American Academy of Neurology qualifications and guidelines for the physician expert witness.
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Credentialing↗
Biomedical subjects
J Gordon
Publications and source records attributed to J Gordon.
Outcomes of patients with rejection post-polyomavirus nephropathy.
INTRODUCTION: We sought to determine the effects of rejection in renal transplant recipients with polyomavirus nephropathy (PVN). METHODS: SCr, biopsy findings, BKV serum and urine loads (Taqman PCR), and BKV antibody titers (HA inhibition assay) were analyzed by two-sample median tests and z tests in 11 patients with median follow-up of 7.3 (2.0 to 31.5) months post-PVN. All patients underwent immunosuppression reduction (ISR) as PVN treatment. RESULTS: Post-PVN, 3 (27%) patients had five rejection episodes, with 80% being mild. Median time to rejection was 18 (2 to 60) weeks. One hundred percent of patients who experienced post-PVN rejection also experienced rejection pre-PVN. Rejection episode treatments consisted of: none in one, increased tacrolimus in two, IVIG in one, IVIG and increased tacrolimus in one. Median viral loads in patients with post-PVN rejection versus those without rejection were not different in serum (2.01 x 10(4) vs 9.00 x 10(4) BKV copies/mL; P = .22) or urine (5.37 x 10(5) vs 8.93 x 10(6) BKV copies/mL; P = .28). Median BKV antibody titers were slightly lower (16384 vs 32768 HA units; P = .02) and median SCr values were significantly higher (2.7 vs 1.9 mg/dL, P = .0003) in patients who had experienced post-PVN rejection. Graft losses occurred in one rejection-free patient (chronic allograft nephropathy) and in one patient who experienced multiple acute rejection episodes, humoral rejection, and worsening PVN. CONCLUSIONS: Patients who experience rejection prior to PVN are at high risk of developing rejection post-ISR and post-PVN; however, low graft loss rates may still be achieved.
Biopsy↗
Assessment of airway function in young children with asthma: comparison of spirometry, interrupter technique, and tidal flow by inductance plethsmography.
The assessment of airway function in young children requires adaptation of techniques designed for adults and/or application of techniques that do not require complex respiratory maneuvers. We sought to assess two methods of measuring airway function: time to peak expiratory flows as a ratio of expiratory time (T(PTEF)/T(E)), derived from respiratory inductance plethysmography, and total respiratory resistance by the interrupter technique (Rint), both obtained during quiet tidal breathing. Both techniques were referenced to FEV1 and flow at 50% expired volume (FEF50) from conventional spirometry in 30 children aged 4-8 years (median age, 6.9; range, 4.5-8.5 years) with a physician diagnosis of asthma and who were able to perform FEV1 with a repeatability of at least 8%. T(PTEF)/T(E) and Rint were performed in random order followed by spirometry, in order to reduce the possible effects of pulmonary stretch on tidal breathing measures. Coefficients of variation (CV) and mean absolute change/baseline standard deviation were derived for each measurement. Baseline FEV1 did not correlate significantly with T(PTEF)/T(E) (r = 0.025), but did correlate with Rint (r = 0.737, P < 0.001); respective relationships for change after bronchodilator were r = 0.09 (ns) and r = 0.64 (P < 0.001). FEF50 also correlated significantly with Rint (R = 0.769, P < 0.001) but not with T(PTEF)/T(E). FEV1 and FEF50 both increased postbronchodilator, with respective mean changes of 11.4% and 28% (P < 0.001), while Rint decreased by 24.3% (P < 0.001). No significant changes were noted for T(PTEF)/T(E). T(PTEF)/T(E) derived from inductance plethysmography does not detect mild airway obstruction or modest changes in airway caliber following bronchodilator in young children with asthma. The interrupter technique may have a role in assessing baseline airway function and response to therapy in children unable to perform reliable spirometry, and/or when the investigator wishes to avoid the possible influence of forced maneuvers on airway tone.
Age Factors↗
Butt in, butt out: pupils' views on the extent to which staff could and should enforce smoking restrictions.
Schools which enforce a no-smoking policy may experience lower rates of pupil smoking. Little is known, however, about how young people view such restrictions and it has been argued that smoking bans might actually encourage adolescent smoking. This paper presents pupils' views on the extent to which staff could, and should, enforce smoking restrictions. Twenty-five single-sex discussion groups were held with 13-year-old pupils who had been purposively selected from two Scottish secondary schools. Both schools served relatively deprived communities and ostensibly had no-smoking policies, but varied in their pupil smoking rates. The pupils' accounts suggested that staff enforcement could interrupt pupil smoking and discourage smoking on school premises, but did not affect whether or not they actually smoked. Pupils viewed staff efforts as ineffective and felt staff did not always have the authority or status needed to enforce a ban. Differences were found between the schools, but these did not explain the variation in their smoking profiles.
