Tourette syndrome and obsessive-compulsive disorder: A comprehensive review of structural alterations and neurological mechanisms.

Currently, it is possible to study the pathogenesis of Tourette's syndrome (TS) in more detail, due to more advanced methods of neuroimaging. However, medical and surgical treatment options are limited by a lack of understanding of the nature of the disorder and its relationship to some psychiatric disorders, the most common of which is obsessive-compulsive disorder (OCD). It is believed that the origin of chronic tic disorders is based on an imbalance of excitatory and inhibitory influences in the Cortico-Striato-Thalamo-Cortical circuits (CSTC). The main CSTCs involved in the pathological process have been identified by studying structural and neurotransmitter disturbances in the interaction between the cortex and the basal ganglia. A neurotransmitter deficiency in CSTC has been demonstrated by immunohistochemical and genetic methods, but it is still not known whether it arises as a consequence of genetically determined disturbances of neuronal migration during ontogenesis or as a consequence of altered production of proteins involved in neurotransmitter production. The aim of this review is to describe current ideas about the comorbidity of TS with OCD, the involvement of CSTC in the pathogenesis of both disorders and the background of structural and neurotransmitter changes in CSTC that may serve as targets for drug and neuromodulatory treatments.

Evaluation of In Vitro Cytotoxic Potential of Avarol towards Human Cancer Cell Lines and In Vivo Antitumor Activity in Solid Tumor Models.

The goal of this study was to determine the activity in vitro and in vivo of avarol, a sesquiterpene hydroquinone originating from the Dysidea avara sponge from the south Adriatic Sea, against different cancer cell lines and two types of mouse carcinoma. To investigate the in vitro cytotoxicity, a human cervix adenocarcinoma cell line (HeLa), human colon adenocarcinoma (LS174), human non-small-cell lung carcinoma (A549), and a normal human fetal lung fibroblast cell line (MRC-5) were used. The in vivo antitumor activity was investigated against two transplantable mouse tumors, the Ehrlich carcinoma (EC) and cervical cancer (CC-5). The effect of avarol on cancer cell survival, which was determined by the microculture tetrazolium test, confirmed a significant in vitro potency of avarol against the investigated cell lines, without selectivity towards MRC-5. The highest cytotoxicity was exhibited against HeLa cancer cells (10.22 ± 0.28 µg/mL). Moreover, potent antitumor activity against two tumor models was determined, as the intraperitoneal administration of avarol at a dose of 50 mg/kg resulted in a significant inhibition of tumor growth in mice. After three administrations of avarol, a 29% inhibition of the EC growth was achieved, while in the case of CC-5, a 36% inhibition of the tumor growth was achieved after the second administration of avarol. Therefore, the results indicate that this marine sesquiterpenoid hydroquinone could be a promising bioactive compound in the development of new anticancer medicine.

Risk modeling of femoral neck fracture based on geometric parameters of the proximal epiphysis.

BACKGROUND: Fractures of the proximal femur epiphysis are problematic for state health care because they are associated with severe medical and social problems and high morbidity and mortality rates. AIM: To model the potential risk of hip fracture via femur geometric parameters. METHODS: Seventy educational cadaveric femurs from people aged 14 to 80 years, 10 X-ray images from the records of the Human Anatomy Department and 10 X-ray images from the Department of Traumatology, Orthopedics and Disaster Surgery of Sechenov University, were evaluated. The parameters of the fractured bone were measured using images captured with a Canon d60 camera. The projection values of the proximal epiphysis of the cadaveric femurs and geometric parameters of the bones shown in the X-ray images were measured with Autodesk software (AutoCAD 2018). Analysis of the video frames showing bone rotation reveal that the greater trochanter can be inscribed in a parallelepiped, where one of the faces is parallel to the plane of view in the frontal standard projection and is rectangular. The angle of bone rotation obtained by turning the cube corresponded to the angle measured with the second technique. This reliable method of calculating the rotation of the bone relative to the anterior projection was employed in subsequent calculations. The geometric parameters of the femur were measured using X-ray images according to the proposed method. RESULTS: The geometric parameters of 70 femurs were analyzed, and correlation coefficients were calculated. Our measurement results were compared with those reported by other authors. The potential influence of femur geometry on force distribution in the proximal epiphysis of the femur was described, and a 2-dimensional model of the femur epiphysis associated with minimal neck fracture risk was provided. The assessment of the geometric parameters of the femoral epiphysis indicated the greatest risk of a varus fracture of the neck if the angle of the minimal resistance zone (AMRZ) index > 24° and the neck-shaft angle (NSA) < 127.5°. In contrast, the minimum risk was observed at AMRZ < 14° and NSA > 128.87°. CONCLUSION: The proposed method provides the potential femur neck fracture risk based on geometric parameters.

