Biomedical subjects

Kenneth W Fishbein

Publications and source records attributed to Kenneth W Fishbein.

10 recordsLinked to original sources

PubMed2006

Fourier transform infrared imaging and MR microscopy studies detect compositional and structural changes in cartilage in a rabbit model of osteoarthritis.

Assessment of subtle changes in proteoglycan (PG) and collagen, the primary macromolecular components of cartilage, which is critical for diagnosis of the early stages of osteoarthritis (OA), has so far remained a challenge. In this study we induced osteoarthritic cartilage changes in a rabbit model by ligament transection and medial meniscectomy and monitored disease progression by infrared fiber optic probe (IFOP) spectroscopy, Fourier transform infrared imaging spectroscopy (FT-IRIS), and magnetic resonance imaging (MRI) microscopy. IFOP studies combined with chemometric partial least-squares analysis enabled us to monitor progressive cartilage surface changes from two to twelve weeks post-surgery. FT-IRIS studies of histological sections of femoral condyle cartilage revealed that compared with control cartilage the OA cartilage had significantly reduced PG content 2 and 4 weeks post-surgery, collagen fibril orientation changes 2 and 4 weeks post-surgery, and changes in collagen integrity 2 and 10 weeks post-surgery, but no significant changes in collagen content at any time. MR microscopy studies revealed reduced fixed charge density (FCD), indicative of reduced PG content, in the OA cartilage, compared with controls, 4 weeks post-surgery. A non-significant trend toward higher apparent MT exchange rate, k(m), was also found in the OA cartilage at this time point, suggesting changes in collagen structural features. These two MR findings for FCD and k(m) parallel the FT-IRIS findings of reduced PG content and altered collagen integrity, respectively. MR microscopy studies of the cartilage at the 12-week time point also found a trend toward longer T (2) values and reduced anisotropy in the deep zone of the OA cartilage, consistent with increased hydration and less ordered collagen. These studies reveal that FT-IRIS and MR microscopy provide complementary data on compositional changes in articular cartilage in the early stages of osteoarthritic degradation.

Animals↗

PubMed2006

Resveratrol improves health and survival of mice on a high-calorie diet.

Resveratrol (3,5,4'-trihydroxystilbene) extends the lifespan of diverse species including Saccharomyces cerevisiae, Caenorhabditis elegans and Drosophila melanogaster. In these organisms, lifespan extension is dependent on Sir2, a conserved deacetylase proposed to underlie the beneficial effects of caloric restriction. Here we show that resveratrol shifts the physiology of middle-aged mice on a high-calorie diet towards that of mice on a standard diet and significantly increases their survival. Resveratrol produces changes associated with longer lifespan, including increased insulin sensitivity, reduced insulin-like growth factor-1 (IGF-I) levels, increased AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PGC-1alpha) activity, increased mitochondrial number, and improved motor function. Parametric analysis of gene set enrichment revealed that resveratrol opposed the effects of the high-calorie diet in 144 out of 153 significantly altered pathways. These data show that improving general health in mammals using small molecules is an attainable goal, and point to new approaches for treating obesity-related disorders and diseases of ageing.

Acetylation↗

PubMed2006

An analysis of the integration between articular cartilage and nondegradable hydrogel using magnetic resonance imaging.

A hydrogel is a highly hydrated polymer gel suitable for use as a scaffold for tissue engineering. One important application is to the repair of cartilage defects due to injury or osteoarthritis. Integration of the hydrogel with surrounding tissue is critical for the long-term functionality of the implant; however direct visualization of integration is difficult and invasive. Accordingly, we used MRI to noninvasively investigate the integration of hydrogel in cartilage. Two integration methods were assessed: (1) cartilage-initiated and (2) chemical, using chondroitin sulphate-methacrylate-aldehyde (CS-MA-ald) as an adhesive. These were compared to a control group, that is, standard, nonintegrated hydrogel photopolymerization. Spatial variation of the transverse relaxation time, T(2), across the transition region was used to determine the effectiveness of integration. In the CS-MA-ald group only, two interfaces were found. This provides evidence of an intermediate adhesive layer between hydrogel and cartilage. Second, the thickness of the transition region between hydrogel to cartilage in the CS-MA-ald group was 1.32 mm as compared to 1.20 mm and 1.17 mm in the tissue-initiated and nonintegrated groups, respectively. We interpret this as a more gradual transition region of hydrogel to cartilage and hence a greater degree of integration when an adhesive layer is present.

Animals↗

PubMed2006

Tendon and neurovascular bundle displacement in the palm with hand flexion and extension: an MRI and gross anatomy correlative study.

