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Biomedical subjects

C A McLean

Publications and source records attributed to C A McLean.

At least 19 recordsLinked to original sources
PubMed2006

Disseminated intravascular coagulation complicating resection of a malignant meningioma.

A 70-year-old woman developed disseminated intravascular coagulation (DIC) during a craniotomy for a parasagittal anaplastic/malignant meningioma. This was successfully treated with rapid resection of the tumour and haematological replacement, but a poor neurological outcome resulted. The tumour was demonstrated to express tissue factor, an important causative factor in other tumour associated DIC and previously shown to be expressed by malignant meningiomas. A link between the two is suggested.

Aged↗
PubMed2006

Granular cell tumours of the gastrointestinal tract: expression of nestin and clinicopathological evaluation of 11 patients.

AIMS: Granular cell tumours (GCTs) in the gastrointestinal (GI) tract are rare, with few series reported in the literature. Nestin is a recently identified intermediate filament protein that is expressed in neuroectodermal stem cells and skeletal muscle progenitor cells and has been shown to be expressed in gastrointestinal stromal tumours (GISTs) and GI schwannomas. Herein, we describe the clinicopathological and immunohistochemical features of 11 GI GCTs, introducing nestin as an additional marker that identifies these tumours. METHODS AND RESULTS: The archives of the departments of pathology at London Health Sciences Centre (London, Ontario) and St Michael's Hospital (Toronto, Ontario) were searched for GCTs occurring in the GI tract, yielding 11 cases. Histological features were assessed and immunohistochemistry was performed with S100 protein, nestin, glial fibrillary acidic protein (GFAP), CD34, desmin, CD117, and inhibin-alpha. Charts were reviewed for clinical information. Ages at diagnosis ranged from 31 to 73 years; there were six males and four females. All GCTs were solitary, six in the oesophagus, three in the caecum, one in the rectum and one perianal. Most lesions were discovered incidentally. The size of the GCTs ranged from 4 mm to 30 mm. All were submucosal, typically firm, with a white-yellow appearance. Histologically, the GCTs showed moderate cellularity, predominantly solid growth with areas of nesting. While lesional cells were mainly plump and polygonal, areas of spindling were present in several tumours, more frequently in the colorectum. Margins were circumscribed. Nuclei were round to oval, with even chromatin and small nucleoli. Mitoses were rare to absent and necrosis was absent in all cases. Staining with periodic acid-Schiff, with diastase predigestion, showed globular and diffuse positivity within the cytoplasm. Moderate to strong expression of S100 protein and nestin was observed in 11 of 11 and seven of seven tumours, respectively. GFAP, CD34, desmin, CD117 and inhibin-alpha were negative. While patients were variably managed with resection or observation, all remain clinically well, without disease progression. CONCLUSIONS: Although rare, GI GCTs have characteristic clinicopathological features. Nestin may be a useful immunohistochemical marker for identifying these tumours; the presence of this persistent stem cell cytoskeletal filament within GI GCTs suggests that these lesions may arise from a multipotential stem cell in the GI tract.

Adult↗
PubMed2005

Transjugular liver biopsy is a safe and effective intervention to guide management for patients with a congenital bleeding disorder infected with hepatitis C.

The prevalence of hepatitis C virus (HCV) infection in adult patients with a congenital bleeding disorder (CBD) approaches 95% and is a major cause of morbidity and mortality. Histological examination of the liver remains the cornerstone of management decisions in patients without a CBD. The reluctance to perform liver biopsies in patients with a CBD has been a major limitation in the management of these patients. We are currently the only haemophilia centre in Australasia performing liver biopsies in patients with a CBD for the purpose of guiding prognostic and therapeutic decisions. We report here the results of our centre's experience with transjugular liver biopsy (TJLB) in patients with a CBD. An adequate specimen for histological assessment was attained from all of the patients. There were no major complications recorded. Patients were hospitalized for < or = 48 h for haemostasis prophylaxis. The diagnostic specimen obtained from patients was integral in guiding their future management. We suggest that with a coordinated multidisciplinary approach, TJLB can be performed in patients with a CBD.

