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Biomedical subjects

J F Fleming

Publications and source records attributed to J F Fleming.

At least 19 recordsLinked to original sources
PubMed1999

Chinese hamster ovary cells require the coexpression of microsomal triglyceride transfer protein and cholesterol 7alpha-hydroxylase for the assembly and secretion of apolipoprotein B-containing lipoproteins.

Due to the absence of microsomal triglyceride transfer protein (MTP), Chinese hamster ovary (CHO) cells lack the ability to translocate apoB into the lumen of the endoplasmic reticulum, causing apoB to be rapidly degraded by an N-acetyl-leucyl-leucyl-norleucinal-inhibitable process. The goal of this study was to examine if expression of MTP, whose genetic deletion is responsible for the human recessive disorder abetalipoproteinemia, would recapitulate the lipoprotein assembly pathway in CHO cells. Unexpectedly, expression of MTP mRNA and protein in CHO cells did not allow apoB-containing lipoproteins to be assembled and secreted by CHO cells expressing apoB53. Although expression of MTP in cells allowed apoB to completely enter the endoplasmic reticulum, it was degraded by a proteolytic process that was inhibited by dithiothreitol (1 mM) and chloroquine (100 microM), but resistant to N-acetyl-leucyl-leucyl-norleucinal. In marked contrast, coexpression of the liver-specific gene product cholesterol 7alpha-hydroxylase with MTP resulted in levels of MTP lipid transfer activity that were similar to those in mouse liver and allowed intact apoB53 to be secreted as a lipoprotein particle. These data suggest that, although MTP-facilitated lipid transport is not required for apoB translocation, it is required for the secretion of apoB-containing lipoproteins. We propose that, in CHO cells, MTP plays two roles in the assembly and secretion of apoB-containing lipoproteins: 1) it acts as a chaperone that facilitates apoB53 translocation, and 2) its lipid transfer activity allows apoB-containing lipoproteins to be assembled and secreted. Our results suggest that the phenotype of the cell (e.g. expression of cholesterol 7alpha-hydroxylase by the liver) may profoundly influence the metabolic relationships determining how apoB is processed into lipoproteins and/or degraded.

Animals↗
PubMed1999

Translocation-arrested apolipoprotein B evades proteasome degradation via a sterol-sensitive block in ubiquitin conjugation.

In this study, we explored how sterol metabolism altered by the expression of cholesterol-7alpha-hydroxylase NADPH:oxygen oxidoreductase (7alpha-hydroxylase) affects the ubiquitin-dependent proteasome degradation of translocation-arrested apoB53 in Chinese hamster ovary cells. Stable expression of two different plasmids that encode either rat or human 7alpha-hydroxylase inhibited the ubiquitin conjugation of apoB and its subsequent degradation by the proteasome. Oxysterols (25-hydroxycholesterol and 7-ketocholesterol) reversed the inhibition of apoB degradation caused by 7alpha-hydroxylase. The combined results suggest that the normally rapid proteasome degradation of translocation-arrested apoB can be regulated by a sterol-sensitive polyubiquitin conjugation step in the endoplasmic reticulum. Blocked ubiquitin-dependent proteasome degradation caused translocation-arrested apoB to become sequestered in segregated membrane domains. Our results described for the first time a novel mechanism through which the "quality control" proteasome endoplasmic reticulum degradative pathway of translocation-arrested apoB is linked to sterol metabolism. Sterol-sensitive blocked ubiquitin conjugation appears to selectively inhibit the proteasome degradation of apoB, but not 7alpha-hydroxylase protein, with no impairment of cell vitality or function. Our findings may help to explain why the hepatic production of lipoproteins is increased when familial hypertriglyceridemic patients are treated with drugs that activate 7alpha-hydroxylase (e.g. bile acid-binding resins).

Animals↗
PubMed1998

Ninety-degree rotation of the thoracic spinal thecal sac. Case report.

This 44-year-old man presented with a 4-year history of progressive spastic weakness of his legs. He was found to have epidural lipomatosis behind the thoracic spinal cord, and the nerve roots exited from the posterior and anterior midline planes of the dura, indicating a 90 degree rotation of the thoracic cord. Magnetic resonance images clearly demonstrated the segmental thoracic nerve roots exiting from the dorsal midline of the dura, a finding confirmed at surgery. The authors found only one previously published case of rotation of the spinal cord. Directed mechanical stress caused by deformation of the rotated spinal cord, rather than compression from adipose tissue, is proposed as the mechanism of the myelopathy. The extent, location, and thickness of the associated extradural adipose tissue is suggestive of epidural lipomatosis. The lipomatous tissue might have been an epiphenomenon and cord rotation an isolated congenital anomaly. Alternatively, asymmetrical growth of epidural fat may have exerted torque, rotating the thecal sac.

