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Biomedical subjects

J Gordon

Publications and source records attributed to J Gordon.

At least 37 records · Page 2Linked to original sources
PubMed2001

Gcm2 and Foxn1 mark early parathyroid- and thymus-specific domains in the developing third pharyngeal pouch.

The thymus and parathyroids originate from a common primordium that develops from the third pharyngeal pouch in mice and humans. The molecular mechanism that specifies this primordium into distinct organ domains is not known. The Gcm2 and Foxn1 transcription factors are required for development of the parathyroid and thymus respectively, and are attractive candidates for this role. However, their embryonic expression patterns during pharyngeal pouch development and early thymus and parathyroid organogenesis have not been described. Here we report that Gcm2 is expressed specifically in the developing second and third pharyngeal pouches at E9.5, and is further confined to a small domain of the third pouch endoderm by E10.5. In contrast, Foxn1 is not expressed until after the common primordium is formed, beginning at E11.25. Our results show that Gcm2 and Foxn1 expression mark two complementary domains that prefigure parathyroid and thymus regions within the common primordium before morphological distinctions are present.

Animals↗
PubMed2001

The immune system gets nervous.

It is becoming increasingly apparent that there exists an intimate bidirectional communication between the immune system and the nervous system. However, the field of 'neuroimmunology' has--for both mainstream immunologists and neuroscientists alike--often seemed more a realm of anecdotal, if not somewhat quirky, observations made by enthusiastic amateurs working at the fringes of each of the 'serious' mainstream disciplines. This perception is gradually changing as the detailed taxonomy of the immune system reveals that the component cells are equipped to respond to a plethora of soluble chemical messengers including serotonin, catecholamines, neurotrophins, opioids and several neuropeptides that, conventionally, have been considered as restricted to the neuroendocrine axis.

Animals↗
PubMed2001

Modelling the human immune response: can mice be trusted? Commentary.

The mouse is now the animal of choice for laboratory-based medical research. Although its contribution to advancing understanding of our inner workings is indisputable, we should acknowledge that mice and humans are tangibly different. This article highlights, and attempts some rationale for, discrepancies between the two species' immune systems.

Animals↗
PubMed2001

Country report: Australia.

The last 10 years has been an interesting time for Australian medical education despite reduced funding. WORKFORCE: There are five main workforce trends: a rural/urban maldistribution, a need for more specialists, public hospital staffing difficulties, increasing female practitioners and under-representation of indigenous practitioners. ISSUES FACING THE DEANS: Lack of resources is a problem facing Deans, with pressure for clinical service in teaching hospitals. Entrepreneurial activities have been undertaken including the enrollment of overseas students. Medical schools have also responded to important government initiatives. DEVELOPMENTS IN MEDICAL EDUCATION: Australia's 11 medical schools have undergone significant reform in the last decade. There is a mix of four (graduate), five and six year courses. AUSTRALIA'S NEW MEDICAL SCHOOL: James Cook University opened the first medical school in northern Australia in 2000. The School admits students from rural, northern Australian and indigenous backgrounds. It has a strong regional mission. RURAL AND COMMUNITY-BASED EDUCATION: Government funding to address the maldistribution of the workforce has led to the establishment of rural clubs, Departments of Rural Health and community-based programs. THE FIRST TWO POSTGRADUATE YEARS: There have been recent moves to improve education in the two years following graduation. This includes the initiation of national projects in curriculum and assessment. POSTGRADUATE AND CONTINUING MEDICAL EDUCATION: Postgraduate programs in Australia are being reformed to build on the changes in undergraduate education. CME is also under review. CONCLUSION: Australian medical educators should build on the recent reforms and take on some of the new directions in medical education.

Australia↗
PubMed2001

Retention and use of patient-centered interviewing skills after intensive training.

PURPOSE: Studies show that residents trained in patient-centered interviewing (PCI) are more effective in handling patients' emotions and are more skillful in gathering patients' data. This study evaluated the long-term use of PCI skills. METHOD: Fourteen residents received PCI training during internship, and their skills were evaluated before, immediately after, and two years after their training through directly observed patient interviews. A confidential survey evaluated the residents' actual use of PCI two years after the intensive training. Control groups of 14 interns prior to PCI training and 14 residents from another program not trained in PCI were also surveyed. RESULTS: Residents' use of PCI skills (optimization of setting, establishment of narrative thread, open-to-closed-ended questioning cone, avoid asking more than one question at a time, and (facilitation) were significantly improved, even two years after their training in PCI. The residents who received intensive block training reported using PCI techniques more frequently than did those in the control groups. However, the only significant difference in use of PCI skills between the intervention and control groups was found in reflection of patient's emotions. CONCLUSION: Medical residents retained PCI skills for two years. Further studies are needed to determine whether successful postgraduate training of physicians in PCI translates into a change in behaviors during their professional lives.

