Current awareness in geriatric psychiatry.
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Aged↗
Biomedical subjects
J Gordon
Publications and source records attributed to J Gordon.
Angiogenesis in a patient with ischemic limb induced by intramuscular injection of vascular endothelial growth factor and fibrin platform.
Direct revascularization of critical ischemia of the limb is often unsuccessful due to the anatomic extent and distribution of arterial occlusive disease, and no pharmacologic treatment has proved effective in treating this condition. Patients with ischemic limb may eventually require amputation and may develop serious morbidity and mortality. The goal of limb salvage in these patients has stimulated research into alternative treatment methods, including angiogenesis. Attempts have been made to apply growth factors directly or to encode DNA for such factors, but it is unknown whether these factors remain at the target site long enough to be effective. We report our strategy of using vascular endothelial growth factor in a fibrin network, which enables the sustained release of biologic material at the target site.
Aged↗
Life stress, anger and anxiety, and delinquency: an empirical test of general strain theory.
General strain theory (Agnew 1992) departs from traditional strain theories by emphasizing the role of the individual's affective responses to negative life experiences in fostering deviant behavior. In this analysis, we examine the central hypotheses of general strain theory using data from a three-wave panel study of high school youths in the Boston metropolitan area (N = 939). Covariance structure models reveal that anger and hostility in response to negative life events do play a causal role in fostering more aggressive forms of delinquency, but are not significantly related to either nonaggressive delinquency or marijuana use. Furthermore, the conditional effects predicted by general strain theory, in which the impact of strain on delinquency varies by youths' personal and social resources, are inconsistent. Discussion centers on the prospect of increasing the utility of general strain theory by further imbuing it with concepts and perspectives from the sociology of mental illness.
Adolescent↗
Managing child and adolescent mental health problems: the views of general practitioners.
OBJECTIVE: To investigate issues influencing the role of general practitioners in managing child and adolescent mental health problems. DESIGN: A postal questionnaire survey inviting respondents to rate statements about managing child and adolescent mental health issues. SETTING: Population of urban Scottish general practitioners. SUBJECTS: General practitioner principals. RESULTS: Of the 56% who responded, 31.3% reported that child and adolescent mental health services (CAMHS) were easy to access. Only a minority agreed that users' concerns prevented them from referring to CAMHS, and that these were more likely with young people or parents than with children. The number of respondents who considered their knowledge base, experience or training in this area to be adequate was particularly low. CONCLUSION: There may be a significant mismatch between what is expected of general practitioners in relation to child and adolescent mental health problems and what general practitioners themselves feel they are equipped to deliver.
Adolescent↗
Identification of the RNA binding domain of T4 RegA protein by structure-based mutagenesis.
The T4 translational repressor RegA protein folds into two structural domains, as revealed by the crystal structure (Kang, C.-H. , Chan, R., Berger, I., Lockshin, C., Green, L., Gold, L., and Rich, A. (1995) Science 268, 1170-1173). Domain I of the RegA protein contains a four-stranded beta-sheet and two alpha-helices. Domain II contains a four-stranded beta-sheet and an unusual 3/10 helix. Since beta-sheet residues play a role in a number of protein-RNA interactions, one or both of the beta-sheet regions in RegA protein may be involved in RNA binding. To test this possibility, mutagenesis of residues on both beta-sheets was performed, and the effects on the RNA binding affinities of RegA protein were measured. Additional sites for mutagenesis were selected from molecular modeling of RegA protein. The RNA binding affinities of three purified mutant RegA proteins were evaluated by fluorescence quenching equilibrium binding assays. The activities of the remainder of the mutant proteins were evaluated by quantitative RNA gel mobility shift assays using lysed cell supernatants. The results of this mutagenesis study ruled out the participation of beta-sheet residues. Instead, the RNA binding site was found to be a surface pocket formed by residues on two loops and an alpha-helix. Thus, RegA protein appears to use a unique structural motif in binding RNA, which may be related to its unusual RNA recognition properties.