Adult↗
PubMed2003

Novel prion protein insert mutation associated with prolonged neurodegenerative illness.

BACKGROUND: Mutations in the prion protein gene (PRNP) are found in approximately 13 to 15% of persons classified as dying from a transmissible spongiform encephalopathy. Point and octapeptide repeat insert and deletion mutations are described in the open reading frame (ORF) of PRNP. The authors present a clinicopathologic study of a patient with a family history of a lengthy and progressive neurodegenerative disorder associated with a novel large octapeptide repeat insert mutation. METHODS: Neuropathologic examination, including immunohistochemistry for the prion protein, was undertaken. The ORF of PRNP was amplified by PCR, cloned, and sequenced. Homogenate of cerebral tissue underwent Western blot analysis for the prion protein before and after proteinase K treatment. RESULTS: The proband died after a 16-year illness commencing at age 29 years. Confident premortem clinical diagnosis was not achieved despite a brain biopsy. Autopsy examination of the brain confirmed a spongiform encephalopathy. Prion protein immunohistochemistry revealed occasional granular deposits in the cerebellar granular layer. The proband was found to harbor a novel PRNP 168 base pair (bp) insert mutation. CONCLUSION: The authors have identified a novel 168 bp octapeptide repeat insert mutation. Prion protein immunohistochemistry differs from previous cases harboring seven octapeptide repeat and other long insert mutations. Optimization of PRNP analysis, especially PCR conditions, is essential to avoid overlooking this type of mutation and delay the correct molecular genetic diagnosis.

Adult↗
PubMed2003

alpha-Synuclein fibrils constitute the central core of oligodendroglial inclusion filaments in multiple system atrophy.

Multiple system atrophy (MSA) belongs to synucleinopathies and is characterized pathologically by oligodendroglial inclusions (GCIs) composed of 20- to 30-nm tubular filaments. alpha-Synuclein fibrils formed in vitro, however, range between 10 and 12 nm in diameter. To understand the relationship between alpha-synuclein and GCI filaments, we conducted structural analyses of GCIs in fixed brain sections and isolated from fresh-frozen MSA brains. In fixed brain sections, GCIs were composed of amorphous material-coated filaments up to 30 nm in size. The filaments were often organized in parallel bundles extending into oligodendroglial processes. In freshly isolated GCIs, progressive buffer washes removed amorphous material and revealed that GCI filaments consisted of 10-nm-sized central core fibrils that were strongly alpha-synuclein immunoreactive. Image analysis revealed that each core fibril was made of two subfibrils, and each subfibril was made of a string of 3- to 6-nm-sized particles probably alpha-synuclein oligomers. Immunogold labeling demonstrated that epitopes encompassing entire alpha-synuclein molecule were represented in the core fibrils, with the N-terminal 11-26 and C-terminal 108-131 amino acid residues most accessible to antibodies, probably exposed on the surface of the fibril. Our study indicates that GCI filaments are multilayered in structure, with alpha-synuclein oligomers forming the central core fibrils of the filaments.

Aged↗
PubMed2003

Cotransfection of heme oxygenase-1 prevents the acute inflammation elicited by a second adenovirus.

The acute inflammatory response elicited by adenovirus vectors results in loss of gene expression and tissue injury in the target organ. This acute inflammation is now believed to be the major limiting factor for the use of adenovirus vectors in gene therapy. While exploring the level of acute inflammation caused by the adenovirus encoding the gene for the anti-inflammatory enzyme heme oxygenase-1, we discovered that this adenovirus not only did not elicit acute inflammation, but could prevent the inflammation caused by a second adenovirus. Here we describe a new approach to gene therapy, which uses the encoding of the potent anti-inflammatory enzyme heme oxygenase-1 to prevent early host inflammatory responses normally associated with adenovirus vectors.

Acute Disease↗
PubMed2002

Creutzfeldt-Jakob disease in Australia 1970-1999.