Case-Control Studies↗
PubMed2001

Heteroresistance to vancomycin in Enterococcus faecium.

This study presents the first report of vancomycin heteroresistance in an Enterococcus faecium isolate from a patient. The original isolate was susceptible in vitro to vancomycin. E-tests showed growth of subcolonies in a zone of inhibition with a vancomycin MIC of >256 microg/ml. Both the susceptible and resistant colonies were from the same strain as determined by PFGE, and both contained the vanA gene as determined by PCR.

Anti-Bacterial Agents↗
PubMed2001

An analysis of consultations with the crowd doctors at Glasgow Celtic football club, season 1999-2000.

OBJECTIVE: To analyse all clinical presentations to the crowd doctors at Scotland's largest football stadium over the course of one complete season. METHODS: A standard clinical record form was used to document all consultations with the crowd doctors including treatment and subsequent referrals. The relevance of alcohol consumption was assessed. RESULTS: A total of 127 casualties were seen at 26 matches, a mean of 4.88 per match. Twenty casualties were transferred to hospital, including one successfully defibrillated after a cardiac arrest. Alcohol excess was a major contributing factor in 26 cases. CONCLUSIONS: The workload of the crowd doctors was very variable and diverse. The social problem of excessive alcohol consumption contributed considerably to the workload. The provision of medical facilities at football grounds means that attendance there is now one of the least adverse circumstances in which to have a cardiac arrest. The study confirmed previous impressions that more casualties are seen at high profile matches.

Adolescent↗
PubMed2001

Dysfunction of early-stage visual processing in schizophrenia.

OBJECTIVE: Schizophrenia is associated with deficits in higher-order processing of visual information. This study evaluated the integrity of early visual processing in order to evaluate the overall pattern of visual dysfunction in schizophrenia. METHOD: Steady-state visual-evoked potential responses were recorded over the occipital cortex in patients with schizophrenia and in age- and sex-matched comparison volunteers. Visual-evoked potentials were obtained for stimuli composed of isolated squares that were modulated sinusoidally in luminance contrast, number of squares, or chromatic contrast in order to emphasize magnocellular or parvocellular visual pathway activity. RESULTS: Responses of patients to magnocellular-biased stimuli were significantly lower than those of comparison volunteers. These lower response levels were observed in conditions using both low luminance contrast and large squares that biased processing toward the magnocellular pathway. In contrast, responses to stimuli that biased processing toward the parvocellular pathway were not significantly different between schizophrenia patients and comparison volunteers. A significant interaction of group and stimulus type was observed in the condition using low luminance contrast. CONCLUSIONS: These findings suggest a dysfunction of lower-level visual pathways, which was more prominent for magnocellular than parvocellular biased stimuli. The magnocellular pathway helps in orienting toward salient stimuli. A magnocellular pathway deficit could contribute to higher-level visual cognitive deficits in schizophrenia.

Cognition Disorders↗
PubMed2001

Oncogenic potential of human neurotropic virus: laboratory and clinical observations.

Cancer is a multi-step disease involving a series of genetic alterations that result in the loss of control of cell proliferation and differentiation. Such genetic alterations could emerge from the activation of oncogenes and the loss or malfunctioning of tumor suppressor gene activity. Our understanding of cancer has greatly increased through the use of DNA tumor viruses and their transforming proteins as a biological tool to decipher a cascade of events that lead to deregulation of cell proliferation and subsequent tumor formation. For the past ten years our laboratory has focused on the molecular biology of the human neurotropic papovavirus, JCV. This virus causes progressive multifocal leukoencephalopathy, a fatal neurodegenerative disease of the central nervous system in immunocompromised patients. JCV is a common human virus that infects more than 80% of humans but does not induce any obvious clinical symptoms. The increased incidence of acquired immune deficiency syndrome and the use of immunosuppressive chemotherapy have dramatically raised the incidence of PML. The coincidental occurrence of malignant astrocytes and oligodendrocytes in PML patients, coupled with the induction of glioblastoma in JCV-infected nonhuman primates, provides intriguing speculation on the association between JCV and CNS malignancies. In this report we discuss clinical data and laboratory observations pointing to the direct involvement of JCV in cancer.

