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Biomedical subjects

C L Jackson

Publications and source records attributed to C L Jackson.

At least 19 recordsLinked to original sources
PubMed2001

Controlling small guanine-nucleotide-exchange factor function through cytoplasmic RNA intramers.

ADP-ribosylation factor (ARF) GTPases and their regulatory proteins have been implicated in the control of diverse biological functions. Two main classes of positive regulatory elements for ARF have been discovered so far: the large Sec7/Gea and the small cytohesin/ARNO families, respectively. These proteins harbor guanine-nucleotide-exchange factor (GEF) activity exerted by the common Sec7 domain. The availability of a specific inhibitor, the fungal metabolite brefeldin A, has enabled documentation of the involvement of the large GEFs in vesicle transport. However, because of the lack of such tools, the biological roles of the small GEFs have remained controversial. Here, we have selected a series of RNA aptamers that specifically recognize the Sec7 domain of cytohesin 1. Some aptamers inhibit guanine-nucleotide exchange on ARF1, thereby preventing ARF activation in vitro. Among them, aptamer M69 exhibited unexpected specificity for the small GEFs, because it does not interact with or inhibit the GEF activity of the related Gea2-Sec7 domain, a member of the class of large GEFs. The inhibitory effect demonstrated in vitro clearly is observed as well in vivo, based on the finding that M69 produces similar results as a dominant-negative, GEF-deficient mutant of cytohesin 1: when expressed in the cytoplasm of T-cells, M69 reduces stimulated adhesion to intercellular adhesion molecule-1 and results in a dramatic reorganization of F-actin distribution. These highly specific cellular effects suggest that the ARF-GEF activity of cytohesin 1 plays an important role in cytoskeletal remodeling events of lymphoid cells.

ADP-Ribosylation Factor 1↗
PubMed2001

Atherosclerotic plaque rupture in the apolipoprotein E knockout mouse.

The rupture of an atherosclerotic plaque is the main underlying cause of coronary artery thrombotic occlusion and subsequent myocardial infarction, but research into the causes and treatment of plaque rupture is hampered by the lack of a suitable animal model. Although complex atherosclerotic plaques can be induced in a number of experimental animal systems, in none of these is plaque rupture an established feature. We have surveyed branch points in the carotid arteries and aortas of apolipoprotein E knockout mice fed a diet supplemented with 21% lard and 0.15% cholesterol for up to 14 months. Six male and five female mice were used. Four of the male mice and four of the female mice died, after 46+/-3 weeks of feeding (range 37-59 weeks). Lumenal thrombus associated with atherosclerotic plaque rupture was observed in three male and all four female mice. In six of these seven mice, an atherosclerotic plaque rupture was found where the brachiocephalic artery branches into the right common carotid and right subclavian arteries. The ruptures were characterised by fragmentation and loss of elastin in the fibrous caps of relatively small and lipid-rich plaques overlying large complex lesions, with intraplaque haemorrhage. Immunocytochemical analysis revealed loss of smooth muscle cells from ruptured caps. These data suggest that long-term fat-feeding of apolipoprotein E knockout mice is a useful and reproducible model of atherosclerotic plaque rupture, and that these ruptures occur predominantly in the brachiocephalic artery.

Animals↗
PubMed2001

Effects of probucol on rat carotid artery responses to balloon catheter injury.

Balloon catheter injury to the rat common carotid artery has been widely used for testing potential therapies for post-angioplasty restenosis. However, the model has become somewhat discredited because a number of drugs that inhibit intimal thickening, measured 14 days after balloon catheter injury, have been found to be ineffective in clinical trials. Probucol has recently been shown to reduce the incidence of post-angioplasty restenosis in a number of small clinical trials, making it possible to reassess the validity of the rat balloon injury model. The effects of probucol on the underlying causes of intimal thickening in balloon-injured rat carotid arteries were quantified. Probucol inhibited medial smooth muscle cell proliferation by 23% on day 4 after injury (P=0.009), and by 65% on day 10 after injury (P=0.026). Smooth muscle cell migration was reduced by 64% (P=0.008) in probucol-treated animals. In marked contrast, intimal smooth muscle cell proliferation was significantly increased by 41% (P=0.024) by probucol. There was no significant effect on intimal thickening or smooth muscle cell death. These data suggest that drugs that inhibit both medial smooth muscle cell proliferation and migration in the rat balloon injury model may prove useful in the treatment of post-angioplasty restenosis.