1-Isobutanoil-2-isopropylisothiourea Phosphate, T1082: A Safe and Effective Prevention of Radiotherapy Complications in Oncology.

The radioprotective effects of a new 1-isobutanoil-2-isopropylisothiourea derivative named T1082 are presented. Research methods included toxic characteristics, radioprotective activity (Till-McCulloch's test and 30-day survival test) in γ-ray total-body-irradiated mice, and a clinical and histological study of the effect of T1082 on acute radiation skin reactions (RSR) in rats after a single or fractionated ß-ray local irradiation. T1082 is more effective than its analogue, the NOS inhibitor T1023, at low concentrations and doses (1/12-1/8 LD10), both parenterally and intragastrically. In this case, its therapeutic index (LD50/ED50) reaches 30, and the optimal radioprotective doses (ED84-98-141-224 mg/kg) are an order less than the maximum tolerated doses-1/16-1/10 LD10. These properties allowed T1082, at a low intragastrical dose (160 mg/kg; 1/14 LD10), to significantly limit the severity of acute RSR after single (40 Gy) and fractionated (78 Gy) ß-ray irradiation. The results confirm T1082 as one of the safest emergency radioprotectors and indicate the prospects for its further development as a pharmacological agent for the prevention of RT complications.

Combination of NOS- and PDK-Inhibitory Activity: Possible Way to Enhance Antitumor Effects.

We have previously demonstrated a high antitumor potential of NOS inhibitor T1023 (1-isobutanoyl-2-isopropylisothiourea hydrobromide): antitumor antiangiogenic activity in several animal tumor models and its ability to synergistically enhance the antitumor effects of bevacizumab, cyclophosphamide and γ-radiation. At the same time, rather rapid adaptation of experimental neoplasias to T1023 treatment was often observed. We attempted to enhance the antitumor activity of this NOS inhibitor by supplementing its molecular structure with a PDK-inhibiting fragment, dichloroacetate (DCA), which is capable of hypoxia-oriented toxic effects. We synthesized compound T1084 (1-isobutanoyl-2-isopropylisothiourea dichloroacetate). Its toxic properties, NOS-inhibiting and PDK-inhibiting activity in vivo, and antitumor activity on the mouse Ehrlich carcinoma model (SEC) were investigated in compare with T1023 and Na-DCA. We found that the change of the salt-forming acid from HBr to DCA does not increase the toxicity of 1-isobutanoyl-2-isopropylisothiourea salts, but significantly expands the biochemical and anti-tumor activity. New compound T1084 realizes in vivo NOS-inhibiting and PDK-inhibiting activity, quantitatively, at the level of the previous compounds, T1023 and Na-DCA. In two independent experiments on SEC model, a pronounced synergistic antitumor effect of T1084 was observed in compare with T1023 and Na-DCA at equimolar doses. There were no signs of SEC adaptation to T1084 treatment, while experimental neoplasia rapidly desensitized to the separate treatment of both T1023 and Na-DCA. The totality of the data obtained indicates that the combination of antiangiogenic and hypoxia-oriented toxic effects (in this case, within the molecular structure of the active substance) can increase the antitumor effect and suppress the development of hypoxic resistance of neoplasias. In general, the proposed approach can be used for the design of new anticancer agents.