Animals↗
PubMed2000

Genetic mapping of a mouse modifier gene that can prevent ALS onset.

Mutations in the cytoplasmic Cu/Zn superoxide dismutase (SOD1) gene on human chromosome 21q22.1 cause 10-20% of familial amyotrophic lateral sclerosis (ALS) cases. The expression of the ALS phenotype in mice carrying the murine G86R SOD1 mutation is highly dependent upon the mouse genetic background. This is similar to the phenotypic variation observed in ALS patients containing identical SOD1 mutations. In the FVB/N background, mice expressing mG86R SOD1 develop an ALS phenotype at approximately 100 days. However, when these mice were bred into a mixed background of C57Bl6/129Sv, the onset of the ALS phenotype was delayed (143 days to >2 years). Using 129 polymorphic autosomal markers in a whole genome scan, we have identified a major genetic modifier locus with a maximum lod score of 5.07 on mouse chromosome 13 between D13mit36 and D13mit76. This 5- to 8-cM interval contains the spinal muscular atrophy (SMA)-associated gene Smn (survival motor neuron) and seven copies of Naip (neuronal apoptosis inhibitory protein), suggesting a potential link between SMA and ALS.

Amyotrophic Lateral Sclerosis↗
PubMed2000

Cooperative interaction between HIV-1 regulatory proteins Tat and Vpr modulates transcription of the viral genome.

The virion-associated protein of human immunodeficiency virus, type 1 (HIV-1), Vpr, is a small protein with 96 amino acid residues that has the ability to modulate transcription of HIV-1 long terminal repeat (LTR) promoter activity and affects several cellular functions. In this study we have employed molecular approaches to further investigate the mechanism by which Vpr exerts its regulatory effect upon the LTR. We show that by structural and functional interaction with Tat, a potent viral regulatory protein, Vpr synergistically enhances the transcriptional activity of the HIV-1 LTR. Because Tat utilizes cyclin T1 and its partner, CDK9 to elevate the level of transcription from the LTR, we examined the cooperativity between Vpr, Tat, and cyclin T1/CDK9 on viral gene transcription. Results from co-transfection studies indicated superactivation of LTR by Tat and cyclin T1/CDK9 in the presence of wild type Vpr. This activation was not observed with the R73S mutant of Vpr, which contains arginine to serine transition at residue 73. Interestingly, expression of R73S mutant in cells exerts a negative effect on the observed superactivation of the LTR by Tat, cyclin T1/CDK9, and wild type Vpr. Results from protein-protein interaction studies indicated that Vpr is associated with both Tat and cyclin T1 in cells expressing these proteins. Use of deletion mutant proteins in binding studies revealed that the binding sites for Tat and Vpr within cyclin T1 are distinct and that association of these two viral proteins with cyclin T1 is independent from each other. These observations suggest a working model on the cooperative interaction of Vpr with viral and cellular proteins and its involvement in control of viral gene transcription and replication. Moreover identification of R73S mutant of Vpr provides a new therapeutic avenue for controlling HIV-1 gene transcription and replication in the infected cells.

Arginine↗
PubMed2000

(-)-Spiro[1-azabicyclo[2.2.2]octane-3,5'-oxazolidin-2'-one], a conformationally restricted analogue of acetylcholine, is a highly selective full agonist at the alpha 7 nicotinic acetylcholine receptor.

Neuronal nicotinic acetylcholine receptors are members of the ligand-gated ion channel receptor superfamily and may play important roles in modulating neurotransmission, cognition, sensory gating, and anxiety. Because of its distribution and abundance in the CNS, the alpha 7 nicotinic receptor is a strong candidate to be involved in some of these functions. In this paper we describe the synthesis and in vitro profile of AR-R17779, (-)-spiro[1-azabicyclo[2.2. 2]octane-3,5'-oxazolidin-2'-one] (4a), a potent full agonist at the rat alpha 7 nicotinic receptor, which is highly selective for the rat alpha 7 nicotinic receptor over the alpha 4 beta 2 subtype. Preliminary SAR of AR-R17779 presented here indicate that there is little scope for modification of this rigid molecule as even minor changes result in significant loss of the alpha 7 nicotinic receptor affinity.

Acetylcholine↗
PubMed2000

TNFR-associated factor family protein expression in normal tissues and lymphoid malignancies.

