Biomedical subjects
Publications and source records attributed to D Wakefield.
A young man is presented who developed an akinetic-rigid syndrome shortly after a minor illness. Rituals and stereoptypies were prominent. At its most severe he was unable to feed himself. There was no response to L-dopa/cardopa treatment. A course of ECT was followed by a marked improvement in his condition. Attempts to stop ECT for more than a week have led to recurrence of his bradykinesia.
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Our aim was to determine the relationships between interleukin-6 and immunoglobulin levels within small intestinal luminal secretions. Twenty adult subjects with small intestinal bacterial overgrowth (N = 13), irritable bowel syndrome (N = 4), and nonulcer dyspepsia (N = 3) underwent endoscopic aspiration of secretions from the small intestinal mucosal surface for assessment of IL-6, IgA1, IgA2, IgM, IgG1, IgG2, IgG3, and IgG4 concentrations. Serum immunoglobulin concentrations and small intestinal histology were also determined. IgA2 and IgG3 were the predominant IgA and IgG subclasses in luminal secretions in 19/20 (95%) and 20/20 (100%) subjects, respectively. IgA1 and IgG1 predominated in serum in all subjects. No subject had villous atrophy. Luminal IL-6 concentrations correlated significantly with luminal IgA2, IgM, and IgG3 concentrations but not with IgA1 or any other IgG subclass levels. Conversely, luminal IL-6 or immunoglobulin concentrations did not correlate significantly with levels of any immunoglobulin isotype in serum. These observations suggest that important relationships exist between local IL-6 and IgA2, IgM, and IgG3 responses in human small intestinal luminal secretions. Local investigation is mandatory when assessing intestinal immune activity.
OBJECTIVE: To investigate the expression and source of chemokines in minor salivary gland biopsies (MSGs) in patients with Sjögren's syndrome (SS). METHODS: Immunohistochemical analysis was used to determine the pattern of chemokine expression in MSGs from patients with (n=6) and without (n=5) SS, as well as to examine the phenotype of both resident and infiltrating cells expressing chemokines. RESULTS: Significant differences in the number of infiltrating mononuclear (MN) cells in patients with and without SS were noted. Ductal epithelial cells of SS biopsies expressed significantly increased levels of macrophage inflammatory protein (MIP)-1alpha, MIP-1beta, interleukin-8 (IL-8) and RANTES (Regulated upon Activation, Normal T cell Expressed and Secreted). Biopsies from patients with SS showed that MIP-1beta was expressed by 51% of infiltrating cells, while 41% expressed MIP-1alpha, whereas 22 and 7% expressed RANTES and IL-8, respectively. CONCLUSION: Chemokines expressed by ductal epithelial cells may attract circulating leucocytes, in particular CD4+ T cells, towards the site of inflammation, thereby orchestrating the influx of MN cells characteristically seen in MSGs in SS. Chemokines may be induced directly by a putative triggering agent for SS, or secondary to the release of pro-inflammatory cytokines produced by epithelial cells. These findings further implicate epithelial cells as playing a major role in the pathogenesis of SS and implicate chemokines in the leucocyte recruitment in this setting.
OBJECTIVE: The aim of this paper is to explore the longitudinal relationships between physical and psychological symptoms and immunological factors following acute infective illnesses. METHOD: Preliminary data from a prospective investigation of patients with serologically proven acute infectious illnesses due to Epstein-Barr virus (EBV), Ross River virus (RRV) or Q fever are reported. Patients were assessed within 4 weeks of onset of symptoms and then reviewed 2 and 4 weeks later. Physical illness data were collected at interview. Psychological and somatic symptom profiles were assessed by standardised self-report questionnaires. Cell-mediated immune (CMI) function was assessed by measurement of delayed-type hypersensitivity (DTH) skin responses. RESULTS: Thirty patients who had been assessed and followed over the 4-week period (including 17 patients with EBV, five with RRV and eight with Q fever) were included in this analysis. During the acute phase, profound fatigue and malaise were the most common symptoms. Classical depressive and anxiety symptoms were not prominent. Initially, 46% of cases had no DTH skin response (i.e. cutaneous anergy) indicative of impaired cellular immunity. Over the 4-week period, there was a marked improvement in both somatic and psychological symptoms, although fatigue remained a prominent feature in 63% of subjects. The reduction in reported fatigue was correlated with improvement in the DTH skin response (p = 0.001) and with improvement in General Health Questionnaire (GHQ) scores (p < 0.01). CONCLUSIONS: Acute infectious illnesses are accompanied by a range of nonspecific somatic and psychological symptoms, particularly fatigue and malaise rather than anxiety and depression. Although improvement in several symptoms occurs rapidly, fatigue commonly remains a prominent complaint at 4 weeks. Resolution of fatigue is associated with improvement in cell-mediated immunity.
