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, specialised tools are used. Three tools have been proven useful to personalise 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 45 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 optimise treatment effects, minimise side effects and ultimately reduce the global burden of diseases, personalised drug treatment has not yet become the standard of care in psychiatry.

Comparison of single-incision and conventional laparoscopic cholecystectomy in terms of quality of life, body image, and cosmesis.

BACKGROUND: Clinical studies indicate that single-incision laparoscopic cholecystectomy (SILC) has many advantages over conventional laparoscopic cholecystectomy (CLC), such as improved cosmesis, reduced postoperative pain, and shorter hospital stay. The aim of this study was to compare quality of life, body image, and cosmesis between single-incision laparoscopic and conventional laparoscopic approaches in patients undergoing cholecystectomies. SUBJECTS AND METHODS: This retrospective study between SILC and CLC and was conducted among 58 patients undergoing SILC and CLC from January 2011 to March 2013 in Turkey. After the surgery, the EuroQol-5 Dimension Questionnaire (EQ-5D™), and body image questionnaire (BIQ) were administered to the patients. RESULTS: Differences between the early and late postoperative scores in the EQ-5D were statistically significant (P < 0.001). Differences between most BIQ areas favored SILC, especially regarding cosmesis (P = 0.016); SILC patients had higher satisfaction with their scar's appearance. CONCLUSION: SILC is a promising alternative to traditional laparoscopic cholecystectomy in terms of quality of life, body image, and cosmesis in selected patients.

Trauma in patients with continuous-flow left ventricular assist devices.

Trauma-related failure of a continuous-flow left ventricular assist device (LVAD) has not previously been reported. We present 4 cases in which LVAD complications were likely caused by external trauma and led to failure of a HeartMate II device. In 1 case, the onset of symptoms was delayed and the patient did not seek medical attention until months after the traumatic event. All 4 patients required surgical intervention, and 1 patient died of respiratory complications several months postoperatively. In conclusion, a history of external trauma should be considered as a possible etiologic factor when LVAD-supported patients in previously stable condition present with device malfunction.

Bivalirudin for treatment of aortic valve thrombosis after left ventricular assist device implantation.

Ventricular assist devices are increasingly being used for mechanical support in patients with advanced heart failure. However, thromboembolism remains a leading cause of mortality in this population. We describe the successful treatment of native aortic valve thrombosis with bivalirudin in a patient with factor V Leiden mutation, who had undergone left ventricular assist device implantation, preventing the need for further surgical intervention.

Who is responsible for inadequate lymph node retrieval after colorectal surgery: surgeon or pathologist?

BACKGROUND: Many factors have been described influencing survival of patients with colorectal cancer. The most important prognostic factor is lymph node involvement. The National Comprehensive Cancer Network indicates that at least 12 lymph nodes (LN12) must be retrieved for proper staging and treatment planning. The surgeon and the pathologist influence the number of retrieved lymph nodes. METHODS: We retrospectively reviewed all patients with diagnosis and subsequent surgery for colorectal cancer from January 2004 to January 2010 at Gulhane Military Medical Academy in Ankara, Turkey. We investigated the relationship between LN 12 and the independent variables of tumour size, lymph node involvement, metastasis, age, gender, surgeon, pathologist, surgical specimen length, tumour stage, and localization. Statistical analysis utilized the Shapiro-Wilk test, interquartile range, Mann-Whitney test, chi-square and chi-square likelihood ratio tests, and Kruskal-Wallis nonparametric variance analysis. In order to identify influencing factors for retrieval of lymph nodes, multiple linear regression was performed. In order to identify the direction and extent of effects of these influencing factors, logistic regression was performed. OR (Odds Ratio) and 95% CI (Confidence Interval) of the OR were calculated. RESULTS: There were 223 study patients, 134 with colon cancer and 89 with rectal cancer. There was no statistical significance in terms of age, gender, cancer type and postoperative tumour size, number of metastatic lymph nodes > 4, or LN12 (p > 0.05). Statistical significance was found between surgeons and LN12, the number of operations and LN12 (p < 0.001), and pathologists and LN12 (p = 0.049). CONCLUSIONS: Harvesting an adequate number of lymph nodes is crucial for patients with colorectal cancer in terms of staging and planning further treatment modalities such as adjuvant chemotherapy. Multidisciplinary collaboration between surgeons and pathologists is vital for optimal patient outcomes.

The relationship of PON1 QR 192 and LM 55 polymorphisms with serum paraoxonase activities of Turkish diabetic patients.