This study evaluated the correlative use of MRI methods and gross anatomy to monitor tendon displacement in the central region of the palm at rest and during flexion and extension of the metacarpophalangeal and interphalangeal joints with respect to the corresponding neurovascular bundles (NVBs). In all of the samples the neutral and extended positions showed the NVB to be palmar with respect to the flexor tendons, while during flexion tendon displacement caused the NVB to be dorsal to both the flexor digitorum superficialis (FDS) and flexor digitorum profundus (FDP) tendons. T1-weighted MR images correlated with gross anatomical slides demonstrated that significant changes occur in the relative positions of the flexor tendons and associated NVBs of the palm upon flexion and extension.

Aged↗

PubMed2005

Compatibility of Gd-DTPA perfusion and histologic studies of the brain.

Histology, including immunohistochemistry, and magnetic resonance imaging microscopy (microMRI) are complementary techniques for the analysis of brain structure. Therefore, microMRI analysis, often of formalin-fixed tissue, precedes histologic evaluation of the same experimental animal in many studies. However, the application of gadopentetate dimeglumine (Gd-DTPA), while of value for MRI studies, has an unknown effect on subsequent histology. We demonstrate here that for the mouse brain, histology with Nissl staining and immunostaining for microtubule-associated protein 2, using standard techniques for tissue preparation, are unaffected by prior perfusion of the tissue with Gd-DTPA. This conclusion was based on qualitative morphologic comparisons of stained sections, as well as quantification of mean immunofluorescence pixel intensities from Gd-treated (mean+/-S.D.=131.2+/-28.4; n=3) as compared to nontreated specimens (116.2+/-34.7; n=3, P=.7). Therefore, Gd-DTPA may be applied as a microMRI contrast agent in formalin-fixed brain tissue prior to histologic studies.

Animals↗

PubMed2004

Glycogen synthase kinase-3beta mediates convergence of protection signaling to inhibit the mitochondrial permeability transition pore.

Environmental stresses converge on the mitochondria that can trigger or inhibit cell death. Excitable, postmitotic cells, in response to sublethal noxious stress, engage mechanisms that afford protection from subsequent insults. We show that reoxygenation after prolonged hypoxia reduces the reactive oxygen species (ROS) threshold for the mitochondrial permeability transition (MPT) in cardiomyocytes and that cell survival is steeply negatively correlated with the fraction of depolarized mitochondria. Cell protection that exhibits a memory (preconditioning) results from triggered mitochondrial swelling that causes enhanced substrate oxidation and ROS production, leading to redox activation of PKC, which inhibits glycogen synthase kinase-3beta (GSK-3beta). Alternatively, receptor tyrosine kinase or certain G protein-coupled receptor activation elicits cell protection (without mitochondrial swelling or durable memory) by inhibiting GSK-3beta, via protein kinase B/Akt and mTOR/p70(s6k) pathways, PKC pathways, or protein kinase A pathways. The convergence of these pathways via inhibition of GSK-3beta on the end effector, the permeability transition pore complex, to limit MPT induction is the general mechanism of cardiomyocyte protection.

Animals↗

PubMed2003

A central nervous system specific mouse model for thanatophoric dysplasia type II.

To investigate the specific effect of the Fgfr3 K644E mutation on central nervous system (CNS) development, we have generated tissue-specific TDII mice by crossing Fgfr3(+/K644E-neo) transgenic mice with CNS-specific Nestin-cre or cartilage-specific Col2a1-cre mice. TDII/Nestin-cre (TDII-N) neonates did not demonstrate a profound skeletal phenotype. TDII-N pups were comparable to their wild-type littermates in terms of tail length, fore and hindlimbs, and body weight; however, many pups exhibited notably round heads. MRI and histochemical analysis illustrated asymmetric changes in cortical thickness and cerebellar abnormalities in TDII-N mice, which correlate with brain abnormalities observed in human TDII patients. Such abnormalities were not seen in TDII/Col2a1-cre (TDII-C) mice. Upon examination of adult TDII-N spinal cord, premature differentiation of oligodendrocyte progenitors was observed. Overall, these data indicate that the tissue-specific mouse model is an excellent system for studying the role of Fgfr3 in the developing CNS.

Amino Acid Substitution↗

PubMed2003

Differences in the bioenergetic response of the isolated perfused rat heart to selective beta1- and beta2-adrenergic receptor stimulation.