Bacteriophage T4↗
Detection of human neurotropic JC virus DNA sequence and expression of the viral oncogenic protein in pediatric medulloblastomas.
Medulloblastoma represents greater than 25% of childhood intracranial neoplasms and is considered a highly malignant tumor. This tumor, which arises predominantly in the cerebellar vermis, preferentially affects children between the ages of 5 and 15. Although the etiology of medulloblastomas in humans remains unknown, results from several experiments have indicated that the human neurotropic JC virus (JCV) is able to induce cerebellar neoplasms in rodents that exhibit a phenotype similar to that of human medulloblastomas. JCV is a polyomavirus that is widespread in the human population, with infection occurring most frequently in early childhood. In this study, we have examined the possible association of JCV with human medulloblastomas. By using PCR techniques we demonstrate that 11 of 23 samples of tumor tissue contain DNA sequences corresponding to three different regions of the JCV genome. More importantly, we demonstrate the presence of DNA sequences encoding the N- and C-terminal regions of the JCV oncogenic protein, T antigen, in 11 of 23 samples and the production of T antigen in the nuclei of 4 samples of tumor tissue. These observations provide evidence for a possible association of JCV with human medulloblastomas.
Adolescent↗
Human neurotropic JC virus early protein deregulates glial cell cycle pathway and impairs cell differentiation.
Progressive multifocal leukoencephalopathy (PML), a human demyelinating disease of the central nervous system (CNS), is induced upon replication of the human neurotropic virus, JCV, in glial cells. Similar to other polyomaviruses, replication of JCV is initiated and orchestrated by the viral early protein, T-antigen, and results in the cytolytic destruction of oligodendrocytes, the subset of glial cells responsible for myelin production, and the appearance of bizarre astrocytic glial cells in affected individuals. Earlier results from studies in transgenic animals have suggested that in the absence of viral replication, expression of JCV T-antigen induces pathology consistent with hypomyelination of the brain. These observations suggest that JCV T-antigen has the ability to deregulate oligodendrocyte and perhaps astrocyte function in the CNS. Here we demonstrate that expression of JCV T-antigen in the bipotential glial cell line, CG-4, severely affects the ability of these cells to differentiate toward oligodendrocyte and astrocyte lineages as evidenced by their distinct morphological changes. Examination of the activity of cell cycle regulatory proteins including cyclins and their associated kinases reveals that in the absence of T-antigen, differentiation of CG-4 cells toward astrocytes and oligodendrocytes is accompanied by a decline in cyclin E, cdk2, cyclin A, and cyclin B activity. In contrast, cdc2 activity increased upon CG-4 differentiation. In T-antigen-producing cells, distinct variations in the activity of several cyclins was observed. For example, while the activity of cdk2 and cyclin E was enhanced in T-antigen expressing astrocytes compared to their levels in control cells, the activity of cdc2 was decreased in this cell type. In oligodendrocytes, expression of T-antigen decreased the activity of several cyclins and cdks including cyclin E and cdc2. On the other hand, the level of expression and activity of cyclin A was increased. Thus, it is evident that JCV T-antigen deregulates several important cell cycle regulators during CG-4 differentiation, and these alterations may contribute to the process of cell growth and differentiation in glial cells. The importance of our findings with regard to the neuropathogenesis of PML is discussed.
Antigens, Polyomavirus Transforming↗
The extrafollicular-to-follicular transition of human B lymphocytes: induction of functional globotriaosylceramide (CD77) on high threshold occupancy of CD40.
Amongst lymphocytes, expression of CD77 (globotriaosylceramide, Gb3) is exclusive to B cells of the germinal center (GC). Its acquisition by extrafollicular B cells may thus herald their commitment to a follicular response. Here we show that high threshold occupancy of CD40 by its cognate ligand (CD40L) promotes rapid induction of CD77 expression in non-GC (CD38(lo)) B cells. The kinetics of CD77 acquisition mirrored those of GC-related markers CD95 and CD86 but contrasted with the more delayed increase in CD38 expression. Induction of CD77 was not a simple consequence of cell cycle entry: other conditions of stimulation equally capable of driving proliferation failed to promote CD77 expression. CD77 was functional in that cells were now sensitive to Verotoxin-1, an Escherichia coli-derived ligand of Gb3. These data indicate that acquisition by extrafollicular B cells of CD77 results from high threshold occupancy of CD40, a situation that should be reached physiologically only once a critical level of T cell priming has been achieved.
