How are we measuring health-related quality of life in patients with a Barrett Esophagus? A systematic review on patient-reported outcome measurements.

PURPOSE: Barrett esophagus (BE) is associated with a significant decrease of health-related quality of life (HRQoL). Too often, patient-reported outcome measures (PROMs) are applied without considering what they measure and for which purposes they are suitable. With this systematic review, we provide researchers and physicians with an overview of all the instruments previously used for measuring HRQoL in BE patients and which PROMs are most appropriate from the patient's perspective. METHODS: A comprehensive search was performed to identify all PROMs used for measuring HRQoL in BE patients, to identify factors influencing HRQoL according to BE patients, and to evaluate each PROM from a patients' perspective. RESULTS: Among the 27 studies, a total of 32 different HRQoL instruments were identified. None of these instruments were designed or validated for use in BE patients. Four qualitative studies were identified exploring factors influencing HRQoL in the perceptions of BE patients. These factors included fear of cancer, anxiety, trust in physician, sense of control, uncertainty, worry, burden of endoscopy, knowledge and understanding, gastrointestinal symptoms, sleeping difficulties, diet and lifestyle, use of medication, and support of family and friends. CONCLUSION: None of the quantitative studies measuring HRQoL in BE patients sufficiently reflected the perceptions of HRQoL in BE patients. Only gastrointestinal symptoms and anxiety were addressed in the majority of the studies. For the selection of PROMs, we encourage physicians and researchers measuring HRQoL to choose their PROMs from a patient perspective and not strictly based on health professionals' definitions of what is relevant.

Animal models of cartilage repair.

Cartilage repair in terms of replacement, or regeneration of damaged or diseased articular cartilage with functional tissue, is the 'holy grail' of joint surgery. A wide spectrum of strategies for cartilage repair currently exists and several of these techniques have been reported to be associated with successful clinical outcomes for appropriately selected indications. However, based on respective advantages, disadvantages, and limitations, no single strategy, or even combination of strategies, provides surgeons with viable options for attaining successful long-term outcomes in the majority of patients. As such, development of novel techniques and optimisation of current techniques need to be, and are, the focus of a great deal of research from the basic science level to clinical trials. Translational research that bridges scientific discoveries to clinical application involves the use of animal models in order to assess safety and efficacy for regulatory approval for human use. This review article provides an overview of animal models for cartilage repair. Cite this article: Bone Joint Res 2014;4:89-94.

Functional analysis of the putative tumor suppressor PTPRD in neuroblastoma cells.

The gene encoding PTPδ is mutated or downregulated in human cancers including neuroblastoma. Here, we functionally tested the tumor-suppressive potential of PTPδ in neuroblastoma cell lines by reconstitution of both short and long PTPδ isoforms. We did not observe any significant difference in colony forming ability between cells expressing wild-type or catalytically inactive PTPδ. Although endogenous PTPδ expression was very low in neuroblastoma cells, it was also low in mouse embryo adrenal glands, suggesting that PTPδ may have little developmental function in early adrenal neuroblasts. This study, therefore, questions the significance of PTPδ as a tumor suppressor protein in neuroblastoma.

Mechanical and biochemical characterization of cartilage explants in serum-free culture.

Allografts of articular cartilage are both used clinically for tissue-transplantation procedures and experimentally as model systems to study the physiological behavior of chondrocytes in their native extracellular matrix. Long-term maintenance of allograft tissue is challenging. Chemical mediators in poorly defined culture media can stimulate cells to quickly degrade their surrounding extracellular matrix. This is particularly true of juvenile cartilage which is generally more responsive to chemical stimuli than mature tissue. By carefully modulating the culture media, however, it may be possible to preserve allograft tissue over the long-term while maintaining its original mechanical and biochemical properties. In this study juvenile bovine cartilage explants (both chondral and osteochondral) were cultured in both chemically defined medium and serum-supplemented medium for up to 6 weeks. The mechanical properties and biochemical content of explants cultured in chemically defined medium were enhanced after 2 weeks in culture and thereafter remained stable with no loss of cell viability. In contrast, the mechanical properties of explants in serum-supplemented medium were degraded by ( approximately 70%) along with a concurrent loss of biochemical content (30-40% GAG). These results suggest that long-term maintenance of allografts can be extended significantly by the use of a chemically defined medium.

Biochemical effects of two different hyaluronic acid products in a co-culture model of osteoarthritis.

