Comprehensive analysis of two Shank3 and the Cacna1c mouse models of autism spectrum disorder.

To expand, analyze and extend published behavioral phenotypes relevant to autism spectrum disorder (ASD), we present a study of three ASD genetic mouse models: Feng's Shank3tm2Gfng model, hereafter Shank3/F, Jiang's Shank3tm1Yhj model, hereafter Shank3/J and the Cacna1c deletion model. The Shank3 models mimick gene mutations associated with Phelan-McDermid Syndrome and the Cacna1c model recapitulates the deletion underlying Timothy syndrome. This study utilizes both standard and novel behavioral tests with the same methodology used in our previously published companion report on the Cntnap2 null and 16p11.2 deletion models. We found that some but not all behaviors replicated published findings and those that did replicate, such as social behavior and overgrooming in Shank3 models, tended to be milder than reported elsewhere. The Shank3/F model, and to a much lesser extent, the Shank3/J and Cacna1c models, showed hypoactivity and a general anxiety-like behavior triggered by external stimuli which pervaded social interactions. We did not detect deficits in a cognitive procedural learning test nor did we observe perseverative behavior in these models. We did, however, find differences in exploratory patterns of Cacna1c mutant mice suggestive of a behavioral effect in a social setting. In addition, only Shank3/F showed differences in sensory-gating. Both positive and negative results from this study will be useful in identifying the most robust and replicable behavioral signatures within and across mouse models of autism. Understanding these phenotypes may shed light of which features to study when screening compounds for potential therapeutic interventions.

Phenozan, a Synthetic Phenolic Antioxidant, Inhibits the Development of Spontaneous Tumors in Rats and Mice.

Synthetic phenolic antioxidant ß-(4-hydroxy-3,5-di-tert-butylphenyl) propionic acid, named phenozan, is a potential antiepileptic drug. In pre-clinical trials this substance did not manifest any toxicity, and also inhibited the development of some spontaneous tumors in animals. The purpose of this study was to evaluate inhibiting effect of phenozan on spontaneous carcinogenesis in rats and mice. In experiments with rats LIO and mice SHR of local breeding, with high spontaneous tumor incidence, phenozan was dissolved in sunflower oil and administered by gavage in therapeutic dose 5 mg/kg 3 times per week for 18 months. There were no any signs of toxicity and differences in weight of animals during the phenozan treatment compared with the control (sunflower oil). Phenozan significantly reduced the overall incidence and multiplicity of all tumors but only multiplicity of malignant tumors, compared with the control. Moreover a significant decrease of overall incidence and multiplicity was observed in pituitary and breast tumors in females and only overall multiplicity of tumors of pituitary and lymphoid tissue in males. In mice phenozan reduced overall incidence and multiplicity of lung tumors (in females) and also overall multiplicity of all tumors (in females) and only malignant tumors (in males). These findings allow us to classify phenozan as anticarcinogenic agent. Anticarcinogenic activity of phenozan is important because clinical study of this drug as the possible antiepileptic drug goes along and it is known that such drugs are designed for long-term use.

[Relationship between benign prostatic hyperplasia and prostate cancer: new opportunities for prostate cancer chemoprevention].

In a review article the relationship between benign prostatic hyperplasia (BPH) and prostate cancer (PC) has been conducted. Epidemiological data on increasing the risk of PC in patients with BPH are presented. There are discussed common for BPH and PC constitutional, food, and life style etiologic factors and also common for the both diseases pathogenetic factors such as androgens, inflammation, metabolic syndrome. Pharmaceutical drugs and natural agents that have unidirectional therapeutic and preventive effect on BPH and PC are presented. Results of experimental studies of the authors to prove the link between BPH and PC are presented. It is concluded that BPH is a risk factor for PC and, ideally, drugs for the treatment of BPH should have a chemo preventive effect on PC.

[Intraperitoneal chemotherapy--a method of improving treatment effectiveness in ovarian cancer].

