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Biomedical subjects

F D Brown

Publications and source records attributed to F D Brown.

At least 19 recordsLinked to original sources
PubMed2001

Phosphatidylinositol 4,5-bisphosphate and Arf6-regulated membrane traffic.

ADP-ribosylation factor (Arf) 6 regulates the movement of membrane between the plasma membrane (PM) and a nonclathrin-derived endosomal compartment and activates phosphatidylinositol 4-phosphate 5-kinase (PIP 5-kinase), an enzyme that generates phosphatidylinositol 4,5-bisphosphate (PIP2). Here, we show that PIP2 visualized by expressing a fusion protein of the pleckstrin homology domain from PLCdelta and green fluorescent protein (PH-GFP), colocalized with Arf6 at the PM and on tubular endosomal structures. Activation of Arf6 by expression of its exchange factor EFA6 stimulated protrusion formation, the uptake of PM into macropinosomes enriched in PIP2, and recycling of this membrane back to the PM. By contrast, expression of Arf6 Q67L, a GTP hydrolysis-resistant mutant, induced the formation of PIP2-positive actin-coated vacuoles that were unable to recycle membrane back to the PM. PM proteins, such as beta1-integrin, plakoglobin, and major histocompatibility complex class I, that normally traffic through the Arf6 endosomal compartment became trapped in this vacuolar compartment. Overexpression of human PIP 5-kinase alpha mimicked the effects seen with Arf6 Q67L. These results demonstrate that PIP 5-kinase activity and PIP2 turnover controlled by activation and inactivation of Arf6 is critical for trafficking through the Arf6 PM-endosomal recycling pathway.

ADP-Ribosylation Factor 6↗
PubMed2000

ACAPs are arf6 GTPase-activating proteins that function in the cell periphery.

The GTP-binding protein ADP-ribosylation factor 6 (Arf6) regulates endosomal membrane trafficking and the actin cytoskeleton in the cell periphery. GTPase-activating proteins (GAPs) are critical regulators of Arf function, controlling the return of Arf to the inactive GDP-bound state. Here, we report the identification and characterization of two Arf6 GAPs, ACAP1 and ACAP2. Together with two previously described Arf GAPs, ASAP1 and PAP, they can be grouped into a protein family defined by several common structural motifs including coiled coil, pleckstrin homology, Arf GAP, and three complete ankyrin-repeat domains. All contain phosphoinositide-dependent GAP activity. ACAP1 and ACAP2 are widely expressed and occur together in the various cultured cell lines we examined. Similar to ASAP1, ACAP1 and ACAP2 were recruited to and, when overexpressed, inhibited the formation of platelet-derived growth factor (PDGF)-induced dorsal membrane ruffles in NIH 3T3 fibroblasts. However, in contrast with ASAP1, ACAP1 and ACAP2 functioned as Arf6 GAPs. In vitro, ACAP1 and ACAP2 preferred Arf6 as a substrate, rather than Arf1 and Arf5, more so than did ASAP1. In HeLa cells, overexpression of either ACAP blocked the formation of Arf6-dependent protrusions. In addition, ACAP1 and ACAP2 were recruited to peripheral, tubular membranes, where activation of Arf6 occurs to allow membrane recycling back to the plasma membrane. ASAP1 did not inhibit Arf6-dependent protrusions and was not recruited by Arf6 to tubular membranes. The additional effects of ASAP1 on PDGF-induced ruffling in fibroblasts suggest that multiple Arf GAPs function coordinately in the cell periphery.

3T3 Cells↗
PubMed2000

Why do children vomit after minor head injury?

