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Biomedical subjects

D O'Connor

Publications and source records attributed to D O'Connor.

At least 55 records · Page 3Linked to original sources
PubMed1999

Insulin-like growth factor I-mediated activation of the transcription factor cAMP response element-binding protein in PC12 cells. Involvement of p38 mitogen-activated protein kinase-mediated pathway.

IGF-I is known to support growth and to prevent apoptosis in neuronal cells. Activation of the nuclear transcription factor cAMP response element-binding protein (CREB) has emerged as a central determinant in neuronal functions. In the present investigation, we examined the IGF-I-mediated phosphorylation and transcriptional activation of CREB in rat pheochromocytoma (PC12) cells, a cellular model for neuronal differentiation, and defined three distinct postreceptor signaling pathways important for this effect including the p38 mitogen-activated protein kinase (MAPK) pathway. CREB phosphorylation at serine 133 and its transcriptional activation as measured by a CREB-specific Gal4-CREB reporter and the neuroendocrine-specific gene chromogranin A was induced 2-3.3-fold by insulin-like growth factor (IGF)-I. This activation was significantly blocked (p < 0.001) by the dominant negative K-CREB or by mutation of the CRE site. IGF-I stimulated chromogranin A gene expression by Northern blot analysis 3.7-fold. Inhibition of MAPK kinase with PD98059, PI 3-kinase with wortmannin, and p38 MAPK with SB203580 blocked IGF-I-mediated phosphorylation and transcriptional activation of CREB by 30-50% (p < 0.001). Constitutively active and dominant negative regulators of the Ras and PI 3-kinase pathways confirmed the contribution of these pathways for CREB regulation by IGF-I. Cotransfection of PC12 cells with p38beta and constitutively active MAPK kinase 6 resulted in enhanced basal as well as IGF-I-stimulated chromogranin A promoter. IGF-I activated p38 MAPK, which was blocked by the inhibitor SB203580. This is the first description of a p38 MAPK-mediated nuclear signaling pathway for IGF-I leading to CREB-dependent neuronal specific gene expression.

Animals↗
PubMed1999

Analysis of the neurotrophic effects of GPI-1046 on neuron survival and regeneration in culture and in vivo.

The putative neurotrophic effects of the immunophilin ligand GPI-1046 were evaluated in established experimental systems of neuron survival and axon growth in vitro and in vivo. GPI-1046 marginally increased neurite outgrowth of chick dorsal root ganglia in culture under conditions where a very robust effect of nerve growth factor was seen. GPI-1046 failed to protect dopaminergic neurons from 1-methyl-4-phenylpyridinium in culture or to protect cultured cortical neurons from experimentally induced apoptosis in vitro. In adult rats in vivo, daily administration of GPI-1046 (10 mg/kg, s.c.) for three days enhanced the maximal regeneration distance of both motor and large myelinated sensory axons measured using an electrophysiological assay. However, detailed morphometric analysis of these animals failed to provide evidence for an increase in axon numbers in GPI-1046-treated animals. The ability of GPI-1046 to promote the recovery of dopaminergic function following unilateral 6-hydroxydopamine lesions of the substantia nigra was also tested in rats. In the first study, the duration of amphetamine (3 mg/kg, s.c.)-induced circling, but not the maximal number of rotations, was significantly reduced in animals treated with GPI-1046 for five days (10 mg/kg/day). In a second study, testing the effects of delayed GPI-1046 administration, chronic treatment with GPI-1046 (10 mg/kg/day) for two weeks, beginning one month after surgery, did not alter circling responses. Morphometric analysis failed to reveal any changes in either the density of tyrosine hyroxylase-positive fibres in dopaminergic target areas or in cell numbers in the substantia nigra in both experiments. Thus, while GPI-1046 produced marginal effects on neurite outgrowth in dorsal root ganglia cultures and on functional paramaters of nerve regeneration in vivo, we failed to obtain evidence in support of the notion of a general neuroprotective effect of the compound or for an effect on morphologic nerve regeneration in vivo.

