumulation in a nondestructive way. We expect these findings to improve our understanding of the relative importance of density, architecture and load in the etiology of spontaneous fractures of the hip and the spine. Eventually, this improved understanding may lead to more successful approaches to the prevention of age-related fractures.

Animals↗
PubMed2001

Pulsatile hemodynamics in congestive heart failure.

Pulse pressure, an indirect measure of vascular stiffness and pulsatile load, predicts clinical events in congestive heart failure (CHF), suggesting that abnormal pulsatile load may contribute to CHF. This study was designed to assess more direct measures of central pulsatile load in CHF. Noninvasive hemodynamic evaluations were performed in 28 subjects with CHF and 40 controls using calibrated tonometry of the brachial, radial, femoral, and carotid arteries along with echocardiographic assessment of left ventricular outflow tract (LVOT) diameter and Doppler flow. Characteristic impedance (Z(c)) was calculated as the ratio of DeltaP (carotid) and DeltaQ (LVOT flow) in early systole. Carotid-radial (CR-PWV) and carotid-femoral (CF-PWV) pulse wave velocities were calculated from tonometry. Augmentation index was assessed from the carotid waveform. Total arterial compliance (TAC) was calculated using the area method. Brachial pulse pressure was elevated (62+/-16 versus 53+/-15 mm Hg, P=0.015) in CHF because of lower diastolic pressure (66+/-10 versus 73+/-9 mm Hg, P=0.003). CHF had higher Z(c) (225+/-76 versus 184+/-66 dyne. sec. cm(-5), P=0.020). CF-PWV did not differ (9.7+/-2.7 versus 9.2+/-2.0, P=0.337), whereas CR-PWV was lower in CHF (8.6+/-1.4 versus 9.4+/-1.5, P=0.038). There was no difference in TAC (1.4+/-0.5 versus 1.4+/-0.6 mL/mmHg, P=0.685), and augmentation index was lower in CHF (8+/-17 versus 21+/-13%, P=0.001). CHF subjects have elevated central pulsatile load (Z(c)), which is not apparent in global measures such as augmentation index or TAC, possibly because of contrasting changes in central and peripheral conduit vessels. This increased pulsatile load represents an important therapeutic target in CHF.

Arteries↗