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Biomedical subjects

D A Cottrell

Publications and source records attributed to D A Cottrell.

At least 19 recordsLinked to original sources
PubMed2002

The role of cytochrome c oxidase deficient hippocampal neurones in Alzheimer's disease.

Defects of mitochondrial function have been proposed as a potential mechanism in the development and pathogenesis of Alzheimer's disease (AD) and neuronal apoptosis. Mitochondrial enzyme-deficient pyramidal neurones are found in greater quantities in the hippocampus of AD patients than in age-matched controls. The presence of these neurones indicates that high levels of mutant mtDNA (mitochondrial DNA), sufficient to cause a biochemical deficiency within individual neurones, occur more frequently in AD than in normal ageing. This study analyses the relationship of cytochrome c oxidase (COX)-deficient neurones with the neuropathological markers of AD, neurofibrillary tangles (NFTs) and amyloid plaques, as well as markers of neuronal apoptosis known to occur in AD brains. Frozen sections of hippocampi from three AD patients were used to directly colocalize in situ the presence of histochemically COX-deficient neurones with immunohistology for the classical neuropathological markers of AD, tau and beta-amyloid. In addition, we also directly colocalized these mitochondrial-enzyme deficient neurones using terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling and cleaved caspase-3. The distribution of amyloid plaques is anatomically distinct from the COX-deficient hippocampal pyramidal neurones and the neurones that contained NFTs or apoptotic labelling were always COX-positive. COX-deficient, succinate dehydrogenase-positive hippocampal neurones indicative of high mtDNA mutation load do not appear to be prone to apoptosis or to directly participate in the over production of tau or beta-amyloid. Biochemically significant mitochondrial defects do occur in AD and are likely to contribute to the overall central nervous system dysfunction in impairing neuronal function and possibly causing neurodegeneration via mechanisms other than apoptosis.

Aged↗
PubMed2001

Mitochondrial enzyme-deficient hippocampal neurons and choroidal cells in AD.

OBJECTIVE: To determine whether hippocampal neurons and choroidal epithelial cells demonstrate a mitochondrial enzyme deficiency in AD more frequently than in normal aging. BACKGROUND: High levels of mutant mitochondrial DNA (mtDNA) cause a deficiency in cytochrome c oxidase (COX) (complex IV activity) because three of its 13 subunits are encoded for by mtDNA. In contrast, succinate dehydrogenase (SDH) (complex II activity) remains intact because all of its subunits are nuclear encoded. The histologic hallmark of cells containing high levels of mtDNA mutation in both primary mtDNA disorders and normal aging muscle is the presence of COX-deficient SDH-positive cells. METHODS: The authors applied a sequential histochemical method for COX and SDH to hippocampal sections in 17 AD and 17 age-matched control brains. This confers the advantages of both looking at individual cells in situ and measuring the actual mitochondrial complex activity rather than simply the complex quantity. RESULTS: COX-deficient SDH-positive hippocampal neurons and choroidal epithelial cells are more prevalent in patients with AD than in controls. In addition the COX-deficient SDH-positive choroidal cells are associated with an enlargement in size. CONCLUSION: This increase in number of COX-deficient SDH-positive hippocampal pyramidal neurons and choroid epithelial cells provides strong evidence that a substantial mitochondrial enzyme activity defect occurs in individual cells more frequently in AD than in normal aging and that mitochondria may play a significant role in the pathogenesis of AD.

Aged↗
PubMed2001

Mitochondrial DNA mutations in disease and ageing.

The chronological accumulation of mitochondrial DNA mutations has been proposed as a potential mechanism in the physiological processes of ageing and age-related disease. We discuss the evidence behind this theory and relate some of the ageing mitochondrial changes to mitochondrial DNA disorders. In particular, we describe the aggregation of cytochrome c oxidase-deficient cells in both skeletal muscle and the CNS in normal ageing as seen in the mitochondrial DNA disorders. These mitochondrial enzyme-deficient cells have been shown to occur in significant quantities in both muscle and CNS in patients with mitochondrial DNA disorders. In both ageing and mtDNA disorder muscle these cytochrome c-deficient fibres contain high levels of a single mutant strain of mitochondrial DNA. Whether these mutations are a primary or secondary event in the physiology of ageing remains to be determined.