Adolescent↗
A fresh perspective on a rank issue: pupils' accounts of staff enforcement of smoking restrictions.
Evidence on the effectiveness of school-based smoking restrictions on reducing pupil smoking rates is mixed. So far, the effect of such policies has only been considered using quantitative methods and 'level of enforcement' has primarily been measured according to data collected from staff. This qualitative study is based on data collected during 25 discussion groups held with 13-year-old pupils concerning whether and how staff in their school addressed pupil smoking. Groups were conducted in two schools. Both served relatively deprived communities but varied in their pupil smoking rates. Pupils made reference to members of the Senior Management Team, teaching and non-teaching staff. They mentioned a range of possible staff reactions and discussed what factors they felt influenced how staff responded. It appeared that a more proactive, firm line was being taken in the 'high' than in the 'low' smoking school.
Faculty↗
Detection of JC virus-specific cytotoxic T lymphocytes in healthy individuals.
The polyomavirus JC (JCV) infects 85% of healthy individuals, and its reactivation in a limited number of immunosuppressed people causes progressive multifocal leukoencephalopathy (PML), a severe demyelinating disease of the central nervous system. We hypothesized that JCV-specific cytotoxic T lymphocytes (CTLs) might control JCV replication in healthy individuals, blocking the evolution of PML. Using 51Cr release and tetramer staining assays, we show that 8 of 11 HLA-A*0201+ healthy subjects (73%) harbor detectable JCV-specific CD8+ CTLs that recognize one or two epitopes of JCV VP1 protein, the HLA-A*0201-restricted VP1p36 and VPp1100 epitopes. We determined that the frequency of JCV VP1 epitope-specific CTLs varied from less than 1/100,000 to 1/2,494 peripheral blood mononuclear cells. More individuals had JCV VP1-specific than cytomegalovirus-specific CTLs (8 of 11 subjects [73%] versus 2 of 10 subjects [20%], respectively). These results show that a CD8+-T-cell response against JCV is commonly found in immunocompetent people and suggest that these cells might protect against the development of PML.
Adult↗
Fibrates and medroxyprogesterone acetate induce apoptosis of primary Burkitt's lymphoma cells and cell lines: potential for applying old drugs to a new disease.
Current therapies for Burkitt's lymphoma (BL) utilise combined cytotoxic chemotherapy, but these treatments are not always available in areas where the disease is endemic and are also markedly less successful in AIDS-related BL. Therefore, additional therapies are urgently required. We demonstrate here that combined fibrates and MPA exert powerful, antiproliferative actions against well-characterised Daudi, Raji and L3055 BL cell lines and primary BL cells. Detailed studies in L3055 demonstrated that this activity was mediated by induced apoptosis and confirmed by observations that overexpression of the antiapoptotic genes bcl-2 or bcl-x(L) conferred significant protection against the drugs. Importantly, since fibrates and MPA are inexpensive and stable with minimal-associated toxicities, we suggest that these drugs should be considered as adjuncts to currently available treatments for BL in endemic and AIDS-related disease.
Antineoplastic Agents, Hormonal↗
Ifs, maybes and butts: factors influencing staff enforcement of pupil smoking restrictions.
Levels of pupil smoking are reported to be associated with the extent to which school staff consistently enforce smoking restrictions. Little is known, however, about factors which might motivate or discourage staff from doing so. Following analysis of interviews conducted with 27 members of school personnel purposively selected from two Scottish secondary schools serving relatively deprived communities, this paper identifies various issues that hinder staff intervention when confronted with pupil smoking. Both schools had no-smoking policies. In each, staff assumed or understood that smoking within the buildings was forbidden, yet were unsure about how far the bans extended. While the risk of fire in the school buildings prompted staff to intervene when smoking was witnessed indoors, where this risk was absent, decisions were largely context dependent or motivated by personal and professional values. Concerns about staff-pupil relationships, attention to pupils' wider welfare, lack of authority and staff levels of discomfort were salient issues inhibiting intervention. Implications for smoking policies and their enforcement are discussed. The concept of the Health Promoting School is considered in the light of the findings and inherent tensions highlighted.
Adolescent↗
School differences in pupil smoking: a consequence of a trade-off between health and education agendas?