OBJECTIVE: The aim of this study is to review research examining an immunological basis for chronic fatigue syndrome (CFS) and to discuss how a disturbance in immunity could produce central nervous system (CNS)-mediated symptoms. METHOD: Data relevant to the hypothesis that abnormal cytokine release plays a role in the pathogenesis of CFS are reviewed as well as recent evidence relating to potential mechanisms by which immune products may enter the brain and produce a disturbance in CNS processes. RESULTS: Examinations of cytokine levels in patients with CFS have produced inconclusive results. Recent evidence suggests that abnormal release of cytokines within the CNS may cause neural dysfunction by a variety of complex mechanisms. CONCLUSION: Neuropsychiatric symptoms in patients with CFS may be more closely related to disordered cytokine production by glial cells within the CNS than to circulating cytokines. This possibility is discussed in the context of unresolved issues in the pathogenesis of CFS.
Tumor necrosis factor-alpha (TNF-alpha) is a potent pro-inflammatory cytokine and mediator of the inflammatory response. It has been implicated in the pathogenesis of many inflammatory disorders, including rheumatoid arthritis (RA), septic shock, and Crohn's disease. Using a specific anti-human TNF-alpha antibody we detected immunoreactivity for this cytokine in the cytoplasm of inflammatory cells in several chronic inflammatory disorders, including RA, scleritis, and polyarteritis nodosa. These cells were identified predominantly as IgG-expressing plasma cells. Lymph nodes from patients with Hodgkin's lymphoma and breast cancer, but not from control subjects, were also found to contain TNF-alpha-positive plasma cells. Cultured EBV-B lymphocytes and a human plasma cell line (ARH-77) when stimulated with phorbol myristate acetate demonstrated cytoplasmic TNF-alpha immunoreactivity. Western blot analysis of cell membranes and conditioned media from both cell types revealed the presence of the 26-kDa membrane-bound from and the 17-kDa soluble from of TNF-alpha, respectively. TNF-alpha was quantitated by enzyme-linked immunosorbent assay and found to be biologically active as determined by the L929 cytotoxicity assay. This is the first demonstration that plasma cells may be capable of modulating immune and inflammatory responses, not only by antibody production, but also by their secretion of a key inflammatory mediator, TNF-alpha.
PURPOSE: To determine whether the reported therapeutic benefit of intravenous immunoglobulin in patients with chronic fatigue syndrome (CFS) is dose dependent. PATIENTS AND METHODS: Ninety-nine adult patients, who fulfilled diagnostic criteria for CFS, participated in this double-blind, randomized, and placebo-controlled trial. Patients received intravenous infusions with either a placebo solution (1% albumin) or one of three doses of immunoglobulin (0.5, 1, or 2 g/kg) on a monthly basis for 3 months, followed by a treatment-free follow-up period of 3 months. Outcome was assessed by changes in a series of self-reported measures (quality-of-life visual analog scales, standardized diaries of daily activities, the profile of mood states questionnaire) and the Karnofsky performance scale. Cell-mediated immunity was evaluated by T-cell subset analysis and delayed-type hypersensitivity (DTH) skin testing. RESULTS: No dose of intravenous immunoglobulin was associated with a specific therapeutic benefit. Adverse reactions, typically constitutional symptoms, were reported by 70% to 80% of patients, with no relationship to immunoglobulin treatment. CONCLUSIONS: Intravenous immunoglobulin cannot be recommended as a therapy for the treatment of CFS. A better understanding of the pathophysiology of this disorder is needed before effective treatment can be developed.
