Therapygenetics in mindfulness-based cognitive therapy: do genes have an impact on therapy-induced change in real-life positive affective experiences?

Positive affect (PA) has an important role in resilience against depression and has been shown to increase with mindfulness-based cognitive therapy (MBCT). To elucidate the underlying mechanisms of change in PA as well as develop insights that may benefit personalized medicine, the current study examined the contribution of genetic variation to individual differences in change in PA in response to MBCT. Individuals (n=126) with residual depressive symptoms were randomized to either an MBCT group or treatment as usual. PA was assessed using experience sampling methodology (ESM). Single-nucleotide polymorphisms (SNPs) in genes known to be involved in reward functioning were selected. SNPs in the genes for brain-derived neurotrophic factor (BDNF), the muscarinic acetylcholine receptor M2 (CHRM2), the dopamine receptor D4 (DRD4) and the µ1 opioid receptor (OPRM1) significantly moderated the impact of treatment condition over time on PA. Genetic variation in the genes for CHRM2 and OPRM1 specifically had an impact on the level of PA following MBCT. The current study shows that variation in response to MBCT may be contingent on genetic factors associated with the regulation of PA. These findings contribute to our understanding of the processes moderating response to treatment and prediction of treatment outcome.

Short- and long-term effects of neonatal glucocorticoid therapy: is hydrocortisone an alternative to dexamethasone?

AIM: To compare short-term effects and neurodevelopmental outcome of neonatal glucocorticoid therapy between two centres. METHODS: A retrospective study was performed in two centres using a tapering course of either 5 to 1 mg kg(-1) hydrocortisone (HC; 22 d) or 0.5 to 0.1 mg kg(-1) dexamethasone (DEX; 21 d). In both centres glucocorticoid-treated infants and control patients were matched for gestational age, birthweight, severity of infant respiratory distress syndrome and periventricular-intraventricular haemorrhage. The following short-term glucocorticoid-induced effects were investigated in 25 HC-treated and 25 control patients in centre A, and in 23 DEX-treated and 23 control patients in centre B: oxygen dependency (inspiratory oxygen fraction), arterial pressure, blood glucose and urea concentrations, weight gain and head circumference before, during and after therapy (in treated infants), or at an interval comparable to treated infants (in control infants). Neurological outcome, psychomotor development and school performance at 5-7 y of age was evaluated in all groups. RESULTS: HC and DEX were equally potent in reducing oxygen dependency. Mean arterial pressure as well as blood glucose and urea concentrations were significantly increased during DEX, but not during HC treatment. Weight gain stopped during DEX therapy, but not during HC. Head circumference in both treatment groups was decreased after therapy compared with controls. Neonatally DEX-treated children needed special school education significantly more often (p < 0.01) than controls at 5-7 y of age. No differences between neonatally HC-treated children and controls on neurodevelopmental outcome were found at 5-7 y of age. CONCLUSION: Neonatal HC therapy has fewer short- and long-term adverse effects than neonatal DEX therapy.

Sequential map-guided endocardial resection for ventricular tachycardia improves outcome.

OBJECTIVE: Surgery for ventricular tachycardias late after myocardial infarction is frequently associated with high mortality including sudden death, and arrhythmia recurrences. We examined our results of sequential map-guided endocardial resection at normothermia in patients with ventricular tachyarrhythmias late after myocardial infarction to assess the efficacy of this technique as well as the early and long-term outcome. METHODS: From 1995 to 1999, 22 patients underwent normothermic sequential map-guided endocardial resection for ventricular tachyarrhythmias late after myocardial infarction. Mean age was 61.2+/-6.5 years and left ventricular ejection fraction 32.5+/-8.7%. Adjunctive procedures included endoventricular patch repair of left ventricular aneurysm in 21 patients, coronary artery bypass grafting in 15 patients, and mitral valve replacement in one patient. Inducibility of ventricular tachycardia was evaluated postoperatively and patients were treated with sotalol or defibrillator implantation. RESULTS: The intraoperative number of inducible different ventricular tachycardia morphologies was 4.0+/-2.7. More than one mapping-resection sequence was needed in ten patients. In only one patient, sustained ventricular tachycardia was induced postoperatively, sotalol was not tolerated and a defibrillator was implanted. Five patients with inducible non-sustained ventricular tachycardia became non-inducible while on sotalol. There was one operative death (4.5%). During a median follow-up of 26 (1--62) months, there were neither cardiac deaths nor ventricular tachycardia recurrences. Two patients died from non-cardiac causes. Cumulative probability of survival at 5 years was 0.83+/-0.09. CONCLUSIONS: Sequential map-guided endocardial resection at normothermia was associated with low operative mortality and low postoperative inducibility of sustained ventricular tachycardia. The selected therapeutic approach resulted in freedom of arrhythmia recurrence and cardiac mortality including sudden death, during long-term follow-up.

