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J Ironside

Publications and source records attributed to J Ironside.

At least 19 recordsLinked to original sources
PubMed2004

Fibre reinforced composite dental bridge. Part I: Experimental investigation.

This experimental investigation aims at revealing the mechanical behaviour and failure pattern of direct fibre-reinforced resin-bonded dental bridge with various designs. To evaluate the overall effects of some newly developed dental materials, in the experiment, genuine composite dental bridge specimens are prepared and tested. The ultimate load, stiffness and mode at the failure of the bridges are measured and compared with the design variations. A good agreement between test and some clinical observations is demonstrated. It is verified that the weakest region appears across the pontic-abutment interface in the composite bridges. This study suggests that the composite bridges reinforced by fibres and supported by adjacent teeth could be of a higher structural strength and stiffness; therefore would provide better clinical performances.

Composite Resins↗
PubMed2004

Fibre reinforced composite dental bridge. Part II: Numerical investigation.

Motivated by the clinical success and limitations on experimental investigation of the fibre-reinforced composite dental bridge, this paper aims at providing a numerical investigation into the bridge structure. The finite element (FE) model adopted here is constructed from computer tomography images of a physical bridge specimen. The stress and strain distributions in the bridge structure especially in the bonding interfaces are analyzed in detail. The peak stresses and their variations with the different bridge designs are evaluated. Due to the lower bond strengths of adhesives and the high stress concentration in the pontic-abutment interface, the likelihood of failure in the interface is predicted by finite element analysis. The validity of the numerical results is established by a good agreement between the FE prediction and the tests in the load-deflection responses, the structural stiffness as well as the failure location of the composite dental bridge.

Composite Resins↗
PubMed2002

Temozolomide in malignant gliomas of childhood: a United Kingdom Children's Cancer Study Group and French Society for Pediatric Oncology Intergroup Study.

PURPOSE: To determine the response rate of the malignant gliomas of childhood to an oral, daily schedule of temozolomide. PATIENTS AND METHODS: A multicenter, phase II evaluation of an oral, daily schedule of temozolomide (200 mg/m(2) on 5 consecutive days) was undertaken in children with relapsed or progressive, biopsy-proven, high-grade glioma (arm A) and progressive, diffuse, intrinsic brainstem glioma (arm B). Evidence of activity was defined by radiologic evidence of a sustained reduction in tumor size on serial magnetic resonance imaging scans. RESULTS: Fifty-five patients were recruited (34 to arm A and 21 to arm B) and received 215 cycles of chemotherapy. Grade 3/4 thrombocytopenia was the most frequent toxic event (7% of cycles). Prolonged myelosuppression resulted in significant treatment delays and dose reductions (17% and 22% of cycles, respectively). Two toxic deaths were documented and were related to myelosuppression and sepsis in one patient and pneumonia in a second. The overall (best) response rate was 12% for arm A (95% confidence interval [CI], 3 to 28 in the study cohort, and 2 to 31 for eligible patients) and 5% and 6%, respectively, for arm B (95% CI, 0 to 26 in the study cohort, and 0 to 27 for eligible patients). Stabilization of disease was also documented and was most noteworthy for brainstem gliomas, where two patients achieved both radiologic static disease and discontinued steroid medication. CONCLUSION: Despite moderate toxicity, objective response rates to temozolomide have been low, indicating that temozolomide has minimal activity in the high-grade gliomas of childhood.

Adolescent↗
PubMed2001

Changing a single amino acid in the N-terminus of murine PrP alters TSE incubation time across three species barriers.

The PrP gene of the host exerts a major influence over the outcome of transmissible spongiform encephalopathy (TSE) disease, but the mechanism by which this is achieved is not understood. We have introduced a specific mutation into the endogenous murine PrP gene using gene targeting to produce transgenic mice with a single amino acid alteration (proline to leucine) at amino acid position 101 in their PrP protein (P101L). The effect of this alteration on incubation time, targeting and PrP(Sc) formation has been studied in TSE-infected animals. Transgenic mice carrying the P101L mutation in PrP have remarkable differences in incubation time and targeting of central nervous system pathology compared with wild-type littermates, following inoculation with infectivity from human, hamster, sheep and murine sources. This single mutation can alter incubation time across three species barriers in a strain-dependent manner. These findings suggest a critical role for the structurally 'flexible' region of PrP in agent replication and targeting of TSE pathology.

