Optimisation of pharmacotherapy in psychiatry through therapeutic drug monitoring, molecular brain imaging and pharmacogenetic tests: focus on antipsychotics.

BACKGROUND: For psychotic disorders (i.e. schizophrenia), pharmacotherapy plays a key role in controlling acute and long-term symptoms. To find the optimal individual dose and dosage strategy, specialized tools are used. Three tools have been proven useful to personalize drug treatments: therapeutic drug monitoring (TDM) of drug levels, pharmacogenetic testing (PG), and molecular neuroimaging. METHODS: In these Guidelines, we provide an in-depth review of pharmacokinetics, pharmacodynamics, and pharmacogenetics for 50 antipsychotics. Over 30 international experts in psychiatry selected studies that have measured drug concentrations in the blood (TDM), gene polymorphisms of enzymes involved in drug metabolism, or receptor/transporter occupancies in the brain (positron emission tomography (PET)). RESULTS: Study results strongly support the use of TDM and the cytochrome P450 (CYP) genotyping and/or phenotyping to guide drug therapies. Evidence-based target ranges are available for titrating drug doses that are often supported by PET findings. CONCLUSION: All three tools discussed in these Guidelines are essential for drug treatment. TDM goes well beyond typical indications such as unclear compliance and polypharmacy. Despite its enormous potential to optimize treatment effects, minimize side effects and ultimately reduce the global burden of diseases, personalized drug treatment has not yet become the standard of care in psychiatry.

Elevated CYP2C19 expression is associated with depressive symptoms and hippocampal homeostasis impairment.

This corrects the article DOI: 10.1038/mp.2016.204.

Flexible intramedullary nailing for treatment of proximal humeral and humeral shaft fractures in children: A retrospective series of 118 cases.

BACKGROUND: The aim of this study was to analyze outcomes of treatment and complications in children treated with flexible intramedullary nailing (FIN) due to humeral fracture. HYPOTHESIS: The FIN for treatment of humeral fractures in children would allow an early functional and cast-free follow-up with a quick pain reduction and low complication rate. PATIENTS AND METHODS: From May 2002 until May 2016 case records of all children who underwent fixation with titanium intramedullary nails because of humeral fracture were retrospectively reviewed. The study included 118 patients treated with FIN for proximal humeral or humeral shaft fracture. The average age at the time of trauma was 12 years. Mean follow-up was 77 months. Left hand was affected in 51% of patients. The most common mechanism of injury was fall (n=58), followed by sports injuries, road traffic accidents, pathological fractures, motorbike accidents and bicycle riding. RESULTS: There were no residual valgus/varum deformities. All patients achieved complete radiographic healing at a mean of 7.5 weeks. Nine complications were recorded: 1 humeral shaft fracture in patient with osteogenesis imperfecta, 4 entry site skin irritations, 2 skin infections and 2 radial nerve injuries. There were no cases of delayed union, nonunion or mal-union. After removal of the nails, all patients regained full function and all complications resolved. DISCUSSION: The FIN for humeral fractures is a minimally invasive, simple and well reproducible technique with very low complication rate. CONCLUSION: The FIN for treatment of humeral fractures shows very good functional and cosmetic results. It allows an early functional and cast-free follow-up with a quick pain reduction. LEVEL OF EVIDENCE: Level IV - retrospective study.

Myocardial bridging as one of the causes of atypical chest pain in young women.

INTRODUCTION: Myocardial bridging is congenital anomaly which usually has benign prognosis but there are also reports suggesting that it can be associated with ischemic clinical syndromes presenting with chest pain. Coronary computed tomography angiography is a well-established method for detecting myocardial bridging. However, clinical significance of this anomaly still remains unclear. METHODS: We studied 977 patients who presented with recurrent typical or atypical chest pain in outpatient clinic. All patients have undergone detailed clinical examination, ECG stress testing and coronary computed tomography angiography. RESULTS: Highest positive prediction for having myocardial bridging was for patients presenting with atypical chest pain with negative ECG stress test and who were younger women. CONCLUSION: Coronary computed tomography angiography may be preferable method for evaluation of chest pain in younger women presenting with atypical chest pain.