It is unknown whether bacteriolysis due to luminal complement activation contributes to local defense mechanisms against small intestinal bacterial overgrowth, particularly with gram-negative bacteria. This study addressed this issue. Thirty adult subjects were investigated with culture of luminal secretions adherent to proximal small intestinal mucosa. Luminal and plasma concentrations of C3 and C3d and C3d/C3 ratios were determined. Activated terminal complement complex was sought in surface epithelium to which aspirated secretions had been adherent. Small intestinal bacterial overgrowth with gram-negative bacteria was present in 12/30 (40.0%) subjects. C3, C3d, and C3d/C3 profile indicated that increased local but not systemic C3 activation occurs in this group. Conversely, no activation of terminal complement complex was evident in this circumstance. Thus, complement-mediated bacteriolysis is unlike to contribute to local defense mechanisms against small intestinal bacterial overgrowth, even when overgrowth flora includes gram-negative bacteria. Factors preventing full local activation of the complement cascade in this circumstance require investigation.
PURPOSE: The aim of this study was to define the expression of chemoattractant cytokines (chemokines) in human aqueous humor, obtained from patients with idiopathic acute anterior uveitis (AU). The chemokines assayed included macrophage inflammatory proteins-1 alpha and -1 beta (MIP-1 alpha and -1 beta), monocyte chemoattractant protein-1 (MCP-1), interleukin-8 (IL-8), interferon-inducible protein-10 (IP-10), and regulated on activation, normal T-expressed and secreted (RANTES). METHODS: We studied fifteen patients (7 females) with idiopathic acute AU, at various stages of disease activity, and two control subjects undergoing elective cataract extraction. Aqueous humor was collected under aseptic conditions, after obtaining informed consent. Chemokine concentrations were measured using specific ELISA. Correlation was sought between chemokine concentrations and disease activity, evaluated by slit lamp biomicroscopy and graded using a standardized scale of disease severity. RESULTS: IL-8 was detected (35.9 +/- 13.6, mean +/- SE) in three of seven subjects in active, untreated stages of AU (clinical score 2-4), and it was undetectable in subjects sampled in the quiescent phase of the disease. IP-10 had a mean concentration of 40.6 ng/ml +/- 20.9 in the active group (N = 7), declining to 0.8 ng/ml +/- 0.3 in the samples from patients with inactive disease (N = 7, P = 0.001). Similarly, substantial expression of MCP-1 was noted, with a maximum concentration of 145 ng/ml, in acute (active) AU (N = 6), (26.7 +/- 19.7), falling to undetectable levels in those with inactive disease, and in control subjects (P = 0.001). MIP-1 beta (N = 7), (3.4 +/- 1.5, P = 0.001) and RANTES (N = 7, 8.8 +/- 4.2) levels were significantly increased in acute disease (P = 0.001) and related to the activity of the disease, although the concentrations were not as high as MCP-1, IP-10 and IL-8. IP-10, RANTES and MIP-1 beta were detected at low concentrations in the aqueous humor of the control subjects. CONCLUSIONS: This is the first study of chemokine concentrations in the aqueous humor of patients with acute anterior uveitis. The concentration of chemokines: IL-8, IP-10, MCP-1, RANTES and MIP-1 beta were significantly increased during the active stages of AU, and correlated with the clinical severity of the disease. These chemoattractant cytokines probably play a critical role in leucocyte recruitment in acute AU.
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PURPOSE: To illustrate the spectrum of sarcoidosis involving the eye and brain and the difficulties of confirming its clinical diagnosis. METHODS: The presentation of two unusual case reports of patients with ocular and cerebral involvement with sarcoidosis. RESULTS: Tissue biopsy, an essential component in the differential diagnosis, was required to confirm the diagnosis of sarcoidosis in each patient. CONCLUSIONS: Sarcoidosis remains an enigmatic disease with protean manifestations and widely differing outcomes.
OBJECTIVE: To localise and characterise follicular dendritic cells (FDC) present in autoimmune lesions of primary Sjögren syndrome. METHODS: Cryostat sections of labial salivary glands from 15 patients with primary Sjögren syndrome were examined by an indirect immunoperoxidase technique and monoclonal antibodies to a panel of dendritic cell markers. Tonsils from two controls were also examined for the same markers. RESULTS: FDC were localised in the centre of 75% of lymphoid focal structures in labial salivary glands biopsies. FDC in labial salivary glands of patients with primary Sjögren syndrome expressed CD35, CD11c, and CD106 (VCAM-1) in a pattern similar to FDC in tonsils, but they did not express either CD14 or CD11b. This indicates that they may not be of myeloid origin, while FDC in tonsillar lymphoid follicles strongly expressed both CD14 and CD11b. FDC in labial salivary glands of patients also lacked VLA-2 alpha and VLA-3 alpha, which were expressed by FDC in tonsils. CONCLUSIONS: The characteristic phenotype and origin of these cells may be of importance in the immune responses involved in Sjögren syndrome and the retention of infiltrating lymphocytes in the glands.