Paraoxonase (PON1) is a serum esterase responsible for the protection against xenobiotics toxicity such as paraoxon. Alterations in PON1 concentrations have been reported in a variety of diseases including diabetes mellitus (DM). It has been shown that the serum PON1 concentration and activity are decreased in patients with both type 1 and type 2 DM. This study aimed to investigate the lipid profiles and the relationship between PON1 activity and PON1, QR192 and LM55 polymorphisms in Turkish type 2 diabetic patients and non-diabetic control subjects. According to our results, RR variant had significantly higher PON activity than QQ and QR variants (p < 0.01) and LL variant had significantly higher PON activity than MM variant in both control and patient groups (p < 0.05). In conclusion, we found that PON1 192RR and 55LL genotypes are associated with higher PON activity than QQ and MM genotypes. This may be more protective to lipid peroxidation.

Are PON1 Q/R 192 and M/L 55 polymorphisms risk factors for diabetes complications in Turkish population?

OBJECTIVES: We investigated whether the human serum paraoxonase (PON1) Q/R 192 and M/L 55 polymorphisms are associated with the complications of the type 2 diabetes (T2D). DESIGN AND METHODS: Study group was consisted of 50 healthy subjects and 100 type 2 diabetes mellitus (DM) patients. Following measuring of serum PON1 activity, isolation of DNA and genotyping analyses were performed. RESULTS: PON1 activity of the patients with complications was significantly reduced by 23.5% compared to the group of diabetic patients and by 26.3% than the controls. According to multivariate analysis, we observed a three times significant effect of Q/R 192 polymorphism on the susceptibility to the occurrence of complications. CONCLUSIONS: Protective effects of paraoxonase against peroxidation of LDL particles are important in T2D complications. Although both of the two polymorphisms are associated, 192 polymorphism seems to be stronger predictor of the risk of diabetic complications.

Possible effect of gene polymorphisms on the release of TNFα and IL1 cytokines in coal workers' pneumoconiosis.

It has been shown that coal dust exposure stimulates inflammatory response leading to increased release of cytokines from monocytes such as TNF-alpha and IL1. These released cytokines play the key role in the pathogenesis of pneumoconiosis including coal workers' pneumoconiosis. In this study, we investigated TNFA, IL1A, IL1B and IL1RA genes variations on basal, lipopolysaccharide and coal dust-induced cytokine release from blood monocytes of homozygous allele and minor variant allele carriers in Turkish coal workers and CWP patients. According to the genotyping results, TNFA -238 gene polymorphism was found as a risk factor in CWP development (OR=3.79) and to in vitro results; release of both TNF-alpha and IL1 cytokines from the monocytes in CWP patients was significantly increased compared to the healthy workers. Also, LPS and coal dust stimulated release of TNF-alpha, which was significantly higher in allele 2 carriers compared to subjects carrying allele 1 in both the groups. These data suggest that the coal dust-induced release of TNF-alpha from monocytes may be a useful biomarker of CWP.

Prevalence of respiratory symptoms in patients with achalasia.

Achalasia is a primary esophageal motor disorder that results in poor clearance of the esophagus. Although an esophagus filled with debris and undigested food should put these patients at risk for aspiration, the frequency with which the latter occurs has never been documented. In this study, we sought to determine the incidence of respiratory symptoms and complaints in patients with achalasia. A comprehensive symptom questionnaire was administered to 110 patients with achalasia presenting to the Swallowing Center at the University of Washington between 1994 and 2008 as part of their preoperative work-up. Questionnaires were analyzed for the frequency of respiratory complaints in addition to the more typical symptoms of dysphagia, regurgitation, and chest pain. Twenty-two achalasia patients with respiratory symptoms who had also undergone Heller myotomy and completed a post-op follow-up questionnaire were analyzed as a subset. Ninety-five patients (86%) complained of at least daily dysphagia. Fifty-one patients (40%) reported the occurrence of at least one respiratory symptom daily, including cough in 41 patients (37%), aspiration (the sensation of inhaling regurgitated esophagogastric material) in 34 patients (31%), hoarseness in 23 patients (21%), wheezing in 17 patients (15%), shortness of breath in 11 patients (10%), and sore throat in 13 patients (12%). Neither age nor gender differed between those with and those without respiratory symptoms. In the subset of patients with respiratory symptoms who had undergone Heller myotomy, respiratory symptoms improved in the majority after the procedure. Patients with achalasia experience respiratory symptoms with much greater frequency than the approximately 10% that was previously believed. Awareness of this association may be important in the workup and ultimate treatment of patients with this uncommon esophageal disorder.

The effects of inguinal hernia repair on testicular function in young adults: a prospective randomized study.

