Two target gene activation pathways for orphan ERR nuclear receptors.

Estrogen-related receptors (ERRα/ß/γ) are orphan nuclear receptors that function in energy-demanding physiological processes, as well as in development and stem cell maintenance, but mechanisms underlying target gene activation by ERRs are largely unknown. Here, reconstituted biochemical assays that manifest ERR-dependent transcription have revealed two complementary mechanisms. On DNA templates, ERRs activate transcription with just the normal complement of general initiation factors through an interaction of the ERR DNA-binding domain with the p52 subunit of initiation factor TFIIH. On chromatin templates, activation by ERRs is dependent on AF2 domain interactions with the cell-specific coactivator PGC-1α, which in turn recruits the ubiquitous p300 and MED1/Mediator coactivators. This role of PGC-1α may also be fulfilled by other AF2-interacting coactivators like NCOA3, which is shown to recruit Mediator selectively to ERRß and ERRγ. Importantly, combined genetic and RNA-seq analyses establish that both the TFIIH and the AF2 interaction-dependent pathways are essential for ERRß/γ-selective gene expression and pluripotency maintenance in embryonic stem cells in which NCOA3 is a critical coactivator.

Three dimensional patient-specific guides for guide pin positioning in reverse shoulder arthroplasty: An experimental study on different glenoid types.

INTRODUCTION: Incorrect positioning is one of the main factors for glenoid component loosening in reverse shoulder arthroplasty and component placement can be challenging. This study aimed to assess whether Patient-Specific Instrumentation (PSI) provides better guide pin positioning accuracy and is superior to standard guided and freehand instrumentation methods in cases of glenoid bone deformity. MATERIALS AND METHODS: Based on the Walch classification, five different scapula types were acquired by computed tomography (CT). For each type, two different surgeons placed a guide pin into the scapula using three different methods: freehand method, conventional non-patient-specific guide, and PSI guide. Each method was repeated five times by both surgeons. In these experiments, a total of 150 samples of scapula models were used (5 × 2 × 3 × 5 = 150). Post-operative CT scans of the samples with the guide pin were digitally assessed and the accuracy of the pin placement was determined by comparison to the preoperative planning on a three-dimensional (3D) model. RESULTS: The PSI method showed accuracies to the preoperative plan of 2.68 (SD 2.10) degrees for version angle (p < .05), 2.59 (SD 2.68) degrees for inclination angle (p < .05), and 1.55 (SD 1.26) mm for entry point offset (p < .05). The mean and standard deviation errors compared to planned values of version angle, inclination angle, and entry point offset were statistically significant for the PSI method for the type C defected glenoid and non-arthritic glenoid. CONCLUSION: Using the PSI guide created by an image processing software tool for guide pin positioning showed advantages in glenoid component positioning over other methods, for defected and intact glenoid types, but correlation with clinical outcomes should be examined.

A tree based approach for multi-class classification of surgical procedures using structured and unstructured data.

BACKGROUND: In surgical department, CPT code assignment has been a complicated manual human effort, that entails significant related knowledge and experience. While there are several studies using CPTs to make predictions in surgical services, literature on predicting CPTs in surgical and other services using text features is very sparse. This study improves the prediction of CPTs by the means of informative features and a novel re-prioritization algorithm. METHODS: The input data used in this study is composed of both structured and unstructured data. The ground truth labels (CPTs) are obtained from medical coding databases using relative value units which indicates the major operational procedures in each surgery case. In the modeling process, we first utilize Random Forest multi-class classification model to predict the CPT codes. Second, we extract the key information such as label probabilities, feature importance measures, and medical term frequency. Then, the indicated factors are used in a novel algorithm to rearrange the alternative CPT codes in the list of potential candidates based on the calculated weights. RESULTS: To evaluate the performance of both phases, prediction and complementary improvement, we report the accuracy scores of multi-class CPT prediction tasks for datasets of 5 key surgery case specialities. The Random Forest model performs the classification task with 74-76% when predicting the primary CPT (accuracy@1) versus the CPT set (accuracy@2) with respect to two filtering conditions on CPT codes. The complementary algorithm improves the results from initial step by 8% on average. Furthermore, the incorporated text features enhanced the quality of the output by 20-35%. The model outperforms the state-of-the-art neural network model with respect to accuracy, precision and recall. CONCLUSIONS: We have established a robust framework based on a decision tree predictive model. We predict the surgical codes more accurately and robust compared to the state-of-the-art deep neural structures which can help immensely in both surgery billing and scheduling purposes in such units.