The study or antitumor effects of dioxadet, cisplatin, melphalan, paclitaxel, mitomycin C, cyclophosphamide and gemcitabine at intraperitoneal (i.p.) and intravenous (i.v.) administration as monochemotherapy and polychemotherapy in a rat model of ascitic ovarian cancer was carried out in 244 female Wistar rats. Ovarian cancer was transplanted i.p. at a number of 1 x 10(7) tumor cells. The drugs were administered once in 48 hours after ovarian cancer transplantation i.p. or i.v. for monotherapy--in maximum tolerated doses, for i.p. polychemotherapy--in half doses from maximum tolerated doses. Antitumor effects of the treatment were estimated in increase in median survival time (MST) compared to control rats who were administered saline i.p. At i.p. administration dioxadet, cisplatin and melphalan increased MST by 79%, 88% and 144%, respectively, while at i.v. administration these drugs didn't affect MST. Mitomycin C and paclitaxel had stronger antitumor action at i.v. administration increasing MST by 152% and 81%, respectively, while at i.p. administration these drugs increased MST by 35 and 45%, respectively. Combinations dioxadet + cisplatin, dioxadet + cyclophosphamide and dioxadet + paclitaxel at i.p. administration increased MST by 305%, 277% and 133%, respectively, and had additive antitumor action compared to mono-effects of these drugs. Gemcitabine and combination dioxadet + gemcitabine at i.p. administration didn't significantly affect survival of rats with ovarian cancer. Intraperitoneal monochemotherapy and polychemotherapy could be more effective in the treatment of peritoneal carcinomatosis from ovarian cancer compared to systemic administration of the drugs.

[Therapeutic activity of gemcitabine in intracranial tumors].

Gemcitabine is known to exert a therapeutic effect on brain tumors despite the limited permeability of the blood-brain barrier (BBB). In our experimental research single intraperitoneal (i.p.) injection of gemcitabine 25 mg/kg provided increase in median survival of mice with intracranially transplanted Ehrlich carcinoma by 41-89% (p < 0.001). In this experimental model i.p. administration of gemcitabine (permeability of the BBB of less than 10%), carmustine (good permeability of the BBB), cyclophosphamide (poor permeability of the BBB) and cisplatin (doesn't penetrate through the BBB) increased median survival of mice by 88% (p < 0.001), 59% (p = 0.001), 35% (p = 0.005) and 18% (p = 0.302) respectively. Considering strong correlation between antitumor activity of the drugs (carmustine, cyclophosphamide and cisplatin) and their permeability of the BBB, efficacy of gemcitabine in intracranial tumors could be due to its wide range of therapeutic doses.

Confinement effects for ionic carriers in SrTiO3 ultrathin films: first-principles calculations of oxygen vacancies.

One-dimensional confinement effects are modelled within the hybrid HF-DFT LCAO approach considering neutral and single-charged oxygen vacancies in SrTiO(3) ultrathin films. The calculations reveal that confinement effects are surprisingly short-range in this partly covalent perovskite; already for film thickness of 2-3 nm (and we believe, similar size nanoparticles) only the surface-plane defect properties differ from those in the bulk. This includes a pronounced decrease of the defect formation energy (by ∼1 eV), a much deeper defect band level and a noticeable change in the electronic density redistribution at the near-surface vacancy site with respect to that in the bulk. The results also show that the size effect pertains to the interactions between the oxygen vacancy and two neighboring titanium atoms and orientation (parallel or perpendicular to the surface) of the Ti-V(O)-Ti complex. In particular, we predict considerable oxygen vacancy segregation towards the surface.

Ab initio modeling of spin and charge ordering and lattice dynamics in CaFeO(3) crystals.

Results of first-principles simulations on both orthorhombic and monoclinic phases of CaFeO(3) crystal are presented. The obtained atomic structures are consistent with x-ray diffraction data. The transition from a metallic orthorhombic to a narrow-gap semiconducting monoclinic phase is ascribed to the larger distortion of the Fe-O-Fe bond angle in the latter case. Calculations of Raman and optic active phonon modes at the Gamma point of the Brillouin zone are performed and discussed. The isotopic substitution technique is applied to analyze the vibration modes obtained. The found charge/spin disproportionation is analyzed and compared with available experimental estimates.

Prefrontal control of respiration.