1-Methyl-4-phenylpyridinium↗
PubMed1999

A novel source of wheat fiber and protein: effects on fecal bulk and serum lipids.

BACKGROUND: Wheat fiber is a laxative and wheat protein may affect blood lipids. OBJECTIVE: We therefore tested the effects on laxation and serum lipid metabolism of a novel source of wheat fiber and protein produced by the amylolytic digestion of starch from wheat. DESIGN: Twenty-four healthy men and women consumed 3 different test cereals in random order, each for 2 wk. The test supplement and the positive control, American Association of Cereal Chemists wheat bran supplement, both provided the same amount of fiber (21 g/d) and the negative control supplement provided 1.7 g fiber/d. RESULTS: The test supplement and the positive control supplement increased fecal bulk similarly (239.5+/-19 and 216.7+/-19 g/d, respectively) and significantly more than did the negative control supplement (165.6+/-16 g/d, P < 0.010). Compared with the negative and positive control supplements, the week 2 value of the test supplement for the ratio of total to HDL cholesterol was significantly reduced (P = 0.046). CONCLUSION: We conclude that the product of amylolytic digestion of starch from wheat flakes, which is high in wheat fiber and protein, has a fecal bulking effect similar to that of wheat bran and may have a beneficial effect on serum lipids.

Adult↗
PubMed1999

Localization of chromogranin, synaptophysin, serotonin, and CXCR2 in neuroendocrine cells of the minor vestibular glands: an immunohistochemical study.

Sections of vulvar tissue containing minor vestibular glands (15 sections from 14 women with vulvar vestibulitis syndrome and six control sections from five asymptomatic women) were immunohistochemically stained with antibodies against chromogranin, synaptophysin, serotonin, and CXCR2. The degree of inflammation in vestibular tissue from women with and without vulvar vestibulitis syndrome was not significantly different. All vulvar minor vestibular glands contained neuroendocrine cells that expressed chromogranin to some degree. Only one case failed to express synaptophysin. The number of cells expressing chromogranin and synaptophysin was the same regardless of the degree of inflammation. However, moderate to severe inflammation was associated with a statistically significant increase in the number of cells expressing serotonin (p < 0.001) and CXCR2 (p < 0.02). It is concluded that neuroendocrine cells are present within minor vestibular glands of the vulva. The number of cells expressing the inflammatory mediator serotonin and CXCR2, the shared interleukin-8 receptor, are upregulated with inflammation. Chronic inflammation is a normal finding in vestibular tissue and does not serve as a histologic marker for vulvar vestibulitis.

Adult↗
PubMed1999

Obtaining resources for evidence-based public health initiatives at the local level: insights from the Central Sydney Tobacco Control Plan.

OBJECTIVE: In response to inquiries regarding the processes of developing a Tobacco Control Plan (TCP) for the Central Sydney Area Health Service (which in 1997 allocated dedicated funding of $ 800,000 over 2 1/2 years to implement the plan), this article describes the strengths and weaknesses of the TCP and outlines the process which contributed to its funding. CONCLUSIONS: Consistent with national and state priorities, the TCP recommended strategies based on best available evidence in the four action areas: reducing sales of cigarettes to minors, marketing, passive smoking and smoking cessation. Funding of this amount for a single public health issue at a local level represents a unique achievement in the application of an evidence-based approach to population health. IMPLICATIONS: Key elements of our advocacy methods included the involvement of all key primary health care and clinical stakeholders; comprehensive background research to identify evidence-based strategies; careful attention to budget options; strategic lobbying of senior staff and decision makers; the proposal for a multidisciplinary management structure for the TCP and specifications for funding allocation and evaluation. Early achievements and other reflections are discussed.

Adolescent↗
PubMed1999

Late shunt infections.