Reconstitution of Pol II (G) responsive form of the human Mediator complex.

RNA polymerase II (Pol II) is a 12 subunit protein complex from yeast to human that is required for gene expression. Gdown1 containing Pol II [Pol II (G)] is a special form of Pol II that is catalytically inactive and heavily depends on the 30-subunit Mediator complex for its activator and basal dependent function in vitro. Here we report for the first time, the identification and the generation of a 15-subunit human Mediator complex via the novel multibac baculovirus expression system that is fully responsive to Pol II (G). Our results show complete recovery of Pol II (G) dependent transcription both with full 30-subunit Mediator and also with 15-subunit recombinant Mediator that we synthesized. Moreover, we also show that the recombinant Mediator interacts with Pol II (G) as well. These results enlighten us towards understanding how a certain population of Pol II that is involved in selected gene regulation is activated by Mediator complex.

Automated Surgical Term Clustering: A Text Mining Approach for Unstructured Textual Surgery Descriptions.

High costs in health care and everlasting need for quality improvement in care delivery is increasingly becoming the motivating factor for novel predictive studies in health care informatics. Surgical services impact both the operating theatre costs and revenues and play critical role in care quality. Efficiency of such units relies extremely on effective operational planning and inventory management. A key ingredient to such planning activities is the structured and unstructured data available prior to the surgery day from the electronic health records and other information systems. Unstructured data, such as textual features of procedure description and notes, provide additional information while structured data alone is not sufficient. To effectively utilize textual information using text mining, textual features should be easily identifiable, i.e., without typographical errors and ad hoc abbreviations. While there exists numerous spelling correction and abbreviation identification tools, they are not suitable for the surgical medical text as they require a dictionary and cannot accommodate ad hoc words such as abbreviations. This study proposes a novel preprocessing framework for surgical text data to detect misspellings and abbreviations prior to the application of any text mining and predictive modeling. The proposed approach helps extract the most salient text features from the unstructured principal procedure and additional notes by effectively reducing the raw feature set dimension. The transformed (text) feature set thus improves subsequent prediction tasks in surgery units. We test and validate the proposed approach using datasets from multiple hospitals' surgical departments and benchmark feature sets.

Facing the Inevitable: Being Prepared for Regulatory Requirements for Laboratory Developed Tests.

OBJECTIVES: We introduce regulatory terms, definitions, and the Quality System Regulation as proposed by the US Food and Drug Administration in the 2014 draft guidance entitled Framework for Regulatory Oversight of Laboratory Developed Tests and explore medical device requirements applicable to a laboratory environment to design, develop, and validate laboratory developed tests (LDTs). METHODS: We performed nine interviews with laboratory professionals to explore concerns and challenges regarding the draft, translated the results into operational factors, and surveyed professionals to test the factors that would comprise a regulatory quality management system framework. RESULTS: Nine interviewees and 35 survey respondents shared concerns of risk classification, process validation, patient safety, and general ambiguity regarding the proposed requirements for development of LDTs. CONCLUSIONS: Respondents agree that a regulatory quality management system is needed in laboratories that develop LDTs, but the translation and method for design control to a clinical laboratory do not exist. As a result, laboratories are taking the wait-and-see approach.

A cost sensitive inpatient bed reservation approach to reduce emergency department boarding times.

Emergency departments (ED) in hospitals are experiencing severe crowding and prolonged patient waiting times. A significant contributing factor is boarding delays where admitted patients are held in ED (occupying critical resources) until an inpatient bed is identified and readied in the admit wards. Recent research has suggested that if the hospital admissions of ED patients can be predicted during triage or soon after, then bed requests and preparations can be triggered early on to reduce patient boarding time. We propose a cost sensitive bed reservation policy that recommends optimal bed reservation times for patients. The policy relies on a classifier that estimates the probability that the ED patient will be admitted using the patient information collected and readily available at triage or right after. The policy is cost sensitive in that it accounts for costs associated with patient admission prediction misclassification as well as costs associated with incorrectly selecting the reservation time. Results from testing the proposed bed reservation policy using data from a VA Medical Center are very promising and suggest significant cost saving opportunities and reduced patient boarding times.