Amino Acid Sequence↗
PubMed2001

Adaptation of the bovine spongiform encephalopathy agent to primates and comparison with Creutzfeldt-- Jakob disease: implications for human health.

There is substantial scientific evidence to support the notion that bovine spongiform encephalopathy (BSE) has contaminated human beings, causing variant Creutzfeldt-Jakob disease (vCJD). This disease has raised concerns about the possibility of an iatrogenic secondary transmission to humans, because the biological properties of the primate-adapted BSE agent are unknown. We show that (i) BSE can be transmitted from primate to primate by intravenous route in 25 months, and (ii) an iatrogenic transmission of vCJD to humans could be readily recognized pathologically, whether it occurs by the central or peripheral route. Strain typing in mice demonstrates that the BSE agent adapts to macaques in the same way as it does to humans and confirms that the BSE agent is responsible for vCJD not only in the United Kingdom but also in France. The agent responsible for French iatrogenic growth hormone-linked CJD taken as a control is very different from vCJD but is similar to that found in one case of sporadic CJD and one sheep scrapie isolate. These data will be key in identifying the origin of human cases of prion disease, including accidental vCJD transmission, and could provide bases for vCJD risk assessment.

Adaptation, Biological↗
PubMed2001

A neuropsychological-neuropathological case study of variant Creutzfeldt-Jakob disease.

We report the first neuropsychological-neuropathological case study of a patient with variant Creutzfeldt-Jakob disease (vCJD) who was seen at the early stages of the disease, and whose cognitive functioning was monitored in the following months until his death. At presentation, his neuropsychological profile included impaired ability to retain new episodic information, deficits on tests of retrieval from semantic memory, and impairments on tests of memory for public knowledge, such as famous personalities. Tests of executive function were also performed poorly. Picture recognition memory and autobiographical memory were relatively spared, as was performance on tests of face perception and complex copying ability. Neuropsychological testing may be useful in monitoring the progression of vCJD, and we provide evidence to show a steady rate of decline in perceptual and naming tasks over a 4-month period. Post-mortem findings showed neuronal loss in the caudate, putamen, dorsal thalamus, cerebellum and occipital cortex. Spongiform changes were found throughout the brain, including the entorhinal cortex and anterior thalamus. Prion protein accumulation was noted in the hippocampus. We hypothesize that primary subcortical damage to structures in the thalamus and neostriatum, together with secondary frontal lobe dysfunction, combine to yield the pattern of neuropsychological impairment and neuropsychological sparing that was found.

Adult↗
PubMed2000

Reversion of prion protein conformational changes by synthetic beta-sheet breaker peptides.

BACKGROUND: Transmissible spongiform encephalopathies are associated with a structural transition in the prion protein that results in the conversion of the physiological PrPc to pathological PrP(Sc). We investigated whether this conformational transition can be inhibited and reversed by peptides homologous to the PrP fragments implicated in the abnormal folding, which contain specific residues acting as beta-sheet blockers (beta-sheet breaker peptides). METHODS: We studied the effect of a 13-residue beta-sheet breaker peptide (iPrP13) on the reversion of the abnormal structure and properties of PrP(Sc) purified from the brains of mice with experimental scrapie and from human beings affected by sporadic and variant Creutzfeldt-Jakob disease. In a cellular model of familial prion disease, we studied the effect of the peptide in the production of the abnormal form of PrP in intact cells. The influence of the peptide on prion infectivity was studied in vivo by incubation time assays in mice with experimental scrapie. FINDINGS: The beta-sheet breaker peptide partly reversed in-vitro PrP(Sc) to a biochemical and structural state similar to that of PrPc. The effect of the peptide was also detected in intact cells. Treatment of prion infectious material with iPrP13 delayed the appearance of clinical symptoms and decreased infectivity by 90-95% in mice with experimental scrapie. INTERPRETATION: Beta-sheet breaker peptides reverse PrP conformational changes implicated in the pathogenesis of spongiform encephalopathies. These peptides or their derivatives provide a useful tool to study the role of PrP conformation and might represent a novel therapeutic approach for prion-related disorders.