PURPOSE: The two most common procedures for open tension-free groin hernia repair with prosthetic mesh are the Lichtenstein operation and the mesh plug (Rutkow-Robbins) technique. Our study evaluated these two techniques on testicular blood flow and volume, and sperm function in young adults. METHODS: We randomized operation types with a systematic sampling method, and handled consecutive patients of age 20-30 years having unilateral inguinal hernia repair at our institution from March to August 2008. The study subjects were divided into the Lichtenstein group (LG) and the mesh plug group (MPG). All subjects received color Doppler ultrasonography to determine testicular volume and resistive index (RI) the day before surgery and 3 months postoperatively by a physician blinded for the type of planned or performed operation. Spermiograms done preoperatively and at 3 months postoperatively measured sperm concentration and the rate of progressive motility. RESULTS: Sixty-four patients met the study criteria, with 32 patients each in the LG and MPG. RI levels were elevated postoperatively in both the LG (P = 0.027) and MPG (P = 0.012); there was no significant alteration in terms of testicular volume and spermiogram in the LG and MPG. CONCLUSION: The Lichtenstein and mesh plug techniques in unilateral inguinal hernia increase the RI level significantly in the early postoperative period, but do not have a significant effect on sperm concentration and the rate of progressive motility.

Deoxycholic acid at neutral and acid pH, is genotoxic to oesophageal cells through the induction of ROS: The potential role of anti-oxidants in Barrett's oesophagus.

Bile acids are often refluxed into the lower oesophagus and are candidate carcinogens in the development of oesophageal adenocarcinoma. We show here that the secondary bile acid, deoxycholic acid (DCA), is the only one of the commonly refluxed bile acids tested here, to show genotoxicity, in terms of chromosome damage and mutation induction in the human p53 gene. This genotoxicity was apparent at both neutral and acidic pH, whilst there was a considerable increase in bile-induced toxicity at acidic pH. The higher levels of cell death and low cell survival rates at acidic pH may imply that acid bile exposure is toxic rather than carcinogenic, as dead cells do not seed cancer development. We also show that DCA (at neutral and acid pH) induced the release of reactive oxygen species (ROS) within the cytoplasm of exposed cells. We further demonstrate that the genotoxicity of DCA is ROS mediated, as micronucleus induction was significantly reduced when cells were treated with DCA + the anti-oxidant vitamin C. In conclusion, we show that DCA, is an effective genotoxin at both neutral and acidic pH. As bile acids like DCA can induce DNA damage at neutral pH, suppressing the acidity of the refluxate will not completely remove its carcinogenic potential. The genotoxicity of DCA is however, ROS dependent, hence anti-oxidant supplementation, in addition to acid suppression may block DCA driven carcinogenesis in Barrett's patients.

Intraoperative assessment of mitral regurgitation: role of phenylephrine challenge.

OBJECTIVES: We defined the effects of the operative (OP) state and phenylephrine challenge on the assessment of mitral regurgitation (MR) severity. METHODS: In all, 57 patients underwent transesophageal echocardiographic assessment of MR severity pre-OP (PREOP) and intra-OP. MR severity was assessed PREOP under conscious sedation and intra-OP with general anesthesia, before and after hemodynamic manipulation with vasoactive agents, to match intra-OP and PREOP transesophageal echocardiographic mean arterial blood pressures. RESULTS: Intra-OP MR and mean arterial pressure were less than PREOP in 27 patients (both P < .001). When PREOP and OP blood pressures were matched using phenylephrine, there was no significant difference in MR severity between the two states (P = 1.0). Nonetheless, MR severity was still underestimated in 6 patients and overestimated in 7 patients intra-OP. CONCLUSIONS: Intra-OP transesophageal echocardiography underestimates MR severity. Phenylephrine reduces, yet does not eliminate, intra-OP underestimation of MR severity.

Polymorphisms of cytochrome P450 1A1, glutathione S-transferases M1 and T1 in a Turkish population.

Intra-ethnic as well as inter-ethnic differences are known to exist in the frequencies of cytochrome P450 (CYP) 1A1, glutathione S-transferase (GST) M1, and GSTT1 gene polymorphisms with which associations have been shown for several cancers. In this study, CYP1A1 m2, GSTM1, and GSTT1 gene polymorphisms were determined among 133 healthy individuals of a Turkish population. On the basis of polymerase chain reaction/restriction fragment length polymorphism (PCR/RFLP) methodology, the frequency of CYP1A1 m2 mutation was determined. The multiplex PCR protocol was used to determine the frequency of the deleted genotypes of both GSTM1 and GSTT1 genes. The frequencies of Ile/Ile (wild type), Ile/Val (heterozygous variant), and Val/Val (homozygous variant) CYP1A1 m2 genotypes were 90.2%, 9.8%, and 0%, respectively. The frequencies of the deleted GSTM1 (null) and GSTT1 (null) genotypes were 51.9% and 17.3%, respectively. These results show that the frequencies of the CYP1A1 m2, GSTM1, and GSTT1 gene polymorphisms in a Turkish population are similar to Caucasian populations.