Current policy documents stress that raising standards in education and health are inextricably linked, with schools identified as well placed to advance both agendas. This paper considers these assumptions in the light of data derived from 27 staff interviews conducted in two secondary schools. These schools served relatively disadvantaged communities, but differed in their pupil smoking rates with one school being 'high-smoking', the other 'low-smoking'. It explores whether this difference reflects the differential emphasis placed by each school on education or health. Analysis reveals that the 'low-smoking' school subscribes to holistic values and operates according to a child-centred bottom-up philosophy offering a differentiated programme of pupil support contingent on needs. In contrast, the 'high-smoking' school maintains a narrow focus on educational outcomes, and its high expectations are viewed as running counter to those held by pupils and parents. The contrasting school philosophies bring different unintended consequences. The holistic focus of the low-smoking school is associated with tempered educational expectations, thus conflicting with recommendations in education policies. The singular education focus of the high-smoking school leaves little room for a health agenda, and can overlook and disenfranchise the educationally disinclined. The school systems' impact on pupil engagement may explain their different smoking rates.
Adolescent↗
Expression of JC virus T-antigen in a patient with MS and glioblastoma multiforme.
OBJECTIVE: To investigate the presence of human polyomavirus JC virus genome and the expression of the viral oncoprotein T-antigen in neoplastic cells of a patient with MS and a glioblastoma multiforme. BACKGROUND: The postmortem examination of an immunocompetent patient with a neurologic disorder revealed the concurrence of MS plaques in the white matter of the brain and a glioblastoma multiforme in the region of the thalamus. METHODS AND RESULTS: PCR analysis of DNA from demyelinated plaques and the tumor area using primers derived from specific regions of the JC virus genome revealed the presence of viral DNA corresponding to the viral early and late genes. Further examination of the samples for the JC virus regulatory region identified the presence of sequences identical to JC virus Mad-4 and JC virus W1 viral isolates in the tumor and the demyelinated regions. Results from immunohistochemistry showed the detection of the viral early protein, T-antigen, and the cellular tumor suppressor protein, p53, in the nuclei of neoplastic cells. Interestingly, expression of T-antigen, but not p53, was observed in neurofilament-positive cells with neuronal morphology and in glial fibrillary acidic protein-positive astrocytes in the cortex juxtaposed to the MS plaques. Examination of viral late gene expression by immunohistochemistry showed no evidence for viral capsid proteins, thus ruling out productive replication of JC virus in the tumor and MS demyelinated plaques. CONCLUSIONS: These observations provide molecular and clinical evidence of the association of JC virus in the brain of a patient with concurrent glioblastoma multiforme and MS.
Aged↗
Can global co-operation enhance quality in medical education? Some lessons from an international assessment consortium.
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Education, Medical↗
Genome sequence of the plant pathogen and biotechnology agent Agrobacterium tumefaciens C58.
Agrobacterium tumefaciens is a plant pathogen capable of transferring a defined segment of DNA to a host plant, generating a gall tumor. Replacing the transferred tumor-inducing genes with exogenous DNA allows the introduction of any desired gene into the plant. Thus, A. tumefaciens has been critical for the development of modern plant genetics and agricultural biotechnology. Here we describe the genome of A. tumefaciens strain C58, which has an unusual structure consisting of one circular and one linear chromosome. We discuss genome architecture and evolution and additional genes potentially involved in virulence and metabolic parasitism of host plants.
Agrobacterium tumefaciens↗
Molecular analysis of single colonies reveals a diverse origin of initial clonal proliferation in B-precursor acute lymphoblastic leukemia that can precede the t(12;21) translocation.
The pathogenesis of pediatric B-precursor acute lymphoblastic leukemia is largely unknown, and even with nonrandom chromosomal translocations present, the precise order of clonal molecular events is undefined. We developed an in vitro system using cytokines interleukin (IL)-3, IL-7, IL-10, and FMS-like tyrosine kinase 3 ligand with CD40 ligand-expressing fibroblasts to obtain single blast colonies from which clonal immunoglobulin heavy chain (IgH), T-cell receptor delta gene rearrangements, and, in t(12;21)-positive cases, TEL-AML1 fusion transcripts could be simultaneously PCR amplified. The proliferation of early tumor progenitors increased subclone detection enabling us, in seven diagnostic samples, to determine the stage of differentiation at which each leukemia occurred. Four were derived from the stage before initiation of IgH rearrangement, one during recombination of variable, joining, and diversity segments of the heavy chain gene VDJ(H), and two after completion of IgH rearrangement. Furthermore, analysis of a t(12;21)-positive leukemia with unusually late onset, identified both TEL-AML1-positive and -negative colonies carrying a clonal T-cell receptor delta rearrangement, inferring the presence of clonal expansion before the occurrence of the t(12;21). In contrast, in a typical, early onset t(12;21)-positive leukemia, the t(12;21) appeared to be the first clonal event. In both leukemias, the t(12;21) occurred before recombination of variable, joining and diversity segments of the heavy chain gene VDJ.
