Cumulative exposure to childhood adversity, and treated attention deficit/hyperactivity disorder: a cohort study of 543 650 adolescents and young adults in Sweden.

BACKGROUND: Though childhood adversity (CA) has been associated with the risk of attention deficit/hyperactivity disorder (ADHD), little is known about the effect of cumulative CAs and whether there are clusters of CAs that are more closely related with ADHD. METHODS: We used a Swedish cohort of 543 650 individuals born 1987-1991. Register-based CAs included familial death, substantial parental substance abuse and psychiatric disorder, substantial parental criminality, parental separation, household public assistance recipiency, and residential instability. Individuals were followed from year 2006 when they were 15-19 years of age, for treated ADHD, defined as a registered ICD diagnosis and/or prescription of medications to treat ADHD. Logistic regression analysis was used to calculate odds ratios (OR) with 95% confidence intervals (CI). Latent Class Analyses (LCA) were used to identify clusters based on the different CAs. RESULTS: All CAs increased the odds of ADHD in late adolescence and early adulthood; ORs ranged from 1.6 (95% CI 1.5-1.8) for familial death to 2.7 (95% CI 2.6-2.9) for household public assistance. We found a dose-response relationship between cumulative CA and ADHD; individuals with 4+ CAs had a markedly increased risk for ADHD (OR 5.5, 95% CI 5.0-6.0). LCA analyses revealed six distinct classes of CA associated with ADHD, of which 'exposure to most adversities' entailed highest risk. CONCLUSION: CA is a strong risk factor for ADHD, particularly when accumulated. Early and efficient detection of CA is of importance for interventions targeted to improve long-term mental health outcomes among disadvantaged children.

The assessment of serum concentration of adiponectin, leptin and serum carbohydrate antigen-19.9 in patients with pancreatic cancer and chronic pancreatitis.

UNLABELLED: Pancreatic cancer and chronic pancreatitis are still significant diagnostic and clinical problems. The clinical impact of preoperative serum carbohydrate antygen 19-9 (CA 19-9) levels have been disscussed. The aim of this study was a comparative analysis of the concentrations in serum of adipocytokines: adiponectin and leptin and CA 19-9 in patients with pancreatic cancer (PC), chronic pancreatitis (CP) and control group (CG). The study was performed in a group of 90 patients. Group 1 consisted of 30 patients with PC, group 2 consisted of 30 patients with CP. There was no coincidence of pancreatic cancer in CP group. Group 3 (CG) consisted of 30 persons and were recruited among patients operated for cholelithiasis. The serum samples were taken from patients and the concentration of adiponectin, leptin, CA 19-9 and CEA were evaluated. The revealed concentrations levels of the adiponectin were significantly higher in the PC serum samples compared to the CP and CG. There was no significant correlation between increased adiponectin concentration and body fat mass in the PC group. The concentration of leptin was significantly lower in CP serum samples compared to PC and CG. The concentration of leptin was similar in the PC and CG. The concentration of leptin was mainly dependent on body fat mass and fat distribution. Additionally, measurement of waist circumference and body composition was recorded using bioelectrical impedance analysis. CONCLUSIONS: significantly higher concentration levels of adiponectin in the PC group, independent of body fat mass, may play a potential role as a new tumor marker in PC and might be useful in the differential diagnosis between PC and CP, but this statement needs further investigation. To our knowledge, this was the first study evaluating not only body mass index but also the content and distribution of body fat in patients with PC and CP.

Concentrations and activities of metalloproteinases 2 and 9 and their inhibitors (TIMPS) in chronic pancreatitis and pancreatic adenocarcinoma.

