Discovery of potent and selective inhibitors of procollagen C-proteinase for the treatment of fibrotic disorders

Introduction   Fibrosis is a component of many tissue pathologies leading to loss of normal tissue function, primarily due to excessive collagen deposition. Collagen is deposited following cleavage of the C- and N- terminal peptides from the pro-collagen molecule. The cleavage of the globular C-peptide by PCP reduces solubility of the fibrillar collagen molecule, resulting in deposition of insoluble collagen. Increased insoluble collagen deposition is a feature of all organ fibroses, with inhibition of this process, a key potential anti-fibrotic mechanism. The aim of this work was to discover potent and selective PCP inhibitors as experimental, topically applied, anti-fibrotic drugs for clinical evaluation.
Materials and methods   PCP was cloned from human osteosarcoma cells and enzymatic activity demonstrated using a PCP-specific peptide cleavage assay. Activities were confirmed by measuring cleavage of [³H]C-peptide from type-I pro-collagen. A cell-based fibroplasias model was employed to demonstrate compound efficacy using collagen deposition, liberated C-peptide and histological endpoints. The activities of PCP inhibitors in fibroblast and epithelial in vitro cell proliferation and migration assays, and selectivity vs. a panel of MMPs were also determined.
Discussion   In summary, we have identified and characterized potent and selective inhibitors of PCP for progression to clinical studies for investigation as a treatment paradigm for fibrotic disease.  

  Results     

64.

Soundings: Saving lives on the Silk Road     

James Owen Drife 《British medical journal》2004,329(7460):299

     

65.

Saccadic trajectory in Huntington's disease.     

Joanne Fielding  Nellie Georgiou-Karistianis  Lynette Millist  Michael Fahey  Owen White 《Journal of the International Neuropsychological Society》2006,12(4):455-464

Trajectories of saccadic eye movements can be modulated by the presence of a competing visual distractor. It is proposed that the superior colliculus (SC) controls the initial deviation through competitive lateral interactions. Given the ramifications of connections between basal ganglia (BG) thalamo-cortical circuitry and the SC, it was anticipated that this modulation would be differentially effected in those with Huntington's disease, which in its early stages is primarily a disorder of the BG. Horizontal deviation was determined for exogenously driven and endogenously driven vertical saccades in the presence of peripheral distractors. For neurologically healthy participants, the initial trajectories of both saccade types curved away from distractor locations, as predicted. However, for HD participants exogenous saccades consistently deviated leftwards, irrespective of distractor location. Endogenous saccades also revealed anomalous horizontal deviation, with significant leftward deviation evident for saccades directed upward and significant rightward deviation for saccades directed downward. Further, both groups generated a comparable proportion of erroneous responses to distractor stimuli, but only neurologically healthy participants demonstrated a response time advantage for compatible target/distractor presentation. These results suggest anomalous regulation of distractor-related activity in HD.     

66.

GlaxoSmithKline to set up comprehensive online clinical trials register     

Owen Dyer 《British medical journal》2004,329(7466):590

     

67.

Reliability of radiographic measurement of fracture angulation in children with femoral shaft fractures          下载免费PDF全文

Janice L. Owen  Derek Stephens    James G. Wright 《Canadian journal of surgery》2007,50(2):115-118

INTRODUCTION: Clinical decisions are based on x-ray measures of radiographs. However, the reliability of assessing the angular measurement of fractured femurs in children is unknown. The purpose of this study was to determine the intra- and interrater reliability of an x-ray assessment of femoral shaft fracture angulation in children. METHODS: On 2 occasions, 3 raters evaluated 30 radiographs of children aged 4 to 10 years, 3 to 24 months after a femoral fracture. The radiographs were evaluated by an orthopedic surgeon, an orthopedic fellow and a research assistant, using a standardized methodology. Reliability was assessed with the intraclass correlation coefficient (ICC), an index of concordance that ranges from 01, where > 0.75 indicates excellent concordance. RESULTS: The ICC for the intrarater ranged from 0.75 to 0.97. The interrater reliability ICC for anterior or posterior angulation was 0.91 (95% confidence interval [CI] 0.840.95) and for varus or valgus angulation was 0.90 (95% CI 0.790.95). A change in measurement of more than 5 degrees exceeds the variation in measurement and, therefore, can be attributed to a true shift in fracture position. CONCLUSIONS: With specific standardized protocols, radiographic assessment of femoral fractures is reliable, irrespective of the examiner's level of experience.     