Administration, Oral↗
PubMed2001

Physical and transcriptional map of the hereditary inclusion body myopathy locus on chromosome 9p12-p13.

Hereditary inclusion body myopathy (HIBM) is a group of neuromuscular disorders characterised by adult-onset, slowly progressive distal and proximal muscle weakness and typical muscle pathology. Previously, we have mapped the gene responsible for a recessive form of HIBM to chromosome 9p1 and narrowed the interval to one single YAC clone of 1 Mb in size. As a further step towards the identification of the HIBM gene, we have constructed a detailed physical and transcriptional map of this region. A high resolution BAC contig that includes the HIBM critical region, flanked by marker 327GT4 and D9S1859, was constructed. This contig allowed the precise localisation of 25 genes and ESTs to the proximal region of chromosome 9. The expression pattern of those mapped genes and ESTs was established by Northern blot analysis. In the process of refining the HIBM interval, 13 new polymorphic markers were identified, of which 11 are CA-repeats, and two are single nucleotide polymorphisms. Certainly, this map provides an important integration of physical and transcriptional information corresponding to chromosome 9p12-p13, which is expected to facilitate the cloning and identification not only of the HIBM gene, but also other disease genes which map to this region.

Chromosomes, Artificial, Bacterial↗
PubMed2001

Modulation of smooth muscle proliferation in rat carotid artery by platelet-derived mediators and fibroblast growth factor-2.

Endothelial denuding injury to the rat carotid artery stimulates smooth muscle cell proliferation in the tunica media. Fibroblast growth factor-2 (FGF2) is responsible for a significant portion of this proliferation but other factors may contribute, particularly those released from adherent platelets. We therefore tested the effects of a range of platelet-derived factors. After filament injury, which minimises FGF2 release, the proliferation rate in thrombocytopaenic rats was decreased by 74% (P < 0.02). After balloon injury, antibody neutralisation of platelet-derived growth factor (PDGF) caused a 27% decrease in proliferation (P < 0.05), while inhibition of histamine H(1) receptors caused a 53% increase (P < 0.05). When filament injury was performed 1 h after FGF2 injection, the proliferation rate increased from 2.3+/-0.7 to 32.8+/-2.7% (P < 0.001), while filament injury alone caused a proliferation rate of only 18.3+/-2.9% (P < 0.01 versus filament plus FGF2). These data suggest that platelet-derived factors interact with FGF2 that is adsorbed to the vessel wall in the control of smooth muscle cell proliferation, and that the net effect of platelets is to stimulate smooth muscle cell proliferation. PDGF, but no other platelet agonist tested, contributes to that stimulation.

Animals↗
PubMed2001

Three dimensional configuration of the secretory pathway and segregation of secretion granules in the yeast Saccharomyces cerevisiae.