Correlation of Cystatin-C and radionuclidic measurement method of glomerular filtration rate in patients with lung cancer receiving cisplatin treatment.

OBJECTIVE: Cisplatin is a chemotherapeutic agent which affects renal functions adversely. The best indicator of renal functions is glomerular filtration rate (GFR) measurement. Cystatin-C appears to be a good alternative to existing methods of measuring GFR. However, it is controversial whether Cystatin-C demonstrates GFR correctly for patients receiving chemotherapy. This study aimed to investigate the correlation between GFR values calculated by Cystatin-C based formulas, radionuclidic method (multiple blood sampling) and blood Cystatin-C values in patients with lung cancer, receiving cisplatin treatment in both pre-treatment and post-treatment periods. MATERIALS AND METHODS: Thirty-six patients with lung cancer who were going to receive cisplatin treatment were included in this study. However, the evaluation was performed with 20 patients since 16 of them could not complete the treatment. Blood Cystatin-C values, GFR values calculated via Cystatin-C based formulas, and radionuclidic method were investigated before and after the cisplatin treatment. RESULTS: After treatment significant decreases were detected in GFR values, obtained via radionuclidic measuring method. However, there was no significant difference in Cystatin-C values between pre-treatment and post-treatment periods. Also GFR values obtained by Cystatin-C based formulas were not significantly different in pre-treatment and post-treatment periods. There were meaningful correlations between radionuclidic method and Cystatin-C values and Cystatin-C based formulas before treatment. However, all correlations disappeared after the treatment. CONCLUSION: GFR values, calculated by Cystatin-C may not be reliable in following renal functions in patients receiving chemotherapy. When reliable monitoring of the renal functions is necessary radionuclidic method may be preferred in these patients.

Electronic-topological and neural network approaches to the structure- antimycobacterial activity relationships study on hydrazones derivatives.

That the implementation of Electronic-Topological Method and a variant of Feed Forward Neural Network (FFNN) called as the Associative Neural Network are applied to the compounds of Hydrazones derivatives have been employed in order to construct model which can be used in the prediction of antituberculosis activity. The supervised learning has been performed using (ASNN) and categorized correctly 84.4% of them, namely, 38 out of 45. Ph1 pharmacophore and Ph2 pharmacophore consisting of 6 and 7 atoms, respectively were found. Anti-pharmacophore features socalled "break of activity" have also been revealed, which means that APh1 is found in 22 inactive molecules. Statistical analyses have been carried out by using the descriptors, such as EHOMO, ELUMO, ΔE, hardness, softness, chemical potential, electrophilicity index, exact polarizibility, total of electronic and zero point energies, dipole moment as independent variables in order to account for the dependent variable called inhibition efficiency. Observing several complexities, namely, linearity, nonlinearity and multi-co linearity at the same time leads data to be modeled using two different techniques called multiple regression and Artificial Neural Networks (ANNs) after computing correlations among descriptors in order to compute QSAR. Computations resulting in determining some compounds with relatively high values of inhibition are presented.

ETM and ANN study for polysubstituted 2H-pyran-2-ones.

The structure glutamate pyruvate transaminase (GPT), glutamate oxaloacetate transaminase (GOT), acid phosphatase (ACP), alkaline phosphatase (ALP) and glutamate dehydrogenase (GlDH) activity relationships of 2H-pyran-2- ones polysubstitutes being a new class of hepatoprotective agents have been investigated by means of the Electronic- Topological Method (ETM) and two Statistical Analysis. Molecular fragments specific for active compounds were calculated for 2H-pyran-2-ones polysubstitutes by applying the ETM. QSAR descriptors such as molecular weight, EHOMO, ELUMO, ΔE, chemical potential, softness, electrophilicity index, dipole moment, etc were calculated. In order to examine the relationship between independent and dependent variables, both Partial Least Squares Regression and ANNs are employed to determine the relationship since the data set consists of highly nonlinearity and multicolinearity. It is observed that ANN has surpassed both PLS2 and PLS1 in terms of better modeling and validation.

