Dysconnection in schizophrenia: from abnormal synaptic plasticity to failures of self-monitoring

Over the last 2 decades, a large number of neurophysiological and neuroimaging studies of patients with schizophrenia have furnished in vivo evidence for dysconnectivity, ie, abnormal functional integration of brain processes. While the evidence for dysconnectivity in schizophrenia is strong, its etiology, pathophysiological mechanisms, and significance for clinical symptoms are unclear. First, dysconnectivity could result from aberrant wiring of connections during development, from aberrant synaptic plasticity, or from both. Second, it is not clear how schizophrenic symptoms can be understood mechanistically as a consequence of dysconnectivity. Third, if dysconnectivity is the primary pathophysiology, and not just an epiphenomenon, then it should provide a mechanistic explanation for known empirical facts about schizophrenia. This article addresses these 3 issues in the framework of the dysconnection hypothesis. This theory postulates that the core pathology in schizophrenia resides in aberrant N-methyl-D-aspartate receptor (NMDAR)–mediated synaptic plasticity due to abnormal regulation of NMDARs by neuromodulatory transmitters like dopamine, serotonin, or acetylcholine. We argue that this neurobiological mechanism can explain failures of self-monitoring, leading to a mechanistic explanation for first-rank symptoms as pathognomonic features of schizophrenia, and may provide a basis for future diagnostic classifications with physiologically defined patient subgroups. Finally, we test the explanatory power of our theory against a list of empirical facts about schizophrenia

Expression of ABC Efflux Transporters in Placenta from Women with Insulin-Managed Diabetes

Drug efflux transporters in the placenta can significantly influence the materno-fetal transfer of a diverse array of drugs and other xenobiotics. To determine if clinically important drug efflux transporter expression is altered in pregnancies complicated by gestational diabetes mellitus (GDM-I) or type 1 diabetes mellitus (T1DM-I), we compared the expression of multidrug resistance protein 1 (MDR1), multidrug resistance-associated protein 2 (MRP2) and the breast cancer resistance protein (BCRP) via western blotting and quantitative real-time polymerase chain reaction in samples obtained from insulin-managed diabetic pregnancies to healthy term-matched controls. At the level of mRNA, we found significantly increased expression of MDR1 in the GDM-I group compared to both the T1DM-I (p<0.01) and control groups (p<0.05). Significant changes in the placental protein expression of MDR1, MRP2, and BCRP were not detected (p>0.05). Interestingly, there was a significant, positive correlation observed between plasma hemoglobin A1c levels (a retrospective marker of glycemic control) and both BCRP protein expression (r = 0.45, p<0.05) and BCRP mRNA expression (r = 0.58, p<0.01) in the insulin-managed DM groups. Collectively, the data suggest that the expression of placental efflux transporters is not altered in pregnancies complicated by diabetes when hyperglycemia is managed; however, given the relationship between BCRP expression and plasma hemoglobin A1c levels it is plausible that their expression could change in poorly managed diabetes

Delta-9-tetrahydrocannabinol, neural oscillations above 20 Hz and induced acute psychosis

Rationale: An acute challenge with delta-9-tetrahydrocannabinol (THC) can induce psychotic symptoms including delusions. High electroencephalography (EEG) frequencies, above 20 Hz, have previously been implicated in psychosis and schizophrenia. Objectives: The objective of this study is to determine the effect of intravenous THC compared to placebo on high-frequency EEG. Methods: A double-blind cross-over study design was used. In the resting state, the high-beta to low-gamma magnitude (21–45 Hz) was investigated (n=13 pairs+4 THC only). Also, the event-related synchronisation (ERS) of motor-associated high gamma was studied using a self-paced button press task (n=15). Results: In the resting state, there was a significant condition × frequency interaction (p=0.00017), consisting of a shift towards higher frequencies under THC conditions (reduced high beta [21–27 Hz] and increased low gamma [27–45 Hz]). There was also a condition × frequency × location interaction (p=0.006), such that the reduction in 21–27-Hz magnitude tended to be more prominent in anterior regions, whilst posterior areas tended to show greater 27–45-Hz increases. This effect was correlated with positive symptoms, as assessed on the Positive and Negative Syndrome Scale (PANSS) (r=0.429, p=0.042). In the motor task, there was a main effect of THC to increase 65–130-Hz ERS (p=0.035) over contra-lateral sensorimotor areas, which was driven by increased magnitude in the higher, 85–130-Hz band (p=0.02) and not the 65–85-Hz band. Conclusions: The THC-induced shift to faster gamma oscillations may represent an over-activation of the cortex, possibly related to saliency misattribution in the delusional state