Elevated CYP2C19 expression is associated with depressive symptoms and hippocampal homeostasis impairment.

The polymorphic CYP2C19 enzyme metabolizes psychoactive compounds and is expressed in the adult liver and fetal brain. Previously, we demonstrated that the absence of CYP2C19 is associated with lower levels of depressive symptoms in 1472 Swedes. Conversely, transgenic mice carrying the human CYP2C19 gene (2C19TG) have shown an anxious phenotype and decrease in hippocampal volume and adult neurogenesis. The aims of this study were to: (1) examine whether the 2C19TG findings could be translated to humans, (2) evaluate the usefulness of the 2C19TG strain as a tool for preclinical screening of new antidepressants and (3) provide an insight into the molecular underpinnings of the 2C19TG phenotype. In humans, we found that the absence of CYP2C19 was associated with a bilateral hippocampal volume increase in two independent healthy cohorts (N=386 and 1032) and a lower prevalence of major depressive disorder and depression severity in African-Americans (N=3848). Moreover, genetically determined high CYP2C19 enzymatic capacity was associated with higher suicidality in depressed suicide attempters (N=209). 2C19TG mice showed high stress sensitivity, impaired hippocampal Bdnf homeostasis in stress, and more despair-like behavior in the forced swim test (FST). After the treatment with citalopram and 5-HT1A receptor agonist 8OH-DPAT, the reduction in immobility time in the FST was more pronounced in 2C19TG mice compared with WTs. Conversely, in the 2C19TG hippocampus, metabolic turnover of serotonin was reduced, whereas ERK1/2 and GSK3ß phosphorylation was increased. Altogether, this study indicates that elevated CYP2C19 expression is associated with depressive symptoms, reduced hippocampal volume and impairment of hippocampal serotonin and BDNF homeostasis.

Deciphering the spatio-temporal expression and stress regulation of Fam107B, the paralog of the resilience-promoting protein DRR1 in the mouse brain.

Understanding the molecular mechanisms that promote stress resilience might open up new therapeutic avenues to prevent stress-related disorders. We recently characterized a stress and glucocorticoid-regulated gene, down-regulated in renal cell carcinoma - DRR1 (Fam107A). DRR1 is expressed in the mouse brain; it is up-regulated by stress and glucocorticoids and modulates neuronal actin dynamics. In the adult mouse, DRR1 was shown to facilitate specific behaviors which might be protective against some of the deleterious consequences of stress exposure: in the hippocampal CA3 region, DRR1 improved cognitive performance whereas in the septum, it specifically increased social behavior. Therefore DRR1 was suggested as a candidate protein promoting stress-resilience. Fam107B (family with sequence similarity 107, member B) is the unique paralog of DRR1, and both share high sequence similarities, predicted glucocorticoid response elements, heat-shock induction and tumor suppressor properties. So far, the role of Fam107B in the central nervous system was not studied. The aim of the present investigation, therefore, was to analyze whether Fam107B and DRR1 display comparable mRNA expression patterns in the brain and whether both are modulated by stress and glucocorticoids. Spatio-temporal mapping of Fam107B mRNA expression in the embryonic and adult mouse brain, by means of in situ hybridization, showed that Fam107B was expressed during embryogenesis and in the adulthood, with particularly high and specific expression in the forming telencephalon suggestive of an involvement in corticogenesis. In the adult mouse, expression was restricted to neurogenic niches, like the dentate gyrus. In contrast to DRR1, Fam107B mRNA expression failed to be modulated by glucocorticoids and social stress in the adult mouse. In summary, Fam107B and DRR1 show different spatio-temporal expression patterns in the central nervous system, suggesting at least partially different functional roles in the brain, and where the glucocorticoid receptor (GR)-induced regulation appears to be a unique property of DRR1.

Sperm DNA integrity testing: big halo is a good predictor of embryo quality and pregnancy after conventional IVF.

