Tommy Lewander

Monitoring of Reactive Oxygen Species Production after Traumatic Brain Injury in Rats with Microdialysis and the 4-Hydroxybenzoic Acid Trapping Method

The detection of reactive oxygen species (ROS) after traumatic brain injury (TBI) is based on indirect methods due to the high reactivity and short half-life of ROS in biological tissue. The commonly used salicylate trapping method has several disadvantages making it unsuitable for human use. We have evaluated 4-hydroxybenzoic acid (4-HBA) together with microdialysis (MD) in the rat as an alternative method. 4-HBA forms one stable adduct, 3,4-dihydroxybenzoic acid (3,4-DHBA), when reacting with ROS and has not previously been used together with MD after TBI. Twenty-seven rats were used for the assessment of 3,4-DHBA production as an indicator of ROS formation in a controlled contusion injury model using intracerebral MD with 3 mM 4-HBA in the perfusate. For comparison, salicylate trapping was used in eight rats. TBI caused a 250% increase of 3,4-DHBA that peaked at 30 min after injury in severely injured rats and remained significantly elevated as compared to baseline for 90 min after trauma. The mild injury level caused a 100% increase in 3,4-DHBA formation at 30 min after the injury. When the MD probe was placed in the perimeter of the injury site, no significant increase in ROS formation occurred. Salicylate trapping showed a similar increase in adduct formation after severe injury. In addition, high cortical concentrations of 4-HBA and salicylate were found. It is concluded that microdialysis with 4-HBA as a trapping agent appears to be a useful method for ROS detection in the rat with a potential clinical utility.

Effects of the Nitrone Radical Scavengers PBN and S-PBN on In vivo Trapping of Reactive Oxygen Species after Traumatic Brain Injury in Rats:

In previous studies, the authors showed that the nitrone radical scavenger α-phenyl-N-tert-butyl nitrone (PBN) and its sulfo-derivative, 2-sulfo-phenyl-N-tert-butyl nitrone (S-PBN), attenuated cognitive disturbance and reduced tissue damage after traumatic brain injury (TBI) in rats. In the current study, the production of reactive oxygen species (ROS) after TBI was monitored with microdialysis and the 4-hydroxybenzoic acid (4-HBA) trapping method. A single dose of PBN (30 mg/kg) or an equimolar dose of S-PBN (47 mg/kg) was administered intravenously 30 minutes before a controlled cortical contusion injury in rats. Plasma and brain tissue drug concentrations were analyzed at the end of the microdialysis experiment (3 hours after injury) and, in a separate experiment with S-PBN, at 30 and 60 minutes after injury. Traumatic brain injury caused a significant increase in ROS formation that lasted for 60 minutes after the injury as evidenced by increased 3,4-dihydroxybenzoic acid (3,4-DHBA) concentrations in the dialysate. PBN and S-PBN equally and significantly attenuated the posttraumatic increase in 3,4-DHBA formation. High PBN concentrations were found bilaterally in brain tissue up to 3 hours after injury. In contrast, S-PBN was rapidly cleared from the circulation and was not detectable in brain at 30 minutes after injury or at any later time point. The results suggest that scavenging of ROS after TBI may contribute to the neuroprotective properties observed with nitrone spin-trapping agents. S-PBN, which remained undetectable even in traumatized brain tissue, reduced ROS production to the same extent as PBN that readily crossed the blood–brain barrier. This finding supports an important role for ROS production at the blood–endothelial interface in TBI.

ADHD-related symptoms among adults in out-patient psychiatry and female prison inmates as compared with the general population.