Influence of Maternal Dysmetabolic Conditions During Pregnancy on Cardiovascular Disease

Pathogenic factors associated with maternal hypercholesterolemia, obesity, and diabetic conditions during pregnancy influence fetal development and predispose offspring to cardiovascular disease. Animal models have established cause–effect relationships consistent with epidemiological findings in humans and have demonstrated, in principle, that interventions before or during pregnancy can reduce or prevent pathogenic in utero programming. However, little is known about the mechanisms by which maternal dysmetabolic conditions enhance disease susceptibility in offspring. Identification of these mechanisms is rendered more difficult by the fact that programming effects in offspring may be latent and may require conventional risk factors and inherited genetic co-factors to become clinically manifest. Given the increasing prevalence of maternal risk factors, which is expected to lead to a wave of cardiovascular disease in the coming decades, and the length of prospective studies on developmental programming in humans, greater-than-usual emphasis on experimental models and translational studies is necessary

Serum levels of soluble int. 2 receptors and neopterin in renal transplant patients

In order to evaluate if soluble Interleukin 2 receptor (slL2R) and neopterin (Npt) levels can help in the differentiation between acute rejection, nephrotoxicity due to Cyclosporin and infection, we studied prospectively 26 patients, who underwent kidney transplantation. (In 16 patients cadaveric, and in 8 from live related donnor). We measured the slL2R and Npt levels before and immediately after the transplantation, 24 hours later and subsequently every three days till the patient was discharged from the Transplantation Unit. Pre transplant levels of both slL2R and Npt were higher than normal controls. Immediately after the transplantation the levels of both parameters were significantly decreased. In the 16 patients, in whom the postoperative period was uneventful, slL2R and Npt levels decreased gradually.sll2R levels were comparable elevated in all cases of postoprative complications, namely acute rejection, Cyclosporin nephrotoxicity or infection. Serum Npt were highly raised in cases of acute graft rejection or infection. However raised Npt levels due to infection are easily identified because of the moderately raised creatinine levels. We conclude that concomitant evaluation of Npt and creatinine levels, with or without sll2R levels, is helpfull in the differential diagnosis of postoperative kidney transplantation complications.Στην προοπτική αυτή μελέτη μετρήθηκαν οι τιμές των κυκλοφορούντων υποδοχέων της ιντερλευκίνης-2 (soluble interleukin-2 receptors, S-IL2R) και νεοπτερίνης (Νεοπτ) σε 26 ασθενείς που υποβλήθηκαν σε μεταμόσχευση νεφρού. Σκοπός της μελέτης ήταν η ταυτόχρονη αξιολόγηση των παραμέτρων αυτών στην διαφορική διάγνωση μεταξύ οξείας απόρριψης, νεφροτοξικότητας από κυκλοσπορίνη και λοίμωξη. Έγιναν διαδοχικές μετρήσεις πριν, αμέσως μετά την μεταμόσχευση, 24 ώρες μετά και στην συνέχεια ανά τριήμερο μέχρι της εξόδου των ασθενών από την Μονάδα Μεταμόσχευσης. Πριν την επέμβαση οι τιμές τόσον των S-IL2R όσον και της Νεοπτερίνης ήταν υψηλές, παρουσίασαν όμως σημαντική πτώση αμέσως μετά την λειτουργία του μοσχεύματος. Σε 16 ασθενείς με ομαλή μετεγχειρητική πορεία οι τιμές των S-IL2R και της Νεοπτερίνης παρουσίασαν περαιτέρω προοδευτική μείωση. Σε 2 ασθενείς με οξεία απόρριψη νεφρού, μετά την πρώτη κάμψη, παρατηρήθηκε άνοδος της τιμής της νεοπτερίνης σε επίπεδα πάνω από 100 nmol/L (φυσιολογικές τιμές 100nmol/L, αλλά η αντίστοιχη άνοδος των τιμών της κρεατινίνης ήταν μικρή (<0.7 mg/dl). Τα επίπεδα των S-IL2R ανήλθαν τόσο στην οξεία απόρριψη, όσο και στις λοιμώξεις, την νεφροτοξικότητα λόγω κυκλοσπορίνης και τις χειρουργικές επιπλοκές. Συμπερασματικά, η μέτρηση των επιπέδων των slL2R δεν βοηθά στην διαφορική διάγνωση μεταξύ οξείας απόρριψης, νεφροτοξικότητας λόγω κυκλοσπορίνης και λοίμωξης. Αντίθετα, οι τιμές της νεοπτερίνης σε συνδυασμό με την τιμή της κρεατινίνης βοηθούν στην διαφορική διάγνωση των