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Biomedical subjects

J P Phillips

Publications and source records attributed to J P Phillips.

At least 37 records · Page 2Linked to original sources
PubMed1998

Spontaneous spinal epidural hematoma in children.

Spontaneous spinal epidural hematoma is rare in children. It is usually confined to the dorsal epidural space. Ventral spontaneous spinal epidural hematoma (SSEH) is rarer, with only two previous reports. The authors present three children, two with dorsal and one with ventral spinal epidural hematoma, and review the literature. No etiology of the hematoma was found in the authors' patients and there was no history of trauma. A review of 24 patients of children younger than 18 years of age reported in the literature and the authors' three patients revealed that the cervicothoracic region was the most common site of SSEH, the mode of onset was frequently subacute, and there was no male preponderance as has been reported in adults. We found that the initial symptoms were often nonspecific, leading to a delay in diagnosis, especially in younger children. Follow-up data revealed that 15 of the 27 patients recovered completely, 11 had residual neurologic deficits, and one patient died. Irritability and neck pain with restricted movements of the cervical spine in an afebrile child may be early signs of SSEH and often precede onset of neurologic deficits by several hours to days. These signs should alert the clinician to consider spinal epidural hematoma and the need for urgent magnetic resonance imaging (MRI) of the spine for early diagnosis and treatment to minimize morbidity.

Child, Preschool↗
PubMed1998

Extension of Drosophila lifespan by overexpression of human SOD1 in motorneurons.

Reactive oxygen (RO) has been identified as an important effector in ageing and lifespan determination. The specific cell types, however, in which oxidative damage acts to limit lifespan of the whole organism have not been explicitly identified. The association between mutations in the gene encoding the oxygen radical metabolizing enzyme CuZn superoxide dismutase (SOD1) and loss of motorneurons in the brain and spinal cord that occurs in the life-shortening paralytic disease, Familial Amyotrophic Lateral Sclerosis (FALS; ref. 4), suggests that chronic and unrepaired oxidative damage occurring specifically in motor neurons could be a critical causative factor in ageing. To test this hypothesis, we generated transgenic Drosophila which express human SOD1 specifically in adult motorneurons. We show that overexpression of a single gene, SOD1, in a single cell type, the motorneuron, extends normal lifespan by up to 40% and rescues the lifespan of a short-lived Sod null mutant. Elevated resistance to oxidative stress suggests that the lifespan extension observed in these flies is due to enhanced RO metabolism. These results show that SOD activity in motorneurons is an important factor in ageing and lifespan determination in Drosophila.

Aging↗
PubMed1998

Transgenic analysis of the cSOD-null phenotypic syndrome in Drosophila.

Cu-Zn superoxide dismutase (cSOD) is an enzyme of critical importance for the inactivation of superoxide radicals generated by cellular metabolic processes. A phenotypic syndrome has been characterized for homozygotes for a null mutation of the Drosophila cSOD gene, many features of which may be relevant to current studies of cSOD mutations in mammals. However, it was possible that some of the features of this syndrome were at least partially attributable to genetic background differences between control and mutant strains. The results reported in this paper document that the previously described features of the cSOD-null phenotype, namely (i) adult sensitivity to paraquat, (ii) male sterility, (iii) female semisterility, (iv) adult life-span reduction, (v) adult hyperoxia sensitivity, (vi) larval radiation sensitivity, and (vii) developmental sensitivity to glutathione depletion, are all rescued by a cSOD+ transgene in a controlled cSOD-null genetic background. This clearly confirms that the phenotype is largely attributable to the cSOD mutation per se. We describe two new features of the cSOD-null phenotype, namely (viii) adult sensitivity to glutathione depletion, and (ix) adult sensitivity to ionizing radiation, which are ameliorated by the cSOD+ transgene. The distinct sensitivity of cSOD-deficient individuals, and the uniform resistance of the cSOD+ control strains, clearly establish the requirement for cSOD in protection against intrinsic and applied oxygen stress and set the stage for tissue-specific expression studies with the goal of elucidating the critical target(s) of damage in cSOD-deficient animals.

Animals↗
PubMed1997

Expression of a bacterial endo (1-4)-beta-glucanase gene in mammalian cells and post translational modification of the gene product.