Animals↗
PubMed2000

a controlled trial of intratumoral ONYX-015, a selectively-replicating adenovirus, in combination with cisplatin and 5-fluorouracil in patients with recurrent head and neck cancer.

ONYX-015 is an adenovirus with the E1B 55-kDa gene deleted, engineered to selectively replicate in and lyse p53-deficient cancer cells while sparing normal cells. Although ONYX-015 and chemotherapy have demonstrated anti-tumoral activity in patients with recurrent head and neck cancer, disease recurs rapidly with either therapy alone. We undertook a phase II trial of a combination of intratumoral ONYX-015 injection with cisplatin and 5-fluorouracil in patients with recurrent squamous cell cancer of the head and neck. There were substantial objective responses, including a high proportion of complete responses. By 6 months, none of the responding tumors had progressed, whereas all non-injected tumors treated with chemotherapy alone had progressed. The toxic effects that occurred were acceptable. Tumor biopsies obtained after treatment showed tumor-selective viral replication and necrosis induction.

Adenoviruses, Human↗
PubMed2000

Preliminary studies on the optimum shape of dental bridges.

Several pre-existing anterior and posterior dental bridge models using Finite elements and the new ceramic material In-Ceram have been developed. The mechanical behaviour of these models has been compared with optimised profiles obtained from a newly developed evolutionary algorithm known as Evolutionary Structural Optimisation (ESO). The results show that the mechanical behaviour of the bridges was mainly restricted by the properties of the porcelain veneer and the design of the bridges themselves. For the case of the anterior bridge, it was found that there existed a specific thickness of veneer that minimised the maximum principal stress. This was related to peak stresses that occurred at the bridge surface. Peak stresses also occurred in the material interface between the In-Ceram and the veneer. These extreme stresses were attributed to the notch size and shape. For the case of the posterior bridge, it was concluded that the shape of the bottom of the Pontic tooth is crucial in reducing the magnitude of the maximum principal tensile stress. The ESO process produced bridge designs which have uniformly stressed bridge surfaces, and which also have significantly lower maximum principal tensile stresses compared to the pre-existing designs (up to 44%).

Biomechanical Phenomena↗
PubMed2000

Ultrastructural analysis of the florid plaque in variant Creutzfeldt-Jakob disease.

We report here the first description of florid plaques--the hallmark of variant Creutzfeldt-Jakob disease (vCJD). These plaques are composed of broad bundles of amyloid, are highly neuritic and exhibited astrocytes and microglial cells. Collectively, they are more similar to neuritic plaques of Alzheimer's disease than to kuru plaques of kuru--Creutzfeldt-Jakob disease--Gerstmann-Sträussler-Sheinker disease.

Alzheimer Disease↗
PubMed1999

Compelling transgenetic evidence for transmission of bovine spongiform encephalopathy prions to humans.

There is growing concern that bovine spongiform encephalopathy (BSE) may have passed from cattle to humans. We report here that transgenic (Tg) mice expressing bovine (Bo) prion protein (PrP) serially propagate BSE prions and that there is no species barrier for transmission from cattle to Tg(BoPrP) mice. These same mice were also highly susceptible to a new variant of Creutzfeldt-Jakob disease (nvCJD) and natural sheep scrapie. The incubation times (approximately 250 days), neuropathology, and disease-causing PrP isoforms in Tg(BoPrP)Prnp(0/0) mice inoculated with nvCJD and BSE brain extracts were indistinguishable and differed dramatically from those seen in these mice injected with natural scrapie prions. Our findings provide the most compelling evidence to date that prions from cattle with BSE have infected humans and caused fatal neurodegeneration.