Relation between body surface mapping and endocardial spread of ventricular activation in postinfarction heart.

INTRODUCTION: Body surface mapping (BSM) can be used to identify the site of earliest endocardial activation of ventricular tachycardias (VTs). The multielectrode QRS morphology during VT is determined by both the site of earliest activation and the subsequent spread of electrical activation through the ventricles. This study investigated the relationship between the site of earliest endocardial activation, endocardial spread of activation, and the morphology of the multielectrode surface map in patients with remote myocardial infarction. METHODS AND RESULTS: In 14 patients with VT late (8.2+/-5.2 years) after myocardial infarction, BSM and simultaneous left ventricular 64-site basket endocardial mapping was performed during a total of 17 monomorphic VTs. In addition, multisite pacing by sequential use of the 64 basket electrodes was performed in 9 patients. BSM and basket mapping revealed the same endocardial breakthrough sites in 8 (47%) of 17 VTs and 189 (59%) of 322 pacing sites; adjacent sites were found in 2 (12%) of 17 VTs and 36 (11%) of 322 pacing sites. Large zones of conduction block explained the mismatch in localization in 2 (12%) of 17 VTs and 52 (16%) of 322 pacing sites. Regional differences in endocardial electrogram amplitudes were found as a cause for dissimilarity in 3 (18%) of 17 VTs and 73 (23%) of 322 pacing sites. Multiple endocardial breakthrough sites were found in 1 (6%) of 17 VTs and 8 (2%) of 322 pacing sites Finally, an epicardial exit site was suggested in 3 (18%) of 17 VTs as an explanation for mismatch, as no early endocardial activity could be recorded. CONCLUSION: Zones of conduction block, regional differences in signal amplitude, and multiple endocardial breakthrough sites are frequent causes for mismatch between BSM and basket catheter activation mapping.

Effects of short-term dexamethasone treatment during pregnancy on the development of the immune system and the hypothalamo-pituitary adrenal axis in the rat.

The effects of glucocorticoid (GC) treatment on the mature immune and neuroendocrine system are known to be reversible. However, prenatal GC exposure may have irreversible consequences on the development of the newborn. In this study, possible long-lasting effects of short-term prenatal GC treatment were examined on the developing thymus, spleen and hypothalamo-pituitary adrenal axis (HPA axis). Female rats were given dexamethasone (DEX, 400 micrograms, i.p.) on day 17 and 19 of pregnancy and offspring was studied at several time intervals (1-20 days) after birth, for examination of thymus, spleen, hypothalamus and blood plasma. Examination of thymus and spleen revealed that prenatal exposure to DEX resulted in decreased T cell numbers in thymus and spleen on day 1 after birth. Thymus regeneration after DEX exposure both during pregnancy and in adult life was completed after 24 days. However, the kinetics of regeneration of the thymi after prenatal DEX exposure were different from that seen after DEX in adult life. Whereas DEX treatment during pregnancy resulted in an increased ratio of CD4+/CD8- thymocytes over CD4-/CD8+ thymocytes compared to control groups on day 7 and day 20 after birth (time X treatment interaction; P < 0.05), DEX treatment in adult life did not change this ratio. T cell numbers in the spleen were significantly decreased at all neonatal ages studied. Regarding the hypothalamus, prenatal exposure to DEX altered the pattern of neonatal changes in peptide expression in corticotropin-releasing hormone neurons, with a selective reduction in CRH storage in the median eminence (7 and 9 days after birth) and an increase in AVP storage (9 and 20 days after birth). The ratio of AVP over CRH was significantly increased at all developmental ages studied. No effects were seen on basal ACTH and corticosterone levels in plasma. In conclusion, the kinetics of thymus regeneration after DEX exposure during pregnancy were different from that seen after DEX exposure in adult life. Prenatal DEX exposure also seemed to delay the migration of T cells into the spleen. Furthermore, prenatal DEX treatment exerted major effects on hypothalamic CRH neurons that maintained for at least 20 days after birth, which points towards an enhanced stress responsiveness of the HPA axis in later life.