Abstract Objective. To compare the prevalence of symptoms consistent with attention deficit hyperactivity disorder (ADHD) and related problems in adults in the general population, out-patient psychiatry (where females are in majority), and female convicts. Method. A questionnaire based on the DSM-IV criteria of ADHD, reported childhood symptoms, reading and spelling problems, difficulties and suffering, and general assessment of functioning (GAF) was distributed to samples of the general population, open care psychiatry, and female prison inmates. Completed questionnaires were received from 517/1000, 349/400, and 50/65 of the three samples, respectively. Results. Symptoms consistent with ADHD were more than three times higher in out-patient psychiatry than in the general population (6.6% versus 2.1%), with a male-to-female ratio of 1.6–1.7. The severity of symptoms and frequencies of associated disabilities were similar in men and women. ADHD symptoms and related problems occurred in 50% of the female prisoners, which is similar to male prisoners according to the literature. Conclusion. The high prevalence of symptoms and disabilities of ADHD in women should lead to awareness of the disorder in both sexes and be addressed in terms of diagnostic work-up, treatment, and rehabilitation.

Assessment of patient satisfaction with psychiatric care. Development and clinical evaluation of a brief consumer satisfaction rating scale (UKU-ConSat)

Quality management and quality control of health services has become increasingly important. Central to the concept of quality of care is the patients (the health care consumers) own view of the care provided and the treatment outcome. UKU (Udvalg for Kliniske Undersøgelser; that is, Committee for Clinical Trials), a working group within the Scandinavian Society for Psychopharmacology (SSP), has designed a brief consumer satisfaction rating scale, the UKU-ConSat. Based on an extensive literature review, a number of principles related to content, assessment, interview techniques, documentation and standardisation steered the design of the rating scale. UKU-ConSat consists of six items related to the structure and process of treatment care, and two items related to outcome and well-being. A manual accompanies the rating scale with guidelines for how to solicit information from the patient and how to rate each item. A first field trial of the rating scale in 135 inpatients at multiple clinical sites in Finland and Sweden showed that it could be applied to several relevant patient categories (psychotic, affective, neurotic, organic and alcohol and substance abuse disorders). According to both patients and staff the rating scale promises to become useful both for research and for improvement of routine psychiatric services.

Gender differences of axis I and II comorbidity in subjects diagnosed with attention-deficit hyperactivity disorder as adults

Objective To investigate gender differences in psychiatric comorbidity patients diagnosed with attention-deficit hyperactivity disorder (ADHD) as adults. Methods Interviews about current ADHD symptoms and psychiatric comorbidity on axis I and II (Structured Clinical Interview for DSM-IV axis I and axis II) were conducted in a clinical cohort of 168 patients (78 women, 90 men). Independent information on childhood and current symptoms was collected from parents, partners and patient files. Results The lifetime prevalence of psychiatric comorbidity on axis I reached 92%, and current comorbidity, including autism spectrum disorders and Tourettes syndrome, was 47%. Women had a higher lifetime prevalence of mood and eating disorders compared with men, where substance-use disorders were more frequent. Ten per cent of patients fulfilled diagnostic criteria for a personality disorder. When excluding the general diagnostic criteria, 46% of the patients endorsed the specific criteria for at least one personality disorder. Gender differences were identified with predominance of histrionic personality traits in women and conduct disorder in men. Conclusion Patients diagnosed with ADHD as adults display an extremely high lifetime axis I comorbidity with a gender-specific pattern similar to the general population. No gender differences were identified with regard to personality disorders; however, an increased prevalence of deviant personality traits was confirmed. This study stresses the importance of evaluating comorbidity among patients diagnosed with ADHD as adults to secure optimal treatment.