B-Lymphocytes↗
beta(2)-microglobulin induces apoptosis in HL-60 human leukemia cell line and its multidrug resistant variants overexpressing MRP1 but lacking Bax or overexpressing P-glycoprotein.
In this study, we examined whether exogenous beta(2)-microglobulin (beta(2)m) can induce apoptosis in the drug sensitive HL-60 leukemia cell line and its drug resistant variants and investigated the molecular mechanism of beta(2)m-induced apoptosis. Our data revealed that beta(2)m is very significantly down-regulated in two multidrug resistant variants of the HL-60 cells: (a) the MRP1-bearing, Bax-deficient HL-60/ADR cell line, and (b) the P-glycoprotein (P-gp) overexpressing HL-60/VCR cell line. However, exogenous beta(2)m induced similar levels of apoptosis in HL-60 cells and these drug resistant variants. beta(2)m-induced apoptosis in HL-60 and HL-60/VCR cells was associated with decreased mitochondrial membrane potential (Deltapsim) but did not affect Deltapsim in HL-60/ADR cells. Surprisingly, cyclosporin A (CsA), a known inhibitor of the mitochondrial permeability transition (MPT) pore, inhibited beta(2)m-induced apoptosis in HL-60/ADR cells but not in HL-60 and HL-60/VCR cells, suggesting that the pro-apoptotic effect of beta(2)m in these cells is not through MPT pore formation. Furthermore, beta(2)m induced the release of cytochrome c and the apoptosis-inducing factor (AIF) from mitochondria in HL-60 and HL-60/VCR cells, but not in HL-60/ADR cells. Additionally, Z-VAD-fmk, a general inhibitor of caspases which inhibited cytochrome c release in HL-60 and HL-60/VCR cells, had no effect on AIF release in any of these cell lines, but inhibited beta(2)m-induced apoptosis in all three cell lines. However, Western blot analysis revealed that caspases-1, -3, -6, -8, and -9 are not activated during beta(2)m-induced apoptosis in these cells. Therefore, beta(2)m-induces apoptosis through an unknown caspase-dependent mitochondrial pathway in HL-60 and HL-60/VCR cells and by a Bax-independent, non-mitochondrial, caspase-dependent pathway in HL-60/ADR cells.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Activation of the IGF-IR system contributes to malignant growth of human and mouse medulloblastomas.
Insulin-like growth factor I receptor (IGF-IR) has been implicated in the normal and malignant growth of many cell types including cells from the central nervous system. In the cerebellar cortex IGF-IR mRNA is found in granular cells and IGF-I stimulation is mitogenic and protects cells from low-potassium-induced apoptosis. Since primitive neuroectodermal tumors/medulloblastomas (PNETs/medulloblastomas) are suspected to originate from the external cerebellar granular layer, it is reasonable to postulate that IGF-IR and/or its signaling molecules may contribute to the transformation of these poorly differentiated cells. To study activation of the IGF-IR system in medulloblastomas, we have utilized an antibody (anti-pY1316) that specifically recognizes the phosphorylated (active) form of the IGF-IR. Medulloblastoma biopsy specimens were positive when examined immunohistochemically with anti-Y1316 antibody. Further analysis of the IGF-IR system was performed in three human (Daoy, TE-671, D283 Med) and four mouse (BsB8, BsB13, Bs-1b, Bs-1c) medulloblastoma cell lines. All the murine cell lines examined express IGF-IR and PI3-kinase at relatively normal levels, and grossly overexpress IRS-1, when compared with normal mouse cerebellum. Within 15 min following IGF-I stimulation both mouse and human cell lines phosphorylate the beta subunit of the IGF-IR, IRS-1, Akt, and MAP kinases. They respond with cell proliferation when stimulated solely with IGF-I and are strongly inhibited when challenged with a dominant negative mutant of the IGF-IR (486/STOP), or with antisense oligonucleotides against the IGF-IR mRNA.
Animals↗
Detection of JC virus DNA sequences and expression of the viral regulatory protein T-antigen in tumors of the central nervous system.