BACKGROUND: Patients with chronic fatigue syndrome (CFS) report neuro-psychological symptoms as a characteristic feature. We sought to assess cognitive performance in patients with CFS, and compare cognitive performance and subjective workload experience of these patients with that of two disease comparison groups (non-melancholic depression and acute infection) and healthy controls. METHOD: A computerized performance battery employed to assess cognitive functioning included tests of continuous attention, response speed, performance accuracy and memory. Severity of mood disturbance and subjective fatigue were assessed by questionnaire. RESULTS: All patient groups demonstrated increased errors and slower reaction times, and gave higher workload ratings than healthy controls. Patients with CFS and non-melancholic depression had more severe deficits than patients with acute infection. All patient groups reported more severe mood disturbance and fatigue than healthy controls, but patients with CFS and those with acute infection reported less severe mood disturbance than patients with depression. CONCLUSIONS: As all patients demonstrated similar deficits in attention and response speed, it is possible that common pathophysiological processes are involved. The differences in severity of mood disturbance, however, suggest that the pathophysiological processes in patients with CFS and acute infection are not simply secondary to depressed mood.
OBJECTIVE: To highlight the potential role of molecular biological studies in examining the expression of genes of interest in brain tissue to elucidate the pathophysiological basis of the major psychoses. METHOD: To review the principles underlying the available techniques for expression studies. RESULTS: Detection of messenger RNA by in situ hybridisation and quantitation by Northern analysis are powerful tools to detect abnormalities in gene expression in brain tissue. CONCLUSION: The availability of simple techniques to examine the expression of RNA and protein products of individual genes, including examination at the level of individual cells, offers a clear opportunity to define the molecular basis of the major psychoses.
OBJECTIVE: There is increasing acceptance that schizophrenia is associated with a generalised disorder in cortical neurodevelopment. The aim of this paper is to review the evidence that this disorder may be accounted for by abnormalities in mechanisms mediated by the main family of excitatory neuroreceptors in cortical brain systems, the N-methyl-D-aspartate (NMDA) glutamatergic receptors. METHOD: The neurobiological evidence is presented for an abnormality in cortical development related to synaptic pathology in schizophrenia. The unique functions of the NMDA receptor in information processing are described, especially its role in learning and memory, and in neural plasticity and brain development. It is argued that the cellular and molecular mechanisms which underlie learning and memory also govern normal brain development. Studies examining abnormalities in glutamatergic transmission in schizophrenia are reviewed. RESULTS: There is a substantial literature in support of the possibility that NMDA receptor abnormalities may be involved in the neurodevelopmental predisposition to schizophrenia, as well as in symptom production. CONCLUSIONS: Research to determine the role of the NMDA receptor in the pathophysiology of schizophrenia is warranted and now feasible. To be successful, this research will require the application of molecular biology techniques to postmortem brain tissue studies, in addition to traditional histochemical approaches.
OBJECTIVE: To describe the rationale for investigating the dopaminergic system in patients with melancholia by applying molecular biological (notably, in situ hybridisation) and histopathological techniques in postmortem brain tissue. METHOD: Relevant advances in the functional neuroanatomy of frontostriatal circuits, as well as insights from clinical neuroimaging studies in primary and secondary depressive disorders, are presented. These are integrated with developments in the pharmacological and molecular characteristics of dopamine receptor subtypes and recognition of their selective anatomical distribution. RESULTS: Converging data from the basic and clinical neurosciences suggest that the pathophysiology of depressive disorders characterised by psychomotor phenomena, such as melancholia, may involve dysregulation of dopaminergic mechanisms within complex frontostriatal circuits. CONCLUSIONS: The key feature of in situ hybridisation is its capacity to test for variations in the functional components of designated biochemical systems within highly specific anatomical regions. We utilise this approach, in combination with relevant histopathological techniques, to test the structural and functional integrity of the dopaminergic system within key fronto-striatal circuits in patients who had exhibited psychomotor phenomena. The same approach can also be used to study the integrity of other relevant biochemical systems, such as the serotoninergic and noradrenergic systems, in patients with other mood disorders.
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