Extent of recovery in the first 12 months of complex regional pain syndrome type-1: A prospective study.

BACKGROUND: The literature concerning the outcomes of complex regional pain syndrome (CRPS) is contradictory, with some studies suggesting high rates of symptom resolution, whilst others demonstrate that CRPS symptoms can persist and lead to significant disability. The aim of the present study was to carefully document the extent of recovery from each of the signs and symptoms of CRPS. METHODS: A sample of 59 patients with recently onset (<12 weeks) CRPS-1 were followed prospectively for 1 year, during which time they received treatment-as-usual. At baseline, 6 and 12 months, the following were measured: CRPS severity scores (symptoms and signs of CRPS), pain, disability, work status and psychological functioning. RESULTS: Analyses showed that rates of almost all signs and symptoms of CRPS reduced significantly over 1 year. Reductions in symptom severity were clinically relevant and were greatest in the first 6 months and plateaued thereafter. However, at 1 year, nearly 2/3 of patients continued to meet the IASP-Orlando criteria for CRPS and 1/4 met the Budapest research criteria for CRPS. Only 5.4% of patients were symptom-free at 12 months. CONCLUSIONS: Overall the results were less optimistic than several previously conducted prospective studies and suggest that few cases of CRPS resolve completely within 12 months of onset. Improvements were generally greater in the first 6 months, and suggest that it may be worth exploring early interventions to prevent long-term disability in CRPS.

Pharmacokinetics of 'party pill' drug N-benzylpiperazine (BZP) in healthy human participants.

There have been many reports of benzylpiperazine (BZP) and trifluoromethylphenylpiperazine (TFMPP) being used as recreational drugs which have been widely marketed in the form of 'party pills' since the late 1990's. However, there is no information currently available describing the pharmacokinetics of these drugs in humans. Human plasma concentrations of BZP were measured in blood and urine samples taken from healthy adults (n=7) over 24h following a 200mg oral dose of BZP. Plasma concentrations of BZP were found to peak at 262 ng/mL (C(max)) and 75min (T(max)). Plasma concentrations of the major metabolites of BZP, 4-OH BZP and 3-OH BZP, were found to peak at 7 ng/mL (at 60 min) and 13 ng/mL (at 75 min) respectively. The elimination half-life (t(1/2)) for BZP was found to be 5.5h. Clearance (Cl/F) was found to be 99L/h. The results of this study indicate that BZP may be detectable in plasma for up to 30 h following an oral dose. Additionally, several urinary metabolites can be detected.

Proteomic analysis of the brain in Alzheimer's disease: molecular phenotype of a complex disease process.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder accounting for about 50% of all dementias, yet its pathogenic mechanisms remain poorly understood. In order to provide a more complete picture of pathogenesis in AD, we analysed six human brain regions for alterations in their proteomes. Quantitative proteome analysis was used to compare signals corresponding to individual proteins between post mortem brain tissues from persons with AD, and those from age-matched nondemented control (NC) tissues. In severely injured brain regions, 76 proteins were differentially expressed in AD hippocampus compared with NC, 62 proteins were differentially expressed in temporal cortex, and 39 proteins were differentially expressed in entorhinal cortex. Significant differences were also present in relatively spared regions. Thus, 34 proteins were differentially expressed in AD cerebellum compared with NC, 125 proteins were differentially expressed in cingulate gyrus, and 75 proteins were differentially expressed in sensorimotor cortex. The identity of 37 of these proteins was determined, and the possible relevance of changes in key pathogenic pathways analysed. These studies provide a unique snapshot illustrating the complexity of interrelated disease mechanisms at work in a complex, multifactorial disease, and show that comparative proteome analysis is a method with the power to develop important new insights into pathogenic mechanisms in the dementias.

Comparative proteome analysis of the hippocampus implicates chromosome 6q in schizophrenia.

Comparative brain proteome analysis is a new strategy to discover proteins and therefore genes whose altered expression may underlie schizophrenia. This strategy does not require an a priori theory of the pathogenesis or the mode of inheritance of schizophrenia. Using proteome analysis we previously compared the hippocampal proteome, that is, those proteins expressed by the hippocampal genome, of seven schizophrenic individuals with the hippocampal proteome of seven control individuals, matched for age and post mortem delay.1 We found 18 proteins that were significantly altered in concentration in the schizophrenic hippocampus (P < 0.05), when compared to control tissue. One of these proteins was characterised, by N-terminal sequencing, as diazepam binding inhibitor whose gene maps to 6q12-q21. Here we characterise a further three of the 18 proteins as: manganese superoxide dismutase, 6q25.3, T-complex protein 1, 6q25.3-q26 and collapsin response mediator protein 2, 8p21. That three of these four characterised proteins should map to the long arm of the same chromosome is significant (P < 0.002) and suggests the importance of chromosome 6q in schizophrenia. These results indicate that antioxidant defence is altered in the schizophrenic hippocampus and suggest that segregation distortion, of schizophrenia susceptibility genes, may be a possible causative factor in the high incidence of schizophrenia. Molecular Psychiatry (2000) 5, 85-90.