OBJECTIVES: To compare the effects of two hyaluronic acid (HA) formulations on mediators of matrix turnover and inflammation in an IL-1-treated cartilage-synovium co-culture model with the aim of elucidating mechanisms by which viscosupplementation exerts beneficial effects in osteoarthritic joints. DESIGN: A co-culture model (100 ng/ml interleukin-1beta (IL-1beta) added to canine synovial and cartilage explants) was used to investigate the effects of HA on cartilage-synovium interactions. Three concentrations (1x, 0.5x, and 0.1x) of two commercial sources of HA (A: Synvisc [hylan G-F 20]; B: Hyalgan [sodium hyaluronate]) were used. Co-cultures without IL-1beta (negative) or with IL-1beta (positive) but neither HA product served as controls. The liquid media were collected every 3 days and explants of cartilage and synovium were collected on days 3, 6, and 20. Media and explants were analyzed histologically, biochemically, and immunohistochemically. RESULTS: Glycosaminoglycan (GAG) content was measured in cartilage explants. GAG content in explants was higher in both HA groups at the beginning and the conclusion of the study compared to the IL-1beta-treated group. GAG content of the media was significantly (P<0.05) lower in the Synvisc group than all other groups early. The Hyalgan group demonstrated progressively less GAG release later in the study. The addition of Synvisc did not decrease the matrix metalloproteinase (MMP)-3 concentrations at any point. MMP-3 concentrations were significantly (P<0.05) lower among the 1x and 0.5x Hyalgan groups on day 20 compared to the IL-1beta-treated group. On day 3, prostaglandin E(2) concentrations were significantly (P<0.05) higher in the IL-1beta-treated group compared to other groups. Both HA groups had less nitric oxide production than the control groups throughout the study. CONCLUSIONS: This study supports two potential mechanisms for viscosupplementation: a biosynthetic-chondroprotective mechanism, with a possible delay in onset depending on the form of HA; and an anti-inflammatory mechanism.

[A global intervention program for institutionalized demented patients]. / Méthode de prise en charge globale non médicamenteuse des patients déments institutionnalisés.

INTRODUCTION: Over the last decades many approaches have been developed to manage cognitive and behavioral disturbances in dementia. The present work describes a global intervention program carried out with moderately to severely demented institutionalized patients. The aims of the intervention program are to stimulate and maintain the preserved abilities of demented patients in a supportive context, to decrease the behavioral disturbance and to avoid burnout of care-unit staff. METHODS: This intervention combines different means: psychosocial care (validation therapy, social interaction), cognitive stimulation (memory and verbal training), and motor and sensitive stimulation. The global intervention program requires a special trained team composed of a supervisor, six aid-nurses, an occupational therapist, a speech therapist, a psychomotor therapist and a psychologist. The team cared for the patients five days per week over a three-month period. Assessments were conducted before and after the intervention program to measure the benefit. RESULTS: Positive effects were shown for cognitive abilities, nutritional problems and staff burnout. However, due to the small sample size for this study, more research is needed to verify the effectiveness of this global intervention program, particularly the implications for nutrition. CONCLUSION: This global intervention combined with pharmacological treatment seems to be useful for managing psychological and behavioral disorders of institutionalized demented patients.

Characterizing osteochondrosis in the dog: potential roles for matrix metalloproteinases and mechanical load in pathogenesis and disease progression.

OBJECTIVE: To address possible roles of matrix metalloproteinases (MMPs) and mechanical stress in the pathogenesis of osteochondrosis (OC). METHODS: Naturally-occurring canine OC lesions (n=50) were immunohistochemically analyzed for MMP-1, -3, and -13, and normal canine articular cartilage explants (n=6) cultured under 0-, 2-, or 4-MPa compressive loads (0.1 Hz, 20 min every 8 h up to 12 days) were compared to OC samples (n=4) biochemically and molecularly. RESULTS: MMP-1 and -3 immunoreactivities were readily detected in both OC samples and control tissues obtained from age-matched dogs (n=11) whereas MMP-13 was only detectable in OC samples. MMP-13 gene expression as determined by real-time reverse transcription polymerase chain reaction was elevated in OC samples and cartilage explants cultured without mechanical stimuli (0 MPa groups) compared to normal cartilage (day 0 controls). Glycosaminoglycan content (per weight) in cartilage explants cultured under no load was significantly (P<0.05) lower on day 12 than in the day 0 controls. Gene expression levels of aggrecan and type II collagen in OC samples were lower than those in the day 0 controls. High levels of aggrecan and collagen II expression were seen in the 2 MPa groups. CONCLUSIONS: These findings imply that impaired biochemical characteristics in OC-affected cartilage may be attributable to decreased extracellular matrix production that may stem from disruption of normal weight bearing forces.