Sperm DNA integrity is a sperm functional parameter of male fertility evaluation. Two parameters of sperm DNA integrity were observed: DNA damage expressed as DNA fragmentation index (DFI) and percentage of the DNA undamaged spermatozoa expressed as big halo. Halosperm test was used for sperm DNA integrity determination. The aim of this study was to evaluate which DNA integrity parameter is better as an embryo quality and pregnancy prognostic parameter after the conventional IVF. We evaluated two embryo groups (positive and negative group) according to the 3rd day cumulative embryo score. Big halo and DFI, as we expected, showed good correlation (r = -0.69; p < 0.001). Receiver operating characteristic (ROC) analyses show that DFI and big halo are significant (p < 0.001) as prognostic parameters of embryo quality. ROC curves comparison of DFI and big halo revealed the AUC value for big halo to be significantly higher (DFI AUC = 0.71 vs. big halo AUC = 0.83; p = 0.025) than for DFI. Big halo was found to be the only independent predictor of embryo quality. Sperm DNA integrity both parameters are good prognostic parameters of embryo quality after the conventional IVF where big halo seems to be better. ROC analyses show DFI and big halo as significant prognostic parameters for achieved pregnancy (AUC ± SE for DFI was 0.67 ± 0.06 and 0.75 ± 0.06 for big halo). To our knowledge, this is the first study demonstrating the correlation between sperm DNA undamaged rate expressed as big halo parameter and semen characteristics as well as the influence on fertilization rate, embryo quality and pregnancy in conventional IVF.

New Doppler index for prediction of perinatal brain damage in growth-restricted and hypoxic fetuses.

OBJECTIVE: To evaluate the new vascular score, hypoxia index (HI), in the prediction of sonographically detected structural brain lesions in neonates within the first week after delivery of growth-restricted fetuses. METHODS: This prospective study included 29 growth-restricted fetuses delivered between 31 and 40 gestational weeks. Doppler umbilical artery (UA) and middle cerebral artery (MCA) resistance indices (RI) were recorded at 48-h intervals for at least 2 weeks before delivery. The cerebroumbilical ratio (C/U ratio = MCA-RI/UA-RI) and the HI (the sum of the daily reductions in C/U ratio, i.e. percentage below the cut-off value of 1, over the period of observation) were calculated. After delivery, neonatal outcome was evaluated according to obstetric parameters and ultrasound examinations of the brain. Doppler indices, C/U ratio and HI, as well as neonatal clinical and biochemical parameters, were tested as potential predictors of brain lesions using the C4.5 data-mining algorithm. RESULTS: Neonatal brain lesions were detected in 13 growth-restricted fetuses. Of all the parameters tested by the C4.5 data-mining algorithm, only HI was identified as a predictor of neonatal brain lesions. HI also showed better correlation with neonatal biochemical parameters, such as umbilical venous partial pressure of oxygen and umbilical venous pH, compared with the C/U ratio. CONCLUSIONS: HI, which takes into account cumulative oxygen deficit, could significantly improve the prediction of a poor neurological outcome in pregnancies complicated by growth restriction and hypoxia.

The antitumor activity of thymoquinone and thymohydroquinone in vitro and in vivo.

AIM: The aim of the study was to investigate antitumor activity of thymoquinone (TQ) and thymohydroquinone (THQ) in vitro and in vivo. MATERIALS AND METHODS: In the in vitro experiments, L929 mouse broblasts and two tumor cell lines (squamous cell carcinoma (SCC VII) and fibrosarcoma (FsaR)) were used. The cells were cultured with 0.1 or 0.01 mg/ml TQ or THQ for 24 h, and cytotoxicity assay was performed with the use of crystal violet staining technique. For in vivo antitumor efficiency evaluation of new compounds two murine tumor models (fibrosarcoma (FsaR) and squamous cell carcinoma (SCC VII)) were used. The used dose was equal for both substances. Antitumor effect of 4 intratumoral injections of TQ and THQ at the dose of 5 mg/kg was evaluated by comparison of tumor growth kinetics between treated and control animals. RESULTS: In vitro study showed that TQ and THQ exhibit statistically significant cytotoxic activity (p less, similar 0.01). The cytotoxic activity was dose dependent and more expressed against tumor cells than against L929 fibroblasts. The result of antitumor activities of TQ and THQ in vivo reached TGI = 52% and it was statistically significant (p less, similar 0.05). CONCLUSION: The results indicate that THQ antitumor activity may be improved with further dose increase of the investigated substance.