An endo (1-4)-beta-glucanase gene C6.5 from Bacillus subtilis has been expressed in Chinese hamster ovary (CHO) cells and pancreatic 266-6 cells. The fusion gene, stably transfected into CHO cells consisted of the mouse Amy-2.2 signal peptide coding sequence and the endoglucanase gene C6.5 transcribed from the early SV40 promoter/enhancer, using the dihydrofolate reductase gene as a selective marker. The gene construct transfected into pancreatic 266-6 cells consisted of the mouse Amy-2.2 promoter/enhancer and signal peptide coding sequence and the same C6.5 sequences using the xanthine-guanine phosphoribosyl transferase gene (gpt) as the selective marker. The stably transfected CHO cells synthesized endoglucanase at 1.1 U/mg cell protein in a 72 h culture, with 89% of the activity secreted into the culture fluid in a glycosylated form of 66 kDa as compared with the unglycosylated 53 kDa form expressed in E. coli. Glycosylation did not change the specific activity, protease resistance, or cellulose binding of the endoglucanase as compared to the unglycosylated form of the enzyme from E. coli. The level of expression in the stably transfected pancreatic cells was substantially lower at 0.3 mU/mg cell protein with all detectable activity present in the culture fluid. The secreted enzyme from pancreatic cells was glycosylated with a mass similar to that secreted from CHO cells.

Amino Acid Sequence↗
PubMed1997

Acute motor axonal neuropathy in childhood: clinical and MRI findings.

Clinical and radiologic findings in a child with acute motor axonal neuropathy are reported. A 16-year-old boy with mild cerebral palsy presented 1 week after an upper respiratory tract infection with low back pain, ascending weakness, and areflexia. Cerebrospinal fluid (CSF) examination revealed albuminocytological dissociation. Serial electromyograms (EMGs) with nerve conduction velocity (NCV) studies revealed findings of motor axonal neuropathy. Spine MRI revealed enhancement of the cauda equina. Acute motor axonal neuropathy (AMAN) may be an underrecognized cause of acute flaccid paralysis, and to our knowledge no pediatric cases have been reported in the United States. MRI findings have not been reported previously.

Adolescent↗
PubMed1997

The manganese superoxide dismutase gene of Drosophila: structure, expression, and evidence for regulation by MAP kinase.

The gene encoding manganese superoxide dismutase (MnSOD) from Drosophila melanogaster has been isolated and its expression has been studied. In contrast to several mammalian MnSOD genes, the Drosophila gene contains a single intron and is transcribed into a single 0.8-kb transcript. Whole-mount in situ hybridization reveals extensive transcript accumulation in ovarian nurse cells and a heavy maternal contribution to the early embryo. Larval imaginal discs are enriched with MnSOD transcripts relative to other larval tissues, further suggesting a possible relationship between high MnSOD expression and mitotic activity. The 5'-upstream region contains several well-known regulatory elements including metal response, antioxidant response, and xenobiotic response elements (MRE, ARE, and XRE, respectively), sites for activator protein-1 (AP-1), nuclear factor-kappaB (NF-kappaB), adenosine 3',5'-cyclic monophosphate regulator binding element factor (CREB), as well as classic TATA and CAAT boxes. That MnSOD expression in Drosophila is regulated in part by the transcription factor AP-1 via the MAP kinase signal transduction pathway is suggested by experiments which show that a hypomorphic mutation of the MAP kinase-encoding rolled gene substantially reduces levels of MnSOD transcripts and correlates with reduced resistance to oxidative stress in rolled mutants.

Animals↗
PubMed1997

Targeted overexpression of Cu/Zn superoxide dismutase protects pancreatic beta-cells against oxidative stress.

Current evidence suggests that reactive oxygen species (ROS) may participate in the destruction of pancreatic beta-cells leading to type 1 diabetes. Genetic factors pre-disposing individual susceptibility to type 1 diabetes might therefore include those affecting the efficacy of ROS metabolism. In a direct in vivo test of this hypothesis, we have generated strains of mice carrying transgenes that supplement basal levels of the radical-scavenging enzyme Cu/Zn superoxide dismutase in the pancreas via directed expression in beta-cells. Expression of these transgenes significantly enhances resistance to alloxan-induced diabetogenesis above that of control animals, thereby providing direct in vivo evidence that genetic variation in ROS metabolism can affect susceptibility to oxidative stress-mediated diabetogenesis.