BACKGROUND: In the heart, striking functional differences exist after stimulation of the beta1- and beta2-adrenergic receptor (AR) subtypes. These may be linked to differences in metabolic response during beta1- and beta2-AR stimulation. METHODS AND RESULTS: The relation between work and metabolism was examined during selective beta1- and beta2-AR stimulation (beta1 and beta2 groups, respectively) in the isolated perfused rat heart. Measurements were made of rate-pressure product (RPP=LV developed pressure x heart rate), phosphorus-containing metabolites, and pH by 31P nuclear magnetic resonance spectroscopy and of O2 consumption by fiber-optic oximetry. Experiments were performed under high constant flow (HCF) and under flow-limiting conditions (constant pressure, CP). Despite substantially greater RPP increases relative to baseline during beta1-AR (HCF, 475%; CP, 150%) than beta2-AR (HCF, 90%; CP, 72%) stimulation, the relative decrease in the intracellular energy charge relative to baseline was similar for the beta1 (HCF, 49%; CP, 64%) and beta2 (HCF, 59%; CP, 55%) groups. For each group, an increase in oxygen consumption (MVO2) occurred commensurate with workload during HCF (beta1, 141%; beta2, 30%). During CP, however, the MVO2 increase was similar (beta1, 39%; beta2, 34%), despite the large RPP difference between the groups. During both protocols, there was greater acidosis during beta1-AR than during beta2-AR stimulation. Thus, at a given workload, intracellular energy charge decreased, and MVO2 (CP) increased to a greater extent during beta2 than beta1-AR stimulation. CONCLUSIONS: The bioenergetic differences are consistent with access to an additional substrate pool during beta1-AR stimulation. This may occur via increased glycogenolysis during beta1-AR stimulation, facilitating increased energy production by oxidative phosphorylation, and under flow-limiting conditions, anaerobic glycolysis.

Adrenergic beta-1 Receptor Agonists↗

PubMed2003

Matrix fixed-charge density as determined by magnetic resonance microscopy of bioreactor-derived hyaline cartilage correlates with biochemical and biomechanical properties.

OBJECTIVE: To use noninvasive magnetic resonance imaging (MRI), biochemical analyses, and mechanical testing of engineered neocartilage grown in a hollow- fiber bioreactor (HFBR) to establish tissue properties, and to test the hypothesis that MRI can be used to monitor biochemical and biomechanical properties of neocartilage. METHODS: Chondrocytes from day 16 embryonic chick sterna were inoculated into an HFBR and maintained for up to 4 weeks with and without exposure to chondroitinase ABC. The fixed-charge density (FCD) of the cartilage was determined using the MRI gadolinium exclusion method. The sulfated glycosaminoglycan (S-GAG), hydroxyproline, and DNA contents were determined using biochemical procedures, while dynamic and equilibrium moduli were determined from mechanical indentation tests. RESULTS: S-GAG content, tissue cross-sectional area, and equilibrium modulus of the neocartilage increased with development time. There was a gradient of S-GAG content across the length of control neocartilage at the 4-week time point, with higher values being found toward the inflow region. Exposure to chondroitinase ABC resulted in a decrease in tissue area, negative FCD, proteoglycan content, and equilibrium and dynamic moduli. The treated bioreactors displayed a lengthwise variation in S-GAG content, with higher values toward the outflow end. Linear correlations were established among FCD, proteoglycan content, and biomechanical properties. CONCLUSION: HFBR-derived neocartilage showed regional variation in S-GAG content under control conditions, and in the decrease of S-GAG in response to enzyme treatment. In addition, the results support the hypothesis that tissue parameters derived from MRI can be used to noninvasively monitor focal neocartilage formation and biochemical and biomechanical properties.

Animals↗

PubMed2003

Ex vivo magnetic resonance microscopy of an osteochondral transfer.

A 49-year-old woman with right knee pain and a chondral defect on the medial femoral condyle underwent an osteochondral transfer. The patient initially had pain relief, but then sustained a twisting injury and had progressive chondromalacia and pain on the affected side. She subsequently underwent a total knee replacement, and the tissue from the osteochondral transfer (OATS) site was harvested for analysis. In vitro MR microimaging of the excised joint segment revealed undamaged, full-thickness cartilage on the OATS plug, intact cartilage on the posterior condyle, and severely thinned and damaged cartilage on the anterior condyle. Alcian blue-stained sections revealed that proteoglycans were present throughout the OATS core but were nearly absent in the native cartilage. Quantitative T(1) data acquired after equilibration with Gd-DTPA indicated a distribution of matrix fixed charge in the OATS plug and anterior tissue that agreed well with histology and literature observations, while the posterior native cartilage appeared to have fixed charge similar to that of the OATS tissue. Histology revealed poor graft integration between OATS and native cartilage, with a distinct layer of fibrous tissue at the posterior interface. MRI images, by comparison, showed a hypointense feature at the posterior interface but uniform intensity across the anterior interface. Quantitative T(2), magnetization transfer and T(1) data acquired with and without gadolinium contrast showed dependences on depth, location, and pathology that were consistent with measurements reported in the literature for articular cartilage.

Arthroscopy↗