ADP-ribosyl Cyclase↗
The interplay between T helper subset cytokines and IL-12 in directing human B lymphocyte differentiation.
This study asks how T helper (TH) subset cytokines impact upon IL-12-directed change in B cells engaged in signaling via the B cell receptor and CD40, essential components in the initiation of T-dependent B cell responses. For B cells stimulated in this way, IL-12 promoted a distinct phenotype highlighted by the hyper-expression of CD38: the Th1 cytokine IFN-gamma reproduced the IL-12 effects while neutralizing antibody to IFN-gamma reversed IL-12-dependent change. The divergent pathway of differentiation promoted by the Th2 cytokine IL-4 (characterized by hyper-induction of CD23) was left unchecked by IL-12. IL-10 was found to dampen IL-12 actions by suppressing IL-12-dependent IFN-gamma production but failed to perturb the effects of exogenous IFN-gamma. Thus, IL-12--by invoking autocrine IFN-gamma production--promotes phenotypic deviation in B cells engaging T-dependent signals. The reversal of such Th1 driving of B cells by IL-10 only when the source of IFN-gamma is endogenous and the inability of IL-12 to impact upon IL-4-directed differentiation suggest a progressive and hierarchical commitment of B cells to polarization during a developing T-dependent response dominated at the level of the Th cell rather than that of the dendritic cell.
B-Lymphocytes↗
Utililization of experimental animal model for correlative multispectral MRI and pathological analysis of brain tumors.
Magnetic resonance imaging is the method of choice for non-invasive detection and evaluation of tumors of the central nervous system. However, discrimination of tumor boundaries from normal tissue, and the evaluation of heterogeneous lesions have proven to be limitations in traditional magnetic resonance imaging. The use of post-image acquisition processing techniques, such as multispectral tissue segmentation analysis, may provide more accurate clinical information. In this report, we have employed an experimental animal model for brain tumors induced by glial cells transformed by the human neurotropic JC virus to examine the utility of multispectral tissue segmentation for tumor cell identification. Six individual tissue types were discriminated by segmentation analysis, including heterogeneous tumor tissue, a clear demarcation of the boundary between tumor and non-tumor tissue, deep and cortical gray matter, and cerebrospinal fluid. Furthermore, the segmentation analysis was confirmed by histopathological evaluation. The use of multispectral tissue segmentation analysis may optimize the non-invasive determination and volumetric analysis of CNS neoplasms, thus providing improved clinical evaluation of tumor growth and evaluation of the effectiveness of therapeutic treatments.
Animals↗
Epitope-dependent synergism and antagonism between CD40 antibodies and soluble CD40 ligand for the regulation of CD23 expression and IgE synthesis in human B cells.
BACKGROUND: The induction of IgE synthesis in naive B cells requires two T-cell-derived signals: one delivered through CD40 and the other via interleukin-4 (IL-4). The natural counterstructure to CD40 is the CD40 ligand (CD40L). We have asked about the interplay between CD40L and CD40 mAb that recognize distinct epitopes in delivering signals for regulating IL-4-dependent IgE synthesis and the expression of CD23, the low-affinity IgE receptor, in resting B cells. METHODS: After culture of purified human tonsillar B cells with CD40 agonists and IL-4, surface CD23 was determined by flow cytometric analysis. CD23 levels in cell lysates and supernatants were quantified by ELISA, as were those of secreted IgE. RESULTS: With regard to both induction of CD23 and IgE production, soluble CD40L trimer (sCD40LT) showed synergistic interaction with two mAb to CD40 which bind to epitopes located outside the ligand binding site (EA5 and 5C3), but not with a mAb (G28-5) which effectively competes for CD40L binding to CD40. Each of the two noncompeting mAb to CD40 was able to cooperate strongly with sCD40LT in promoting high-level induction of CD23 even in the absence of IL-4, an effect mirrored in the promotion of strong homotypic clustering and high-rate DNA synthesis. G28-5, uniquely, induced a down-regulation in IL-4-induced CD23 expression with time, a change that was accompanied by an increase in the amount of soluble CD23 detected. While the two noncompeting mAb consistently synergized with sCD40LT for the promotion of IL-4-dependent IgE synthesis, sCD40LT and G28-5 (which, by itself, was the most potent of the CD40 mAb at inducing IL-4-dependent IgE production) exhibited mutual antagonism in this regard, the level of which could be quite profound. CONCLUSIONS: This study demonstrates that appropriate targeting of CD40 can modulate IgE synthesis either positively or negatively.