Adipose Tissue↗
PubMed1993

Amyloid destructive spondyloarthropathy causing cord compression: related to chronic renal failure and dialysis.

Destructive spondyloarthropathy is a recently recognized disease that has not been reported in the neurosurgical literature. It is associated with spinal amyloid deposition in long-term renal failure and dialysis, and it occurs increasingly as the number of dialysis patients and their survival times increase. Clinically, there is a multisegmental and often rapidly progressive radiculomyelopathy that may require emergency stabilization. The radiological features are disc space narrowing with erosion of vertebral end plates and subarticular cysts. The pathological features include deposition of amyloid, which stains with Congo Red and antibodies to beta-2-microglobulin. We present two cases with clinical, radiological, and pathological features and a review of the literature.

Aged↗
PubMed1993

Corneal asphericity and visual function after radial keratotomy.

Corneal asphericity was measured before and after surgery in 81 radial keratotomy eyes. Asphericity was calculated between keratoscope rings 2 and 9, representing corneal diameters of 2.3 mm and 7.6 mm. Statistical methods were used to assess the relationship between postoperative asphericity and undilated, uncorrected visual acuity. Smaller radial keratotomy clear zones resulted in greater negative asphericity after surgery (R = 0.74, p < 0.0001). For eyes with smaller clear zones of < 4.0 mm, postoperative negative asphericity was high (mean -6.44). Eyes in this smaller clear zone range had better uncorrected visual acuity if they possessed higher levels of negative asphericity (Mann-Whitney U test, p < 0.0001). The study suggests that eyes with smaller clear zones gain a beneficial increase in depth of field as the degree of negative asphericity increases. The study offers this as one reason that radial keratotomy patients with residual refractive error often have better uncorrected visual acuity than expected.

Adult↗
PubMed1987

Significance of hemorrhage into brain tumors: clinicopathological study.

A retrospective clinical and pathological review of 905 consecutive brain tumor cases (excluding pituitary adenoma and recurrent tumor) was conducted to identify cases in which intratumoral hemorrhage was confirmed grossly and/or pathologically. There were 132 cases so identified, for an overall tumor hemorrhage rate of 14.6%; of these, 5.4% were classified as macroscopic and 9.2% as microscopic. The presence of hemorrhage was correlated with the neurological presentation. The highest hemorrhage rate (70.0%) was found in patients with prior neurological history who experienced apoplectic deterioration (acute-on-chronic presentation). Only 57.1% of patients with acute deterioration in the absence of prior neurological symptoms had hemorrhages. The highest hemorrhage rate for primary brain tumors was 29.2% for mixed oligodendroglioma/astrocytoma, while the highest hemorrhage rate for any tumor type was 50% for metastatic melanoma. The clinical relevance of tumor hemorrhage is discussed.

Brain Neoplasms↗
PubMed1986

Chiari malformation in adults: a review of 40 cases.

Forty adult patients (average age 40 years), with the clinical and radiological features of the Chiari malformations, were seen at the Toronto Western Hospital between 1967 and 1984. Surgical confirmation of the diagnosis was obtained in 32 cases; of these, 23 were classified as Chiari I malformation while 9 fulfilled the anatomic criteria of Chiari II. The patient population consisted of 22 males and 18 females. Common presenting symptoms included head and neck pain (60%), sensory complaints (60%), upper extremity weakness (42%), and gait disturbance (40%). Neurological findings included signs of central cord dysfunction (73%), long-tract motor and/or sensory findings (58%), brainstem signs (38%), cerebellar dysfunction (18%), and increased intracranial pressure (15%). The majority of patients underwent myelography with or without computed tomography of the cervical-medullary junction. Two recent patients had 0.15T MRI scans which helped demonstrate an intramedullary syrinx. Thirty-three patients underwent 47 operative procedures (discounting spinal fusion and CSF shunt revisions). Open surgical management was performed in 32 patients, with CSF shunting along in one patient. Five patients (15%) incurred surgical complications within a six week postoperative period. Follow-up to date, ranges from one month to 11 years. In the 33 surgically treated patients, 18 are improved (55%), 10 are neurologically stable (30%), and five have worsened clinically (15%), including one death. Based on this study it appears that the Chiari II malformation may be more common in adults than previously recognized. Surgical intervention has a favourable outcome in the majority of patients but a significant proportion continue to deteriorate.

Adolescent↗
PubMed1985

Compressive optic neuropathy and ependymoma of the third ventricle.

Progressive monocular visual loss was the presenting manifestation of a cystic ependymoma arising from the third ventricle. Extracerebral extension of the tumor into the prechiasmatic cistern compressed the right optic nerve. Subfrontal extension caused erosion of the planum sphenoidale. Subtotal excision of the tumor was followed by cranial irradiation, and no further visual loss occurred. Extracerebral growth of primary intracerebral gliomas may cause optic neuropathy that is indistinguishable from other compressive neuropathies.