The aim of the present study was to test the hypothesis that different parts of the prefrontal cortex could be involved in respiratory control. This hypothesis was tested by examining the changes in respiratory pattern produced by low intensity electrical stimulation of the insular and infralimbic cortex. The experiments were performed on the anaesthetised rats. It was found that the sites capable of inducing different kinds of respiratory responses were localized to the insular and infralimbic cortices. Microstimulation of the anterior insular cortex produced responses which manifested themselves in a decrease of inspiratory flow and tidal volume, but the respiratory time remained stable. Responsive sites within caudal insular and infralimbic cortex produced other alterations in breathing which included an increase of inspiratory flow, and decreases of tidal volume and respiratory time. These observations support the hypothesis proposed and localize distinct patterns of respiratory responses to different parts of the prefrontal cortex in the rat.

A mathematical model of the response of semicircular canal and otolith to head rotation under gravity.

The mathematical model of the system composed of two sensors: semicircular canal and sacculus, is presented. The system is described by three series of blocks: biomechanical block, mechanoelectrical transduction mechanism and hair cell ionic currents and membrane potential dynamics. The response of the aforecited system to various stimuli (head rotation under gravity and falling) was investigated. The identification of the model parameters was fulfilled for the experimental data, obtained for the axolotle (Ambystoma tigrinum) in Institute of Physiology, Autonomous University of Puebla, Mexico. The comparative analysis of canal and sacculus membrane potential was realized.

Chemoprevention of mammary, cervix and nervous system carcinogenesis in animals using cultured Panax ginseng drugs and preliminary clinical trials in patients with precancerous lesions of the esophagus and endometrium.

The anticarcinogenic effects and mechanisms of the biotechnological drugs of Panax ginseng C.A. Meyer cultivated in Russia, bioginseng, panaxel and panaxel- 5, were studied. Bioginseng was produced from a tissue culture of ginseng root cultured on standard medium, whereas panaxel and panaxel-5 were produced from ginseng tissue root cultures using standard mediums enriched with 2-carboxyethylgermanium sesquioxide and 1-hydroxygermatran-monohydrate respectively. All three ginseng drugs inhibited the development of mammary tumors induced by intramammary injections of N-methyl-N-nitrosourea (MNU) in rats, the development of the brain and spinal cord tumors induced by transplacental administration of N-ethyl-N-nitrosourea (ENU) in rats, and the development of uterine, cervical and vaginal tumors induced by intravaginal applications of 7,12-dimethylbenz(a)anthracene (DMBA) in mice. The ginseng drugs induced the cytotoxic activity of macrophages in mice, enhanced T-lymphocyte rosette formation in guinea pigs exposed to cyclophosphamide, and stimulated the production of thyroid hormones in rats. These mechanisms may contribute to the anticarcinogenic action of the ginseng drugs. The organic germanium compounds present in panaxel and panaxel-5 did not potentiate the anticarcinogenic or immuno- stimulatory effects as much as biogeinseng. Preliminary clinical trials with panaxel and bioginseng were carried out in patients with precancerous lesions of the esophagus and endometrium. Panaxel was found to have a strong therapeutic effect in patients suffering from chronic erosive esophagitis. Bioginseng induced the regression of adenomatous-cystic hyperplasia of the endometrium in some patients. Thus, we conclude that the drugs of ginseng appear to hold considerable promise for future cancer chemoprevention.

PartsList: a web-based system for dynamically ranking protein folds based on disparate attributes, including whole-genome expression and interaction information.

As the number of protein folds is quite limited, a mode of analysis that will be increasingly common in the future, especially with the advent of structural genomics, is to survey and re-survey the finite parts list of folds from an expanding number of perspectives. We have developed a new resource, called PartsList, that lets one dynamically perform these comparative fold surveys. It is available on the web at http://bioinfo.mbb.yale.edu/partslist and http://www.partslist.org. The system is based on the existing fold classifications and functions as a form of companion annotation for them, providing 'global views' of many already completed fold surveys. The central idea in the system is that of comparison through ranking; PartsList will rank the approximately 420 folds based on more than 180 attributes. These include: (i) occurrence in a number of completely sequenced genomes (e.g. it will show the most common folds in the worm versus yeast); (ii) occurrence in the structure databank (e.g. most common folds in the PDB); (iii) both absolute and relative gene expression information (e.g. most changing folds in expression over the cell cycle); (iv) protein-protein interactions, based on experimental data in yeast and comprehensive PDB surveys (e.g. most interacting fold); (v) sensitivity to inserted transposons; (vi) the number of functions associated with the fold (e.g. most multi-functional folds); (vii) amino acid composition (e.g. most Cys-rich folds); (viii) protein motions (e.g. most mobile folds); and (ix) the level of similarity based on a comprehensive set of structural alignments (e.g. most structurally variable folds). The integration of whole-genome expression and protein-protein interaction data with structural information is a particularly novel feature of our system. We provide three ways of visualizing the rankings: a profiler emphasizing the progression of high and low ranks across many pre-selected attributes, a dynamic comparer for custom comparisons and a numerical rankings correlator. These allow one to directly compare very different attributes of a fold (e.g. expression level, genome occurrence and maximum motion) in the uniform numerical format of ranks. This uniform framework, in turn, highlights the way that the frequency of many of the attributes falls off with approximate power-law behavior (i.e. according to V(-b), for attribute value V and constant exponent b), with a few folds having large values and most having small values.