Antibodies, Monoclonal↗
Fluid percussion brain injury exacerbates glutamate-induced focal damage in the rat.
The role of glutamate-mediated neuronal damage in neurotrauma remains controversial. The cerebral levels measured in patients by microdialysis are sufficient to kill neurons in culture, but not in the intact brain of the normal rat. A synergistic effect between excitatory amino acid-mediated damage and other posttrauma mechanisms must therefore be proposed, if glutamate is indeed a significant cause of posttraumatic brain damage. The presence of such a synergistic mechanism was therefore investigated by combining in vivo glutamate perfusion and fluid percussion injury (FPI). Twenty-four adult male Sprague Dawley rats were randomly assigned to three groups: (1) vehicle (n = 9): mock cerebrospinal fluid (CSF) perfusion plus FPI; (2) glutamate + FPI (n = 9): 0.1 M glutamate intracortical perfusion plus FPI; and (3) glutamate without FPI (n = 6). After preparation for central FPI, at a moderate level of injury (2 +/- 0.5 atm), glutamate or mock CSF perfusion was performed via a CMA/12 microdialysis probe (3 mm). Animals were then perfusion fixed, under deep anesthesia, after 3-h survival, for volumetric histopathology. The glutamate perfusion + FPI group (2.42 +/- 1.63 mm3) produced a significantly bigger lesion than mock CSF perfusion + FPI (0.063 +/- 0.41 mm3) and glutamate perfusion alone (1.00 +/- 0.47 mm3). Traumatic brain injury thus seems to enhance glutamate-mediated brain damage, and this may be due to qualitative changes induced in ion channels and receptors, such as the N-methyl-D-aspartate channel, after shear injury.
Animals↗
Influencing antibiotic prescribing in general practice: a trial of prescriber feedback and management guidelines.
BACKGROUND: The extent of use of antibiotics to treat upper respiratory infections in general practice is an area for concern due to the increasing problem of bacterial resistance. Effective educational strategies to promote rational prescribing are needed. OBJECTIVES: We aimed to examine the effectiveness of prescriber feedback and management guidelines in reducing antibiotics prescribing by GP trainees for undifferentiated upper respiratory tract infection, and in improving the choice of antibiotic for tonsillitis/streptococcal pharyngitis. The research tested a stepwise approach to targeting educational input to high prescribers. METHOD: General Practice trainees in New South Wales (n = 157) were randomly allocated to a treatment group (n = 78) which received an education intervention on antibiotic use, or to a control group (n = 79) which received an intervention on an unrelated topic. Trainees completed three practice activity surveys, each of 110 consecutive patient encounters, with 6-month intervals between surveys. Prescriber feedback and management guidelines on use of antibiotics for URTI and choice of antibiotic for tonsillitis/streptococcal pharyngitis were delivered in a written form between surveys 1 and 2. An educational outreach visit to high prescribers occurred between surveys 2 and 3. Outcome measures were the rate of antibiotic prescribing for all indications, for URTI and prescribing of select antibiotics for tonsillitis/streptococcal pharyngitis. RESULTS: Antibiotic prescribing by the intervention group declined over three occasions from 25.0 to 23.3 to 19.7 per 100 URTI problems, while the control group increased from 22.0 to 25.0 to 31.7 per 100 URTI problems (P = 0.002). Prescribing in agreement with accepted guidelines for tonsillitis/streptococcal pharyngitis increased over time in the intervention group from 55.6 to 69.8 to 73.0 per 100 problems, but decreased in the control group from 59.6 to 57.5 to 58.5 (P = 0.05). CONCLUSION: Prescriber feedback and management guidelines were shown to influence antibiotic prescribing for URTI and choice of antibiotic for tonsillitis/streptococcal pharyngitis. This study provides a model for targeting educational input to those prescribers who most need to change their behaviour.
