Neuroplasticity and psychiatry

Objective: There is increasing concern that the course of psychiatric disorders may be affected by parameters such as the duration and intensity of symptoms of initial episodes of illness. As this indicates that abnormal function produces long-term changes within the brain, a review of the neuroscience literature regarding neuroplasticity is warranted. Method: This article is a selective review, focusing in particular on results obtained from physiological experiments assessing plasticity within the mammalian neocortex. The possible relevance of results to psychiatry is discussed. Results: While the most dramatic examples of neuroplasticity occur during a critical period of neural development, neuroplasticity can also occur in adult neocortex. Neuroplasticity appears to be activity-dependent: synaptic pathways that are intensively used may become strengthened, and conversely, there may be depression of transmission in infrequently used pathways. Conclusions: Results from neurophysiological experiments fend support to the clinical observation that the intensity and duration of a psychiatric disorder may adversely alter its long-term course. Rapid aggressive treatment may prevent this from occurring. While pharmacotherapy may reduce the duration and severity of symptoms, it may also have an independent, as yet unknown, effect on neuroplasticity.

Ester prodrugs of a potent analgesic, morphine-6-sulfate: syntheses, spectroscopic and physicochemical properties

The aim of this work is to develop 3-acyl prodrugs of the potent analgesic morphine-6-sulfate (M6S). These are expected to have higher potency and/or exhibit longer duration of analgesic action than the parent compound. M6S and the prodrugs were synthesized, then purified either by recrystallization or by semi-preparative HPLC and the structures confirmed by mass spectrometry, IR spectrophotometry and by detailed 1- and 2-D NMR studies. The lipophilicities of the compounds were assessed by a combination of shake-flask, group contribution and HPLC retention methods. The octanol-buffer partition coefficient could only be obtained directly for 3-heptanoylmorphine-6-sulfate, using the shake-flask method. The partition coefficients (P) for the remaining prodrugs were estimated from known methylene group contributions. A good linear relationship between log P and the HPLC log capacity factors was demonstrated. Hydrolysis of the 3-acetyl prodrug, as a representative of the group, was found to occur relatively slowly in buffers (pH range 6.15-8.01), with a small buffer catalysis contribution. The rates of enzymatic hydrolysis of the 3-acyl group in 10% rat blood and in 10% rat brain homogenate were investigated. The prodrugs followed apparent first order hydrolysis kinetics, with a significantly faster hydrolysis rate found in 10% rat brain homogenate than in 10% rat blood for all compounds. (C) 1998 Elsevier Science B.V. All rights reserved.

Vaccine-induced Th1-type responses are dominant over Th2-type responses in the short term whereas pre-existing Th2 responses are dominant in the longer term

The effect of adjuvant on induction of human papillomavirus type 16 E7 protein-specific cytotoxic T lymphocytes (CTL) and immunoglobulin G (IgG)(2a) antibody was studied in C57BL/6 J mice immunized with various adjuvants and E7 protein. Quil-A adjuvant, but not complete Freund's adjuvant (CFA) or Algammulin, induced a T-helper 1 (Th1)-type response to E7, which was characterized by CTL activity against a tumour cell line transfected with E7 protein and by E7-specific IgG(2a). All tested adjuvants elicited comparable levels of E7-specific IgG(1). The longest duration and greatest magnitude of CTL response was seen following two immunizations with the highest dose of E7 and Quil-A. Simultaneous immunization with a Th1 and a T helper 2 (Th2)-promoting adjuvant gave a Th1-type response. However, E7 and Quil-A were unable to induce a Th1-type response (as measured by the inability to generate anti-E7 IgG(2a) antibody) in animals with a pre-existing Th2-type response to E7. These results suggest that saponin adjuvants may be suitable for immunotherapy in humans where a Th1-type response is sought, provided that there is no pre existing Th2-type response to the antigen.

A mathematical model of HIV transmission in NSW prisons

A mathematical model was developed to estimate HIV incidence in NSW prisons. Data included: duration of imprisonment; number of inmates using each needle; lower and higher number of shared injections per IDU per week; proportion of IDUs using bleach; efficacy of bleach; HIV prevalence and probability of infection. HIV prevalence in IDUs in prison was estimated to have risen from 0.8 to 5.7% (12.2%) over 180 weeks when using lower (and higher) values for frequency of shared injections. The estimated minimum (and maximum) number of IDU inmates infected with HIV in NSW prisons was 38 (and 152) in 1993 according to the model. These figures require confirmation by seroincidence studies. (C) 1998 Published by Elsevier Science Ireland Ltd. All rights reserved.