Rocuronium attenuates oculocardiac reflex during squint surgery in children anesthetized with halothane and nitrous oxide.

BACKGROUND: The oculocardiac reflex (OCR) may be activated during squint surgery. The aim of this study was to test whether rocuronium 0.4 mg kg(-1) could reduce the frequency of OCR, and also whether a single dose of succinylcholine 1 mg kg(-1) could affect the frequency of OCR during anesthesia with halothane in a nitrous oxide/oxygen mixture. METHODS: A total of 161 ASA I children, 3-10 years old, undergoing elective surgery of the medial rectus muscle (MRM) were randomly assigned to three groups. Group R (n = 51), received 0.4 mg kg(-1) of rocuronium intravenously before endotracheal intubation. Group S (n = 58) received 1 mg kg(-1) of succinylcholine. Group C (controls, n = 52) received no relaxant. Oculocardiac reflex was defined as a reduction in heart rate (HR) > or = 15% and/or the appearance of any other arrhythmias, during manipulation of the MRM. Analysis of variance (anova), chi-squared, Kruskal-Wallis, and Student's t-tests were used for statistical analysis; P< 0.05 was considered statistically significant. RESULTS: In group R, OCR occurred in 15/51 (29%) of children, in group S in 31/58 (53%), and in group C in 23/52 (44%) (chi2 = 6.46, P = 0.049). In group R, the incidence of arrhythmias such as nodal rhythms, supraventricular and ventricular premature beats was 6%, compared with 22% in group S and 19% in group C (chi2 = 6.01, P = 0.040). However, there was no reduction in the occurrence of bradycardia (chi2 = 0.16, P = 0.924). CONCLUSION: Rocuronium reduced the frequency of OCR, mainly by reducing the incidence of supraventricular and ventricular premature beats.

[Determination of blood volume in pulmonary capillaries in patients with chronic obstructive lung disease]. / Odredivanje volumena krvi plucnih kapilara bolesnika s kronicnom opstruktivnom bolescu pluca.

The subjects were divided into four groups, three of which consisted of patients with various degrees of lung obstruction, while the fourth was the control group. The patients were divided according to the spirometric values: VC, FEV1, FEV1/VC%. The diffusing capacity was determined on the basis of the single breath method and graphical separation of the diffusion components was performed. It was found that the diffusing lung capacity was slightly lower in patients with mild to severe obstructive lung disease. The capillary blood volume was also slightly lower. Correlations between the degree of obstruction of the respiratory system and the diffusing lung capacity or the lung capillary blood volume was not statistically significant (p greater than 0.5). In studying patients with obstructive lung disease we were unable to establish which of the diffusion components significantly affected the value of the total diffusing lung capacity.

[Pressure and flow measurements in the choledochus in acute pancreatitis of biliary origin (author's transl)]. / Cholangiodébitmanométrie dans la pancréatite aiguë d'origine biliaire.

During 4,528 operations on the biliary tract 216 cases showed proof of acute pancreatitis. In 153 instances hemorrhagic and necrotic pancreatitis was diagnosed. Pressure and flow measurements in the choledochus allow us to distinguish 3 categories: Immediate surgery (14) demonstrated marked oedemes of the duodenum at the papille of Vater (twice "cocarde" sign) with sustained high pressures and cascade-like flow. Operations 72 to 96 hours past the onset of pancreatitis (68) demonstrated intolerance duodenal anti-peristaltic waves and reflux into the enlarged Wirsung under physiological pressures (20 cm). Cases operated 8 days past the onset (71) showed under pressures (+/- 10 cm) massive and permanent reflux into the canal of Wirsung with low residual pressures and images representative of low duodenal tone. A single case of massive pancreatitis necrosis showed visualisation of the entire pancreatic ductal system under low pressure. The mechanism of reflux is discussed.