We reviewed the records of the 957 shunt-related operations performed at Cardinal Glennon Children's Hospital over a 10-year period. During that time, 94 shunt infections were recognized. Eight of the infections occurred more than 9 months postoperatively. These differed from early infections in two ways: (1) Staphylococcus aureus was not found to be a pathogen in any late infection. (2) Abdominal pseudocysts were much more frequently found in patients with late-developing infections. In addition, the pathogens involved and the temporal distribution of cases suggest most infections that occur more than 9 months postoperatively are more likely caused by secondary bacterial seeding than by bacterial inoculation at the time of operation.

Adolescent↗
PubMed1998

Pseudomeningocele nerve root entrapment after lumbar discectomy.

STUDY DESIGN: A case report of pseudomeningocele with nerve root entrapment after lumbar discectomy. OBJECTIVES: To report a rare cause of recurrent sciatica. METHODS: A unique case of delayed nerve root entrapment within the neck of an iatrogenic pseudomeningocele is described. The relevant literature is reviewed. CONCLUSIONS: This case illustrates the possible consequences of not repairing a dural tear and reinforces the importance of a careful surgical approach to the lumbar spine.

Adolescent↗
PubMed1998

Crystal structure of Y34F mutant human mitochondrial manganese superoxide dismutase and the functional role of tyrosine 34.

Tyrosine 34 is a prominent and conserved residue in the active site of the manganese superoxide dismutases in organisms from bacteria to man. We have prepared the mutant containing the replacement Tyr 34 --> Phe (Y34F) in human manganese superoxide dismutase (hMnSOD) and crystallized it in two different crystal forms, orthorhombic and hexagonal. Crystal structures of hMnSOD Y34F have been solved to 1.9 A resolution in a hexagonal crystal form, denoted as Y34Fhex, and to 2.2 A resolution in an orthorhombic crystal form, denoted as Y34Fortho. Both crystal forms give structures that are closely superimposable with that of wild-type hMnSOD, with the phenyl rings of Tyr 34 in the wild type and Phe 34 in the mutant very similar in orientation. Therefore, in Y34F, a hydrogen-bonded relay that links the metal-bound hydroxyl to ordered solvent (Mn-OH to Gln 143 to Tyr 34 to H2O to His 30) is broken. Surprisingly, the loss of the Tyr 34 hydrogen bonds resulted in large increases in stability (measured by Tm), suggesting that the Tyr 34 hydroxyl does not play a role in stabilizing active-site architecture. The functional role of the side chain hydroxyl of Tyr 34 can be evaluated by comparison of the Y34F mutant with the wild-type hMnSOD. Both wild-type and Y34F had kcat/Km near 10(9) M-1 s-1, close to diffusion-controlled; however, Y34F showed kcat for maximal catalysis smaller by 10-fold than the wild type. In addition, the mutant Y34F was more susceptible to product inhibition by peroxide than the wild-type enzyme. This activity profile and the breaking of the hydrogen-bonding chain at the active site caused by the replacement Tyr 34 --> Phe suggest that Tyr 34 is a proton donor for O2* - reduction to H2O2 or is involved indirectly by orienting solvent or other residues for proton transfer. Up to 100 mM buffers in solution failed to enhance catalysis by either Y34F or the wild-type hMnSOD, suggesting that protonation from solution cannot enhance the release of the inhibiting bound peroxide ion, likely reflecting the enclosure of the active site by conserved residues as shown by the X-ray structures. The increased thermostability of the mutant Y34F and equal diffusion-controlled activity of Y34F and wild-type enzymes with normal superoxide levels suggest that evolutionary conservation of active-site residues in metalloenzymes reflects constraints from extreme rather than average cellular conditions. This new hypothesis that extreme rather than normal substrate concentrations are a powerful constraint on residue conservation may apply most strongly to enzyme defenses where the ability to meet extreme conditions directly affects cell survival.

Binding Sites↗
PubMed1998

Dislocation of the pisiform in a 9-year-old child.

A dislocated pisiform associated with type II Salter-Harris fractures of the distal radius and ulna in a 9-year-old child is described. Closed reduction followed by immobilization achieved good radiological and clinical results. The current literature on dislocation of the pisiform is reviewed.