A comparative proteome analysis of hippocampal tissue from schizophrenic and Alzheimer's disease individuals.

The proteins expressed by a genome have been termed the proteome. Comparative proteome analysis of brain tissue offers a novel means to identify biologically significant gene products that underlie psychopathology. In this study we collected post mortem hippocampal tissue from the brains of seven schizophrenic, seven Alzheimer's disease (AD) and seven control individuals. Hippocampal proteomes were visualised by two-dimensional gel electrophoresis of homogenised tissue. A mean of 549 (s.d. 35) proteins were successfully matched between each disease group and the control group. In comparison with the control hippocampal proteome, eight proteins in the schizophrenic hippocampal proteome were found to be decreased and eight increased in concentration, whereas, in the AD hippocampal proteome, 35 proteins were decreased and 73 were increased in concentration (P<0.05). One protein, which was decreased in concentration in both diseases, was characterised as diazepam binding inhibitor (DBI) by N-terminal sequence analysis. DBI can regulate the action of the GABA(A) receptor. Protein changes involved 6% of the assessed AD hippocampal proteome, whereas, in schizophrenia protein changes involved less than 1% of the assessed hippocampal proteome. We conclude that schizophrenia has a subtle neuropathological presentation and comparative proteome analysis is a viable means by which to investigate diseases of the brain at the molecular level.

Proteome map of the human hippocampus.

The proteins expressed by a genome have been termed the proteome. By comparing the proteome of a disease-affected tissue with the proteome of an unaffected tissue it is possible to identify proteins that play a role in a disease process. The hippocampus is involved in the processing of short-term memory and is affected in Alzheimer's disease. Any comparative proteome analysis that can identify proteins important in a disease affecting the hippocampus requires the characterization of the normal hippocampal proteome. Therefore, we homogenised normal hippocampal tissue and separated the proteins by two-dimensional polyacrylamide gel electrophoresis (2DE). Seventy-two unique protein spots were collected from Coomassie blue-stained 2DE gels and subjected to in-gel digestion with trypsin, reversed-phase high-pressure liquid chromatography peptide separation, and N-terminal protein sequencing. Sufficient protein sequence was obtained to successfully characterize 66 of the 72 protein spots chosen (92%). Three of the 66 proteins were not present in any database (4.5%). The characterized proteins comprised two dominant functional groups, i.e., enzymes involved in intermediary cellular metabolism (40%), and proteins associated with the cytoskeleton (15%). The identity, molecular mass, isoelectric point, and relative concentration of the characterized proteins are described and constitute a partial proteome map of the normal human hippocampus.

Zinc and Alzheimer's Disease: An Update.

Zinc is an essential metal in human nutrition. A growing number of observations have implicated zinc in the pathophysiology of Alzheimer's disease (AD). Zinc binds and interacts with both the amyloid-ß peptide (the major component of senile plaques) and its larger parent protein known as amyloid precursor protein. Nevertheless, the pathophysiological position of zinc in AD remains unclear. Recently, much research has been published that supports the involvement of zinc in AD pathophysiology. Consistent reports show cerebral zinc to be elevated in selected regions of AD brain, and is highly concentrated within senile plaques. Quantitative assessment of zinc in plaques estimates the zinc concentration to be enriched to the near millimolar concentration range. Furthermore, zinc is also detected in neurons that are positively identified to contain neurofibrillary tangles. This paper reviews current available data that indicate a role for zinc in AD pathology.

Early intervention for schizophrenic disorders. Implementing optimal treatment strategies in routine clinical services. OTP Collaborative Group.

BACKGROUND: Early detection and intervention in schizophrenic disorders is an important challenge for psychiatry. METHOD: Review of literature on effective biomedical and psychosocial intervention strategies. RESULTS: Comprehensive programmes of drug and psychosocial interventions with adults who show early signs and symptoms of schizophrenic disorders may contribute to a lower incidence and prevalence of major episodes of schizophrenia. These programmes combine early detection of psychotic features by primary care services, with close liaison with mental health professionals. Long-term monitoring of signs of recurrence, with further intervention, appears essential to maintain these benefits. CONCLUSIONS: Field trials demonstrate that effective early treatment strategies can be routinely applied in clinical practice.

Calcitriol in the management of secondary hyperparathyroidism of renal failure.