Clinical trial: transcutaneous interferential electrical stimulation in individuals with irritable bowel syndrome - a prospective double-blind randomized study.

BACKGROUND: The exact etiology of irritable bowel syndrome (IBS) remains unclear. Curative treatment is not available and current treatment modalities are mainly directed against the predominant symptoms. There are a few studies reporting the beneficial effects of transcutaneous electrical stimulation in patients with chronic constipation, gastroparesis, and functional dyspepsia. AIM: To investigate whether transcutaneous electrical stimulation is an effective procedure in IBS patients. METHODS: IBS patients were randomly placed in vacuum interferential current (IFC) and placebo groups. Both treatments consisted of 12 sessions administered over 4 weeks. Symptoms due to IBS were documented via questionnaires, including the IBS Global Assessment of Improvement Scale, numeric rating scales, visual analogue scale, and IBS Quality of Life Scale at the beginning of, end of, and 1 month after the treatment. RESULTS: Patients in the therapy (29 cases) and placebo (29 cases) groups were homogeneous with respect to demographic data and gastrointestinal system symptoms. When compared to the beginning scores, severity of abdominal discomfort, bloating, and abdominal distension and rumbling improved significantly in either interference or placebo groups at both the end of treatment and 1 month after treatment. In the IFC group, severity of symptoms continued to decrease significantly at 1 month after treatment when compared to scores at just the end of treatment, whereas in the placebo group severity of these symptoms did not change significantly on numeric severity scales. Also, the visual analogue scale of the first month after treatment continued to decrease significantly when compared to the level at the end of treatment in the IFC group. Total quality score increased significantly in the IFC group. CONCLUSIONS: Vacuum IFC therapy can significantly improve symptoms and quality of life in patients with IBS. It may represent a novel treatment modality for drug-refractory IBS patients.

Reduced heart rate response to dipyridamole in patients undergoing myocardial perfusion SPECT.

OBJECTIVE: A mild decrease in blood pressure and increase in heart rate (HR) are considered normal hemodynamic responses to dipyridamole. In this study, we tried to investigate HR response to dipyridamole and its predictors in patients undergoing gated myocardial perfusion single photon emission computed tomography (SPECT). METHODS: 201 consecutive patients undergoing dipyridamole stress Tc99m-MIBI or Tl-201 gated myocardial perfusion SPECT were prospectively enrolled. Dipyridamole was infused over 4 min and radiopharmaceutical was injected 3 min after the end of infusion. A reduced heart rate response to dipyridamole considered if the HR ratio (peak HR/rest HR) was 1.20 or less. Stress (sLVEF), rest (rLVEF) left ventricular ejection fractions, stress and rest motion (SMS, RMS) and thickening scores (STS, RTS) were derived automatically by QGS. Summed stress score (SSS), summed rest score (SRS), and summed difference score (SDS) for myocardial perfusion were calculated. Patients were grouped according to HR response and groups were compared. A logistic regression analysis was used to determine independent predictors of reduced HR response. RESULTS: Reduced HR response was found in 78 % of patients. Patients with abnormal HR response were more frequently had a history of diabetes mellitus, chronic renal failure, and had lower high-density lipoprotein (HDL) levels. Peak HR, SSS, SRS, sLVEF and rLVEF were lower; rest HR, RTS, and the number of patients with ≤ 45 % sLVEF and rLVEF were higher in reduced HR response group (all p < 0.05). There was no difference between groups by means of gender, rest and peak systolic or diastolic tension, SDS, SMS, STS, RMS, history of hypertension, peripheral arterial disease, metabolic syndrome, coronary interventions, digoxin, calcium channel blocker or beta blocker usage. Multivariable logistic regression analysis demonstrated that the independent predictors of reduced HR response were HDL, rest HR and SSS. When HDL was removed from the model, chronic renal failure also emerged as an independent predictor. CONCLUSION: Reduced HR response to dipyridamole is associated with ventricular dysfunction, cardiac autonomic neuropathy. Low HDL levels also seem to be related with reduced HR response.

