Characterization of the 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-provoked strong and rapid aversion to unfamiliar foodstuffs in rats

A conspicuous but scantly studied feature of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) toxicity is avoidance of unfamiliar foodstuffs, which seems to be one of the very few exquisitely sensitive behavioural effects in adult laboratory animals. Here we characterized this peculiar response further after low doses of TCDD. The time-course of the novelty avoidance, the role of nutriment form and dependence of the aversion on the time lag between TCDD exposure and the presentation of a novel food item was determined using rats with different sensitivities to lethality of TCDD. Rats were offered chocolate, liquid nutriment or familiar feed with an unfamiliar texture and the consumptions were measured for varying periods. Aversion to a novel food item (chocolate) emerged within 5.5h after TCDD exposure. A lag of a week or more between TCDD exposure and the presentation of chocolate abolished the avoidance whereas simultaneous presentation of chocolate with TCDD treatment rendered the rats oblivious to the chocolate's presence for over 40 days. Rats avoided also liquid nutriments when these were coupled with TCDD administration but this faded much sooner than chocolate aversion. Even a change in feed texture at the exposure was able to elicit the response. However, habituation was found to interfere with the aversion. These findings indicate that temporal proximity to TCDD exposure is a requisite for the avoidance response which emerges rapidly and may linger on for extended periods, but is not strictly confined to any specific food type. The molecular mechanisms of this tantalizing behavioural alteration remain to be determined.     

Immediate and highly sensitive aversion response to a novel food item linked to AH receptor stimulation

Aversion to novel food items was studied in male rats and mice after 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure using chocolate consumption as an indicator. The correlation of this phenomenon with susceptibility to acute toxicity and CYP1A1 induction was examined by determining the dose-response of chocolate aversion in differently dioxin-sensitive rat lines after TCDD (0.01-10 μg/kg). Furthermore, the dependence of this behavioral alteration on the AH receptor (AHR) was studied employing AHR-deficient and wild-type mice. We offered chocolate for both species as a novel food item immediately after the exposure, and it was available with standard rodent chow for 3 days. The ED₅₀ value for the extremely resistant rat line A (LD₅₀ value > 10,000 μg/kg) was 0.36 μg/kg, for the semi-resistant line B (LD₅₀ value 830 μg/kg) 1.07 μg/kg and for the TCDD-sensitive line C (LD₅₀ value 40 μg/kg) 0.34 μg/kg. Interestingly, the ED₅₀ values for chocolate aversion were very similar to those for CYP1A1 induction in these rat lines. Findings on AHR-deficient and wild-type mice implied the involvement of the AHR in this intriguing response, which may thus represent a mechanism to restrict exposure to potentially toxic dietary substances causing hepatic induction of drug-metabolizing enzymes.     

Mass spectrometric tools for cell and tissue studies

Mass spectrometry (MS) is a powerful tool for identification and quantitation of organic molecules from various matrices, especially when combined with liquid chromatography (LC). The aim of this review is to present different MS techniques and methods which can be utilized in drug and metabolism studies using cells and tissues. The first part focuses on the use of LC/MS in permeability studies across cell lines as well as in ABC transporter protein experiments. The second part describes the utilization of MS in drug metabolism studies using cell lines. The third part presents a relatively new application area of MS, namely mass spectrometric imaging (MSI) or imaging mass spectrometry (IMS). Several different MSI techniques can be used for characterization of surfaces, in terms of abundance of proteins and peptides but also small molecules, such as drug compounds and their metabolites, at the surface. The final part gives a review of MS based techniques for direct analysis of cell contents.     

Physical ill health and risk of psychosis

Patients with psychosis have been found to suffer from physical illnesses more commonly than the general population. In this report, self-reported physical ill health and its correlates among subjects with and without vulnerability to psychosis in a sample of first-degree relatives, help-seekers and controls were investigated. Perceived physical health was statistically significantly poorer among subjects with minor symptoms on the Structured Interview for Prodromal Symptoms and those vulnerable to psychosis than among those without symptoms measured by 13 somatoform symptom sum scores of the Symptom Checklist-90. Those at current risk of psychosis had a significantly higher mean sum score on the 13 somatic items (mean=21.1) than others (mean=9.6). Having physical symptoms or a self-reported physician-diagnosed illness was significantly associated with vulnerability to psychosis (odds ratio=3.05). The subjects with a mood disorder (odds ratio=4.33) had significantly more commonly physician-diagnosed illnesses than those who had no diagnosis or any other diagnosis. Physical ill health seems to be common among those vulnerable to psychosis.     

Recruitment and treatment practices for help-seeking "prodromal" patients

The prodrome of psychosis has become a target for early identification and for treatments that address both symptoms and risk for future psychosis. Interest and activity in this realm is now worldwide. Clinical trials with rigorous methodology have only just begun, making treatment guidelines premature. Despite the sparse evidence base, treatments are currently applied to patients in the new prodromal clinics, usually treatments developed for established psychosis and modified for the prodromal phase. This communication will describe representative samplings of how treatment-seeking prodromal patients are currently recruited and treated in prodromal clinics worldwide. Recruitment includes how prodromal patients are sought, initially evaluated, apprised of their high-risk status, and informed of the risks and benefits of prodromal treatments and how their mental state is monitored over time. The treatment modalities offered (and described) include engagement, supportive therapy, case management, stress management, cognitive behavioral treatment, family-based treatment, antipsychotic pharmacotherapy, and non-antipsychotic pharmacotherapy. References for details are noted.     