68.

Childhood convulsive status epilepticus: epidemiology, management and outcome   总被引：4，自引：0，他引：4  

B. G. R. Neville  R. F. M. Chin  R. C. Scott 《Acta neurologica Scandinavica》2007,115(S186):21-24

Convulsive status epilepticus (CSE) in childhood is a medical emergency and its aetiology and outcome mean that it should be studied separately from adult CSE. The incidence in developed countries is between 17 and 23/100,000 with a higher incidence in younger children. Febrile CSE is the commonest single group with a good prognosis in sharp distinction to CSE related to central nervous system infections which have a high mortality. The aim of treatment is to intervene at 5 min and studies indicate that intravenous (i.v.) lorazepam may be a better first-line treatment than rectal diazepam and i.v. phenytoin a better second-line treatment than rectal paraldehyde. An epidemiological study strongly supports the development of prehospital treatment with buccal midazolam becoming a widely used but unlicensed option in the community. More than two doses of benzodiazepines increase the rate of respiratory depression without obvious benefit. The 1 year recurrence rate is 17% and the hospital mortality is about 3%.     

69.

Self‐report versus interview assessment of purging in a community sample of women     

J. M. Mond  P. J. Hay  B. Rodgers  C. Owen 《European eating disorders review》2007,15(6):403-409

     

70.

Self-regulation as a mediator of the effects of childhood traumatic brain injury on social and behavioral functioning.     

Kalaichelvi Ganesalingam  Ann Sanson  Vicki Anderson  Keith Owen Yeates 《Journal of the International Neuropsychological Society》2007,13(2):298-311

This study builds on our earlier investigation (see Ganesalingam et al., 2006). We showed previously that children with moderate to severe traumatic brain injuries (TBI) had poorer self-regulation and social and behavioral functioning than their uninjured peers and that self-regulation predicted significant variance in parent- and teacher-rated social and behavioral outcomes, regardless of the presence or absence of TBI. In this study, we examine self-regulation as a mediator of the relationship between TBI and the outcomes. Participants included 65 children with moderate to severe TBI and 65 children without TBI matched for age and gender. Participants were between 6 and 11 years of age. Children completed an assessment of cognitive, emotional, and behavioral self-regulation, and social and behavioral functioning. Mediation was assessed using a bootstrapping approach (a relatively novel statistical method for assessing specific indirect effects in models with multiple mediators). Analyses indicated that, after controlling for socioeconomic status (SES), aspects of self-regulation accounted for individual variation in the outcomes, and acted as a significant mediator of the effects of TBI on the outcomes. Self-regulatory deficits may reflect the relative vulnerability of the prefrontal cortex to TBI and may help account for post-injury difficulties in social and behavioral functioning.     

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Saccadic trajectory in Huntington's disease.

Trajectories of saccadic eye movements can be modulated by the presence of a competing visual distractor. It is proposed that the superior colliculus (SC) controls the initial deviation through competitive lateral interactions. Given the ramifications of connections between basal ganglia (BG) thalamo-cortical circuitry and the SC, it was anticipated that this modulation would be differentially effected in those with Huntington's disease, which in its early stages is primarily a disorder of the BG. Horizontal deviation was determined for exogenously driven and endogenously driven vertical saccades in the presence of peripheral distractors. For neurologically healthy participants, the initial trajectories of both saccade types curved away from distractor locations, as predicted. However, for HD participants exogenous saccades consistently deviated leftwards, irrespective of distractor location. Endogenous saccades also revealed anomalous horizontal deviation, with significant leftward deviation evident for saccades directed upward and significant rightward deviation for saccades directed downward. Further, both groups generated a comparable proportion of erroneous responses to distractor stimuli, but only neurologically healthy participants demonstrated a response time advantage for compatible target/distractor presentation. These results suggest anomalous regulation of distractor-related activity in HD.     