Analysis of Variance↗
Minimal cross-linking and epitope requirements for CD40-dependent suppression of apoptosis contrast with those for promotion of the cell cycle and homotypic adhesions in human B cells.
Eight different CD40 mAb shared with soluble trimeric CD40 ligand (sCD40LT) the capacity to rescue germinal center (GC) B cells from spontaneous apoptosis and to suppress antigen receptor-driven apoptosis in group I Burkitt's lymphoma cells. Three mAb (G28-5, M2 and M3) mimicked sCD40LT in its ability to promote strong homotypic adhesion in resting B cells, whereas others (EA5, BL-OGY/C4 and 5C3) failed to stimulate strong clustering. Binding studies revealed that only those mAb that promoted strong B cell clustering bound at, or near to, the CD40L binding site. While all eight mAb and sCD40LT were capable of synergizing with IL-4 or phorbol ester for promoting DNA synthesis in resting B cells, co-stimulus-independent activation of the cells into cycle through CD40 related directly to the extent of receptor cross-linking. Thus, mAb which bound outside the CD40L binding site synergized with sCD40LT for promoting DNA synthesis; maximal levels of stimulation were achieved by presenting any of the mAb on CD32 transfectants in the absence of sCD40LT or by cross-linking bound sCD40LT with a second antibody. Monomeric sCD40L, which was able to promote rescue of GC B cells from apoptosis, was unable to drive resting B cells into cycle. These studies demonstrate that CD40-dependent rescue of human B cells from apoptosis requires minimal cross-linking and is essentially epitope independent, whereas the requirements for promoting cell cycle progression and homotypic adhesion are more stringent. Possible mechanisms underlying these differences and their physiological significance are discussed.
Apoptosis↗
AR-R17779, and alpha7 nicotinic agonist, improves learning and memory in rats.
Nicotinic acetylcholine systems have been found to be important for learning and memory function. The prototypic nicotinic agonist nicotine has been shown in a variety of studies to improve aspects of cognitive function. The specific involvement of nicotinic receptor subtypes is now being investigated. The involvement of alpha7 nicotinic receptors was assessed in this project using a novel alpha7 nicotinic agonist, AR-R 17779. Repeated doses (subcutaneous injection 20 min before testing) of the racemic mixture AR-R 13489 and its active isomer AR-R 17779 were assessed in adult female Sprague-Dawley rats using the eight-arm radial maze. AR-R 13489 (2 mg/kg) caused a significant improvement of long-term win-shift acquisition after 3 weeks of training (n = 10 per group). The same dose of AR-R 17779 also caused a significant improvement in repeated acquisition within each daily session in the radial-arm maze. In another study, the active isomer AR-R 17779 significantly improved radial-arm maze working memory function in rats with lesions to the septohippocampal projection. Fimbria-fornix lesions significantly impaired working memory performance and AR-R 17779 significantly reversed that impairment. These studies showed that alpha7 nicotinic agonist treatment improved learning in two radial-arm maze tasks and reversed working memory impairment caused by fimbria-fornix sections, providing evidence for alpha7 involvement in learning and memory, and the potential therapeutic use of AR-R 17779.
Animals↗
Comparison of phacotrabeculectomy with 5-fluorouracil, mitomycin-C, and without antifibrotic agents.