Animals↗
PubMed1996

A plasmid rescue to investigate mutagenesis in transgenic D. melanogaster.

We present a plasmid rescue from transgenic Drosophila to study spontaneous and mutagen-induced mutations in vivo. Transgenic Drosophila lines were established by transformation with a shuttle vector containing the bacterial lacZ gene as a target for mutagenesis. The target gene can be recovered into bacteria by restriction endonuclease treatment of total genomic DNA, followed by ligation of the recircularized shuttle vectors. The resulting circular plasmids are then transformed back into E. coli lacZ- mutants, where the activity of the lacZ genes is scored on the induction substrate X-Gal. The number of inactivated versus intact lacZ genes directly indicates the mutation frequency. By the described target gene rescue procedure up to 5000 lacZ gene copies can be rescued from one fly routinely. Spontaneous background mutation rates using this system are 2.6 +/- 0.6 x 10(-4). Treatment of larvae with ethylnitrosourea (ENU) resulted in a dose-dependent increase of the mutation frequency to 4.8 +/- 0.6 x 10(-4) for 0.5 mM and 6.9 +/- 1.2 x 10(-4) for 1 mM ENU, respectively.

Animals↗
PubMed1996

Hypoxic-ischemic encephalopathy in areas of primary myelination: a neuroimaging and PET study.

The stage of regional structural and biochemical development of the central nervous system appears as a critical factor determining the distribution of hypoxic-ischemic lesions during the perinatal period. We describe the brain lesions in 12 patients who suffered hypoxia-ischemia during the perinatal period. The gestational age ranged from 35 to 42 weeks and the age at death from 2 to 16 weeks. There is one patient alive at age 18 years and a second patient at age 1 year. The cerebral cortical damage is mainly restricted to areas of primary myelination and adjacent subcortical white matter. In addition, there is thalamic, basal ganglia, brainstem, and spinal cord damage. It is postulated that selective damage occurs in those areas which at the moment of the hypoxic-ischemic insult had achieved higher rates of oxygen-glucose utilization. This hypothesis is supported by studies utilizing positron emission tomography which indicates that glucose utilization in the normal human neonatal brain follows a phylogenetic order. Regions that achieved higher levels of glucose consumption are those that suffered the brunt of the damage in our term neonates.

Adolescent↗
PubMed1996

Progressive spasticity in an infant.

A 15-month-old girl with progressive spasticity presented for evaluation of cerebral palsy. Neurological examination revealed severe asymmetric spasticity with normal cranial nerves. Bayley developmental assessment showed a mental age of 12 months and a motor age of 9 months. Magnetic resonance imaging scan of the brain was normal, however a scan of the cervical spine showed an enhancing intramedullary lesion. Surgical exploration revealed an aneurysm which was successfully embolized. The differential diagnosis of cervical cord lesions in infants is discussed.

Brain↗
PubMed1996

Genetic analysis of oxygen defense mechanisms in Drosophila melanogaster and identification of a novel behavioural mutant with a Shaker phenotype.

Mutants of Drosophila melanogaster that lack Cu/Zn superoxide dismutase or urate are hypersensitive to reactive oxygen species (ROS) generated in vivo by the redox-cycling agent paraquat. We have subsequently employed paraquat as a selective agent to identify adult viable mutants potentially defective in other, perhaps unknown, components of ROS metabolism. Paraquat screening of ethyl methanesulfonate-induced second- and third-chromosome mutations yielded 24 paraquat hypersensitive mutants. Two mutants were identified as being new alleles of the previously identified doublesex (dsx) and pink (p) genes. The remainder of the mutations identified previously undescribed genes, including one second chromosome paraquat hypersensitive mutant that was found to exhibit shaking legs, abdomen pulsations, and body shuddering under ether anaesthesia. This recessive mutation was mapped to the polytene chromosome region of 48A5-48B2 and defines a new gene we named quiver (qvr). This mutation is similar in phenotype to the Shaker (Sh), ether-a-gogo (eag), and Hyperkinetic (Hk) mutations, all of which affect potassium channel function in D. melanogaster.