UNLABELLED: Pancreatic cancer (PC) and chronic pancreatitis (CP) are still significant problems. The aim of this study was a comparative analysis of the activity and concentrations of matrix metalloproteinases 2 and 9 and the concentrations of their tissue inhibitors (TIMP 1 and 2) in the PC compared to CP tissue homogenates. The study was performed in a group of 63 patients with pancreatic cancer or chronic pancreatitis selected for resection procedures. Group 1 consisted of 31 patients with CP, group 2 consisted of 32 patients with PC. There was no coincidence of pancreatic cancer in CP group. The pancreatic tumor samples have been properly prepared in order to perform electrophoresis and immunoassay testing. The activity of MMPs and the concentrations of MMPs and TIMPs were evaluated. RESULTS: the revealed activities of gelatinases and concentrations levels of the gelatinases and their inhibitors were significantly higher in the PC tissue samples compared to CP. In both groups, higher concentrations of MMP9 compared to MMP2 and TIMP2 compared to TIMP1 were shown. High potential for tumor invasiveness demonstrated by the formation of lymph node metastases was characterized by the higher concentrations of MMP9 and TIMP2. However, in the case of infiltration of the nerve fibers, a decrease in the concentration of MMP2 was found. CONCLUSIONS: gelatinases and their inhibitors play important role in the pathogenesis of the CP as well as PC. The activity and concentration of gelatinases and the concentration of their inhibitors were all significantly higher in the PC group.

Ethnicity, socio-economic status and self-harm in Swedish youth: a national cohort study.

BACKGROUND: Previous studies have shown an elevated risk for self-harm in adolescents from ethnic minorities. However, potential contributions to this risk from socio-economic factors have rarely been addressed. The main aim of this article was to investigate any such effects. METHOD: A national cohort of 1009 157 children born during 1973-1982 was followed prospectively from 1991 to 2002 in Swedish national registers. Multivariate Cox analyses of proportional hazards were used to estimate the relative risk of hospital admission for self-harm. Parental country/region of birth was used as proxy for ethnicity. RESULTS: Youth with two parents born outside Sweden (except those from Southern Europe) had higher age- and gender-adjusted hazard ratios (HRs) of self-harm than the majority population (HR 1.6-2.3). The HRs decreased for all immigrant groups when socio-economic factors were accounted for but remained significantly higher for immigrants from Finland and Western countries and for youth with one Swedish-born and one foreign-born parent. CONCLUSIONS: Socio-economic factors explain much of the variation by parental country of birth of hospital admissions for self-harm in youth in Sweden.

Serum cartilage oligomeric matrix protein (COMP) in rheumatoid arthritis and knee osteoarthritis.

The cartilage oligometrix matrix protein (COMP) is a noncollagenous protein, a glycoprotein, the function of which is to bind to type II collagen fibres and stabilise the collagen fibre network in the articular cartilage. In the serum of the normal population the COMP level is 5 mug/ml. An increased level of COMP in the synovial fluid was described in the early stage of rheumatoid arthritis (RA), whereas in advanced stages of RA, the level of COMP decreased. In this study we assessed the serum COMP level in patients with RA and knee osteoarthritis (OA) and found a correlation between the serum COMP level and other markers as well as bone mass density (BMD) changes, activity of disease, disease duration and the age of the patients. The blood was collected from 30 RA patients and 30 OA patients who constituted the control group. The serum COMP level was determined using an inhibition enzyme-linked immunosorbent assay (ELISA). The average value of the serum COMP level in RA patients was 10.4+/-3.6 U/l. There was a correlation between the serum COMP level and the age of RA patients (p<0.005) and disease activity score (DAS) value (p<0.01). According to correlation coefficients, the serum COMP level was independent of stage of disease, number of painful and swollen joints, duration of morning stiffness, disease duration and titre of the Waaler-Rose test. The influence of rheumatoid nodule presence on the serum COMP level was shown (p<0.05). In RA patients with erythrocyte sedimentation rate (ESR) values below 20 mm/h compared with patients with ESR values over 60 mm/h, the serum COMP level was observed to be significantly lower (p<0.05). The average value of COMP in OA patients was 10.4+/-2.7 U/l. No correlation was found between the serum COMP level and patients' age and disease duration. There was a correlation between the serum COMP level and Western Ontario and McMaster Universities (WOMAC) index pain scale for the lower limbs (p<0.005) and T-score value of densitometry examinations (p<0.036) in OA patients. No statistical differences were found between the average serum COMP level in RA and OA patients.

Cartilage oligomeric matrix protein in serum in systemic lupus erythematosus and knee osteoarthritis. Preliminary communication.