Probability backflow for a Dirac particle

The phenomenon of probability backflow, previously quantified for a free nonrelativistic particle, is considered for a free particle obeying Dirac's equation. It is known that probability backflow can occur in the opposite direction to the momentum; that is to say, there exist positive-energy states in which the particle certainly has a positive momentum in a given direction, but for which the component of the probability flux vector in that direction is negative. It is shown thar the maximum possible amount of probability that can flow backwards, over a given time interval of duration T, depends on the dimensionless parameter epsilon = root 4h/mc(2)T, where m is the mass of the particle and c is the speed of light. At epsilon = 0, the nonrelativistic value of approximately 0.039 for this maximum is recovered. Numerical studies suggest that the maximum decreases monotonically as epsilon increases from 0, and show that it depends on the size of m, h, and T, unlike the nonrelativistic case.

Temperature and sowing date affect the linear increase of sunflower harvest index

The linearity of daily linear harvest index (HI) increase can provide a simple means to predict grain growth and yield in field crops. However, the stability of the rate of increase across genotypes and environments is uncertain. Data from three field experiments were collated to investigate the phase of linear HI increase of sunflower (Helianthus annuus L,) across environments by changing genotypes, sowing time, N level, and solar irradiation level. Linear increase in HI was similar among different genotypes, N levels, and radiation treatments (mean 0.0125 d(-1)). but significant differences occurred between sowings, The linear increase in HI was not stable at very low temperatures (down to 9 degrees C) during grain filling, due to possible limitations to biomass accumulation and translocation (mean 0.0091 d(-1)). Using the linear increase in HI to predict grain yield requires predictions of the duration from anthesis to the onset of linear HI increase (lag phase) and the cessation of linear RT increase. These studies showed that the lag phase differed, and the linear HI increase ceased when 91% of the anthesis to physiological maturity period had been completed.

Methadone maintenance treatment reduces heroin injection in New South Wales prisons

The purpose of this study was to examine whether methadone maintenance treatment reduces injecting risk behaviour land therefore transmission of blood-borne viral infections) among prisoners in New South Wales (NSW), using comparison of retrospective reports of drug use in prisons for people who received standard drug treatment, time-limited methadone treatment and methadone maintenance treatment, The setting for the study was the NSW prison system. One hundred and eighty-five injecting drug users who had been recently released from NSW prisons were recruited in 1993, Self-reported drug use and injecting risk behaviour were compared in inmates who received standard drug treatment (counselling), time-limited methadone treatment and methadone maintenance treatment. HIV status was determined by serology, Intervention comprised high and low dose methadone treatment and counselling. The groups were similar in terms of most basic demographic characteristics but subjects who had been maintained on methadone reported a significantly lower prevalence of heroin injection, syringe sharing and scored lower on an HIV Risk-taking Behavioural Scale than subjects who received standard drug treatment and time-limited methadone treatment, This study suggests that methadone treatment is associated with reduced injecting risk behaviour in prison with adequate (greater than 60 mg) dose and duration in treatment. These treatment conditions are known to increase effectiveness in community-based methadone programmes. Prospective studies are required to evaluate the effectiveness of methadone programmes in the prevention of HIV and other blood-borne viral infections among IDU prisoners.

An investigation of the interrelationship between manipulative therapy-induced hypoalgesia and sympathoexcitation

Objective: To investigate a proposed model in which manipulative therapy produces a treatment-specific initial hypoalgesic and sympathoexcitatory effect by activating a descending pain inhibitory system. The a priori hypothesis tested was that manipulative therapy produces mechanical hypoalgesia and sympatho-excitation beyond that produced by placebo or control. Furthermore, these effects would be correlated, thus supporting the proposed model. Design: A randomized, double-blind, placebo-controlled, repeated-measures study of the initial effect of treatment. Setting: Clinical neurophysiology laboratory. Subjects: Twenty-four subjects (13 women and 11 men; mean age, 49 yr) with chronic lateral epicondylalgia (average duration, 6.2 months). Intervention: Cervical spine lateral glide oscillatory manipulation, placebo and control. Outcome Measures: Pressure pain threshold, thermal pain threshold, pain-free grip strength test, upper limb tension test 2b, skin conductance, pileous and glabrous skin temperature and blood flux. Results: Treatment produced hypoalgesic and sympathoexcitatory changes significantly grater than those of placebo and control (p < .03). Confirmatory factor-analysis modeling, which was performed on the pain-related measures and the indicators of sympathetic nervous system function, demonstrated a significant correlation (r = .82) between the latencies of manipulation-induced hypoalgesia and sympathoexcitation. The Lagrange Multiplier test and Wald test indicated that the two latent factors parsimoniously and appropriately represented their observed variables. Conclusions: Manual therapy produces a treatment-specific initial hypoalgesic and sympathoexcitatory effect beyond that of placebo or control. The strong correlation between hypoalgesic and sympathoexcitatory effects suggests that a central control mechanism might be activated by manipulative therapy.