OBJECTIVE: To ascertain all persons who developed a transmissible spongiform encephalopathy (TSE) within Australia during the 30-year period 1970 to 1999 through a comprehensive national surveillance program and subject the group to detailed epidemiologic analysis. METHODS: Cases were ascertained through reviews of morbidity separation coding data from all university-affiliated tertiary referral hospitals, as well as the centralized data bases of state and territory health departments, regular national death certificate searches, and semiannual mailout questionnaires to all neurologists and pathologists throughout Australia. Prospective monitoring commenced in September 1993. RESULTS: A total of 387 patients were confirmed as having TSE during this epoch. The majority of cases were sporadic Creutzfeldt-Jakob disease (CJD) (90.7%), with 7.2% heredofamilial and 2.1% iatrogenic. Over this 30-year period, the national average annual sporadic CJD incidence rate per million progressively increased from 0.31 for the decade 1970 through 1979 to 0.77 for 1980 through 1989, reaching 1.03 for 1990 through 1999. Death certificates were found to have a false-positive rate of 11.5% and sensitivity of 83.0% for sporadic CJD. CONCLUSIONS: Within Australia, there has been a gradual increase in the incidence of transmissible spongiform encephalopathy over the three-decade period 1970 through 1999, peaking in 1999 at 1.4/million/year for sporadic Creutzfeldt-Jakob disease. This increase is believed secondary to improved case ascertainment. Variant Creutzfeldt-Jakob disease was not identified during this period. Age- and sex-adjusted comparisons showed a decline in incidence rates in the elderly in both sexes, usually from age 74 years. Death certificates were a useful but imperfect method of case detection.

Adult↗
PubMed2001

Variable phenotype of Alzheimer's disease with spastic paraparesis.

A variant form of Alzheimer's disease (AD), in which spastic paraparesis (SP) precedes dementia, is characterised by large, noncored, weakly neuritic Abeta-amyloid plaques resembling cotton wool balls and is caused by genomic deletion of presenilin 1 exon 9. A pedigree with a 5.9 kb exon 9 deletion shows a phenotypic spectrum including subjects with typical AD or with SP and numerous cotton wool plaques. In SP subjects, dementia onset is delayed and modified. This phenotypic variation suggests that modifying factors are associated with exon 9 deletions.

Adult↗
PubMed2001

Treatment with a copper-zinc chelator markedly and rapidly inhibits beta-amyloid accumulation in Alzheimer's disease transgenic mice.

Inhibition of neocortical beta-amyloid (Abeta) accumulation may be essential in an effective therapeutic intervention for Alzheimer's disease (AD). Cu and Zn are enriched in Abeta deposits in AD, which are solubilized by Cu/Zn-selective chelators in vitro. Here we report a 49% decrease in brain Abeta deposition (-375 microg/g wet weight, p = 0.0001) in a blinded study of APP2576 transgenic mice treated orally for 9 weeks with clioquinol, an antibiotic and bioavailable Cu/Zn chelator. This was accompanied by a modest increase in soluble Abeta (1.45% of total cerebral Abeta); APP, synaptophysin, and GFAP levels were unaffected. General health and body weight parameters were significantly more stable in the treated animals. These results support targeting the interactions of Cu and Zn with Abeta as a novel therapy for the prevention and treatment of AD.

Age Factors↗
PubMed2001

The solubility of alpha-synuclein in multiple system atrophy differs from that of dementia with Lewy bodies and Parkinson's disease.

Intracellular inclusions containing alpha-synuclein (alpha SN) are pathognomonic features of several neurodegenerative disorders. Inclusions occur in oligodendrocytes in multiple system atrophy (MSA) and in neurons in dementia with Lewy bodies (DLB) and Parkinson's disease (PD). In order to identify disease-associated changes of alpha SN, this study compared the levels, solubility and molecular weight species of alpha SN in brain homogenates from MSA, DLB, PD and normal aged controls. In DLB and PD, substantial amounts of detergent-soluble and detergent-insoluble alpha SN were detected compared with controls in grey matter homogenate. Compared with controls, MSA cases had significantly higher levels of alpha SN in the detergent-soluble fraction of brain samples from pons and white matter but detergent-insoluble alpha SN was not detected. There was an inverse correlation between buffered saline-soluble and detergent-soluble levels of alpha SN in individual MSA cases suggesting a transition towards insolubility in disease. The differences in solubility of alpha SN between grey and white matter in disease may result from different processing of alpha SN in neurons compared with oligodendrocytes. Highly insoluble alpha SN is not involved in the pathogenesis of MSA. It is therefore possible that buffered saline-soluble or detergent-soluble forms of alpha SN are involved in the pathogenesis of other alpha SN-related diseases.