Tryptophan Transport in Human Fibroblast Cells— A Functional Characterization

There are indications that serotonergic neurotransmission is disturbed in several psychiatric disorders. One explanation may be disturbed transport of tryptophan (precursor for serotonin synthesis) across cell membranes. Human fibroblast cells offer an advantageous model to study the transport of amino acids across cell membranes, since they are easy to propagate and the environmental factors can be controlled. The aim of this study was to functionally characterize tryptophan transport and to identify the main transporters of tryptophan in fibroblast cell lines from healthy controls. Tryptophan kinetic parameters (Vmax and Km) at low and high concentrations were measured in fibroblasts using the cluster tray method. Uptake of 3H (5)-L-tryptophan at different concentrations in the presence and absence of excess concentrations of inhibitors or combinations of inhibitors of amino acid transporters were also measured. Tryptophan transport at high concentration (0.5 mM) had low affinity and high Vmax and the LAT1 isoform of system-L was responsible for approximately 40% of the total uptake of tryptophan. In comparison, tryptophan transport at low concentration (50 nM) had higher affinity, lower Vmax and approximately 80% of tryptophan uptake was transported by system-L with LAT1 as the major isoform. The uptake of tryptophan at the low concentration was mainly sodium (Na+) dependent, while uptake at high substrate concentration was mainly Na+ independent. A series of different transporter inhibitors had varying inhibitory effects on tryptophan uptake. This study indicates that tryptophan is transported by multiple transporters that are active at different substrate concentrations in human fibroblast cells. The tryptophan transport trough system-L was mainly facilitated by the LAT1 isoform, at both low and high substrate concentrations of tryptophan.

Neurocognitive functioning and outcome of the Illness Management and Recovery Program for clients with schizophrenia and schizoaffective disorder.

Abstract The relationship between psychosocial programming and neurocognition has been established in previous research, but has not been explored in the context of the Illness Management and Recovery Program (IMR). This study examined associations between neurocognition and illness self-management skills acquisition, based on two previous trials of IMR. Neurocognitive functioning was assessed at baseline and post-treatment in 53 participants with schizophrenia or schizoaffective disorder who completed the IMR. Illness self-management was measured by the client and clinician versions of the Illness Management and Recovery Scale. Statistical analyses investigated improvements in neurocognitive functioning and possible association between illness self-management skills acquisition and neurocognitive functioning. Speed of processing as measured by the Trail Making Test A, was related to client-reported acquisition of illness self-management skills, before and after controlling for psychiatric symptoms and medication, but did not predict improvement in clinician ratings of client illness self-management skills. However, when controlling for client session attendance rates, the association between speed of processing and client-reported illness self-management skills acquisition ceased to be statistically significant, which suggests that compromised neurocognitive functioning does not reduce response to training in illness self-management in itself. The association between the frequency of attended IMR sessions and outcome of the IMR seems to decrease the negative impact of compromised neurocognition on illness self-management skills acquisition. Also, clients with slower speed of processing may experience less benefit from the IMR and may attend fewer sessions.

Genetic and Functional Study of L-Type Amino Acid Transporter 1 in Schizophrenia.

Schizophrenia involves neural catecholaminergic dysregulation. Tyrosine is the precursor of catecholamines, and its major transporter, according to studies on fibroblasts, in the brain is the L-type amino acid transporter 1 (LAT1). The present study assessed haplotype tag single-nucleotide polymorphisms (SNPs) of the SLC7A5/LAT1 gene in 315 patients with psychosis within the schizophrenia spectrum and 233 healthy controls to investigate genetic vulnerability to the disorder as well as genetic relationships to homovanillic acid (HVA) and 3-methoxy-4-hydroxyphenylglycol (MHPG), the major catecholamine metabolites in the cerebrospinal fluid (CSF). Moreover, the involvement of the different isoforms of the system L in tyrosine uptake and LAT1 tyrosine kinetics were studied in fibroblast cell lines of 10 patients with schizophrenia and 10 healthy controls. The results provide suggestive evidence of individual vulnerability to schizophrenia related to the LAT1 SNP rs9936204 genotype. A number of SNPs were nominally associated with CSF HVA and MHPG concentrations but did not survive correction for multiple testing. The LAT1 isoform was confirmed as the major tyrosine transporter in patients with schizophrenia. However, the kinetic parameters (maximal transport capacity, affinity of the binding sites, and diffusion constant of tyrosine transport through the LAT1 isoform) did not differ between patients with schizophrenia and controls. The present genetic findings call for independent replication in larger samples, while the functional study seems to exclude a role of LAT1 in the aberrant transport of tyrosine in fibroblasts of patients with schizophrenia.