A novel proteochemometrics model for predicting the inhibition of nine carbonic anhydrase isoforms based on supervised Laplacian score and k-nearest neighbour regression.

Carbonic anhydrases (CAs) are essential enzymes in biological processes. Prediction of the activity of compounds towards CA isoforms could be evaluated by computational techniques to discover a novel therapeutic inhibitor. Studies such as quantitative structure-activity relationships (QSARs), molecular docking and pharmacophore modelling have been carried out to design potent inhibitors. Unfortunately, QSAR does not consider the information of target space in the model. We successfully developed an in silico proteochemometrics model that simultaneously uses target and ligand descriptors to predict the activities of CA inhibitors. Herein, a strong predictive model was built for the prediction of protein-ligand binding affinity between nine human CA isoforms and 549 ligands. We applied descriptors obtained from the PROFEAT webserver for the proteins. Ligands were encoded by descriptors from PaDEL-Descriptor software. Supervised Laplacian score (SLS) and particle swarm optimization were used for feature selection. Models were derived using k-nearest neighbour (KNN) regression and a kernel smoother model. The predictive ability of the models was evaluated by an external validation test. Statistical results (Q2ext = 0.7806, r2test = 0.7811 and RMSEtest = 0.5549) showed that the model generated using SLS and KNN regression outperformed the other models. Consequently, the selectivity of compounds towards these enzymes will be predicted prior to synthesis.

QSAR modelling using combined simple competitive learning networks and RBF neural networks.

The aim of this study was to propose a QSAR modelling approach based on the combination of simple competitive learning (SCL) networks with radial basis function (RBF) neural networks for predicting the biological activity of chemical compounds. The proposed QSAR method consisted of two phases. In the first phase, an SCL network was applied to determine the centres of an RBF neural network. In the second phase, the RBF neural network was used to predict the biological activity of various phenols and Rho kinase (ROCK) inhibitors. The predictive ability of the proposed QSAR models was evaluated and compared with other QSAR models using external validation. The results of this study showed that the proposed QSAR modelling approach leads to better performances than other models in predicting the biological activity of chemical compounds. This indicated the efficiency of simple competitive learning networks in determining the centres of RBF neural networks.

Sialic acid removal modulates the myocardial and vascular activity of calcium channel ligands.

Selective removal of sialic acid from isolated guinea pig left atrial strips and rabbit thoracic aortic ring segments was performed by neuraminidase prepared from Clostridium perfringens and was controlled electron microscopically. Preincubation of these organs (2 units/mL; 2 hr) resulted in enzyme mediated hydrolysis of total tissue sialic acid; 55.2% for atria and 60.9% for aorta. Contractile force of atria and arterial diameter of thoracic aorta were measured isometrically and isotonically by means of a force displacement transducer. Pretreatment of both organs with neuraminidase (2 units/mL; 2 hr) in a carbogen saturated organ bath caused a moderate left-hand shift of the cumulative concentration response curves for the dihydropyridine type calcium antagonist nisoldipine, the phenylalkylamine derivative gallopamil and the benzothiazepine diltiazem. EC50 values were significantly lower (P less than 0.05), particularly in the atrial muscle, when compared to untreated preparations. There was no effect of neuraminidase on the negative inotropic and vasodilator potency of the calcium channel modulator fendiline. Conversely, neuraminidase induced a right-hand shift in the concentration response curves shown by the pure calcium agonist (-)-S-Bay K 8644 leading to significantly higher EC50 values in both organs. Similarly, the contractile potency of calcium chloride (atria) and potassium chloride (aorta) was attenuated upon neuraminidase treatment. From the results obtained it is concluded that sialic acid removal may modulate the action of calcium channel ligands through an inhibitory effect on transmembrane calcium fluxes and/or by decreasing the external calcium availability. Whether the present results suggest a functional role for sialic acid in the regulation of calcium channels warrants further investigation.

Endometriosis in diagnostic laparoscopy in Isfahan, Iran.

In 200 consecutive routine diagnostic laparoscopies, 31 cases (15.5%) of endometriosis were found. Of these 200 cases, 131 patients (65.5%) were referred for laparoscopy because of infertility. In 22 (71.0%) out of 31 patients with endometriosis infertility was the indication for laparoscopy. In the remainder of the patients laparoscopy was performed because of other indications. Half of the patients with endometriosis showed moderate or severe degrees of the disease. Seventy-one percent of the patients were below the age of 29. According to our findings, the presumption that endometriosis is a rare disease in Iran is considered to be erroneous.

Congestive heart failure in valvular heart disease in pregnancies with and without valvular prostheses and anticoagulant therapy.

The course and complications of pregnancies in 46 patients with valvular disease and congestive heart failure with or without valve prostheses are described. In group I consisting of 33 women without valve replacement and without anticoagulant therapy one thromboembolic event was seen, emergency closed or open heart surgery was necessary five times. One still-birth happened after open heart surgery. In group II, of 13 patients with prosthetic valve replacement and anticoagulation therapy there was no thromboembolism, but 2 spontaneous abortions and 2 premature stillbirths; 2 fetuses died after delivery, 3 had congenital abnormalities. Pregnancies in patients with valvular disease and congestive heart failure can be sustained relatively safely for the mother, even if emergency heart surgery becomes necessary. Heart surgery and anticoagulation treatment carry a higher risk for the fetus. Uterine blood loss is not increased, if coumadine treatment is switched to heparin administration shortly before delivery.

Clinical and hormonal response of patients with galactorrhea syndrome treated with bromergocryptine.

Tne patients with galactorrhea syndrome were treated with two different daily dosages (5 mg and 7.5 mg) of Bromergocryptine. The 5 mg daily dosage often did not produce the desired hormonal and clinical response. Five patients were treated with this regimen for 38 to 90 days, with treatment extending over more than one menstrual cycle. However, the 7.5 mg daily dosage resulted in complete cessation of galactorrhea in all patients, restoration of menstrual cycles in five patients, and pregnancies in four patients. Disappearance of lactation proved to be a very good indicator of the general responsiveness of patients. Nausea, vomiting, and occasional dizziness were side effects of the drug. The case histories and hormonal findings of four typical patients are reported.