Animals↗
PubMed1995

Subunit-destabilizing mutations in Drosophila copper/zinc superoxide dismutase: neuropathology and a model of dimer dysequilibrium.

Mutations in Cu/Zn superoxide dismutase (SOD), a hallmark of familial amyotrophic lateral sclerosis (FALS) in humans, are shown here to confer striking neuropathology in Drosophila. Heterozygotes with one wild-type and one deleted SOD allele retain the expected 50% of normal activity for this dimeric enzyme. However, heterozygotes with one wild-type and one missense SOD allele show lesser SOD activities, ranging from 37% for a heterozygote carrying a missense mutation predicted from structural models to destabilize the dimer interface, to an average of 13% for several heterozygotes carrying missense mutations predicted to destabilize the subunit fold. Genetic and biochemical evidence suggests a model of dimer dysequilibrium whereby SOD activity in missense heterozygotes is reduced through entrapment of wild-type subunits into unstable or enzymatically inactive heterodimers. This dramatic impairment of the activity of wild-type subunits in vivo has implications for our understanding of FALS and for possible therapeutic strategies.

Amino Acid Sequence↗
PubMed1995

Intracranial metastases from pituitary adenoma.

Two patients with histologically benign pituitary adenomas subsequently underwent resections of a frontal and a cerebellar tumour each of which had histological appearances identical to those of classic pituitary adenomas. The frontal tumour was immunoreactive for prolactin, and the cerebellar metastasis was immunoreactive for thyrotropin and gonadotrophins. There was no evidence of residual or recurrent intrasellar pituitary adenoma, nor was there a connection between the frontal or cerebellar masses and the sella turcica. Extracranial tumours have not developed. Both tumours fulfil criteria for diagnosis of pituitary carcinoma. These rare tumours are reviewed with emphasis on diagnosis and management.

Adenoma↗
PubMed1994

Transgenic copper/zinc superoxide dismutase modulates susceptibility to type I diabetes.

A growing body of evidence suggests that active oxygen is an important participant in the destruction of the pancreatic beta cell, which, in turn, leads to type I or insulin-dependent diabetes mellitus. Consequently, genetic factors predisposing susceptibility to insulin-dependent diabetes mellitus may include those that determine active oxygen metabolism. A direct test of this hypothesis is provided by a transgenic model for increased activity of Cu/Zn superoxide dismutase (EC 1.15.1.1), a principal radical scavenging enzyme. Here we demonstrate that elevated levels of this enzyme provided by a Cu/Zn superoxide dismutase transgene enhance the tolerance of pancreatic beta cells to oxidative stress-induced diabetogenesis. These results show that this transgenic approach holds promise for revealing the role of reactive oxygen in autoimmune models of diabetogenesis as well as in other models of disease pathology in which active oxygen has been implicated.

Animals↗
PubMed1994

Subperiosteal hematoma of the orbit associated with subfrontal extradural hematoma: case report.

A patient admitted to hospital with a painful proptosis, diminished visual acuity, and mental status changes was proven to have a large left subfrontal epidural hematoma and an associated subperiosteal orbital hematoma. Surgical intervention resulted in complete recovery of neurologic function and visual acuity. This case demonstrates the unique and previously unreported concurrent diagnosis of epidural and subperiosteal orbital hematoma. The literature is reviewed and surgical management is discussed.

Adult↗
PubMed1994

CSF findings in adrenoleukodystrophy: correlation between measures of cytokines, IgG production, and disease severity.

The childhood-onset cerebral form of adrenoleukodystrophy has a devastating neurologic prognosis. Unfortunately, there is no early method of distinguishing it from the more benign forms of adrenoleukodystrophy, such as adrenomyeloneuropathy. To evaluate the manner in which this disease entity may be reflected in the cerebrospinal fluid, we studied a consecutive series of 19 patients, all with biochemically proved adrenoleukodystrophy. total protein, immunoglobulin production, cytokine levels, and cerebrospinal fluid pressure were measured. In this single sample of cerebrospinal fluid, a significant correlation existed between clinical stage of the illness and cerebrospinal fluid myelin basic protein. No correlation existed with total protein, cytokines, or measures of immunoglobulin production.

Adolescent↗