OBJECTIVE: To determine factors associated with vomiting after minor head injury in a paediatric population with the intention of defining the role of vomiting in management decisions. METHODS: A prospective study of all patients presenting with minor head injury to the Royal Hospital for Sick Children, Edinburgh, between 1 May and 30 June 1997. Information regarding basic demographics, features of the head injury and past and family history was noted on a proforma. This included mechanism of injury, site of impact, presence or absence of scalp haematoma, skull fracture or brain injury and intrinsic factors such as age, family history of migraine and a personal history of migraine, its childhood variants and associated conditions. The relation between vomiting and these features was analysed using chi2 and Fisher's exact tests. RESULTS: 563 children aged from birth to 13 years presented with minor head injury. Complete data were obtained on 463 patients. Some 15.8% vomited after minor head injury. Comparing vomiters with non-vomiters the only associated factors that could be identified were a past history of recurrent vomiting or motion sickness (p= 0.0035, p=0.036 respectively). CONCLUSIONS: Vomiting after minor head injury seems to be related to individual intrinsic factors rather than specific features of the head injury and its role in management decisions needs to be explored further.

Adolescent↗
PubMed1998

Phospholipase D1 localises to secretory granules and lysosomes and is plasma-membrane translocated on cellular stimulation.

Phospholipase D (PLD) activity has been implicated in the regulation of membrane trafficking [1,2], superoxide generation and cytoskeletal remodelling [3,4]. Several PLD genes have now been identified and it is probable that different isoforms regulate distinct functions. Defining the subcellular localisation of each isoform would facilitate understanding of their roles. Previous PLD localisation studies have been based largely on enzyme activity measurements, which cannot distinguish between isoforms [2,5]. We have cloned the cDNAs encoding human PLD1a and PLD1b from an HL60 cell cDNA library and expressed them as catalytically active fusion proteins with green fluorescent protein (GFP) in COS-1 cells and RBL-2H3 cells, a mast cell model which degranulates upon cross-linking of the high-affinity immunoglobulin E (IgE) receptor. In unstimulated cells, GFP-PLD1b colocalised with secretory granule and lysosomal markers; it was not found at the plasma membrane or nucleus and did not colocalise with markers for the Golgi. Stimulation or RBL-2H3 cells through IgE receptor cross-linking caused plasma membrane recruitment of GFP-PLD1b. Inhibition of IgE-receptor-stimulated, PLD-catalysed phosphatidate formation suppressed secretion of granule and lysosomal contents, but did not affect translocation of GFP-PLD1b. These experiments suggest that PLD1 plays a role in regulated exocytosis rather than endoplasmic reticulum (ER) to Golgi membrane transport.

Animals↗
PubMed1996

Prospective, multicenter study of spinal cord stimulation for relief of chronic back and extremity pain.

STUDY DESIGN: This prospective, multicenter study was designed to investigate the efficacy and outcome of spinal cord stimulation using a variety of clinical and psychosocial outcome measures. Data were collected before implantation and at regular intervals after implantation. This report focuses on 70 patients who had undergone 1 year of follow-up treatment at the time of data analysis. OBJECTIVES: To provide a more generalizable assessment of long-term spinal cord stimulation outcome by comparing a variety of pain and functional/quality-of-life measures before and after management. This report details results after 1 year of stimulation. SUMMARY OF BACKGROUND DATA: The historically diverse methods, patient selection criteria, and outcome measures reported in the spinal cord stimulation literature have made interpretation and comparison of results difficult. Although short-term outcomes are generally consistent, long-term outcomes of spinal cord stimulation, as determined by prospective studies that assess multidimensional aspects of the pain complaint among a relatively homogeneous population, are not well established. METHODS: Two hundred nineteen patients were entered at six centers throughout the United States. All patients underwent a trial of stimulation before implant of the permanent system. Most were psychologically screened. One hundred eighty-two patients were implanted with a permanent stimulating system. At the time of this report, complete 1-year follow-up data were available on 70 patients, 88% of whom reported pain in the back or lower extremities. Patient evaluation of pain and functional levels was completed before implantation and 3, 6, 12, and 24 months after implantation. Complications, medication usage, and work status also were monitored. RESULTS: All pain and quality-of-life measures showed statistically significant improvement during the treatment year. These included the average pain visual analogue scale, the McGill Pain Questionnaire, the Oswestry Disability Questionnaire, the Sickness Impact Profile, and the Back Depression Inventory. Overall success of the therapy was defined as at least 50% pain relief and patient assessment of the procedure as fully or partially beneficial and worthwhile. Using this definition, spinal cord stimulation successfully managed pain in 55% of patients on whom 1-year follow-up is available. Complications requiring surgical intervention were reported by 17% (12 of 70) of patients. Medication usage and work status were not changed significantly. CONCLUSIONS: This prospective, multicenter study confirms that spinal cord stimulation can be an effective therapy for management of chronic low back and extremity pain. Significant improvements in many aspects of the pain condition were measured, and complications were minimal.