Carpal Bones↗
PubMed1998

Binding of 2,4-disubstituted morpholines at human D4 dopamine receptors.

The synthesis of a series of 2,4-disubstituted morpholines is described and their affinities at human dopamine receptors reported. The orally bioavailable 7-azaindole compound 11 has nanomolar affinity at the hD4 receptor with > 1000-fold selectivity over the hD2 receptor.

Administration, Oral↗
PubMed1998

Scrotal leiomyomas with bizarre nuclei: a report of three cases.

We discuss here three cases of scrotal leiomyoma with bizarre nuclei. The patients, ranging in age from 44 to 58 years, presented with painless scrotal masses that were clinically diagnosed as cysts. Clinical follow-up, available for two of the patients, revealed no evidence of local recurrence or distant metastasis 5 years after resection. The tumors were well circumscribed and ranged from 2 to 3 cm in maximal diameter. They were characterized by interlacing fascicles of spindle-shaped cells with pleomorphic nuclei. Nuclei were large and multilobulated with hyperchromatic chromatin and macronucleoli. Multinucleated tumor cells were infrequent. Intranuclear invagination of eosinophilic globules of cytoplasm produced pseudonucleoli. There was no mitotic activity. Immunohistochemically, the tumor cells expressed vimentin, desmin, smooth muscle actin, and muscle-specific actin, but not cytokeratin, neurofilament, or glial fibrillary acidic protein. In contrast to scrotal leiomyosarcomas, scrotal leiomyomas with bizarre nuclei are not hypercellular, and they lack mitotic activity.

Actins↗
PubMed1998

Isolated plantar fracture-dislocation of the middle cuneiform.

A previously unreported case of plantar dislocation of the medial cuneiform is described. The significance of this injury does not lie in its rarity, but in the amount of force required to cause such an injury. This large force may cause bony disruption, along with significant soft-tissue injury, and even compartment syndrome. Analysis of the preoperative evaluation, including the importance of a computed axial tomographicscan, operative intervention, and postoperative care are discussed.

Adult↗
PubMed1998

Primary total knee replacement: short-term outcomes in an Australian population.

This study evaluated the short-term outcome of primary total knee replacement, using standard and reliable outcome measures, for osteoarthritis in an Australian population. This study also compared the pre-operative health status of the patient population with population norms using a quality of life questionnaire. Using the medical outcome study (MOS) 36-item short form health survey (SF-36), there was a statistically significant improvement in physical functioning and bodily pain in males and bodily pain, vitality, role-emotional and mental health in females (P < 0.05). A statistically significant improvement was also seen in Knee Society Scores following surgery for both males and females (P < 0.05). Comparison of pre-operative SF-36 data to age-matched Australian normative values demonstrate that female patients requiring total knee replacement were significantly below the norms in virtually all health dimensions while males were significantly below the norms in mainly physical health dimensions (P < 0.01).

Activities of Daily Living↗
PubMed1997

Enhanced stability of uncemented canine femoral components by bone ingrowth into the porous coatings.

The following questions were answered in this study: (1) What is the initial stability of proximally porous-coated canine femoral components? (2) Does bone ingrowth occur under these conditions? (3) Is the stability enhanced by tissue ingrowth in vivo? The stability of proximally porous-coated femoral components of canine total hip arthroplasties after 6 months to 2 years of in vivo service in dogs was measured in vitro using displacement transducers under loads simulating canine midstance. This was compared with the stability of identical components under the same loading conditions immediately after implantation in vitro in the contralateral femurs. The femurs were then sectioned and bone ingrowth into the porous coatings was quantified. The results showed that immediately after implantation the implants can move as much as 50 microns, but that the bone ingrowth into porous coatings of canine femoral components can occur even under such conditions. These data also suggested that the relative motion existing at the time of insertion can be reduced to very small amounts (< 10 microns) by bone ingrowth.

Alloys↗