Aging↗
PubMed2001

Accelerated ageing changes in the choroid plexus of a case with multiple mitochondrial DNA deletions.

Mitochondrial abnormalities, in particular the accumulation of mitochondrial DNA mutations, have been proposed as a potential cause of normal ageing. One group of patients with mtDNA disorders have a nuclear DNA defect which accelerates the chronological accumulation of mitochondrial DNA mutations. These patients provide an ideal means of investigating whether accelerated mitochondrial DNA defects can cause accelerated ageing pathology. The choroid plexus demonstrates a robust accumulation of pathological changes, in the form of Biondi bodies, with normal ageing. We have therefore examined the choroid plexus of a case with multiple mitochondrial DNA deletions for evidence of accelerated ageing and compared it with two cases with point mutation mitochondrial DNA disorders and several age-matched and elderly controls with and without clinical and neuropathological evidence of neurodegenerative disease. We also demonstrate that the choroid plexus of the mitochondrial DNA cases contain cells with levels of mitochondrial DNA mutation sufficient to cause a biochemical deficiency in the oxidative phosphorylation pathway. As previously reported, both cases with point mutation mitochondrial DNA disorders exhibit a characteristic oncocytic type transformation of the choroidal epithelial cells. However, in the case with multiple mitochondrial DNA deletions we demonstrate pathological changes in choroid plexus that are strongly suggestive of accelerated ageing. We believe that this finding supports the theory that the accumulation of mitochondrial DNA mutations can lead to pathological changes typical of ageing cells.

Adult↗
PubMed2001

Eagle's syndrome: a report of 4 patients treated using a modified extraoral approach.

PURPOSE: This study evaluated a slightly modified extraoral approach to removing the symptomatic elongated styloid process. A brief description of this surgical technique and its comparison to the intraoral approach is provided. PATIENTS AND METHODS: Four patients in whom an extraoral approach was used to expose and remove the elongated calcified stylohyoid complex were evaluated. Five sides were treated and reviewed individually. All patients were interviewed preoperatively and postoperatively, and their records were thoroughly examined. Patients were objectively evaluated for pain, function, sensory and motor nerve deficits, and aesthetics. RESULTS: Follow-up time ranged from 6 to 39 months with an average of 21 months. Improvement in the original symptoms was reported for 4 of the 5 operated sides. Three of 5 procedures resulted in more than an 80% reduction in pain and improvement in function. All patients had a satisfactory cosmetic result and no paresthesia. CONCLUSIONS: The advantages of the extraoral approach are reflected in this small retrospective study by the absence of perioperative complications and the minimal blood loss, surgical morbidity, and hospital stay.

Adult↗
PubMed2000

Management of heparin therapy in the high-risk, chronically anticoagulated, oral surgery patient: a review and a proposed nomogram.

PURPOSE: This study analyzes the use of a standard nomogram that can help reduce the level of anticoagulation preoperatively to effectively manage perioperative heparin therapy in chronically anticoagulated oral surgery patients who are at high risk for thromboembolism. PATIENTS AND METHODS: Twenty patients with significant cardiovascular disease, ranging in age from 56 to 79 years and requiring oral surgery, were randomly divided into 2 groups. All patients were on chronic warfarin therapy, and perioperative heparinization was recommended by their cardiologist. Group A (n = 10) had their anticoagulation therapy managed with the use of a standard nomogram. The heparin therapy for group B (n = 10) was managed without the use of the nomogram. The records of all patients were analyzed for therapeutic efficacy of heparinization, number of laboratory tests required, duration of hospitalization, and complications related to heparinization. RESULTS: Patients in group A did significantly better in all parameters when compared with group B patients. There were no complications in group A, whereas there was a 20% incidence of complications related to anticoagulation therapy in group B. CONCLUSIONS: The use of a standard nomogram to manage anticoagulation therapy in the oral surgery patient requiring heparinization is strongly recommended. This provides optimal therapeutic benefit, decreases the incidence of complications, and makes the hospitalization less costly and more comfortable for the patient.