Secondary hyperparathyroidism (HPT) is characterized by persistent hypersecretion of parathyroid hormone (PTH), and produces characteristics of hyperparathyroid bone disease and a variety of biochemical and hormonal derangements. Management of uremic secondary HPT involves both prevention and treatment. Among preventive measures are attempts to control serum phosphate and serum calcium concentrations through dietary restriction, administration of phosphate binders, and calcium supplementation. Treatment with a vitamin D analog such as calcitriol returns plasma calcium concentrations toward normal and suppresses PTH secretion. The availability of a parenteral formulation of calcitriol, and new information regarding alternative routes of administration and regimens employing oral pulse dosing have renewed interest in calcitriol for the management of uremic secondary HPT.

The role of general practitioners in mental health care: a survey of needs and problems.

OBJECTIVE: To assess the attitudes of general practitioners to central Auckland mental health service provision, and their perceived role and educational needs for clinical management of patients with mental disorders. METHOD: A postal questionnaire survey of all general practitioners within the Auckland Healthcare (Central Auckland CHE) area. RESULTS: 140 (49%) valid responses were returned from 287 sampled. 94% supported a shared care role with mental health services; 57% considered their role as main case manager to be important. 79% of the general practitioners considered they had insufficient time to manage patients with mental disorders. 69% of respondents reported difficulties receiving information about changes to treatment; 65% were unsure whether patients had a case manager, and 64% reported general difficulties with liaison with the mental health services. Education about a range of mental health issues was sought by three quarters of the group. CONCLUSION: This survey suggested that liaison between general practice and specialist mental health services in central Auckland is poor, but that general practitioners are eager to seek ways to improve the care of people suffering mental disorders.

Early detection and intervention for initial episodes of schizophrenia.

Comprehensive programs of drug and psychosocial interventions with adults who show early signs and symptoms of schizophrenic disorders may contribute to a lower incidence and prevalence of florid episodes of schizophrenia. These programs combine (1) early detection of psychotic features by family practitioners and other primary care providers and (2) close liaison with mental health professionals well trained in psychiatric assessment and treatment strategies effective in reducing the prevalence of established cases of schizophrenia. Long-term monitoring for signs of recurrence of these subthreshold psychotic episodes, with further intervention as needed, appears essential to maintain these benefits.

Cognitive brain potentials and regional cerebral blood flow equivalents during two- and three-sound auditory "oddball tasks".

Ten healthy volunteers were examined with single photon emission tomography and 99mTc-exametazime. They were studied on 2 occasions, during a 2- and a 3-sound auditory discrimination (oddball) task. Twenty healthy volunteers were used as controls, studied once at rest. During the 2-tone task there was a bilateral posterior (occipito-) temporal and medial frontal activation, a left pericentral increase, and posterior cingulate suppression. During the 3-sound task activation was again found in posterior (occipito-) temporal, medial frontal cortex, left pericentral, with a small non-significant reduction in posterior cingulate uptake. Compared with the 2-tone task, there was a trend towards higher activity in left medial frontal, right posterior temporal and posterior cingulate cortex in the 3-sound task. P3b amplitudes were negatively correlated with posterior cingulate tracer uptake during both tasks. Positive correlations with P3b amplitudes were found in various frontal and temporal regions. These results are consistent with more invasive localisation studies of P3b. Posterior cingulate cortex appears to be inhibited during the oddball tasks, the more so, the more restricted the range of stimuli, and the greater the task-related recruitment of neurones (P3b amplitude). As expected from its more frontal distribution, P3a amplitude was positively correlated with anterior cingulate tracer uptake, and negatively correlated with temporal cortical activity.

Intermediate steps in thymic positive selection. Generation of CD4-8+ T cells in culture from CD4+8+, CD4int8+, and CD4+8int thymocytes with up-regulated levels of TCR-CD3.

Minor thymus subpopulations representing possible intermediates in thymic positive selection were isolated by cell sorting from bcl-2 transgenic mice, and cultured 1 to 4 days in simple medium to assess their ability to spontaneously develop the surface phenotype of mature T cells. Recovery of cells was in the 60 to 80% range, and no cell proliferation occurred. Only cells originally expressing high, near mature T cell levels of CD3 developed further in culture by down-regulation of CD4 or CD8. The main mature cell product was CD4-8+, regardless of whether the starting phenotype of the CD3high intermediates was CD4+8+, CD4int8+, or CD4+8int; only an intermediate subpopulation expressing the highest levels of CD4 (CD4high8int) produced a dominance of CD4+8- mature progeny. Partial down-regulation of CD8 was therefore not a good indicator of CD4+ T lineage commitment. These and previous results indicate that maturation to the CD8+ T lineage involves a rapid up-regulation of the TCR-CD3 complex, but a relatively slow down-regulation of CD4; it may also involve a partial, transient reduction in surface CD8. In contrast, maturation to the CD4+ T lineage involves a relatively rapid down-regulation of CD8, with maintenance of high levels of CD4. There appears to be a marked asymmetry in the developmental steps leading from CD4+8+ thymocytes to the CD8+ or to the CD4+ T cell lineage.