Reliability of radiographic measurement of fracture angulation in children with femoral shaft fractures

INTRODUCTION: Clinical decisions are based on x-ray measures of radiographs. However, the reliability of assessing the angular measurement of fractured femurs in children is unknown. The purpose of this study was to determine the intra- and interrater reliability of an x-ray assessment of femoral shaft fracture angulation in children. METHODS: On 2 occasions, 3 raters evaluated 30 radiographs of children aged 4 to 10 years, 3 to 24 months after a femoral fracture. The radiographs were evaluated by an orthopedic surgeon, an orthopedic fellow and a research assistant, using a standardized methodology. Reliability was assessed with the intraclass correlation coefficient (ICC), an index of concordance that ranges from 01, where > 0.75 indicates excellent concordance. RESULTS: The ICC for the intrarater ranged from 0.75 to 0.97. The interrater reliability ICC for anterior or posterior angulation was 0.91 (95% confidence interval [CI] 0.840.95) and for varus or valgus angulation was 0.90 (95% CI 0.790.95). A change in measurement of more than 5 degrees exceeds the variation in measurement and, therefore, can be attributed to a true shift in fracture position. CONCLUSIONS: With specific standardized protocols, radiographic assessment of femoral fractures is reliable, irrespective of the examiner's level of experience.     

Childhood convulsive status epilepticus: epidemiology, management and outcome

Convulsive status epilepticus (CSE) in childhood is a medical emergency and its aetiology and outcome mean that it should be studied separately from adult CSE. The incidence in developed countries is between 17 and 23/100,000 with a higher incidence in younger children. Febrile CSE is the commonest single group with a good prognosis in sharp distinction to CSE related to central nervous system infections which have a high mortality. The aim of treatment is to intervene at 5 min and studies indicate that intravenous (i.v.) lorazepam may be a better first-line treatment than rectal diazepam and i.v. phenytoin a better second-line treatment than rectal paraldehyde. An epidemiological study strongly supports the development of prehospital treatment with buccal midazolam becoming a widely used but unlicensed option in the community. More than two doses of benzodiazepines increase the rate of respiratory depression without obvious benefit. The 1 year recurrence rate is 17% and the hospital mortality is about 3%.     

Self-regulation as a mediator of the effects of childhood traumatic brain injury on social and behavioral functioning.

This study builds on our earlier investigation (see Ganesalingam et al., 2006). We showed previously that children with moderate to severe traumatic brain injuries (TBI) had poorer self-regulation and social and behavioral functioning than their uninjured peers and that self-regulation predicted significant variance in parent- and teacher-rated social and behavioral outcomes, regardless of the presence or absence of TBI. In this study, we examine self-regulation as a mediator of the relationship between TBI and the outcomes. Participants included 65 children with moderate to severe TBI and 65 children without TBI matched for age and gender. Participants were between 6 and 11 years of age. Children completed an assessment of cognitive, emotional, and behavioral self-regulation, and social and behavioral functioning. Mediation was assessed using a bootstrapping approach (a relatively novel statistical method for assessing specific indirect effects in models with multiple mediators). Analyses indicated that, after controlling for socioeconomic status (SES), aspects of self-regulation accounted for individual variation in the outcomes, and acted as a significant mediator of the effects of TBI on the outcomes. Self-regulatory deficits may reflect the relative vulnerability of the prefrontal cortex to TBI and may help account for post-injury difficulties in social and behavioral functioning.