Anticoagulants↗
PubMed2000

Neuropathological and histochemical changes in a multiple mitochondrial DNA deletion disorder.

The identification of cytochrome c oxidase (COX)-deficient/succinate dehydrogenase (SDH)- positive cells using sequential histochemistry has proved important in the identification of cells with high mitochondrial DNA (mtDNA) mutant load. We demonstrate large numbers of COX-deficient/SDH-positive neurons in a mosaic pattern throughout the CNS of a patient with a multiple mtDNA deletion disorder. This patient had prominent central and peripheral nervous system involvement with marked cerebellar ataxia, a parkinsonian extra-pyramidal movement disorder, external ophthalmoplegia, dysphagia, and a severe peripheral neuropathy. There was degeneration of myelin tracts in the cerebellum and dorsal spinal columns, diffuse astrocytosis, and selective neuronal degeneration particularly in the midbrain and cerebral microvacuolation. The proportional distribution of the COX-deficient neurons did not always correlate directly with the degree of neuropathological damage with regions of high neuronal loss having relatively low proportions of these cells. Other clinically affected CNS regions have high levels of COX-deficient neurons without significant cell loss. The role of these COX-deficient neurons in causing neuronal degeneration and clinical symptoms is discussed.

Adult↗
PubMed2000

Mitochondria and ageing.

Mitochondria have long been proposed as a perpetrator of aging. We review here the accumulating evidence for chronological alterations in the mitochondrion and discuss how these changes may cause cellular dysfunction and death. We conclude that although the evidence for aging changes in the level of oxidative stress, DNA mutations and biochemical deficiencies in mitochondria are convincing, there is little experimental evidence to link these changes directly with the cellular pathology of aging. Promising avenues for addressing this problem include the investigation of established mitochondrial DNA disorders and the development of animal models with mitochondrial defects.

Aging↗
PubMed2000

Role of mitochondrial DNA mutations in disease and aging.

Since Harman in 1972 first proposed a role in the process of aging for the mitochondrial genome, a wealth of evidence has been accumulated to support this theory. We discuss the hereditary mitochondrial DNA disorders, which we believe may give insight into both normal aging and neurodegenerative conditions. We then review the evidence for the role of mitochondrial DNA mutations in both aging and age-related disorders and also discuss new approaches for investigating the mitochondrial genome at a single cell level, by observing the activity of the mitochondrial enzyme cytochrome c oxidase.

Aging↗
PubMed1999

The natural history of multiple sclerosis: a geographically based study. 5. The clinical features and natural history of primary progressive multiple sclerosis.

We report a natural history study of 216 patients with primary progressive (PP)- multiple sclerosis defined by at least 1 year of exacerbation-free progression at onset. This represents 19.8% of a largely population-based patient cohort having a mean longitudinal follow-up of 23 years. This subgroup of PP-multiple sclerosis patients had a mean age of onset of 38.5 years, with females predominating by a ratio of 1.3:1.0. The rate of deterioration from disease onset was substantially more rapid than for relapsing-remitting multiple sclerosis, with a median time to disability status score (DSS) 6 and DSS 8 of 8 and 18 years, respectively. Forty-nine percent of patients were followed through to death. Examination of the early disease course revealed two groups with adverse prognostic profiles. Firstly, a shorter time to reach DSS 3 from onset of PP-multiple sclerosis significantly adversely influenced time to DSS 8. Second, involvement of three or more neurological systems at onset resulted in a median time to DSS 10 of 13.5 years in contrast to PP-multiple sclerosis patients with one system involved at onset where median time to death from multiple sclerosis was 33.2 years. However, age, gender and type of neurological system involved at onset appeared to have little influence on prognosis. Life expectancy, cause of mortality and familial history profile were similar in PP-multiple sclerosis and non-PP-multiple sclerosis (all other multiple sclerosis patients from the total population). From clinical onset, rate of progression was faster in the PP-multiple sclerosis group than in the secondary progressive (SP)-multiple sclerosis group. When the rates of progression from onset of the progressive phase to DSS 6, 8 and 10 were compared, SP-multiple sclerosis had a more rapid progressive phase. A substantial minority (28%) of the PP-multiple sclerosis cohort had a distinct relapse even decades after onset of progressive deterioration. These studies establish natural history outcomes for the subgroup of multiple sclerosis patients with primary progressive disease.