The cartilage oligomeric matrix protein (COMP) is a glycoprotein, which occurs mainly in an articular cartilage. The amount of this protein increases under the influence of cytokines and growth factors. As a result of various diseases that cause damage to cartilage, fragments of matrix protein are released into synovial fluid and then into blood. The assessment of matrix protein level in serum, for example COMP, permits the establishment of the degree of cartilage damage in inflammatory joint diseases, and permits observation of the effectiveness of the treatment. Blood was collected from 30 systemic lupus erythematosus (SLE) patients, and from 30 patients with knee osteoarthritis (OA) who constituted the control group. Serum COMP level was determined using an inhibition enzyme-linked immunosorbent assay (ELISA). The average value of the serum COMP level in SLE patients was 11.3+/-3.7 U/l. According to correlation coefficients, serum COMP level is independent of patients' age, disease duration and the clinical picture of SLE. No correlation was found between serum COMP level and bone mass density (BMD) changes. In SLE patients with decreased haemoglobin levels (<11.0 g/dl) values compared with patients with normal haemoglobin level, the serum COMP level was observed to be significantly higher (P<0.05). Both in SLE patients with erythrocyte sedimentation rate (ESR) values over 60 mm/h and in patients with ESR values below 60 mm/h, the serum COMP level was observed to be significantly higher (P<0.05). A significant positive correlation was found between serum COMP level and ESR value, as well as a number of thrombocytes. Negative correlation occurred between the serum COMP level and the value of haemoglobin. The average value of COMP in OA patients was 10.4+/-2.7 U/l. No correlation was found between serum COMP level and patients' age and disease duration. There was correlation between the serum COMP level and the T-score value of densitometry examinations in OA patients. No statistical differences were found between the average serum COMP levels for SLE and OA patients.

Rapid regulation of GAD67 mRNA and protein level in cortical neurons after sensory learning.

Cortical representations of different modalities can be modified by sensory learning. Our previous studies in the barrel cortex showed that expansion of the cortical representation of a row of vibrissae could be induced by pairing stimulation of a row of vibrissae with a tail shock. The plastic change in cortical reactivity to the input used during the training was accompanied by increased density of GABA immunoreactive neurons in the involved row of cortical barrels. Using the same paradigm, the present study examined the pathway of GABA synthesis-expression of GAD67 mRNA and immunoreactivity of GAD67 isoenzyme in the barrel cortex of mice after sensory learning. In situ hybridization revealed that the GAD67 mRNA level was elevated in one row of barrels in the trained group as well as in controls receiving vibrissae stimulation alone. In contrast, elevation of immunoreactivity of the GAD67 protein occurred only in the trained group. The density of GABA-immunoreactive neurons in the hollows of barrels representing the row of vibrissae activated during the training was increased by 50%. These data indicated that sensory stimulation alone affected expression of the 67 kDa glutamate decarboxylase isoenzyme synthesis pathway, whereas the processes involved in cortical plasticity induced by associative learning modified this pathway additionally at the level of translation.

Laminar specific alterations of thalamocortical projections in organotypic cultures following layer 4 disruption in ferret somatosensory cortex.

The developing neocortex influences the growth of thalamocortical projections. Layer 4 in particular receives the majority of input from the thalamus and is important in instructing thalamic afferents to terminate. Previous in vivo experiments demonstrated that disruption of layer 4 during corticogenesis in ferret somatosensory cortex by application of methylazoxy methanol acetate (MAM) prevents proper termination of thalamic afferents in appropriate cortical regions. To further explore the role of layer 4 in thalamocortical development, we prepared organotypic cocultures consisting of normal gestational day 0 (P0) ferret thalamus paired with normal, embryonic day 33 (E33), or E38 MAM-treated cortex obtained from ferrets at either P0 or P7. Injection of MAM on E33 disrupts layer 4 formation, whereas similar injections on E38 interfere with layer 2 formation. The cocultures grew together for a number of days, then discrete injections of either fluorescent dextrans or 1,1'-dioctadecyl-3,3,3',3'-tetramethyl-indocarbocyanine perchlorate (DiI) were made into the thalamic piece. The labeled thalamic afferents that grew into the cortical slice were analysed and the sites of their terminations quantified after 3, 5, or 7-10 days in culture (DIC). Our results varied somewhat with the amount of time in culture, but the preponderance of thalamic fibers in normal cortex terminated in layer 4, whereas their counterparts in E33 MAM-treated cortex grew beyond the cortical plate and many fibers terminated inappropriately within lower cortical layers or white matter. Terminal distribution of thalamic fibers in E38 MAM-treated cortex looked similar to normal. These results demonstrate that the cells of layer 4 provide thalamic afferents with important positional and termination cues.

