Development of QSAR model based on Monte Carlo optimization for predicting GABAA receptor binding of newly emerging benzodiazepines.

Benzodiazepines and their derivatives belong to a category of new psychoactive substances that have been introduced into the continually expanding illicit market. However, there is a notable absence of available pharmacological data for these substances. To gain a deeper understanding of their pharmacology, we employed the Monte Carlo optimization conformation-independent method as a tool for developing QSAR models. These models were built using optimal molecular descriptors derived from both SMILES notation and molecular graph representations. The resulting QSAR model demonstrated robustness and a high degree of predictability, proving to be very reliable. Moreover, we were able to identify specific molecular fragments that exerted both positive and negative effects on binding activity. This discovery paves the way for the swift prediction of binding activity for emerging benzodiazepines, offering a faster and more cost-effective alternative to traditional in vitro/in vivo analyses.

Human basilar artery abnormalities in the prenatal and postnatal period.

OBJECTIVE: Although complex and varied, adult cerebral angioarchitecture has its origins in embryologic development, where normal components, variations, and abnormalities evolve from modifications of primitive vessels. Therefore, the aim of this report was the study of the morphologic features of the basilar fenestrations in prenatal and postnatal period and associated variants and/or pathologies. METHODS: We studied the brain vessels of 120 fetuses microscopically (i.e., with an operative microscope) and 112 adult cadavers macroscopically. RESULTS: We described 10 cases of basilar abnormalities, five fetal and four adult fenestrations, as well as one adult case with a basilar aneurysm. The location of the vertebrobasilar junction on a caudal myelencephalon and a prolongation of the basilar trunk followed both fetal and adult forms of fenestrations. The same caliber values of the basilar and internal carotid arteries, a variation in the number and origin of some of the basilar side branches, and a tendency of fenestrations to be multiple in number, as particular fetal features, were mostly present in adults. CONCLUSION: The fact that basilar fenestrations in adult specimens shared similar features with fetal ones and without aneurysms, as well as the fact that a basilar aneurysm was without fenestration in its base, lead us to hypothesis that the basilar fenestration is a vascular developmental variant related to the maintenance of vascular symmetry in the midline of the human brain base.

[Evaluation of morphological changes of the liver caused by heroin abuse in forensic practice].

BACKGROUND/AIM: A study of morphological lesions in the liver of heroin addicts enables a precise overview of the type and degree of the liver damages caused by intravenous (i.v.) heroin abuse, additive effects of viral infections and alcohol consumption, as well as whether the expressiveness of these lesions depends on the duration of the time period of heroin application. The aim of the study was to investigate histopathological, ultrastructural and morphometric features of the liver of heroin addicts in forensic samples of the liver. METHODS: The study involved the autopsy conducted on 40 bodies of i.v. heroin addicts and 10 control autopsies. The investigated group consisted of liver samples of 36 male subjects and 4 female subjects aged 35-40 years and the control group of 8 male and 2 female cadaveric bodies aged 15-35 years. The liver tissue samples were prepared for light microscopy. Sections of the tissue paraffin blocks 5 micro thick were stained using classical Hematoxylin and Eosin method (H&E), as well as PAS Van Gieson, Gomori, and Congo Red techniques. For investigation purposes of ultrastructural changes, liver tissue was fixed in glutaraldehyde and molded with epon. The analysis was performed using the method of transmission electron microscopy. Morphometric investigation of the liver sinusoidal macrophages was performed by using the M42 test system. RESULTS: In the investigated group of i.v. heroin addicts, the liver autopsy samples showed degenerative vesicular and fat changes, chronic hepatitis, cirrhosis, sedimentation of pathologic protein amyloidosis, dysplastic changes, reduction in the amount of glycogen in hepatocytes, as well as the change in the number of Kupfer and endothelial cells. The established changes correlated with the duration of i.v. heroin abuse, whereas sinusoidal macrophages were activated in cases with active hepatitis, and no significant change in their number was found in hepatocytes with alcohol-related fatty changes. CONCLUSION. The study showed that the most present change in the hepatocytes of drug addicts was vesicular degeneration, and it is the only direct consequence of the effect of heroin. Other morphological changes were present due to viral infections and they correlated with the duration of narcotic abuse. The finding of dysplastic changes in this susceptible population of young people is particularly significant. The forensic significance of the established changes in the liver tissue is in the possibility of their practical application for determination of the immediate cause of death of i.v. heroin addicts, as well as the differential diagnosis of not only heroin, but also alcohol, sedative and other substances abuse, and all that on the basis of morphological damages of the liver.

Ultrastructural changes in the liver of intravenous heroin addicts.

The ultrastructural research has a decisive role in gathering the knowledge on the liver's response to the influence of some drugs. The aim of the study was to perform an ultrastructural analysis of the liver in chronic intravenous heroin addicts.The study involved the autopsy conducted on 40 bodies of intravenous heroin addicts and 10 control autopsies. The liver tissue was fixed in glutaraldehyde and moulded with epon for investigation purposes of ultrastructural changes. The analysis was performed using the method of transmission electron microscopy.In the group of intravenous heroin addicts, the liver autopsy samples showed degenerative vesicular and fat changes, chronic active and persistent hepatitis, cirrhosis, reduction in the amount of glycogen in hepatocytes, as well as the Kupffer cell's dominant hypertrophy. Various changes occur in organelles, plasma membrane of hepatocytes and biliary channels as well as in the nucleus. The most important ultrastructural findings include: hyperplasia and hypertrophy of the smooth endoplasmic reticulum, which is histologically proven vesicular degeneration of hepatocyte occurring as a result of the increased synthesis of enzymes of smooth endoplasmic reticulum due to chronic intravenous heroin intake, and the presence of continuous basal membrane followed by transformation of the sinusoids into capillaries (in the cases of chronic active hepatitis and cirrhosis) which leads to a disorder of microcirculation and further progress of cirrhosis.

[The influence of glycemia on the left ventricular diastolic function in patients with arterial hypertension].

INTRODUCTION: Arterial hypertension is a disease which has influence on the left ventricular diastolic function. It has been suggested that impairment of the left ventricular diastolic function in patients with diabetes mellitus is due to arterial hypertension and diffuse peripherial and coronary atherosclerosis which appear early in diabetic patients. Now, however, it is thought, that other mechanisms are responsable for the development of diabetic cardiomyopathy. The aim of the study was to investigate the effect of glycemia on the left ventricular diastolic function in patients with arterial hypertension. METHODS: The study included 60 patients with arterial hypertension: 30 (50.00%) patients with diabetes mellitus and 30 (50.00%) without diabetes mellitus. The parameters of diastolic function were measured by the pulsed Doppler echocardiographic technique. Isovolumetric relaxation time, deceleration time, maximum velocity of the early stage of ventricular filling, maximum velocity of the late stage of ventricular filling and the early/late stage of ventricular filling ratio were used to assess the diastolic function. RESULTS: The patients with arterial hypertension and diabetes mellitus compared to the patients with arterial hypertension without diabetes mellitus were significantly obese (p < 0.001), had significantly higher glycemia (p < 0.0001) and left atrial volume (p < 0.05). The patients with arterial hypertension and diabetes mellitus compared to the patients with arterial hypertension without diabetes mellitus had significantlly: longer deceleration time (p < 0.05), lower velocity of early stage of ventricular filling (p < 0.05) and lower early/late stage of ventricular filling ratio (p < 0.01). CONCLUSION: Diastolic function parameters of patients with diabetes mellitus are significantly changed: deceleration time is longer, early stage of ventricular filling and early/late ventricular filling ratio are lower.