[Combined surgical treatment of patients with huge aortic abdominal aneurysms associated with coronary artery lesions]. / Kombinirano khirurgichno lechenie na patsienti s anevrizmi na abdominalnata aorta i s'p'tstvashti porazheniia na koronarnite arterii.

The objective of this study was to define the perioperative risk of simultaneous operations in patients with abdominal aortic aneurysm (AAA) associated with coronary artery disease (CAD). The hospital data of 30 patients with coexistent severe symptomatic AAA and significant CAD, who underwent one stage surgery of the abdominal aorta and the coronary arteries was retrospectively analysed. Most of the pts.--28 were male and only 2 female. The average age consisted 57.7 years. Infrarenal AAA (diameter over 5 cm) was presented in 25 patients and suprarenal extension was in presented in 5 pts, while all patients with coexisting CAD had three vessels disease and significant impairment of left ventricular function (23 pts with ejection fraction (EF) < 50% and 10 pts < 30% EF). The resections of AAA in pts. undergoing simultaneous coronary artery procedure were performed on cardiopulmonary bypass (CPB) and moderate hypothermia. There were 2 early postoperative deaths (6.66%) and 5 major nonfatal postoperative complications (16.6%). Our experience with simultaneous surgery of coexistent huge AAA and CAD demonstrated that: a) Combined procedure can be performed safely in patients with significant AAA and CAD. b) The overall early operative mortality and morbidity after combined surgery compare favourably with the results after CABG of patients with impaired left ventricular function. c) Simultaneous operation seems to be more favourable in patients with coexistent AAA and CAD regarding the high risk of aneurysmal rupture, saving them also the potential morbidity and eventually fatal complications associated with the second procedure. d) Even the management of suprarenal and huge infrarenal AAA can be carried out easier and with less risk of complications under the protection of CPB.

Study of the post-natal effects of chemopreventive agents on ethylnitrosourea-induced transplacental carcinogenesis in rats. II. Influence of low-molecular-weight polypeptide factors from the thymus, pineal gland, bone marrow, anterior hypothalamus, brain cortex and brain white substance.

The influence of the polypeptide factors extracted from thymus, pineal gland, bone marrow, anterior hypothalamus, brain cortex or brain white substance on N-ethyl-N-nitrosourea (ENU)-induced transplacental carcinogenesis was studied in rats. ENU was given to pregnant rats as a single i.v. exposure at a dose of 75 mg/kg body weight on the 21st day of gestation. The polypeptide factors were given to the offspring as a series of s.c. injections, at a dose of 0.5 mg/rat/day, starting at one or 2.5 months of age and continuing throughout the whole of post-natal life. ENU induced tumors of the brain, spinal cord, peripheral nerves and kidneys in 94-98% of the offspring exposed to the carcinogen, with an average number of 2.3-2.6 tumors per rat, and an average survival time of 294 days. Post-natal thymus factor or pineal gland factor administration was followed by an increase in mean lifespan of approximately 2 months and a significant decrease (P < 0.05) in the total tumor number per tumor-bearing rat, as well as the incidence and multiplicity of spinal cord tumors. Pineal gland factor also decreased the incidence of peripheral nerve and kidney tumors and their number per tumor-bearing rat. Brain cortex factor and brain white substance factor treatment was followed by a decrease in total tumor multiplicity of 1.2- to 3.3-fold, and a decrease in incidence of brain tumors of 10 to 33% per rat in comparison to the controls. Brain cortex factor also decreased the total tumor incidence. At the same time, brain white substance factor administration increased the incidence of peripheral nerve tumors and decreased the mean lifespan. Both bone marrow factor and anterior hypothalamus factor did not have any modifying effects on any of the ENU-induced tumors and mean lifespan. Thus, our results show the possibility of attenuation of transplacental ENU-induced carcinogenesis with post-natal administration of some polypeptide substances.