NMDA-induced 45Ca release in the dentate gyrus of newborn rats: in vivo microdialysis study.

This in vivo study, aimed at detecting the N-methyl-D-aspartate (NMDA) evoked Ca(2+)-induced Ca(2+) release from intracellular stores in the neonatal rat brain, demonstrates that the application of 5 mM N-methyl-D-aspartate via a microdialysis probe for 20 min to the dentate gyrus (DG) of halotane-anesthetized 7 day-old (postnatal day 7, PND 7) rats induces a prolonged decrease in Ca(2+) concentration in an initially calcium-free dialysis medium, indicative of a drop in the extracellular concentration of Ca(2+) and Ca(2+) influx to neurons. In parallel experiments, a huge NMDA-evoked release of 45Ca from the pre-labeled endogenous Ca(2+) pool was observed and interpreted as the expression of intracellular Ca(2+) release. Dantrolene (100 microM) significantly inhibited the NMDA-induced 45Ca release, whereas 250 microM ryanodine exerted an unspecific biphasic effect. Autoradiographic and immunocytochemical detection of ryanodine receptors and calbindin D(28K), respectively, in the hippocampal region of PND 7 rats displayed a pronounced expression of [3H]ryanodine binding sites in the DG, but only a slight immunoreactivity of calbindin D(28K). Plastic changes in neurons or excitotoxic neuronal damage induced by the activation of NMDA receptors are mediated by Ca(2+) signals, resulting from an influx of extracellular Ca(2+), and also in some neurons, from the release of intracellular Ca(2+). Our previous in vivo microdialysis experiments visualized NMDA-evoked 45Ca release in the adult rat dentate gyrus, attributable to Ca(2+)-induced Ca(2+) release from the ryanodine-sensitive pool. An additional role of calbindin in the mechanism of this phenomenon has been suggested. This aspect has not been studied in vivo in newborn rats. Our present results indicate that the release of 45Ca from the prelabeled intracellular, dantrolene-sensitive Ca(2+) pool in the DG neurons of immature rats, most probably representing a phenomenon of Ca(2+)-induced Ca(2+) release, significantly participates in the generation of NMDA receptor-mediated intracellular Ca(2+) signals, whereas the role of calbindin D(28K) in the mechanism of 45Ca release is negligible.

Differences between rats and rabbits in NMDA receptor-mediated calcium signalling in hippocampal neurones.

In vivo microdialysis combined with the measurement of (45)Ca(2+) efflux from prelabelled hippocampus demonstrated a pronounced N-methyl-D-aspartate (NMDA)-evoked (45)Ca(2+) release to the dialysate in the rat dentate gyrus (DG) and CA1, whereas in rabbit a slight release of (45)Ca(2+) was observed only in the DG. In vitro, we noticed that the NMDA-evoked increase in Fura-2 detected intracellular Ca(2+) concentration in synaptoneurosomes from the rat, but not from the rabbit hippocampus, was strongly inhibited by the ryanodine receptor (RyR) antagonists dantrolene and ryanodine. To establish the mechanism of these differences, we characterised their possible dependence on the expression of RyR and their co-localisation with the calcium binding protein calbindin D(28k). A pronounced expression of [(3)H]ryanodine binding sites in the rat DG, which is only slight in the CA1, was demonstrated whereas in rabbit they were only found in the DG. The pattern of expression of calbindin D(28k) immunoreactivity and RyR in the rat and rabbit hippocampus was similar. These results suggest that the functional role of RyR in the generation of the NMDA receptor-mediated intracellular Ca(2+) signalling in the rabbit hippocampal neurones is marginal when compared to the rat. These differences reflect a diverse expression of RyR in both species. The corresponding differences in calbindin D(28k) immunoreactivity are most probably secondary in nature.

Deafferentation induced changes in GAD67 and GluR2 mRNA expression in mouse somatosensory cortex.

