Relationship between glycine transporter 1 inhibition as measured with positron emission tomography and changes in cognitive performances in nonhuman primates.

Several lines of evidence suggest that schizophrenia is associated with deficits in glutamatergic transmission at the N-methyl-d-aspartate (NMDA) receptors. Glycine is a NMDA receptor co-agonist, and extracellular levels of glycine are regulated in the forebrain by the glycine type-1 transporters (GlyT-1). GlyT-1 inhibitors elevate extracellular glycine and thus potentiate NMDA transmission. This mechanism represents a promising new avenue for the treatment of schizophrenia. Here, the recently introduced positron emission tomography radiotracer [11C]GSK931145 was used to quantify the relationship between occupancy of GlyT-1 by a GlyT-1 inhibitor, Org 25935, and its impact on spatial working memory performances in rhesus monkeys. The effect of Org 25935 on working memory was assessed both in control conditions and during a state of relative NMDA hypofunction induced by ketamine administration, at a dose selected for each animal to reduce task performance by about 50%. Under control conditions, Org 25935 had no effect on working memory at GlyT-1 occupancies lower than 75% and significantly impaired working memory at occupancies higher than 75%. Under ketamine conditions, Org 25935 reversed the deficit in working memory induced by ketamine and did so optimally in the 40-70% GlyT-1 occupancy range. The results confirm the efficacy of this mechanism to correct working memory deficits associated with NMDA hypofunction. These data also suggest the existence of an inverted-U dose-response curve in the potential therapeutic effect of this class of compounds.

Computerized cognitive remediation training for schizophrenia: an open label, multi-site, multinational methodology study.

A recent single-site study (Fisher et al., 2009. Am J Psychiatry. 166 (7) 805-11) showed that repeated training with the Brain Fitness Program (BFP) improved performance on a battery of neuropsychological tasks. If replicated these data suggest an important non-pharmacological method for ameliorating cognitive impairment in schizophrenia. Our study evaluated the BFP training effects in an open-label, multi-site, multinational clinical trial. Fifty-five stable adult patients with schizophrenia on regular antipsychotic medication completed ≥ 32 BFP training sessions over 8-10 weeks. Training effects on cognitive performance and functional capacity outcome measures were measured using CogState® schizophrenia battery, UCSD Performance based Skills Assessment (UPSA-2) and Cognitive Assessment Interview (CAI). BFP training showed a large and significant treatment effect on a training exercise task (auditory processing speed), however this effect did not generalize to improved performance on independent CogState® assessment. There were no significant effects on UPSA-2 or CAI scores. Our study demonstrated the feasibility of implementing BFP training in a multi-site study. However, BFP training did not show significant treatment effects on cognitive performance or functional capacity outcome measures despite showing large and significant effects on a training exercise.

Serotonin transporter polymorphisms (SLC6A4 insertion/deletion and rs25531) do not affect the availability of 5-HTT to [11C] DASB binding in the living human brain.

Studies in vitro suggest that the expression of the serotonin transporter (5-HTT) is regulated by polymorphic variation in the promoter region of the 5-HTT gene (5-HTTLPR); however, results from human brain imaging studies examining the relation between 5-HTT genotype and 5-HTT radioligand binding in vivo have been inconsistent. This inconsistency could reflect small participant numbers or the use of sub-optimal radiotracer for measuring the 5-HTT. We used positron emission tomography in conjunction with the selective 5-HTT ligand [(11)C] DASB to examine the availability of the 5-HTT in seven brain regions in 63 healthy European caucasian volunteers who were genotyped for short (S) and long (L) variants (SLC6A4 and rs25531) of the 5-HTTLPR. [(11)C] DASB binding potential was not influenced by the allelic status of participants whether classified on a biallelic or triallelic basis in any of the regions studied. Our PET findings, in a relatively large sample with a near optimal radiotracer, suggest that 5-HTTLPR polymorphic variation does not affect the availability of 5-HTT to [(11)C] DASB binding in adult human brain. The reported impact of 5-HTTLPR polymorphic variation on emotional processing and vulnerability to depression are more likely therefore to be expressed through effects exerted during neurodevelopment.

Mesolimbic deficits exacerbate amphetamine treatment. Clinical implications for drug abusers.