Opioid receptors and inhibition of dopamine-sensitive adenylate cyclase in slices of rat brain regions receiving a dense dopaminergic input.

In slices of rat nucleus accumbens, olfactory tubercle, frontal cortex and mediobasal hypothalamus exposed to dopamine (DA), the activation of DA D1 receptors stimulated cyclic AMP (cAMP) formation whereas, in nucleus accumbens slices only, activation of D2 receptors appeared to inhibit D1 receptor-stimulated adenylate cyclase at the same time. Activation of mu-opioid receptors by [D-Ala2,MePhe4,Gly-ol5]enkephalin (DAMGO; 1 microM), but not of delta-opioid receptors by 1 microM [D-Pen2,D-Pen5]enkephalin (DPDPE), inhibited (by 35-40%) DA-stimulated cAMP production in slices of nucleus accumbens and olfactory tubercle. When adenylate cyclase was stimulated by selective D1 receptor activation, i.e. by DA in the presence of (-)-sulpiride, DPDPE reduced cAMP formation (by about 45%) in nucleus accumbens slices but not in slices of the other brain regions. The kappa-agonist, U 50,488, did not affect DA- or D1 receptor-stimulated adenylate cyclase activity in any of the brain regions. Preincubation of nucleus accumbens slices with the irreversible delta-ligand, fentanyl isothiocyanate (FIT; 1 microM), not only antagonized the inhibitory effect of DPDPE but also prevented the antagonism by naloxone of the inhibitory effect of DAMGO. Therefore, in nucleus accumbens opioids may inhibit DA-sensitive adenylate cyclase through activation of a mu/delta-opioid receptor complex, whereas in olfactory tubercle mu-receptors appear to mediate the inhibition of adenylate cyclase activity. Opioids do not seem to affect DA-stimulated cAMP formation in frontal cortex and mediobasal hypothalamus.

The popliteal lymph node assay in mice to screen for the immune disregulating potential of chemicals--a preliminary study.

Low mol. wt compounds were tested in the popliteal lymph node (PLN) assay to study whether PLN reactivity could be related to the ability of the compounds to induce autoimmune disorders in man. PLN reactions were measured 7 days after a single subcutaneous (s.c.) injection of dissolved compounds in amounts of 0.3-2.0 mg into one hind footpad of mice and assessed as the weight increase of the draining PLN relative to the PLN weight of the untreated contralateral paw. Hydralazine, chlorpromazine, diphenylhydantoin, carbamazepine, phenylbutazone and nitrofurantoin, all being drugs with a documented potential to induce systemic immunological disorders in man, caused marked PLN reactions. False negative PLN responses were observed following injection of procainamide and isoniazid. Among systemic drugs without known potential to induce autoimmune reactions in humans, quinacrine, denzimol and niridazole significantly increased PLN weights, while phenobarbital, levamisole and disulfiram had no effect. Chemicals with a well-known capacity to induce contact dermatitis in man like 2,4-dinitro-1-chlorobenzene, alpha-methylene-gamma-butyrolactone, p-phenylenediamine, 5-nitro-2-furaldehyde semicarbazone, 2-mercapto-benzothiazol and 1,3-dibutyl-2-thiourea caused marked PLN reactions, while the non-sensitizer 2,4-dichloro-1-nitrobenzene failed to do so. It is concluded that the PLN assay as applied in this study may give a rapid first indication of immunomodulating potential of low mol. wt compounds, but it does not discriminate as to the kind of immunomodulation.(ABSTRACT TRUNCATED AT 250 WORDS)