TNFR-associated factors (TRAFs) constitute a family of adapter proteins that associate with particular TNF family receptors. Humans and mice contain six TRAF genes, but little is known about their in vivo expression at the single cell level. The in vivo locations of TRAF1, TRAF2, TRAF5, and TRAF6 were determined in human and mouse tissues by immunohistochemistry. Striking diversity was observed in the patterns of immunostaining obtained for each TRAF family protein, suggesting their expression is independently regulated in a cell type-specific manner. Dynamic regulation of TRAFs was observed in cultured PBLs, where anti-CD3 Abs, mitogenic lectins, and ILs induced marked increases in the steady-state levels of TRAF1, TRAF2, TRAF5, and TRAF6. TRAF1 was also highly inducible by CD40 ligand in cultured germinal center B cells, whereas TRAF2, TRAF3, TRAF5, and TRAF6 were relatively unchanged. Analysis of 83 established human tumor cell lines by semiquantitative immunoblotting methods revealed tendencies of certain cancer types to express particular TRAFs. For example, expression of TRAF1 was highly restricted, with B cell lymphomas consistently expressing this TRAF family member. Consistent with results from tumor cell lines, immunohistochemical analysis of 232 non-Hodgkin lymphomas revealed TRAF1 overexpression in 112 (48%) cases. TRAF1 protein levels were also elevated in circulating B cell chronic lymphocytic leukemia specimens (n = 49) compared with normal peripheral blood B cells (p = 0.01), as determined by immunoblotting. These findings contribute to an improved understanding of the cell-specific roles of TRAFs in normal tissues and provide evidence of altered TRAF1 expression in lymphoid malignancies.

Amino Acid Sequence↗
PubMed2000

Pituitary neoplasia induced by expression of human neurotropic polyomavirus, JCV, early genome in transgenic mice.

In recent years, there has been mounting evidence pointing to the association of polyomaviruses with a wide range of human cancers. The human neurotropic polyomavirus, JCV, infecting greater than 75% of the human population produces a regulatory protein named T-antigen which is expressed at the early phase of viral lytic infection and plays a critical role in completion of the viral life cycle. Furthermore, this protein has the ability to transform neural cells in vitro and its expression has been detected in several human neural-origin tumors. To further investigate the oncogenic potential of the JCV early protein in vivo, transgenic mice expressing JCV T-antigen under the control of its own promoter were generated. Nearly 50% of the animals developed large, solid masses within the base of the skull by 1 year of age. Evaluation of the location as well as histological and immunohistochemical data suggest that the tumors arise from the pituitary gland. As T-antigen is known to interact with several cell cycle regulators, the neoplasms were analysed for the presence of the tumor suppressor protein, p53. Immunoprecipitation/Western blot analysis demonstrated overexpression of wild-type, but not mutant p53 within tumor tissue. In addition, co-immunoprecipitation established an interaction between p53 and T-antigen and overexpression of p53 downstream target protein, p21/WAF1. This report describes the analysis of inheritable pituitary adenomas induced by expression of the human polyomavirus, JCV T-antigen in transgenic mice where T-antigen disrupts the p53 pathway by binding to and sequestering wild-type p53. This animal model may serve as a useful tool to further evaluate mechanisms of tumorigenesis by JCV T-antigen.

Adenoma↗
PubMed2000

Identification of a novel p53 mutation in JCV-induced mouse medulloblastoma.

Medulloblastoma, a malignant invasive tumor of the cerebellum, is one of the most common neoplasms of the nervous system in children. Utilization of the human neurotropic virus JC virus (JCV) early gene T-antigen allowed the development of a transgenic animal that models human medulloblastoma. Here we describe the characterization of two distinct populations of cells derived from the JCV-induced mouse medulloblastoma. Results from immunohistochemical and biochemical studies revealed the expression of T-antigen in some but not all tumor cells. In T-antigen-producing cells, T-antigen was found in association with wild-type p53 and pRb, two tumor suppressors that control cell growth and differentiation. In cells that lack expression of T-antigen, a novel mutant p53 with a deletion between residues 35 and 123 was detected. Morphological differences were observed between the two populations of cells, though there was no significant difference in their growth rates. However, subcutaneous transplantation of the T-antigen-positive, but not T-antigen-negative, cells resulted in the development of massive tumors in experimental animals. In light of earlier reports on the association of JCV with human medulloblastoma, the mouse cell lines described in this study may provide a valuable tool for deciphering the pathways involved in the formation and progression of medulloblastoma.

Animals↗