Vulnerability to psychosis increases the risk of depression. Results of the RADEP study

We studied prevalence of depressive symptoms in primary care (PrC) and in psychiatric outpatient care (PsC), and how psychotic and manic symptoms are associated with current depressive symptoms. Altogether 563 patients attending PrC and 163 patients attending PsC filled in a questionnaire including the Depression Scale (DEPS), the Mood Disorder Questionnaire (MDQ) and questions on psychotic symptoms from the Composite International Diagnostic Interview (CIDI). Patients with depressive symptoms (DEPS score > 8) were interviewed by phone using the same checklist 6 months after baseline examination. From the PrC sample, 19.5% and from the PsC sample 73.0% were DEPS positive. In the PrC but not in the PsC sample, patients' background associated strongly with occurrence of depressive symptoms. Both at baseline and at follow-up, depressive symptoms correlated significantly with psychotic and manic symptoms. In multivariate analyses, when the effects of background, health and functioning were taken into account, baseline depressive symptoms associated significantly with lifetime psychotic symptoms. Depressive symptoms at follow-up associated significantly with psychotic symptoms during the follow-up period. In the PrC sample, this association was significant even when the effect of baseline depressive symptoms was controlled. About one-fifth of patients attending primary care and about three-quarters of patients attending psychiatric outpatient patient care suffer from depressive symptoms. Vulnerability to psychosis, indicated by occurrence of psychotic symptoms, increases the risk of and slower recovery from depressive symptoms in the patients attending primary care. Therefore, vulnerability to psychosis should be evaluated when treatment intervention for patients with depressive symptoms is planned.     

Circulating glucocorticoid bioactivity and serum cortisol concentrations in premature infants: the influence of exogenous glucocorticoids and clinical factors

OBJECTIVE: Glucocorticoids are widely used before preterm delivery and in preterm infants may bear serious adverse effects. Better knowledge about the circulating glucocorticoid milieu after glucocorticoid treatment could improve treatment modalities. Therefore, we investigated the influence of exogenous glucocorticoids and clinical factors on serum cortisol (F) levels and circulating glucocorticoid bioactivity (GBA) in preterm infants. DESIGN: Eighty-nine infants (gestational age (GA) 23.6-33.1 weeks at birth) were enrolled in a prospective cohort study in two tertiary neonatal centres. METHODS: Cord, day of birth (D0), fourth day (D4) and 36 weeks postmenstrual age serum F and GBA levels were measured. RESULTS: The cord GBA was 5.8-fold and D0 GBA 2.3-fold higher in the infants exposed to antenatal steroids within 12 h before birth when compared with those unexposed or exposed >7 days before birth (95% CI 3.8-8.6; P<0.0001, and 1.8-3.0; P<0.0001 respectively). In the infants treated with early postnatal dexamethasone, D4 GBA was 1.7-fold (1.3-2.2; P<0.0005) higher when compared with levels in the infants without this treatment. Clinical factors indicating perinatal distress, such as Apgar scores <7 and low GA, were associated with higher cord, D0 and D4 serum F levels. CONCLUSIONS: Both ante- and postnatally administered glucocorticoids increase circulating GBA not attributable to endogenous F. Perinatal distress and preceding glucocorticoid treatment need to be taken into account when circulating glucocorticoid milieu is evaluated in preterm infants. The GBA assay may prove to be a useful instrument in the development of new glucocorticoid treatment strategies.     

Diazepam binding inhibitor overexpression in mice causes hydrocephalus, decreases plasticity in excitatory synapses and impairs hippocampus-dependent learning

Diazepam binding inhibitor (DBI) and its processing products are endogenous modulators of GABAA and linked to various brain disorders ranging from anxiety and drug dependence to epilepsy. To investigate the physiological role of endogenously expressed DBI in the brain we created a transgenic mouse line overexpressing DBI gene. Transgenic mice had a 37x increased protein expression and immunohistochemistry showed excessive glial expression in the infragranular region of the dentate gyrus. Transgenic animals had significantly larger lateral ventricles and decreased plasticity of excitatory synapses without affecting either inhibitory or excitatory synaptic transmission. In behavioral tests transgenic animals had no differences in motor and exploratory activity, yet impaired hippocampus-dependent learning and memory. Overexpression did not cause anxiety or proconflict behavior, nor influenced kainic acid or pentylenetetrazole induced seizure activity. Our transgenic mouse line demonstrates that endogenously overexpressed DBI impairs hippocampus-dependent learning without anxiety or proconflict behavior.     

Decreased T2 signal in the thalami may be a sign of lysosomal storage disease

INTRODUCTION: Lysosomal disorders are rare and are caused by genetically transmitted lysosomal enzyme deficiencies. A decreased T2 signal in the thalamus has occasionally been reported. AIMS: Because the finding of bilateral abnormal signal intensity of the thalamus on T2-weighted images has not been systematically reviewed, and its value as a diagnostic tool critically evaluated, we carried out a systematic review of the literature. METHODS: Articles in English with 30 trios of keywords were collected from PubMed. Exclusion criteria were lack of conventional T2-weighted images in the protocol and not being a human study. Finally, 111 articles were included. The thalamus was considered affected only if mentioned in the text or in the figure legends. RESULTS: Some 117 patients with various lysosomal diseases and five patients with ceruloplasmin deficiency were reported to have a bilateral decrease in T2 signal intensity. At least one article reported a bilateral decrease in signal intensity of the thalami on T2-weighted images in association with GM1 and GM2 gangliosidosis and with Krabbe's disease, aspartylglucosaminuria, mannosidosis, fucosidosis, and mucolipidosis IV. Furthermore, thalamic alteration was a consistent finding in several types of neuronal ceroid lipofuscinosis (NCL) including CLN1 (infantile NCL), CLN2 (classic late infantile NCL), CLN3 (juvenile NCL), CLN5 (Finnish variant late infantile NCL), and CLN7 (Turkish variant late infantile NCL). CONCLUSION: A decrease in T2 signal intensity in the thalami seems to be a sign of lysosomal disease.