Amphetamine, a common drug used by abusers, is able to produce a schizophreniform psychosis in man. The experiment reported here examined amphetamine in relation to its role in the nucleus accumbens septi (NAS) and the globus pallidus. The effects produced by apomorphine, a direct dopamine (DA) agonist, were compared with those of amphetamine, a known indirect DA agonist. The data revealed that amphetamine in NAS-lesioned animals produced very active stereotypy which intensified with time. This effect was blocked by pallidal lesioning. Apomorphine in pallidectomised rats produced persistent stereotypy, but of diminished intensity. The results are discussed in terms of the mediating roles of the NAS and globus pallidus on behavioural sequelae.

Mesolimbic deficits exacerbate amphetamine treatment: clinical implications for drug abusers

Amphetamine, a common drug used by abusers, is able to produce a schizophreniform psychosis in man. The experiment reported here examined amphetamine in relation to its role in the nucleus accumbens septi (NAS) and the globus pallidus. The effects produced by apomorphine, a direct dopamine (DA) agonist, were compared with those of amphetamine, a known indirect DA agonist. The data revealed that amphetamine in NAS-lesioned animals produced very active stereotypy which intensified with time. This effect was blocked by pallidal lesioning. Apomorphine in pallidectomised rats produced persistent stereotypy, but of diminished intensity. The results are discussed in terms of the mediating roles of the NAS and globus pallidus on behavioural sequelae. (AU)

Abdominal hysterectomies at area hospital, Point Fortin, Trinidad, West Indies.

A retrospective analysis of abdominal hysterectomies (3.08% of major operations) at the Area Hospital (52 beds), over a 5-year period revealed that the majority of the patients were multiparous in the reproductive age group. Menstrual irregularity is the most frequent indication, however, hysterectomy in these cases is not justified. High febrile morbidity (38%), blood transfusions and prolonged hospitalization were observed. Peer review, prophylactic antibiotics and survey of the Island hospitals are recommended to make hysterectomy appropriate, safe and to explain any racial variation.

Abdominal hysterectomies at area hospital, Point Fortin, Trinidad, West Indies

A retrospective analysis of abdominal hysterectomies (3.08 percent of major operations) at the Area Hospital (52 beds), over a 5-year period revealed that the majority of the patients were multiparous in the reproductive age group. Menstrual irregularity is the most frequent indication, however, hysterectomy in these cases is not justified. High febrile morbidity (38 percent), blood transfusions and prolonged hospitalization were observed. Peer review, prophlactic antibodies and survey of the Island hospitals are recomended to make hysterectomy approprite, safe and to explain any racial variation.(AU)

Testicular function in rats following immobilization stress.

Stress is believed to influence male reproductive activity. Male rats were subjected to immobilization stress for 2 h/day for 30 days to assess the effects of stress on testicular function. Net mass of the testes, epididymes and the seminal vesicles, sperm morphology, number of epididymal sperms and percent progressive motility of the sperms were determined. Adrenal weights were significantly increased (P less than 0.05) in the stressed animals. There was no significant difference between the control and the stressed animals with respect to testicular and epididymal weight, level of sperm production, progressive motility, seminal vesicular weight and abnormal forms. Histological examination also revealed a similarity in the structure of seminiferous tubules, adequacy of cell types of developing germ cells, structure of Leydig cells and epididymal lumina in both the groups. This study demonstrated a lack of significant effect of immobilization stress on testicular function in rats.

Review of the effects of Cannabis on mental and physiological functions: justification for an Intensive and Comprehensive Programme for the health of the Caribbean people

This paper draws on scientific work done in the English-speaking Caribbean in an attempt to assess the specific effects of the chronic use of Cannabis on psychological and physiological processes. Evidence is reviewed concerning the interaction of this psychotomimetic compound on cognitive functioning and the possible sequelae of altered mental states giving rise to psychopathology. The physiological work evaluates studies relating to Cannabis smoke and lung function. In addition, the work reveals some exciting findings of the impact of Cannabis on the reproductive process. The implications of these findings are discussed in view of our knowledge of the chronic use of Cannabis in Jamaica, and focuses attention on the long-term effects of this substance in the context of the abusing population (AU)

Review of the effects of Cannabis on mental and physiological functions: justification for an intensive and comprehensive programme for the health of the Caribbean people