The effects of sevoflurane and propofol anesthesia on renal sodium-potassium adenosine triphosphatase activity during pneumoperitoneum in rats.

OBJECTIVE: To evaluate the renal sodium-potassium adenosine triphosphatase (Na+/K+ATPase) activity, kidney morphology, and the probable protective effects of 2 different anesthetic agents used during pneumoperitoneum (PP). METHODS: The study was performed at Gazi University Experimental Research Center, Ankara, Turkey between January and July 2009. Twenty-four Wistar albino male rats weighing 320-380 g were randomly allocated to 4 groups after receiving ethics committee approval. All rats were cannulated, intubated, and ventilated under ketamine anesthesia. No further surgical intervention was performed for group I. An intraabdominal pressure (IAP) of 10 mm Hg was created by CO2 insufflation in 18 animals for one hour. The animals in group II received no further anesthetic agents, while the animals in groups III and IV received propofol and sevoflurane. At the end of the protocol, all animals underwent left nephrectomy without sacrificing. Urine was collected from each animal for the following 24 hour for the evaluation of urine creatinine and protein. RESULTS: The activity of renal Na+/K+ATPase was significantly lower in groups II (p=0.014), III (p=0.019), and IV (p=0.032) compared to group I. The pathological score was significantly higher in groups II (p=0.017), III (p=0.028), and IV (p=0.039) compared to group I. No statistically significant difference was found among groups II, III, and IV in terms of Na+/K+ATPase activity and pathological scores. CONCLUSION: Elevated IAP is related with impaired kidney functions and morphology, and the so-called renoprotective agents neither improved, nor worsened PP-related renal impairment.

Investigation of structure-activity relationship between chemical structure and CCR5 anti HIV-1 activity in a class of 1-[N-(Methyl)-N- (phenylsulfonyl)amino]-2-(phenyl)-4-[4-(substituted)piperidin-1-yl]butane derivatives: the electronic-topological approach.

The relationship between chemical structure and CCR5 anti HIV-1 activity was investigated in the series of 1-[N-(Methyl)-N-(phenylsulfonyl)amino]-2-(phenyl)-4-[4-(substituted) piperidin-1-yl]butanes derivatives including 114 molecules by using the Electron-Topological Method (ETM). In the frameworks of this approach, its input data were taken as the results of conformational and quantum-mechanical calculations. Conformational analysis and quantum-chemical calculations were carried out for each molecule. Then molecular fragments being specific for active molecules and non-active molecules were revealed by using ETM. The result of testing showed the high ability of ETM in predicting the activity and inactivity investigated series. In order to classify and to develop a model for those molecules, cluster and discriminant analyses are conducted. First, cluster analysis is implemented in order to classify similar molecules into the groups. Then, discriminant analysis is used to construct models including descriptors. By doing so, two obtained discriminant functions segregate those molecules into three different groups by using the descriptors called EHOMO, Dipole Moment and SEZPE.

The effect of lidocaine on the endothelium damage in rabbit vein grafts.

OBJECTIVE: To investigate the effects of perivascular and intravenous application of lidocaine on venous endothelial morphology of harvested rabbit vein graft. METHODS: This study was conducted in Gazi University Animal Research Laboratory, Ankara, Turkey in March 2009. Three ear veins of each rabbits (n=6) were used. Control group (Group C, n=6 vessels), vein segment was excised from the distal end. Perivascular group (Group P, n=6); 2 ml lidocaine 1% was injected in the perivascular area of the second vein of the same ear, and the vein segment was excised. Intravascular group (Group I, n=6); the vein in the second ear was clamped and 2 ml of lidocaine 1% was administered intravascular, and 5 minutes later, a 2 cm vein segment was excised. Nitric oxide synthase and thiobarbutiric acid reactive substance levels were measured, and histopathologic examination was performed to assess the effects of lidocaine administration. RESULTS: Histopathological findings in groups C, P and I were similar. There were lower thiobarbituric reactive substances level in groups I (p=0.024) and P (p=0.041) than the control group. Nitric oxide synthase activity was higher in groups I (p=0.026) and P (p=0.037) when compared to group C. CONCLUSION: Our results showed both perivascular infiltration and intravascular administration could prevent the consequences of endothelium damage that occurs during the harvesting of veins.