Study of post-natal effect of chemopreventive agents on ethylnitrosourea-induced transplacental carcinogenesis in rats. III. Inhibitory action of indomethacin, voltaren, theophylline and epsilon-aminocaproic acid.

The influence of the arachidonic acid metabolism inhibitors, indomethacin and voltaren; an inhibitor of phosphodiesterase activity, theophylline and the protease inhibitor epsilonaminocaproic acid (EACA) on N-ethyl-N-nitrosourea (ENU)-induced transplacental carcinogenesis was studied in rats. ENU was given to pregnant rats as a single i.v. exposure at a dose of 75 mg/kg body weight on the 21st day after conception. Indomethacin and voltaren (20 p.p.m. in drinking water), theophylline (0.01% in diet) and EACA (1000 p.p.m. in drinking water) were given to the offspring throughout their post-natal life until all survivors were killed at 12 months. In the ENU-only control groups, 100% of the offspring developed tumors of brain, spinal cord, peripheral nervous system or kidneys, with a total average number of 3.1 tumors per rat. The most marked inhibitory effect was exerted by theophylline, which significantly decreased the incidence and multiplicity of total tumors, and at all main sites selectively (brain, spinal cord, peripheral nerves and kidneys). It also prolonged average survival time of the offspring. Indomethacin and voltaren significantly decreased total tumor incidence and multiplicity and brain tumor incidence and multiplicity. Indomethacin also decreased kidney tumor multiplicity and voltaren diminished spinal cord tumor multiplicity. EACA decreased multiplicities of total, brain, peripheral nerve and kidney tumors, and diminished the incidence of brain tumors. These chemopreventive agents decreased tumor incidences 20-33% and tumor multiplicities 1.4-2.7 times, compared with the ENU-only controls.

Perioperative myocardial protection with the calcium antagonist diltiazem.

The effect of the calcium channel blocker, diltiazem, on cardiac performance was examined in 90 patients who underwent isolated aortic valve replacement for aortic valve diseases with marked left ventricular hypertrophy. The patients were randomly assigned to one of five groups dependent on the treatment plan with diltiazem: group 1, 5-day preoperative treatment with oral administration of 60 mg diltiazem 3 times daily, 10 mg diltiazem intravenously as a bolus dose before the beginning of the cardiopulmonary bypass, and 5 mg diltiazem intravenously 10 min before removal of aortic clamp; group 2, 5-day preoperative treatment with oral administration of 60 mg diltiazem 3 times daily; group 3, 10 mg diltiazem intravenously as a bolus dose before the beginning of CPB and 5 mg 10 min before removal of the aortic clamp; group 4, 15 mg diltiazem in 1000 ml cardioplegic solution, given as additive; group 5, control group not receiving diltiazem. All operative procedures were performed in an identical manner with an average cross-clamping time of 57.7 min and cooling the heart down to 16 degrees-17 degrees septal temperature by perfusion of the coronary arteries with 4 degrees C cold cardioplegic solution. In each patient the heart rate (HR), cardiac output and cardiac index (CO, CI), stroke volume index (SVI), left ventricular stroke work index (LVSWI) and systemic vascular resistance index (SVRI) were recorded and calculated before and after the ischemic period. Transmural samples were obtained three times by needle biopsy technique from the anterior free wall of the heart. Analysis of the variables revealed that: (1) complete cessation of electromechanical activity was achieved significantly more rapidly in groups 1 and 3 than in the other groups; (2) recovery of sinus rhythm and function of the conductive system required significantly longer in groups 1 and 3; (3) the time-related values of the important hemodynamic factors (CO, CI, LWSVI and SVRI) showed a significantly more effective postperfusion cardiac performance in groups 1 and 3 than in groups 2, 4 and 5. An oral dose of 180 mg diltiazem for 5 to 7 days preoperatively in combination with intravenous administration of 10 mg before the beginning of CPB and 5-10 mg during reperfusion can be recommended in patients undergoing open-heart surgery for isolated aortic valve diseases and left ventricular hypertrophy.