The effective and environmental half-life of 137Cs at Coral Islands at the former US nuclear test site.

The United States (US) conducted nuclear weapons testing from 1946 to 1958 at Bikini and Enewetak Atolls in the northern Marshall Islands. Based on previous detailed dose assessments for Bikini, Enewetak, Rongelap, and Utirik Atolls over a period of 28 years, cesium-137 (137Cs) at Bikini Atoll contributes about 85-89% of the total estimated dose through the terrestrial food chain as a result of uptake of 137Cs by food crops. The estimated integral 30, 50, and 70-year doses were based on the radiological decay of 137Cs (30-year half-life) and other radionuclides. However, there is a continuing inventory of 137Cs and 90Sr in the fresh water portion of the groundwater at all contaminated atolls even though the turnover rate of the fresh groundwater is about 5 years. This is evidence that a portion of the soluble fraction of 137Cs and 90Sr inventory in the soil is lost by transport to groundwater when rainfall is heavy enough to cause recharge of the lens, resulting in loss of 137Cs from the soil column and root zone of the plants. This loss is in addition to that caused by radioactive decay. The effective rate of loss was determined by two methods: (1) indirectly, from time-dependent studies of the 137Cs concentration in leaves of Pisonia grandis, Guettarda specosia, Tournefortia argentea (also called Messerschmidia), Scaevola taccada, and fruit from Pandanus and coconut trees (Cocos nucifera L.), and (2) more directly, by evaluating the 137Cs/90Sr ratios at Bikini Atoll. The mean (and its lower and upper 95% confidence limits) for effective half-life and for environmental-loss half-life (ELH) based on all the trees studied on Rongelap, Bikini, and Enewetak Atolls are 8.5 years (8.0 years, 9.8 years), and 12 years (11 years, 15 years), respectively. The ELH based on the 137Cs/90Sr ratios in soil in 1987 relative to the 137Cs/90Sr ratios at the time of deposition in 1954 is less than 17 years. The magnitude of the decrease below 17 years depends on the ELH for 90Sr that is currently unknown, but some loss of 90Sr does occur along with 137Cs. If the 15-year upper 95% confidence limit on ELH (corresponding to an effective half-life of 9.8 years) is incorporated into dose calculations projected over periods of 30, 50, or 70 years, then corresponding integral doses are 58, 46 and 41%, respectively, of those previously calculated based solely on radiological decay of 137Cs.

Association between cancer chemotherapy and canine distemper virus, canine parvovirus, and rabies virus antibody titers in tumor-bearing dogs.

OBJECTIVE: To determine the association between cancer chemotherapy and serum canine distemper virus (CDV), canine parvovirus (CPV), and rabies virus antibody titers in tumor-bearing dogs. DESIGN: Prospective study. ANIMALS: 21 client-owned dogs with various malignancies and 16 client-owned dogs with lymphoma. PROCEDURE: In study A, serum antibody titers were measured by use of hemagglutination inhibition (CPV titers) or serum neutralization (CDV titers) before and at least 1 month after initiation of chemotherapy. Baseline values were compared with values obtained from a control population of 122 healthy dogs seen for routine revaccination. Titers were considered protective at > or = 1:96 for CDV and > or = 1:80 for CPV. In study B, serum IgG titers were measured by use of immunofluorescent assay (CDV and CPV titers) and rapid fluorescent focus inhibition test (RFFIT, rabies titers) at baseline and again at weeks 5, 8, and 24 of a standard chemotherapy protocol for treatment of lymphoma. An IgG titer of > or = 1:50 was considered protective for CPV and CDV. An RFFIT titer of > or = 0.5 U/ml was considered protective for rabies virus. RESULTS: Significant changes were not detected in CDV, CPV, and rabies virus titers following chemotherapy in tumor-bearing dogs. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that established immunity to CDV, CPV, and rabies virus from previous vaccination is not significantly compromised by standard chemotherapy used to treat tumor-bearing dogs.

Receptor protein tyrosine phosphatases regulate retinal ganglion cell axon outgrowth in the developing Xenopus visual system.