Adult↗
PubMed1996

Activation of phospholipase D and phosphatidylinositol 4-phosphate 5-kinase in HL60 membranes is mediated by endogenous Arf but not Rho.

Membrane-associated phospholipase D (PLD) in HL60 cells can be activated by the small GTP-binding proteins Arf and RhoA, but polyphosphorylated inositol lipids were required for maximum activity. The intact lipid was required because neither inositol 1,4, 5-trisphosphate nor stearoyl-arachidonyl glycerol could substitute for phosphatidylinositol 4,5-bisphosphate (PIP2). Arf-stimulated but not Rho-stimulated PLD activity was increased by the inclusion of Mg2+ and ATP. ATP-dependent PLD activation occurred when phosphatidylinositol 4-phosphate (PIP), PIP2, or phosphatidylinositol 3,4,5-trisphosphate (PIP3) were included, but PIP2 formation was only detected with PIP; no PIP3 production was detected under any conditions. Therefore, the ATP-dependent increase in PLD activity cannot be explained by PIP2 or PIP3 formation. Association of endogenous Arf and RhoA with membranes was increased by incubation with GTPgammaS. This treatment increased membrane PLD and PIP kinase activities in the absence of exogenous p21 proteins. Reduction of Arf translocation suppressed the increase in PLD and PIP kinase activities, whereas complete removal of Rho but not Arf from membranes with RhoGDI was without effect on PLD activity but increased PIP kinase activity. Therefore, although recombinant Arf and Rho can activate PLD and PIP kinase in HL60 cells, it is the endogenous Arf but not Rho that regulates PLD, and thus a role for Rho in the physiological regulation of PLD in HL60 cells is unlikely.

ADP-Ribosylation Factors↗
PubMed1992

Epidural lipomatosis in steroid-treated patients.

Epidural lipomatosis is a condition in which excess adipose tissue is deposited circumferentially about the spinal cord in the epidural space. It is most frequently seen in patients on chronic steroid treatment for a variety of medical problems and can present as nonspecific back pain, radiculopathy, or frank spinal cord compression. Diagnosis and treatment have generally relied on multi-level decompressive laminectomy after myelography and computed tomography. The immunocompromised state and the reported postoperative mortality (22%) of these patients, however, suggests that nonoperative therapy may be preferable whenever possible. Five cases of epidural lipomatosis are reported, and previous literature is reviewed for presentation, evaluation, and treatment of this condition.

Adult↗
PubMed1990

Cerebral blood flow during the acute therapy of severe hypertension with oral clonidine.

A major risk associated with the acute treatment of severe hypertension is a reduction in cerebral blood flow (CBF) with ischemic injury to the central nervous system. The authors studied CBF before and after the acute treatment of severe hypertension (diastolic blood pressure greater than 115 mm Hg) with clonidine in 13 patients. One patient did not reach goal blood pressure (diastolic blood pressure 105 mm Hg or a decrease by 30 mm Hg) after clonidine alone. In the remaining 12 patients, oral clonidine reduced supine blood pressure from 201.7 +/- 5.0/126.3 +/- 2.1 mm Hg to 149.4 +/- 5.3/96.8 +/- 1.7 mm Hg over an average time period of 85 +/- 7 minutes. Although mean CBF for the group did not change (72.6 +/- 4.2 v 73.7 +/- 3.5 mL/100 mg/min), a significant (greater than 10%) change occurred in 9 of the 12 patients (5 increases and 4 reductions). The magnitude and direction of the change were dependent upon initial CBF (r = -0.65, P less than .05); patients with low pretreatment CBF experienced an increase, whereas those with high initial flow exhibited a decrease. No significant adverse effects were observed. These data confirm previous reports that clonidine is effective in the acute treatment of severe hypertension and demonstrate that its effects on CBF are determined by the pretreatment levels of flow.