The expert witness in forensic psychiatry.

Forensic psychiatry operates at the interface of the Justice and Health systems and has been defined as: "That branch of psychiatry which requires special knowledge and training in the law as it relates to the mental state of the offender, or alleged offender" [1]. As a consequence of working in this area, psychiatrists are often called into court to give evidence as "expert witnesses". This article examines some of the professional and legal issues involved in providing expert testimony. Secondly, it aims to outline some practical guidelines for giving evidence in the court-room. The predominant focus is on criminal, rather than civil, proceedings in which the forensic psychiatrist gives expert testimony; however much of the information is also relevant to other psychiatrists and psychologists undertaking this role in the legal arena.

Mental health needs in Auckland: 1982-6. An analysis using the Jarman index.

Sociodemographic variables obtained from 1986 census data were used to calculate the Jarman index (a measure of underprivilege) for census area units of Auckland. The index was found to correlate with psychiatric admission rates for the years 1982-6 suggesting it might have some utility as an indicator of demand for mental health services. However, the highest admission rates were from particular central city areas reflecting the presence of a deinstitutionalised patient population with chronic mental disorder. This group would appear to require independent assessment of their needs and specific allocation of resources. Factor analysis of the census variable scores comprising the Jarman index revealed principal components equatable with poverty, living without adult company and transient residence.

Autoregression models of EEG. Results compared with expectations for a multilinear near-equilibrium biophysical process.

This paper considers the properties of parameters (natural frequencies and damping coefficients) obtained from segment-by-segment autoregression analysis of ECoG of rat. The use of a reference signal as control for parameter estimate errors, and multiple regression analyses indicate that the dependencies among parameters calculated from ECoG in the alert (desynchronised) state are of a form consistent with imposition of time-invariance assumptions (implicit in autoregression) on an inherently non-stationary, multimodal, linear and near-equilibrium "thermal" process.

Gross electrocortical activity as a linear wave phenomenon with variable temporal damping, regulated by ascending catecholamine neurones.

We report critical tests for a theory of electrocortical wave processes, in which telencephalic dendritic potentials reflect the mass action of coupled oscillatory circuits exhibiting complicated and unspecified non-linearities, the whole system being driven by active cell firing. Specific assumptions were: stochastic independence for instantaneous coupling parameters in the system, an individual central tendency to the cycle time for each circuit, and the maintenance of steady state conditions. Application of the central limit theorem to the state transition matrix shows that the gross electrocortical waves should be linear waves, exhibiting a multitude of invariant resonant modes, with the natural frequencies of all the modes being clustered about a smaller number of center values. Ascending brain-stem neurones of at least the dopaminergic and noradrenergic classes should regulate both the power of noise-like signals driving the telencephalic resonant patterns, and the temporal damping of each resonance. We devised tests which involved between hemisphere comparisons of electrocortical spectra, before and after unilateral lesion of transhypothalamic ascending fibres, thus obtaining ratio power changes attributable to post lesion asymmetry of damping and driving, in modes of equivalent left-right center-frequencies. These ratio spectra were curve-fitted to an approximate theoretical expression, and the parameters obtained enabled tests of several specific predictions. Estimates of the center values for resonant mode frequencies, comparison of the relative changes in left/right phase with that expected from the ratio changes in power, and estimates of the surface-to-signal transformation of left and right signals made by a back-calculation, all conform to expectation from the theory, and are consistent across lesion of different types of ascending neurone.

Mental phenomena as changes of state in a finite-state machine.

This paper examines the classical functions of the psyche--cognition, affection and conation--from a phenomenological viewpoint and finds them to be defined each in terms of the other. It is held that this circularity of definition reflects the fundamental unity of conscious experience and, as a consequence, that the search for the biological substrate underlying individual functions too readily degenerates into a morphological and biochemical phrenology. An alternative approach, based on considerations from the field of artificial intelligence, is discussed. This approach provides a description of mental phenomena as changes of state in a finite-state machine, the next state being determined by both previous states and current inputs. This concept is shown to be compatible with the descriptions of conscious experience outlined in the phenomenology of Karl Jaspers. It is suggested that neurobiological investigations should be directed towards defining the processes by which state changes occur and further seeking to define mental pathology as aberrations of these dynamic processes.

Schizophrenia as a disorder of cerebral state transition.

This paper offers a speculative consideration of the schizophrenic process in the light of recent findings concerning the wave nature of electrocortical activity. These findings indicate that changes of brain state can be described in the terminology of finite-state machines, and both the instantaneous states and the state transitions can be specified. It is suggested that the mental phenomena of schizophrenia may be reducible to events (some specific type of instability) which could be observed by appropriate analytic techniques applied to EEG. Present empirical EEG findings in schizophrenics are reviewed in this light, and the role of dopamine blockade in treatment is also considered.