Receptor protein tyrosine phosphatases (RPTPs) are regulators of axon outgrowth and guidance in a variety of different vertebrate and invertebrate systems. Three RPTPs, CRYP-alpha, PTP-delta, and LAR, are expressed in overlapping but distinct patterns in the developing Xenopus retina, including expression in retinal ganglion cells (RGCs) as they send axons to the tectum (Johnson KG, Holt CE. 2000. Expression of CRYP-alpha, LAR, PTP-delta, and PTP-rho in the developing Xenopus visual system. Mech Dev 92:291-294). In order to examine the role of these RPTPs in visual system development, putative dominant negative RPTP mutants (CS-CRYP-alpha, CS-PTP-delta, and CS-LAR) were expressed either singly or in combination in retinal cells. No effect was found on either retinal cell fate determination or on gross RGC axon guidance to the tectum. However, expression of these CS-RPTP constructs differentially affected the rate of RGC axon outgrowth. In vivo, expression of all three CS-RPTPs or CS-PTP-delta alone inhibited RGC axon outgrowth, while CS-LAR and CS-CRYP-alpha had no significant effect. In vitro, expression of CS-CRYP-alpha enhanced neurite outgrowth, while CS-PTP-delta inhibited neurite outgrowth in a substrate-dependent manner. This study provides the first in vivo evidence that RPTPs regulate retinal axon outgrowth.

Receptor tyrosine phosphatases in axon growth and guidance.

Receptor-like protein tyrosine phosphatases (RPTPs) continue to emerge as important signalling molecules in axons and their growth cones. Recent findings show that Drosophila RPTPs play key roles in guiding retinal axons and in preventing midline crossing of longitudinal axons. Vertebrate RPTPs are now implicated in controlling axon outgrowth, and preliminary evidence suggests that they too may influence axon guidance.

Biochemical and molecular diagnosis of glutaric aciduria type 1 in a black South African male child: case report.

Glutaric aciduria type 1 (GA-1) is an inborn error of metabolism caused by a deficiency of the mitochondrial enzyme glutaryl-Co enzyme A dehydrogenase. GA-1 is not uncommon amongst Caucasians but to the best of our knowledge, it has previously not been reported in black African children. We present a case of GA-1 in a black South African boy who was referred to hospital at the age of five years and ten 10 months with dyskinesia and dystonia accompanied by chorea and athetosis. Radiological examination revealed enlarged basal cisterns with bilateral fluid collection around the sylvian fissures suggestive of GA-1. Analysis of urine showed raised levels of glutaric acid at 520 micromol/mmol creatinine (normal <2.0), 3-hydroxyglutaric acid at 113 micromol/mmol creatinine (normal <3.0) and a low blood carnitine level of 31.5 micromol/l (normal 35-84). A definitive diagnosis was reached through DNA analysis which revealed homozygosity for an A293T mutation in the glutaryl-Co-enzyme A dehydrogenase (GCDH) gene.

Expression of receptor protein tyrosine phosphatases in embryonic chick spinal cord.

Receptor-like protein tyrosine phosphatases potentially play a crucial role in axon growth and targeting. We focus here on their role within the embryonic avian spinal cord, in particular the development and outgrowth of motorneurons. We have used in situ mRNA hybridization to examine the spatiotemporal expression of eight receptor-like protein tyrosine phosphatases and find that it is both dynamic and highly varied, including novel, isoform-specific expression patterns. CRYP alpha 1 is expressed in all of the ventral motorneuron pools, whereas CRYP2, RPTP gamma, and RPTP alpha are only expressed in specific subsets of these neurons. CRYP alpha 2, RPTP psi, and RPTP delta are neuronally expressed elsewhere in the cord, but not in ventral motorneurons, whereas RPTP mu is unique in being restricted to capillaries. The developmentally regulated expression of these genes strongly suggests that the encoded phosphatases play numerous roles during neurogenesis and axonogenesis in the vertebrate spinal cord.

The receptor tyrosine phosphatase CRYPalpha promotes intraretinal axon growth.

Retinal ganglion cell axons grow towards the optic fissure in close contact with the basal membrane, an excellent growth substratum. One of the ligands of receptor tyrosine phosphatase CRYPalpha is located on the retinal and tectal basal membranes. To analyze the role of this RPTP and its ligand in intraretinal growth and guidance of ganglion cell axons, we disrupted ligand- receptor interactions on the retinal basal membrane in culture. Antibodies against CRYPalpha strongly reduced retinal axon growth on the basal membrane, and induced a dramatic change in morphology of retinal growth cones, reducing the size of growth cone lamellipodia. A similar effect was observed by blocking the ligand with a CRYPalpha ectodomain fusion protein. These effects did not occur, or were much reduced, when axons were grown either on laminin-1, on matrigel or on basal membranes with glial endfeet removed. This indicates that a ligand for CRYPalpha is located on glial endfeet. These results show for the first time in vertebrates that the interaction of a receptor tyrosine phosphatase with its ligand is crucial not only for promotion of retinal axon growth but also for maintenance of retinal growth cone lamellipodia on basal membranes.