Administration, Oral↗
PubMed1989

Superior sagittal sinus infection with Petriellidium boydii: case report.

A case of infection of the superior sagittal sinus with Petriellidium boydii is reported. This relatively common fungal pathogen rarely invades the central nervous system. Immunological compromise and poor personal hygiene seem to be common attributes shared by this patient and the 4 previous patients reported to have suffered invasion of the central nervous system by this organism. This report is unique in that it is the first demonstrating apparent hematogenous dissemination of this organism to the central nervous system.

Brain Diseases↗
PubMed1988

The effect of fetal hypothalamus grafts on weight gain resulting from lesions of the ventromedial hypothalamus.

Bilateral ventromedial hypothalamic lesions in female adult rats which resulted in hyperphagia and rapid weight gain were followed by placement of fetal brain tissue in the anterior third ventricle. The treatment group received fetal hypothalamus grafts, and fetal cortical tissue of identical age was grafted into the control group. A significant reduction in average daily weight gain was noted from 4 to 12 weeks following transplantation in the treatment group. At 12 weeks posttransplantation, the animals were sacrificed for histological analysis. Examination of the hypothalamus grafts revealed neurons, ependymal clusters, and axonal processes which appeared to infiltrate the surrounding hypothalamic parenchyma.

Animals↗
PubMed1987

Examination of the utility of the rat as an animal model for human anticoagulation.

The feasibility of employing the rat as an experimental model for investigation of full-dose heparin anticoagulation was assessed. Striking similarities were found to exist between rats and humans regarding baseline-activated partial thromboplastin time (APTT) values, and dosage per kilogram of heparin required to produce an APTT value of 1 1/2-3 times normal, the clinical definition of full-dose heparinization. Based upon these similarities, it appears that the rat can effectively serve as an experimental model for investigating the effects of heparin in humans.

Animals↗
PubMed1985

Treatment of mycotic aneurysms.

Mycotic intracranial aneurysms may be treated by antibiotic therapy alone. Careful evaluation of this mode of treatment has been hampered by inadequate angiographic and microbiological documentation. The present case details the successful conservative management of one of these lesions in a patient who had previously undergone craniotomy for a separate mycotic aneurysm.

Adult↗
PubMed1985

Severe thrombocytopenia associated with phenytoin and cimetidine therapy.

A 67-year-old man developed a sudden onset of severe isolated thrombocytopenia (platelet count, 1000/mm3) after 10 days of phenytoin administration as a prophylactic measure prior to craniotomy. The patient had also been taking cimetidine for 2 months prior to admission. No other hematological complications were noted, and an extensive hematologic investigation was otherwise unremarkable. Rapid resolution of the thrombocytopenia upon discontinuation of phenytoin and cimetidine strongly suggests a drug-induced adverse reaction.

Aged↗
PubMed1985

Evaluation of the risks of anticoagulation therapy following experimental craniotomy in the rat.

The risk of hemorrhagic complications with anticoagulation therapy in patients following intracranial surgery has prevented investigation of the potential use of heparin in the early postoperative period. The authors have evaluated the safety of anticoagulation therapy following experimental craniotomy in male Holtzman rats. The dose and schedule of heparin administration, which elevated and maintained the activated partial thromboplastin time (APTT) within the therapeutic range of 1 1/2 to 3 X control APTT, was alternating doses of 400 and 500 IU/kg injected subcutaneously every 6 hours. This schedule was initiated 2, 4, 7, 10, and 14 days after craniotomy and was continued for 72 hours thereafter. The results demonstrated that the incidence of intracerebral hemorrhage declined as the postoperative interval prior to initiation of anticoagulation increased. If anticoagulation therapy was initiated during the first 7 postoperative days, the risk of intracerebral hemorrhage was high (mean 14.7%): however, if an additional 3 to 7 days elapsed prior to initiation of anticoagulation, the incidence of intracerebral hemorrhage dropped significantly (mean 0%) (p less than 0.05). These results suggest that anticoagulation therapy can be safely initiated 10 to 14 days after craniotomy.

Animals↗