Animals↗
PubMed1999

A single amino acid alteration (101L) introduced into murine PrP dramatically alters incubation time of transmissible spongiform encephalopathy.

A mutation equivalent to P102L in the human PrP gene, associated with Gerstmann-Straussler syndrome (GSS), has been introduced into the murine PrP gene by gene targeting. Mice homozygous for this mutation (101LL) showed no spontaneous transmissible spongiform encephalopathy (TSE) disease, but had incubation times dramatically different from wild-type mice following inoculation with different TSE sources. Inoculation with GSS produced disease in 101LL mice in 288 days. Disease was transmitted from these mice to both wild-type (226 days) and 101LL mice (148 days). In contrast, 101LL mice infected with ME7 had prolonged incubation times (338 days) compared with wild-type mice (161 days). The 101L mutation does not, therefore, produce any spontaneous genetic disease in mice but significantly alters the incubation time of TSE infection. Additionally, a rapid TSE transmission was demonstrated despite extremely low levels of disease-associated PrP.

Alleles↗
PubMed1998

Ki-67 immunolabelling index is a prognostic indicator in childhood posterior fossa ependymomas.

Conventional histological evaluation and subclassification of childhood ependymomas poorly predict their biological behaviour. The Ki-67 labelling index (Ki-67 LI), a measure of growth fraction, correlates with the biological behaviour of several neoplasms, and this retrospective study tested the hypothesis that Ki-67 LI is a prognostic indicator in childhood posterior fossa ependymomas. Immunocytochemistry using an antibody to Ki-67 was undertaken on 5 microns sections of formalin-fixed, paraffin-embedded tissue from 74 cases of childhood (age < 16 years.) posterior fossa ependymoma. A Ki-67 LI was established by counting the proportion of labelled nuclei in more than 1000 cells from several histological fields. Several clinical and histological variables (including Ki-67 LI) potentially associated with survival were entered into univariate and multivariate analyses using a Cox proportional hazards model. Variables that showed a significant and independent association with survival were Ki-67 LI (P < 0.002), whether total surgical resection had been achieved according to operation records (P < 0.03), and whether no adjuvant therapy had been given (P < 0.01). Age, sex, and the presence of necrosis or microvascular proliferation did not correlate with survival. In our defined population of patients with ependymomas, Ki-67 LI is a strong prognostic indicator. We recommend that Ki-67 LI is used in the histological evaluation of childhood posterior fossa ependymomas during trials of novel adjunctive therapies.

Adolescent↗
PubMed1998

Phenotypic variability of Gerstmann-Sträussler-Scheinker disease is associated with prion protein heterogeneity.

Gerstmann-Sträussler-Scheinker disease (GSS), a cerebello-pyramidal syndrome associated with dementia and caused by mutations in the prion protein gene (PRNP), is phenotypically heterogeneous. The molecular mechanisms responsible for such heterogeneity are unknown. Since we hypothesize that prion protein (PrP) heterogeneity may be associated with clinico-pathologic heterogeneity, the aim of this study was to analyze PrP in several GSS variants. Among the pathologic phenotypes of GSS, we recognize those without and with marked spongiform degeneration. In the latter (i.e. a subset of GSS P102L patients) we observed 3 major proteinase-K resistant PrP (PrPres) isoforms of ca. 21-30 kDa, similar to those seen in Creutzfeldt-Jakob disease. In contrast, the 21-30 kDa isoforms were not prominent in GSS variants without spongiform changes, including GSS A117V, GSS D202N, GSS Q212P, GSS Q217R, and 2 cases of GSS P102L. This suggests that spongiform changes in GSS are related to the presence of high levels of these distinct 21-30 kDa isoforms. Variable amounts of smaller, distinct PrPres isoforms of ca. 7-15 kDa were seen in all GSS variants. This suggests that GSS is characterized by the presence PrP isoforms that can be partially cleaved to low molecular weight PrPres peptides.

Adult↗