Cohort trends in age of initiation to heroin use

This paper examines gender differences and trends over time in the age of initiation to heroin use. Data from two large surveys: the Sydney component of the ANAIDUS, conducted in 1989, and the ASHIDU, conducted in 1994, were used to examine this issue. Together, these studies contained information on 1,292 individuals who identified themselves as heroin users. Results indicated that, while there were no significant gender differences in age of initiation to heroin use, there was a significant (p < 0.001) time trend in the mean age at which heroin was first used. Specifically, the mean age of first heroin use among individuals born during the interval 1940-1949 was 20.5 years while among those born during 1970-1979 the mean age of first heroin use was 16.5 years. These findings were confirmed by analyses of the National Household Survey. Further analysis of the ASHIDU data indicated that younger age of initiation to heroin use was associated with polydrug use, overdose and crime after the effects of duration of heroin use had been statistically controlled. These findings suggest that there has been both an increase in the willingness of young people to experiment with heroin and an increased availability of the drug over this time. In combination with evidence that there has been an increase in the amount of heroin being imported into Australia, and an increased demand for treatment for opiate dependence, these data suggest that Australia is experiencing an increase in the use of heroin, particularly among youth.

Brain region-specific studies of the excitatory behavioral effects of morphine-3-glucuronide

This study was designed to determine in rats whether morphine-3-glucuronide (M3G) produces its neuro-excitatory effects most potently in the ventral hippocampus (as has been reported previously for subanalgesic doses of opioid peptides). Guide cannulae were implanted into one of seven regions of the rat brain: lateral ventricle; ventral, CA1 and CA2-CA3 regions of the hippocampus; amygdala; striatum or cortex. After a 7 day recovery period, rats received intracerebral injections of (i) M3G (1.1 or 11 nmol) (ii) DADLE ([D-Ala(2),D-Leu(5)]enkephalin), (45 nmol, positive controls) or (iii) vehicle (deionised water), and behavioral excitation was quantified over 80 min. High-dose M3G (11 nmol) evoked behavioral excitation in all brain regions but the onset, severity and duration of these effects varied considerably among brain regions. By contrast, low-dose M3G (1.1 nmol) evoked excitatory behaviors only when administered into the ventral hippocampus and the amygdala, with the most potent effects being observed in the ventral hippocampus. Prior administration of the nonselective opioid antagonists, naloxone and beta-funaltrexamine into the ventral hippocampus, markedly attenuated low-dose M3G's excitatory effects but did not significantly alter levels of excitation evoked by high-dose M3G. Naloxone given 10 min after M3G (1.1 or 11 nmol) did not significantly attenuate behavioral excitation. Thus, M3G's excitatory behavioral effects occur most potently in the ventral hippocampus as reported previously for subanalgesic doses of opioid peptides, and appear to be mediated through at least two mechanisms, one possibly involving excitatory opioid receptors and the other, non-opioid receptors.

Continuity of care and readmission in two service systems: a comparative Victorian and Groningen case-register study

Objective: We compared service consumption, continuity of care and risk of readmission in a record linkage follow-up study of cohorts of patients with schizophrenia and related disorders in Victoria (Australia) and in Groningen (The Netherlands). These areas are interesting to compare because mental health care is in a different stage of deiustitutionalization. More beds are available in Groningen and more community resources are available in Victoria. Method: The cohorts were followed for 4 years, since discharge from inpatient services using record linkage data available in the psychiatric case-registers in both areas. Survival analysis was used to study continuity of care and risk of readmission. Results: Available indicators showed a higher level of continuity of care in Victoria. While the relative risk of readmission was the same in both areas and not affected by aftercare contact after discharge, the number of days spent in hospital was much higher in the Groningen register area. Conclusion: These findings provide further support for earlier reports that the risk of readmission is predominantly affected by attributes of mental illness. However, the duration of admissions, is strongly affected by service system variables, including the provision of continuity of care.