Aged↗
PubMed2001

Wheat germ agglutinin-binding glycoproteins are decreased in Alzheimer's disease cerebrospinal fluid.

A number of biomarkers (e.g. Abeta, tau) has been identified in Alzheimer's disease CSF. However, none fulfils the criteria of sensitivity and specificity (> 80%) needed for the development of an accurate diagnostic test. The lack of a suitable marker has prompted the search for new CSF biomarkers. In this study, the glycosylation of CSF proteins was examined using lectin blotting. Lumbar CSF was collected ante mortem from 22 non-Alzheimer's disease and 12 probable Alzheimer's disease cases and ventricular CSF collected post mortem from 7 non-Alzheimer's disease and 16 Alzheimer's disease cases confirmed by pathologic examination. When CSF glycoproteins were stained with wheat germ agglutinin (WGA), the staining intensity was found to be significantly lower in the Alzheimer's disease group. No difference in staining was found using other lectins (Canavalia ensiformis agglutinin, Ricinus communis agglutinin, Lens culinaris agglutinin). The measurement of WGA-reactive glycoproteins in CSF may be a useful biomarker for diagnosis of Alzheimer's disease.

Aged↗
PubMed2001

Gerstmann-Sträussler-Scheinker syndrome,fatal familial insomnia, and kuru: a review of these less common human transmissible spongiform encephalopathies.

Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker syndrome (GSS), fatal familial insomnia (FFI) and kuru constitute major human prion disease phenotypes. Each has been successfully transmitted in animal models and all are invariably fatal neurodegenerative disorders, with the brains of affected individuals harbouring variable amounts of an abnormal, protease-resistant form of the prion protein (PrPres), which is inextricably linked to pathogenesis and transmissibility. Classical sporadic CJD is the most common human transmissible spongiform encephalopathy (TSE), but recently the variant form (vCJD), first described in the UK in 1996, has drawn considerable attention. In contrast to sporadic CJD, FFI and GSS are almost invariably genetically determined TSEs, caused by a range of mutations within the open reading frame of the prion protein gene (PRNP) on chromosome 20. By definition, the nosologic term FFI is reserved for patients manifesting prominent insomnia, generally in combination with dysautonomia, myoclonus, and eventual dementia, with the predominant pathologic changes lying within the thalami and a specific underlying mutation in PRNP. GSS, however, encompasses a more diverse clinical spectrum ranging from progressive cerebellar ataxia or spastic paraparesis (both usually in combination with dementia), to isolated cognitive impairment resembling Alzheimer's disease. Additional extra-pyramidal features, which may respond to dopaminergic therapy can also be seen. Neuropathological findings are also relatively diverse, partly overlapping with those found in Alzheimer's disease, especially the presence of neurofibrillary tangles (NFTs). Although GSS and FFI in their classical forms are differentiable clinical profiles, such divisions may have no intrinsic biological validity given the considerable intra-familial clinico-pathological diversity so commonly seen. Kuru constitutes a horizontally transmitted prion disease, which after a lengthy incubation period, presents clinically as a progressive cerebellar ataxia associated with tremors. It has now almost disappeared since the cessation of ritualistic endocannibalism in the late 1950s but was previously exclusively endemic amongst the Fore linguistic group and neighbouring tribes in the Eastern Highlands of New Guinea. Uniform topographical central nervous system histopathology includes spongiform change and neuronal loss, with amyloid (kuru) plaques in approximately 75% of cases.

Gerstmann-Straussler-Scheinker Disease↗
PubMed2001

A potential role for the p75 low-affinity neurotrophin receptor in spinal motor neuron degeneration in murine and human amyotrophic lateral sclerosis.