Adult↗
PubMed1984

Spontaneous arterial subdural hematoma.

the occurrence of spontaneous arterial subdural hematomas is very rare. We report five patients who presented with sudden severe headache and who developed progressive neurological deficits, two becoming comatose. None had a history of trauma. A diagnosis of subarachnoid hemorrhage was suspected in all patients, but all proved to have subdural hematomas caused by "spontaneous" rupture of a cortical artery. Nineteen similar cases have been reported in the English literature. The source of bleeding was identified as a cortical artery located near the sylvian region in four of our five patients and in most of the reported cases. There are several possible anatomical situations that may predispose a cortical artery to "spontaneous" rupture: (a) spontaneous rupture of a cortical artery at the point of origin of a fragile arterial twig, especially a right-angled branch, a point of potential weakness; (b) rupture of a small artery traversing the subdural space and connecting a cortical artery to the dura mater (a "bridging" artery); (c) adhesions between a cortical artery and arachnoid or dura mater; (d) a knuckle of cortical artery protruding through the arachnoid and adherent to the dura mater. In each situation, the artery is probably torn by a sudden movement of the brain during a vigorous head movement, not severe enough to be considered trauma.

Adult↗
PubMed1984

Cerebral hyperperfusion after carotid endarterectomy: a cause of cerebral hemorrhage.

Correction of a very high grade carotid stenosis by endarterectomy in a normotensive man was followed by the development of severe unilateral head, eye, and face pain, seizures, and on the 6th day a fatal intracerebral hemorrhage. Autopsy revealed changes in the cerebral hemisphere ipsilateral to the endarterectomy that resembled the changes seen in malignant hypertension, whereas the opposite hemisphere was normal. These changes included hypercellularity and edema of arterial and arteriolar walls, with necrosis, extravasation of erythrocytes, and exudation of fibrin. We propose that the clinical and pathological features in this case were due to relative hyperperfusion of a cerebral hemisphere in which autoregulation had been impaired because of preoperative chronic hypoperfusion with chronic maximal dilatation of its blood vessels. This state of relative hyperperfusion is probably similar to the normal perfusion pressure breakthrough that occasionally occurs after the resection of cerebral arteriovenous malformations. It is similar to the breakthrough perfusion that occurs in severely hypertensive patients and results in hypertensive encephalopathy.

Arterioles↗
PubMed1982

Thiazolidine-4-carboxylic acid, a physiologic sulfhydryl antioxidant with potential value in geriatric medicine.

Thiazolidine-4-carboxylic acid (TC) is a cyclic sulfur amino acid, a condensation product of cysteine and formaldehyde. The chemistry, biological effects and clinical use of TC are reviewed. Extensive animal experiments and studies on human subjects carried out in Europe indicate that a combination of TC and folic acid, 'Folcysteine', has revitalizing effects on age-related biochemical variables of blood and tissues. Further animal studies confirmed the anti-toxic effects of TC, particularly on the liver. The evidence accumulated so far suggests that addition of TC to the diet slows the aging process in mammals and prolongs their life span. On the other hand, findings suggesting that TC caused reverse transformation of tumor cells into normal cells and was effective against human cancers could not be confirmed in additional studies. TC has been clinically used for about 20 yr, mainly in the treatment of liver diseases and related gastrointestinal disturbances. Derivatives of TC with similar applications have been developed. Djenkolic acid is a naturally occurring relative of TC which is abundant in djenkol beans. The toxic effects of djenkolic acid and its possible conversion into TC are discussed.

Aged↗
PubMed1970

A new look at bimedial prefrontal leukotomy.

Forty-four selected patients with "hard core" functional psychiatric illness were treated by bimedial prefrontal leukotomy, in which only the medial half of the prefrontal white matter of both frontal lobes was divided. This operation differs from the conventional or "standard" leukotomy which divides the entire prefrontal white matter. There were six patients with personality disorders, 25 psychoneurotics, 12 schizophrenics, and one with involutional melancholia. Forty-two of the 44 patients had thorough psychiatric follow-up, ranging from one to seven years postoperatively. They were assessed clinically and also on a point-rating scale of assessment.Seventy-six per cent of these patients had excellent or satisfactory outcomes. The most striking benefit was decrease in anxiety and tension.Modified leukotomy is a safe and effective method of reducing the symptoms of excessive tension, anxiety, fear or depression in patients with a variety of illnesses, including anxiety neurosis, phobic psychoneurosis, obsessional neurosis, neurotic or psychotic depressive reactions and schizophrenia. The operation should be considered in such neurotic, personality and psychotic illnesses when medical treatment has failed.

Adult↗