Partial vibrissectomy in adult mice induces body map plasticity in SI barrel cortex. To examine if the disturbed balance of cortical activation affects the excitatory and inhibitory neurotransmitter systems, we studied glutamic acid decarboxylase (GAD 67) and AMPA receptor subunit GluR2 mRNA expression in the barrel cortex. At varying times post-vibrissectomy, sparing row C of whiskers on one side of the snout, the brains were processed for in situ hybridization using specific [(35)S]oligonucleotides to detect the laminar localization of GAD67 and GluR2 mRNAs. Three and seven days after vibrissectomy, the expression of GAD67 was decreased in the deafferented cortex, while 30 days post-lesion, no effects were observed. At 3 days post-lesion, an ipsilateral decrease in GAD67 mRNA expression was also observed. No decreases in GluR2 transcripts were found in the deafferented cortex, but an increased expression was observed in the representation of the spared row C of whiskers 3 days after vibrissectomy. Seven and 30 days post lesion no changes in GluR2 expression were found. These data indicate that in the barrel cortex, peripheral deafferentation transiently regulates GAD67 and GluR2 expression at the transcriptional level. We suggest that this may be a manifestation of adaptive processes.

Partial blocking of NMDA receptors reduces plastic changes induced by short-lasting classical conditioning in the SI barrel cortex of adult mice.

The effect of blockade of N-methyl-D-aspartate (NMDA) receptors in the barrel cortex upon the learning-induced changes of the cortical body map was examined in adult mice. We have previously found that three sensory conditioning sessions, in which stimulation of a row of vibrissae was paired with a tail shock, produced an enlargement of the functional representation of a row of vibrissae stimulated during training. Implantation of the slow release polymer Elvax, containing 2-amino-5-phosphonovalerate (APV, 50 mM), in the vicinity of the barrel cortex was performed 1 day before conditioning to block NMDA receptors. The cortical representation of a trained row of vibrissae was visualized with 2-deoxyglucose (2DG) functional brain mapping 1 day after the completion of the conditioning procedure. The partial blockade of NMDA receptors within the barrel cortex reduced (by half) the expansion of the cortical representation of a trained row of vibrissae as compared to the enlargement of the cortical representation of a trained row found in untreated (60%) and Elvax-PBS implanted (47%) mice. The results provide evidence that the learning-induced processes of cortical map reorganization involve mechanisms that depend on NMDA receptor activation.

Spatiotemporal changes in hippocampal NMDA receptor binding as a consequence of trimethyltin neurotoxicity in the rat.

In the present study we examined the presumable changes in the distribution of N-methyl-D-aspartate (NMDA) receptors in the hippocampus of rat exposed to a potent neurotoxic drug, trimethyltin (TMT). Using in vitro receptor binding autoradiography, [3H]MK801 labelling was determined at 7, 14, 21, 30 and 60 days after treatment with TMT (single dose of 8 mg/kg, i.p.) in various hippocampal areas thought to be affected by the neurotoxin. At 21-60 days after exposure, a decrease in receptor binding was observed in CA1 hippocampal subfield (10-20%, P< 0.05). A reduction in binding density also occurred in CA4/ CA3c, where labelling vanished completely at longer times. In the molecular layer (ML) of the dentate gyrus (DG), however, 16-37% (P<0.05) increase in receptor binding was found at 14-60 days postexposure. These results suggest that exposure to TMT leads to an altered topography of NMDA receptor density sites in the rat hippocampus. Dynamics of the reduction in receptor binding in CA4/CA3c and CA1 followed the development of the well-known degenerative effects induced by the neurotoxin. In contrast, the enhanced binding density in the ML of the DG may be a part of a mechanism of plastic response of granule cells to denervation/reinnervation.

Development of laminar distributions of kainate receptors in the somatosensory cortex of mice.

Kainate receptors were present at birth in the murine somatosensory cortex as revealed by quantitative in vitro autoradiography. During the first five postnatal days [3H]kainate binding rapidly increased and the maximum density in layer IV was reached at P12. The adult laminar pattern of receptor binding distribution was established by the third postnatal week with the heaviest labeling of infragranular layers. The sharp increase of kainate receptor during the first postnatal week coincides with the critical period for cytoarchitectonic plasticity of the barrels and establishment of functional thalamo-cortical connections in the barrel field.