INTRODUCTION: The p75 neurotrophin receptor has been recognized as a death-signalling molecule under certain circumstances. Its role in motor neuron degeneration in amyotrophic lateral sclerosis (ALS) was analysed in SOD1-G93A transgenic mice and in spinal cords from human amyotrophic lateral sclerosis. METHOD: The precise loss of motor neurons in SOD1-G93A transgenic mice from birth to adulthood was established using the unbiased fractionator/optical dissector neuronal counting technique. RESULTS: This study showed an early trend in the loss of lumbar motor neurons in SOD1-G93A mice, beginning at birth and progressing to a massive 80% reduction by 4 months of age, when the disease is severe. This study also found that the p75 neurotrophin receptor was expressed in lumbar motor neurons in symptomatic SOD1-G93A mice and in motor neurons in the cervical spinal cords of patients with ALS. CONCLUSIONS: The murine and human ALS data suggest that the p75 neurotrophin receptor may play a death-signalling role in the pathogenesis of motor neuron degeneration. The precise mechanism by which this receptor drives the apoptotic process, both in murine SOD1-G93A motor neuron degeneration and in human amyotrophic lateral sclerosis, remains to be determined.

Amino Acid Substitution↗
PubMed2001

Effect of femoral component designs on the contact and tracking characteristics of the unresurfaced patella in total knee arthroplasty.

OBJECTIVES: To determine the effect of 5 different femoral components used in total knee arthroplasty (TKA) on the contact area and tracking characteristics of the nonresurfaced patella and to identify any design features that might adversely affect these characteristics. DESIGN: An in-vitro study. SETTING: The biomechanics laboratory, Department of Mechanical Engineering, McGill University, Montreal. SPECIMENS: Six fresh-frozen cadaveric knee-joint specimens. INTERVENTIONS: An unconstrained quadriceps simulator was used to apply the conditions of static lifting to the specimens first in their normal state and then sequentially implanted with femoral and tibial components of various designs (Miller/Galante II, Anatomic Modular Knee [AMK] System, Whiteside Ortholoc Modular, press-fit condylar and Insall-Burstein II). OUTCOME MEASURES: Patellar 3-dimensional tracking characteristics, determined by using a 6 degrees-of-freedom electromechanical goniometer attached directly to the patella, and patellar contact pressure measurements, obtained using low-range Fuji Prescale film. RESULTS: Articulation of the normal patella on a prosthetic femoral component resulted in alterations in the normal patellofemoral contact and tracking characteristics. The exact departure depended on the design of the prosthetic trochlea. Although all of the selected prostheses demonstrated satisfactory contact characteristics near extension, marked alterations occurred at higher flexion angles. With 90 degrees or more of flexion, there was incompatibility between the geometries of the prosthetic notch of 2 femoral designs (AMK and PFC) and the normal knee. CONCLUSION: The design of the prosthetic femoral component must be taken into account when determining whether or not to resurface the patella at the time of TKA.

Adult↗
PubMed2000

Novel prion protein gene mutation in an octogenarian with Creutzfeldt-Jakob disease.