JC virus (JCV) is a neurotropic polyomavirus infecting greater than 70% of the human population worldwide during early childhood. Replication of JCV in brains of individuals with impaired immune systems results in the fatal demyelinating disease, progressive multifocal leukoencephalopathy (PML). Furthermore, JCV possesses an oncogenic potential and induces development of various neuroectodermal origin tumors including medulloblastomas and glioblastomas in experimental animals. The oncogenecity of JCV is attributed to the viral early gene product, T-antigen, which has the ability to associate with and functionally inactivate well-studied tumor suppressor proteins including p53 and pRB: The observations from laboratory animal experiments have provided a rationale for examining the presence of the JCV DNA sequence and expression of the viral oncogenic protein in human brain tumors. We have examined 85 clinical specimens from the United Kingdom, Greece, and the United States, representing various human brain tumors including oligodendroglioma, astrocytoma, pilocytic astrocytoma, oligoastrocytoma, anaplastic astrocytoma, anaplastic oligodendroglioma, glioblastoma multiforme, gliomatosis cerebri, gliosarcoma, ependymoma, and subependymoma, for their possible association with JCV. We performed gene amplification techniques using a pair of primers that recognize the JCV DNA sequence, and we demonstrated the presence of the viral early sequence in 49 (69%) of 71 samples. More importantly, our results from immunohistochemistry analysis revealed expression of JCV T-antigen in the nuclei of tumor cells in 28 (32.9%) of 85 tested samples. These observations, along with earlier in vitro and in vivo data on the transforming ability of this human neurotropic virus invite additional studies to re-evaluate the role of JCV in the pathogenesis of human brain tumors.
Animals↗
Communication and information technology in medical education.
The past few years have seen rapid advances in communication and information technology (C&IT), and the pervasion of the worldwide web into everyday life has important implications for education. Most medical schools provide extensive computer networks for their students, and these are increasingly becoming a central component of the learning and teaching environment. Such advances bring new opportunities and challenges to medical education, and are having an impact on the way that we teach and on the way that students learn, and on the very design and delivery of the curriculum. The plethora of information available on the web is overwhelming, and both students and staff need to be taught how to manage it effectively. Medical schools must develop clear strategies to address the issues raised by these technologies. We describe how medical schools are rising to this challenge, look at some of the ways in which communication and information technology can be used to enhance the learning and teaching environment, and discuss the potential impact of future developments on medical education.
Computer-Assisted Instruction↗
RegA proteins from phage T4 and RB69 have conserved helix-loop groove RNA binding motifs but different RNA binding specificities.
The RegA proteins from the bacteriophage T4 and RB69 are translational repressors that control the expression of multiple phage mRNAs. RegA proteins from the two phages share 78% sequence identity; however, in vivo expression studies have suggested that the RB69 RegA protein binds target RNAs with a higher affinity than T4 RegA protein. To study the RNA binding properties of T4 and RB69 RegA proteins more directly, the binding sites of RB69 RegA protein on synthetic RNAs corresponding to the translation initiation region of two RB69 target genes were mapped by RNase protection assays. These assays revealed that RB69 RegA protein protects nucleotides -9 to -3 (relative to the start codon) on RB69 gene 44, which contains the sequence GAAAAUU. On RB69 gene 45, the protected site (nucleotides -8 to -3) contains a similar purine-rich sequence: GAAAUA. Interestingly, T4 RegA protein protected the same nucleotides on these RNAs. To examine the specificity of RNA binding, quantitative RNA gel shift assays were performed with synthetic RNAs corresponding to recognition elements (REs) in three T4 and three RB69 mRNAs. Comparative gel shift assays demonstrated that RB69 RegA protein has an approximately 7-fold higher affinity for T4 gene 44 RE RNA than T4 RegA protein. RB69 RegA protein also binds RB69 gene 44 RE RNA with a 4-fold higher affinity than T4 RegA protein. On the other hand, T4 RegA exhibited a higher affinity than RB69 RegA protein for RB69 gene 45 RE RNA. With respect to their affinities for cognate RNAs, both RegA proteins exhibited the following hierarchy of affinities: gene 44 > gene 45 > regA. Interestingly, T4 RegA exhibited the highest affinity towards RB69 gene 45 RE RNA, whereas RB69 RegA protein had the highest affinity for T4 gene 44 RE RNA. The helix-loop groove RNA binding motif of T4 RegA protein is fully conserved in RB69 RegA protein. However, homology modeling of the structure of RB69 RegA protein reveals that the divergent residues are clustered in two areas of the surface, and that there are two large areas of high conservation near the helix-loop groove, which may also play a role in RNA binding.
Bacteriophage T4↗