Treatment of schizophrenia

This selective review on the treatment of schizophrenia provides an update on two important issues. Firstly, new antipsychotic drugs have improved the quality of life for people with schizophrenia. This review outlines some practical issues surrounding the use of these drugs. Secondly, evidence suggests that the prompt identification and treatment of people with psychoses (including schizophrenia and affective psychoses) results in improved clinical outcomes.1 The important role that general practitioners can play in reducing the duration of untreated psychosis is also discussed.

Systemic coadministration of chloramphenicol with intravenous but not intracerebroventricular morphine markedly increases morphine antinociception and delays development of antinociceptive tolerance in rats

Chloramphenicol, an in vitro inhibitor of the glucuronidation of morphine to its putative antianalgesic metabolite, morphine-3-glucuronide (M3G), was coadministered with morphine in adult male Sprague-Dawley rats to determine whether it inhibited the in vivo metabolism of morphine to M3G, thereby enhancing morphine antinociception and/or delaying the development of antinociceptive tolerance. Parenteral chloramphenicol was given acutely (3-h studies) or chronically (48-h studies). Morphine was administered by the i.v. or i.c.v. route. Control rats received chloramphenicol and/or vehicle. Antinociception was quantified using the hotplate latency test. Coadministration of chloramphenicol with i.v. but not i.cv. morphine increased the extent and duration of morphine antinociception by approximate to 5.5-fold relative to rats that received i.v. morphine alone. Thus, the mechanism through which chloramphenicol enhances i.v. morphine antinociception in the rat does not directly involve supraspinal opioid receptors. Acutely, parenteral coadministration of chloramphenicol and morphine resulted in an approximate to 75% increase in the mean area under the serum morphine concentration-time curve but for chronic dosing there was no significant change in this curve, indicating that factors other than morphine concentrations contribute significantly to antinociception. Antinociceptive tolerance to morphine developed more slowly in rats coadministered chloramphenicol, consistent with our proposal that in vivo inhibition of M3G formation would result in increased antinociception and delayed development of tolerance. However, our data also indicate that chloramphenicol inhibited the biliary secretion of M3G. Whether chloramphenicol altered the passage of M3G and morphine across the blood-brain barrier remains to be investigated.

Beyond ovulation: Oral contraceptives and epithelial ovarian cancer

In a case-control study in three Australian states that included 794 women with epithelial ovarian cancer and 853 community controls for whom we had adequate contraceptive and reproductive histories, Re examined the effects of oral contraceptive use after controlling for estimated number of ovulatory cycles. Other covariates included in the multiple logistic regression analysis were parity, smoking, and history of pelvic surgery. The protective effect of duration of oral contraceptive use appeared to be multiplicative, with a 7% decrease in relative risk per year [95% confidence interval (CI) = 4-9%], persisting beyond 15 years of exposure. Use for up to 1 year may have a greater effect than predicted (odds ratio = 0.57; 95% CI = 0.40-0.82), whereas use before the first pregnancy may be additionally beneficial (odds ratio = 0.95; 95% CI = 0.87-1.03, adjusted for overall duration of use). Better control for ovulatory life might attenuate these estimates somewhat. There was little evidence of waning protection with time since last exposure or of extra benefit with early commencement of oral contraceptive use. We found no convincing evidence of effect modification in any factor examined or differences in effect among the three main histologic cancer types or between borderline and malignant tumors. Oral contraceptives may act by both suppressing ovulation and altering the tumor-promoting milieu.

Boston naming test results for healthy older Australians: A longitudinal and cross-sectional study

This study reports on a sample of normal Australian elderly who were assessed for naming ability using the Boston Naming Test (BNT). The study aimed to examine and compare the changes in naming ability, using both longitudinal and cross-sectional analysis, and determine the relationships between naming ability and age, educational level, visual acuity and gender and cultural relevance. Contradictory findings were produced regarding age and were dependent on the research design. Longitudinal analysis showed no age-related change in naming ability in subjects over a four-period. In contrast, cross-sectional analysis showed a weak but significant correlation between age and naming ability. Educational level, visual acuity and gender were unrelated to changes in naming ability over time, and unrelated to naming ability across the cohort of elderly. The Australian elderly performed better on the modified Australian version of the BNT than on the original American version. Thus, clinicians need to be cautious when interpreting the results of the BNT for elderly and for populations outside North America. The results of this study also indicate a need for further longitudinal research of a greater duration to establish age-related decline in naming ability.