BACKGROUND: The transmissible spongiform encephalopathies constitute a fascinating and biologically unique group of invariably fatal neurodegenerative disorders that affect both animals and humans. Creutzfeldt-Jakob disease (CJD), Gerstmann-Straussler-Scheinker syndrome, and fatal familial insomnia represent the more common human phenotypes. Excluding the small number of iatrogenically transmitted cases, approximately 85% to 90% of patients develop CJD without identifiable explanation, with an increasing number of different mutations in the prion protein gene (PRNP) recognized as probably causative in the remainder. OBJECTIVE: To report on an 82-year-old woman with pathologically confirmed CJD found unexpectedly to harbor a novel mutation in PRNP. METHODS: Routine clinical investigations were undertaken to elucidate the cause of the rapidly progressive dementia and neurological decline manifested by the patient, including magnetic resonance imaging of the brain, electroencephalography, and cerebrospinal fluid analysis for the 14-3-3 beta protein. Standard postmortem neuropathological examination of the brain was performed, including immunocytochemistry of representative sections to detect the prion protein. Posthumous genetic analysis of the open reading frame of PRNP was performed on frozen brain tissue using polymerase chain reaction and direct sequencing. RESULTS: Concomitant with the exclusion of alternative diagnoses, the presence of characteristic periodic sharp-wave complexes on the electroencephalogram in combination with a positive result for 14-3-3 beta protein in the cerebrospinal fluid led to a confident clinical diagnosis of CJD, confirmed at autopsy. There was no family history of dementia or similar neurological illness, but patrilineal medical information was incomplete. Unexpectedly, full sequencing of the PRNP open reading frame revealed a single novel mutation consisting of an adenine-to-guanine substitution at nucleotide 611, causing alanine to replace threonine at codon 188. CONCLUSIONS: In addition to expanding the range of PRNP mutations associated with human prion diseases, we believe this case is important for the following reasons. First, from an epidemiological perspective, the avoidance of occasional incorrect classification of patients manifesting neurodegenerative disorders that may have a genetic basis requires systematic genotyping, particularly when there are uncertainties regarding the family history. Second, the incidence of spongiform encephalopathy in elderly patients beyond the typical age range may be underestimated and does not preclude a genetic basis. Finally, as a corollary, this case highlights problematic issues in human transmissible spongiform encephalopathies, as illustrated by disease penetrance and age of onset in genotype-phenotype correlations.

14-3-3 Proteins↗
PubMed2000

Chelation and intercalation: complementary properties in a compound for the treatment of Alzheimer's disease.

Selective application of metal chelators to homogenates of human Alzheimer's disease (AD) brain has led us to propose that the architecture of aggregated beta-amyloid peptide, whether in the form of plaques or soluble oligomers, is determined at least in part by high-affinity binding of transition metals, especially copper and zinc. Of the two metals, copper is implicated in reactive oxygen species generating reactions, while zinc appears to be associated with conformational and antioxidant activity. We tested the copper chelators trientine, penicillamine, and bathophenanthroline for their ability to mobilize brain Abeta as measured against our benchmark compound bathocuproine (BC). All of these agents were effective in solubilizing brain Abeta, although BC was the most consistent across the range of AD brain tissue samples tested. Similarly, all of the copper chelators depleted copper in the high-speed supernatants. BC alone had no significant effect upon zinc levels in the soluble fraction. BC extraction of brain tissue from C100 transgenic mice (which express human Abeta but do not develop amyloid) revealed SDS-resistant dimers as Abeta was mobilized from the sedimentable to the soluble fraction. NMR analysis showed that, in addition to its copper chelating properties, BC interacts with Abeta to form a complex independent of the presence of copper. Such hybrid copper chelating and "chain breaking" properties may form the basis of a rational design for a therapy for Alzheimer's disease.

Alzheimer Disease↗
PubMed2000

Accumulation of insoluble alpha-synuclein in dementia with Lewy bodies.

The alpha-synuclein (alpha SN) protein is thought to play a central role in the pathogenesis of neurodegenerative diseases where it aggregates to form intracellular inclusions. We have used Western blotting to examine the expression levels and solubility of alpha SN in brain homogenates from dementia with Lewy bodies (DLB), Parkinson's disease (PD), Alzheimer's disease (AD), and normal controls using samples from the parahippocampus/transentorhinal cortex. Compared to controls, DLB brains accumulate significantly greater amounts of sodium dodecyl sulfate (SDS)-soluble and SDS-insoluble alpha SN but levels of TBS-soluble alpha SN did not change. Levels of synaptophysin, a marker of synaptic integrity, were significantly lower in DLB cases than in normal aged controls regardless of whether concurrent changes of AD were present. This limbic synaptic dysfunction may contribute to cognitive impairment in DLB. Whether aggregated alpha SN is a cause or effect of the disease process in DLB and PD remains to be determined, but the presence of aggregated alpha SN is consistent with a pathogenesis similar to that associated with aggregates of Abeta amyloid in AD.

Aged↗