Adult↗
PubMed1999

The natural history of multiple sclerosis: a geographically based study. 6. Applications to planning and interpretation of clinical therapeutic trials in primary progressive multiple sclerosis.

The natural history of primary progressive multiple sclerosis (PP-multiple sclerosis) recently has been defined in a geographically based multiple sclerosis population. For a series of prognostically defined hypothetical entry criteria based upon current trends in presentation to the London Multiple Sclerosis Clinic, we determined the number of patients who would have been trial eligible. Using 23 year mean longitudinal natural history data, we identified the observed rate of deterioration for frequently used trial endpoints. Hypothetical entry criteria were based on the practical considerations which would attend the execution of clinical trials in progressive multiple sclerosis. We then developed a series of sample size tables giving the number of patients with PP-multiple sclerosis and the length of observation that would be required to detect a significant result (P = 0.05) for a 25, 50 and 75% decrease in the median time to progression with 80 or 90% power, with treatment efficacy based upon the ability to slow progression on the disability status score. It is expected that the considerations outlined here will prove useful for both trial design and interpretation of trials in PP-multiple sclerosis which will require multi-centre collaborative efforts.

Adult↗
PubMed1998

Long-term evaluation of the use of coralline hydroxyapatite in orthognathic surgery.

PURPOSE: This prospective study was designed to evaluate the long-term clinical and radiographic results of porous block hydroxyapatite (PBHA) used as a synthetic bone graft in orthognathic surgery and craniofacial augmentation. PATIENTS AND MATERIALS: A total of 245 consecutive patients were treated initially. Inclusion criteria for this study included a minimum clinical and radiographic follow-up of 5 years. In addition, all patients with known implant failures were included regardless of whether they met the study criteria. There were 111 patients that met the criteria for inclusion in this study. All patients had undergone orthognathic surgery with rigid fixation and had had inlay or onlay PBHA implants placed. Ninety-six percent of the implants were placed through an intraoral approach. Long-term postoperative radiographs were visually compared with immediate postoperative radiographs for implant position, stability, resorption, and other significant radiographic changes. The clinical examination evaluated for signs and symptoms of infection, wound dehiscence, implant exposure, implant displacement, changes in the overlying mucosa, and development of oronasal or oroantral fistulae. RESULTS: Four hundred seventy-one implants were placed: 403 in the maxilla, 44 in the mandible, and 24 in the periorbital region. There were 289 implants placed in direct communication with the maxillary sinus. The average follow-up time was 7.2 years (range, 5.0 to 10.3 years). Twenty-three implants (4.9%) were removed during the evaluation period. Lateral maxillary wall grafting had 95.7% success, with nine implants being lost in three patients. One chin implant was removed because of dissatisfaction with the aesthetics. Seven (14%) midpalatal implants used for maxillary expansion were lost, primarily because of exposure of the implant to the oral or nasal cavity at the time of surgery. When PBHA was used for alveolar cleft grafting, there was a 100% failure rate. CONCLUSION: The use of PBHA as a bone graft substitute in orthognathic surgery and for facial augmentation showed a high percentage of success and efficacy. However, adequate soft tissue coverage in the nasal floor and on the palate are paramount for success of midpalatal implants. PBHA should not be used for alveolar cleft grafting. Rigid fixation for inlay implants in the maxilla is important to provide stress shielding of the material and minimize micromovement during the initial healing phase.

Adolescent↗