Transient increase of AMPA and NMDA receptor binding in the barrel cortex of mice after tactile stimulation.

The effects of sensory stimulation and sensory conditioning upon [3H]MK-801 [(+)-5-methyl-10,11-dihydro- 5H-dibenzo[a,d]cyclohepten-5, 10-imine] binding to N-methyl- d-aspartate (NMDA) receptor sites and [3H]AMPA (alpha-amino-3-hydroxy-5-methylisoxasole-4-propionic acid) binding to AMPA receptor sites were examined in the primary somatosensory (SI) cortex of mice. Following short-lasting unilateral tactile stimulation of a selected row of vibrissae, and tactile stimulation paired with noxious stimulus (the pairing procedure was found to alter cortical representation of vibrissae), in vitro receptor binding autoradiography was performed on the sections of the barrel cortex of mice. One hour after the end of tactile stimulation or training procedure there was an increase of [3H]MK-801 and [3H]AMPA binding in the corresponding row of barrels in layer IV of the SI cortex of adult mice. These effects disappeared 24 h after the end of each experimental procedure. The results suggest that both subtypes of glutamate receptors are regulated in an activity-dependent way and that sensory stimulation transiently modifies local cortical processing.

Partial blocking of NMDA receptors restricts plastic changes in adult mouse barrel cortex.

Changes of cortical body maps can be evoked in brains of adult animals by injury to sensory nerves. We investigated changes of functional representation of row C of mystacial vibrissae in the barrel cortex of mice. Plastic changes of cortical representations were mapped with 2-deoxyglucose autoradiography. Seven days after lesions of all vibrissae except row C, cortical representation of the spared row increased in width by 60%. Partial blocking of N-methyl-D-aspartate (NMDA) receptors by subdural implants of thin sheets of Elvax impregnated with DL-2-amino-5-phosphonovaleric acid (APV) prevented development of the increase of row C representation. Low level of NMDA receptor blocking did not affect significantly the basal level of 2DG uptake and stimulus evoked uptake but prevented the plastic change of the body map.

Sensory conditioning and sensory stimulation do not affect GABAA receptor binding in the barrel field of mice.

The whisker-to-barrel system of adult mice was used in a study on the effects of short-lasting tactile stimulation and sensory conditioning training on GABAA receptor binding in the barrel field of somatosensory cortex. In vitro receptor binding autoradiography was used to examine the pattern and intensity of [3H]muscimol binding to GABAA receptors. A well-defined pattern of GABAA receptors in the barrel field remained unaffected after both procedures used. Also, no differences in intensity of GABAA receptor binding were observed. These results suggest that GABAA receptors are not involved in the plastic changes developing during sensory conditioning training.

Reduction of GABAA receptor binding of [3H]muscimol in the barrel field of mice after peripheral denervation: transient and long-lasting effects.

The effect of peripheral sensory deprivation upon GABAA receptor binding of [3H]muscimol was investigated in the barrel cortex--cortical representation of mystacial vibrissae of mice--by means of in vitro quantitative autoradiography. Unilateral lesions of all vibrissae or selected rows of whiskers were performed neonatally or in adulthood. [3H]muscimol binding was examined after various survival times up to 60 days. Both types of lesions performed in adult mice resulted in a transient decrease (10-25%) of binding values in the deafferented areas of the barrel field as compared with the unoperated control side. Sixty days after denervation [3H]muscimol binding returned to control values. Similar results were found after neonatal removal of all vibrissae. Neonatal lesion of selected rows of vibrissae, however, resulted in a decrease of [3H]muscimol binding (by about 26%) lasting up to 60 days in corresponding rows of barrels. This last result was accompanied by severe cytoarchitectonic malformation of the barrel field. The results support the hypothesis that a decrease of inhibition plays a facilitatory role in the plastic reorganization of cortical circuitry.

Effects of implantation of Alzet 1007D osmotic minipumps upon 2-deoxyglucose uptake in the cerebral cortex of mice.

The smallest Alzet osmotic minipumps (1007D) were implanted into mouse cerebral cortex. The flow of saline from a minipump produced a large necrosis of cortical tissue and still larger zone of decreased metabolic activity around the site of cannula implantation. Stimulus evoked uptake of 2-deoxyglucose located several millimeters from the implantation site was not affected.