The structural elements of the secretory pathway in the budding yeast Saccharomyces cerevisiae were analyzed by 3D stereo-electron microscopy using relatively thick sections in which membranes were selectively impregnated. In a wild-type strain, tubular networks of various sizes and staining properties were distributed throughout the cytoplasm. As a rule, wide-meshed, lightly stained polygonal networks were connected to more or less fenestrated sheets of endoplasmic reticulum (ER). Some of these networks were continuous with more intensely stained networks and narrower meshes that displayed at their intersections nodular dilations that progressively increased in size and staining properties to reach those of secretion granules. Such networks presumably corresponded to Golgi elements. Indeed, stacked cisternae typical of the mammalian Golgi apparatus are rarely found in wild-type cells. However, if it is assumed that the Golgi apparatus plays a key role in the segregation and maturation of secretion granules, then tubular networks with nodular dilations should be equivalent to parts of this organelle. In correlation with the increase in size and density of the nodules there was a decrease in diameter and staining intensity of the interconnecting tubules. These results parallel observations on the formation of secretory granules in mammalian cells and suggest that the segregation of secretory material is concomitant with the progressive perforation and tubulization of previously unperforated sheets. When the sec21-3 thermosensitive mutant was examined at the nonpermissive temperature (37 degrees C), the secretory pathway was blocked at exit from the ER, which started to accumulate as clusters of narrow, anastomosed, unperforated ribbon-like elements. When the block was released by shifting down to permissive temperature (24 degrees C), tubular networks of various sizes and caliber, presumably Golgi in nature, formed as soon as 5 minutes after release of the block. At later time intervals, granules of various sizes and densities appeared to be released by rupture of these tubular networks or even to form at the edges of ER fenestrae. These observations support a dynamic maturation process in which the formation of secretion granules occurs by means of an oriented series of membrane transformations starting at the ER and culminating with the liberation of secretion granules from Golgi networks.

Biological Transport, Active↗
PubMed2001

The ARF exchange factors Gea1p and Gea2p regulate Golgi structure and function in yeast.

The Sec7 domain guanine nucleotide exchange factors (GEFs) for the GTPase ARF are highly conserved regulators of membrane dynamics. Their precise molecular roles in different trafficking steps within the cell have not been elucidated. We present a functional analysis of two members of this family, Gea1p and Gea2p, in the yeast Saccharomyces cerevisiae. Gea1p and Gea2p can functionally replace each other, but at least one is necessary for viability. Temperature sensitive gea mutants were generated and found to have defects in ER-Golgi and intra-Golgi transport. Similar to mutants in COPI subunits in yeast, gea mutants had a cargo-selective secretion defect, in that some proteins continued to be secreted whereas others were blocked in the ER or early Golgi. Like yeast arf mutants, the rate of transport of those proteins that continued to be secreted was slowed. In addition, the structure of Golgi elements was severely perturbed in gea mutants. We conclude that Gea1p and Gea2p play an important role in the structure and functioning of the Golgi apparatus in yeast.

ADP-Ribosylation Factors↗
PubMed2001

Urologic laparoscopy.

Urologic laparoscopy initially was confined to a diagnostic role or the treatment of benign conditions. Many of these initial procedures, however, have been abandoned because they offered no significant benefit over open surgery. The treatment of urologic malignancies, however, recently has emerged as the most common indication for laparoscopic urologic surgery. Maturing data for laparoscopic radical nephrectomy, nephroureterectomy and partial nephrectomy demonstrate equivalent oncologic results. Newer applications such as laparoscopic radical prostatectomy are evolving. Despite these data demonstrating many advantages as compared with open techniques, urologists have been slow to include laparoscopy in their practice. This reluctance has been seen in other disciplines and is no doubt, at least in part, caused by the steep learning curve. Laparoscopic management of urologic malignancies is complicated and difficult to learn. In a multi-institutional review of laparoscopic complications, 71% of the complications occurred in the first 20 cases. The risk of complications and operative time significantly declines with experience, however. Higashihara et al reported a decline in laparoscopic operative time to levels comparable to open radical nephrectomy. The learning curve seems to be approximately 30 to 40 cases. The scope and practice of urology does not provide a common procedure of relatively low complexity such as the general surgical cholecystectomy or gynecologic tubal ligation to facilitate the adoption of laparoscopy by urologists. Nevertheless, evolving techniques and equipment coupled with the incorporation of laparoscopic training in residency and fellowship programs will help secure laparoscopy a prominent place in the treatment of urologic malignancy.

Adrenalectomy↗
PubMed2000

Regulators and effectors of the ARF GTPases.