BACKGROUND AND OBJECTIVE: To evaluate the potential benefits, complications, and prognostic risk factors for failure of phacotrabeculectomy performed with or without 5-fluorouracil (5-FU) and mitomycin-C (MMC). PATIENTS AND METHODS: Retrospective chart review of 78 patients who underwent phacotrabeculectomy during a 2-year period. Patients were divided into 3 groups, those who received 5-FU (N = 28). MMC (N = 29), or no antifibrotic agent (N = 21). RESULTS: All 3 groups had statistically significant lower intraocular pressures (IOP) on fewer antiglaucomatous medications at 6-month, 12-month, and last follow-up compared to preoperative levels (P < .05). Intraocular pressures were lower in the group that received MMC compared to the 5-FU group, but not in the group that did not receive antimetabolites, at all time intervals measured (P < .05). Black race was a strong predictor of failure of trabeculectomy (P = 009). No differences in final visual acuity or complications were found between groups. CONCLUSIONS: Phacotrabeculectomy is effective regardless of antimetabolite use. Race is a strong predictor of failure.
Aged↗
Sex and attitude: a randomized vignette study of the management of depression by general practitioners.
BACKGROUND: The management and detection of depression varies widely, and the causes of variation are incompletely understood. AIMS: To describe and explain general practitioners' (GPs') current practice in the recognition and management of depression in young adults, their attitudes towards depression, and to investigate associations of GP characteristics and patient sex with management. METHOD: All GP principals in the Greater Glasgow Health Board were randomized to receive questionnaires with vignettes describing increasingly severe symptoms of depression in either male or female patients, and asked to indicate which clinical options they would be likely to take. The Depression Attitude Questionnaire was used to elicit GP attitudes. RESULTS: As the severity of vignette symptoms increased, GPs responded by changing their prescribing and referral patterns. For the most severe vignette, the majority of GPs would prescribe drugs (76.4%) and refer the patient for further help (73.7%). Male and female patients were treated differently: GPs were less likely to ask female patients than male patients to attend a follow-up consultation (odds ratio [OR] = 0.55), and female GPs were less likely to refer female patients (OR = 0.33). GPs with a pessimistic view of depression, measured using the 'inevitable course of depression' attitude scale, were less willing to be actively involved in its treatment, being less likely to discuss a non-physical cause of symptoms (OR = 0.77) or to explore social factors in moderately severe cases (OR = 0.68). CONCLUSIONS: Accepting the limitations of the method, GPs appear to respond appropriately to increasingly severe symptoms of depression, although variation in management exists. Educational programmes should be developed with the aim of enhancing GP attitudes towards depression, and the effects on detection and management of depression should be rigorously evaluated.
Attitude of Health Personnel↗
Silica-induced pulmonary inflammation in rats: activation of NF-kappa B and its suppression by dexamethasone.
The goal of this study was to examine the relationship of the transcriptional regulatory factor nuclear factor-kappaB (NF-kappa B) to the early inflammatory events involved with silica exposure. Male F-344 rats received an intratracheal (i.t.) instillation of silica (100 mg/kg in a volume of 1 ml/kg) of saline. At 1, 3, 6, and 18 h postinstillation, and the rats were sacrificed and underwent bronchoalveolar lavage (BAL) for functional analysis of inflammation. Beginning at 1 h postinstillation, the silica-instilled (Si) rats displayed significant increases in neutrophils in BAL fluid compared to the saline controls. BAL cells from the Si group displayed a significant increase in luminol-dependent chemiluminescence (LDCL) compared to the controls. NF-kappa B activation was measurable at 3 h postinstillation, and this activation continued throughout the 18-h time course. Treatment with dexamethasone (5 mg/kg) at -3 h prior to silica instillation, at the time of instillation (0 h), and +1.5 h postinstillation resulted in both a reduction in NF-kappa B expression (by 70%) at 3 h postinstillation and corresponding reductions in LDCL, BAL cell count, and BAL neutrophils. These results show that activation of NF-kappa B is associated with silica-induced pulmonary inflammation, and the inhibition of its activation correlates temporally with suppression of inflammation.
Animals↗