This paper draws on scientific work done in the English-speaking Caribbean in an attempt to assess the specific effects of the chronic use of Cannabis on psychological and physiological processess. Evidence is reviewed concerning the interaction of this psychotomimetic compound on cognitive functioning and the possible sequelae of altered mental states giving rise to psychopathology. The physiological work evaluates studies relating to Cannabis smoke and lung function. In addition, the work reveals some exciting findings of the impact of Cannabis on the reproductive process. The implications of these findings are discussed in view of our knowledge of the chronic use of Cannabis in Jamaica, and focusses attention on the long-term effects of this substance in the context of the abusing population

Test for autonomic function to establish the norm: a useful tool for evaluation in various clinical disorders

Little information is available regarding the responses of the Jamaican population to the Valsalva manoevre (VM), a test to investigate the integrity of the autonomic nervous system (ANS). This study is aimed at investigating the cardiac autonomic control in the Jamaican population, to explore the range of responses and to establish the norm. Such an explorative investigation provides an important tool to uncover autonomic dysfunction in psychosomatic, cardiopulmonary, metabolic and neural disorders. Fifty male and fifty female Jamaicans, who were apparently healthy and did not indulge in any drug use and smoking, are asked to perform the VM in a semirecumbent position. A tachograph (Grass model) and standard electrocardiographic leads are used for the graphic presentation of the subjects' beat-to-beat heart rate changes. The Valsalva ratio (VR) is calculated by dividing maximum tachycardia and maximum bradycardia during the VM. The mean VR for the female (2.41ñ0.18) is greater than that for the male (1.63ñ0.27) (p<0.001). Female subjects exhibit a higher basal heart rate (88+6 as against 77ñ7 in the male) and a greater magnitude of bradycardia (33 as against 4 in the male). The values for VR are above the minimum of 1.5 proposed in the literature. Relative roles of the sympathetic and parasympathetic nervous systems may differ in the male and female subjects, thus accounting for a higher VR in the female. This test is simple, safe, noninvasive and reproducible and is useful to detect the abnormal autonomic function in various conditions, including states of pregnancy and stress (AU)

Test for autonomic function to establish the norm: a useful tool for evaluation in various clinical disorders

Little information is available regarding the responses of the Jamaica population to the Valsalva manoeuvre (VM), a test to investigate the integrity of the autonomic nervous system (ANS). This study is aimed at investigating the cardiac automonic control in the Jamaican population, to explore the range of responses and to establish the norm. Such an explorative investigation provides an important tool to uncover autonomic dysfunction in psychosomatic, cardiopulmonary, metabolic and neural disorders. Fifity male and fifty female Jamaicans, who were apparently healthy and did not indulge in any drug use and smoking, are asked to perform the VM in a semirecumbent position. A tachograph (Grass model) and standard electrocardiographic leads are used for the graphic presentation of the subjects' beat-to-beat heart changes. The Valsava ratio (VR) is calculated by dividing maximum tachicardia and maximum bradicardia during the VM. The mean VR for the female (2.41 ñ 0.18) is greater than for the male (1.63 ñ 0.27) p < 0.001). Female subjects exhibit a higher basal hearth rate (88 ñ 6 as aginst 77 ñ 7 in the male) and a greater magnitude of bradycardia (33 as against 4 in the male). The values for VR are above the minimum of 1.5 proposed in the literature. Relatice roles of the sympathetic and parasympathetic nervous systems may differ in the male and the female subjects, thus accounting for a higher VR in the female. This test is simple, safe, noninvasive and reproducible and is useful to detect the abnormal autonomic function in various conditions, including states of pregnancy and stress

Evidence to support the influence of the nucleus accumbens on drug-induced psychopathology

This study was designed to evaluate the hypothesis that the mesolimbic dopamine pathways are involved in the manifestations of psychotic symptoms. Rats were injected with amphetamine (5.0 mg/kg) and apomorphine (1.0 mg/kg) following bilateral lesions of the nucleus accumbens. The results showed high levels of stereotypy following amphetamine administrations in contrast to the low levels seen after the administration of apomorphine. These results, in conjunction with previous experiments involving the globus pallidus, were evaluated in terms of the accumbens' influence on drug-induced psychosis (AU)