Retinotectal ligands for the receptor tyrosine phosphatase CRYPalpha.

The cell adhesion molecule-like tyrosine phosphatase CRYPalpha is localized on retinal axons and their growth cones. We present evidence that two isoforms of this type IIa phosphatase, CRYPalpha1 and CRYPalpha2, have extracellular ligands along the developing retinotectal pathway. Using alkaline phosphatase fusion proteins containing the CRYPalpha1 ectodomain, we detect a prominent ligand on basement membranes of the early retina, optic stalk, and chiasm. A second ligand is observed in the endfeet region of radial processes in the developing stratum opticum, the site of initial retinal axon invasion. This latter ligand binds CRYPalpha2 preferentially. Further ligand interactions are detected for both CRYPalpha protein isoforms in retinorecipient tectal laminae and on retinal fibers themselves. CRYPalpha thus has cell- and matrix-associated ligands along the entire retinotectal projection. Moreover, these ligands appear to be heterotypic and interact with CRYPalpha through both its immunoglobulin and fibronectin type III regions. The anteroposterior levels of the ligands are relatively uniform within the retina and tectum, suggesting that the CRYPalpha protein within retinal axons does not directly recognise topographically graded guidance cues. We propose that CRYPalpha may have a permissive role in promoting retinal axon growth across the eye and tectum and that its functions are modulated temporally and spatially by isoform-specific interactions with cell- and matrix-associated ligands.

Expression of receptor tyrosine phosphatases during development of the retinotectal projection of the chick.

Receptor tyrosine kinases and receptor protein tyrosine phosphatases (RPTPs) appear to coordinate many aspects of neural development, including axon growth and guidance. Here, we focus on the possible roles of RPTPs in the developing avian retinotectal system. Using both in situ hybridization analysis and immunohistochemistry, we show for the first time that five RPTP genes--CRYPalpha, CRYP-2, PTPmu, PTPgamma, and PTPalpha--have different but overlapping expression patterns throughout the retina and the tectum. PTPalpha is restricted to Muller glia cells and radial glia of the tectum, indicating a possible function in controlling neuronal migration. PTPgamma expression is restricted to amacrine neurons. CRYPalpha and CRYP-2 mRNAs in contrast are expressed throughout the retinal ganglion cell layer from where axons grow out to their tectal targets. PTPmu is expressed in a subset of these ganglion cells. CRYPalpha, CRYP-2, and PTPmu proteins are also localized in growth cones of retinal ganglion cell axons and are present in defined laminae of the tectum. Thus, the spatial and temporal expression of three distinct RPTP subtypes--CRYPalpha, CRYP-2, and PTPmu--are consistent with the possibility of their involvement in axon growth and guidance of the retinotectal projection.

Phosphotyrosine signalling as a regulator of neural crest cell adhesion and motility.

We demonstrate that neural crest cell-cell adhesion, cell-substrate adhesion, and ultimately cell motility, are highly dependent on the balanced action of tyrosine kinases and tyrosine phosphatases. Neural crest cell migration on fibronectin is diminished in the presence of the tyrosine phosphatase inhibitor vanadate or tyrosine kinase inhibitor herbimycin A, while cadherin-rich cell-cell adhesions are significantly increased. In contrast, cells treated with the kinase inhibitor genistein have decreased motility, rearrange rapidly and reversibly into a pavement-like monolayer, but have no increase in cadherin interactions. Genistein-sensitive tyrosine kinases may therefore abrogate a latent sensitivity of neural crest cells to contact-mediated inhibition of movement. Furthermore, we show that the activity of herbimycin A-sensitive kinases is necessary for focal adhesion formation in these cells. Moreover, the size and distribution of these adhesions are acutely sensitive to the actions of tyrosine phosphatases and genistein-sensitive kinases. We propose that in migrating neural crest cells there is a balance in phosphotyrosine signalling which minimises both cell-cell adhesion and contact inhibition of movement, while enhancing dynamic cell-substrate interactions and thus the conditions for motility.