The small G proteins of the ARF family are key regulators of membrane dynamics. Many functions of ARF proteins in cells are being revealed by studies of their regulators and effectors. Significant progress has been made over the past year, with the identification of a surprisingly large family of novel ARF GTPase-activating proteins. In addition, two new classes of effectors, the PIP kinases and a novel family of monomeric coat-like proteins have been discovered.

ADP-Ribosylation Factors↗
PubMed2000

Turning on ARF: the Sec7 family of guanine-nucleotide-exchange factors.

ARF proteins are important regulators of membrane dynamics and protein transport within the eukaryotic cell. The Sec7 domain is approximately 200 amino acids in size and stimulates guanine-nucleotide exchange on members of the ARF class of small GTPases. The members of one subclass of Sec7-domain proteins are direct targets of the secretion-inhibiting drug brefeldin A, which blocks the exchange reaction by trapping a reaction intermediate in an inactive, abortive complex. A separate subclass of Sec7-domain proteins is involved in signal transduction and possess a domain that mediates membrane binding in response to extracellular signals.

ADP-Ribosylation Factor 1↗
PubMed2000

2E4/Kaptin (KPTN)--a candidate gene for the hearing loss locus, DFNA4.

Stereocilia of the inner ear play an integral role in the mechanotransduction of sound. Their structural support is derived from actin filaments and actin-binding proteins. We have identified a novel actin-binding protein, 2E4-kaptin (KPTN), which appears to be involved in this structural network. Using double label immunofluorescence, we now show that KPTN extends beyond the barbed ends of actin filaments at the tips of stereocilia, and using cloned human cDNA, we mapped KPTN to chromosome 19q13.4. A combination of FISH, radiation hybrid mapping and YAC screening localized KPTN between markers D19S412 and NIB1805, making this gene an excellent functional and positional candidate for DFNA4, a form of autosomal dominant non-syndromic hearing loss. We identified a second family with inherited deafness that also maps to the DFNA4 region. To screen KPTN for deafness-causing mutations, we first determined its genomic structure and then completed a mutational analysis by direct sequencing and SSCP in affected family members. Although no deafness-causing mutations were identified in the coding region, KPTN remains an excellent candidate gene for hearing loss; by synteny, its murine orthologue also remains a candidate gene for the Nijmegan waltzer (nv) mouse mutant, which has vestibular defects and a variable sensorineural hearing loss.

Adult↗
PubMed2000

Clinical pathways involving general practice--a new approach to integrated health care?

The Mater Mothers' Hospital, South Brisbane recently identified a number of difficulties with the maternity share-care program it runs with 1100 local GPs. This paper describes an integration approach developed at the Mater which has addressed these problems via the use of clinical management guidelines across the whole episode of care, the provision of a patient held record/pathway as a clinical practice prompt, clear communication and information management protocols between hospital and general practice, and the provision of continuing medical education for share-care practitioners.

Attitude of Health Personnel↗
PubMed2000

Home phototherapy for neonatal jaundice--technology and teamwork meeting consumer and service need.

32 babies with uncomplicated physiological jaundice received home phototherapy from a hospital/community team in southern Brisbane. All babies showed acceptable reductions in their serum bilirubin on home therapy, and none required hospital re-admission for phototherapy. Their families were highly satisfied with the home program, and recorded high levels of confidence in their therapeutic responsibilities. Community providers were able to deliver a high quality 24-hour service, integrated with appropriate neonatology support. The cost of delivering the home program was significantly less than a comparable hospital stay.

Bilirubin↗
PubMed1999

Coordinated polar localization of auxin efflux carrier PIN1 by GNOM ARF GEF.

The plant hormone auxin is transported in a polar manner along the shoot-root axis, which requires efflux carriers such as PIN1. Asymmetric localization of PIN1 develops from a random distribution in Arabidopsis early embryogenesis. Coordinated polar localization of PIN1 is defective in gnom embryos. GNOM is a membrane-associated guanine-nucleotide exchange factor on ADP-ribosylation factor G protein (ARF GEF). Thus, GNOM-dependent vesicle trafficking may establish cell polarity, resulting in polar auxin transport.

ADP-Ribosylation Factors↗