Roadmap for the expression of canonical and extended endocannabinoid system receptors and metabolic enzymes in peripheral organs of preclinical animal models.

The endocannabinoid system is widely expressed throughout the body and is comprised of receptors, ligands, and enzymes that maintain metabolic, immune, and reproductive homeostasis. Increasing interest in the endocannabinoid system has arisen due to these physiologic roles, policy changes leading to more widespread recreational use, and the therapeutic potential of Cannabis and phytocannabinoids. Rodents have been the primary preclinical model of focus due to their relative low cost, short gestational period, genetic manipulation strategies, and gold-standard behavioral tests. However, the potential for lack of clinical translation to non-human primates and humans is high as cross-species comparisons of the endocannabinoid system have not been evaluated. To bridge this gap in knowledge, we evaluate the relative gene expression of 14 canonical and extended endocannabinoid receptors in seven peripheral organs of C57/BL6 mice, Sprague-Dawley rats, and non-human primate rhesus macaques. Notably, we identify species- and organ-specific heterogeneity in endocannabinoid receptor distribution where there is surprisingly limited overlap among the preclinical models. Importantly, we determined there were no receptors with identical expression patterns among mice (three males and two females), rats (six females), and rhesus macaques (four males). Our findings demonstrate a critical, yet previously unappreciated, contributor to challenges of rigor and reproducibility in the cannabinoid field, which has implications in hampering progress in understanding the complexity of the endocannabinoid system and development of cannabinoid-based therapies.

Dynamics of coexisting rotating waves in unidirectional rings of bistable Duffing oscillators.

We study the dynamics of multistable coexisting rotating waves that propagate along a unidirectional ring consisting of coupled double-well Duffing oscillators with different numbers of oscillators. By employing time series analysis, phase portraits, bifurcation diagrams, and basins of attraction, we provide evidence of multistability on the route from coexisting stable equilibria to hyperchaos via a sequence of bifurcations, including the Hopf bifurcation, torus bifurcations, and crisis bifurcations, as the coupling strength is increased. The specific bifurcation route depends on whether the ring comprises an even or odd number of oscillators. In the case of an even number of oscillators, we observe the existence of up to 32 coexisting stable fixed points at relatively weak coupling strengths, while a ring with an odd number of oscillators exhibits 20 coexisting stable equilibria. As the coupling strength increases, a hidden amplitude death attractor is born in an inverse supercritical pitchfork bifurcation in the ring with an even number of oscillators, coexisting with various homoclinic and heteroclinic orbits. Additionally, for stronger coupling, amplitude death coexists with chaos. Notably, the rotating wave speed of all coexisting limit cycles remains approximately constant and undergoes an exponential decrease as the coupling strength is increased. At the same time, the wave frequency varies among different coexisting orbits, exhibiting an almost linear growth with the coupling strength. It is worth mentioning that orbits originating from stronger coupling strengths possess higher frequencies.

Roadmap For The Expression Of Canonical and Extended Endocannabinoid System Receptors and Proteins in Peripheral Organs of Preclinical Animal Models.

The endocannabinoid system is widely expressed throughout the body and is comprised of receptors, ligands, and enzymes that maintain metabolic, immune, and reproductive homeostasis. Increasing interest in the endocannabinoid system has arisen due to these physiologic roles, policy changes leading to more widespread recreational use, and the therapeutic potential of Cannabis and phytocannabinoids. Rodents have been the primary preclinical model of focus due to their relative low cost, short gestational period, genetic manipulation strategies, and gold-standard behavioral tests. However, the potential for lack of clinical translation to non-human primates and humans is high as cross-species comparisons of the endocannabinoid system has not been evaluated. To bridge this gap in knowledge, we evaluate the relative gene expression of 14 canonical and extended endocannabinoid receptors in seven peripheral organs of C57/BL6 mice, Sprague-Dawley rats, and non-human primate rhesus macaques. Notably, we identify species- and organ-specific heterogeneity in endocannabinoid receptor distribution where there is surprisingly limited overlap among the preclinical models. Importantly, we determined there were only five receptors (CB2, GPR18, GPR55, TRPV2, and FAAH) that had identical expression patterns in mice, rats, and rhesus macaques. Our findings demonstrate a critical, yet previously unappreciated, contributor to challenges of rigor and reproducibility in the cannabinoid field, which has profound implications in hampering progress in understanding the complexity of the endocannabinoid system and development of cannabinoid-based therapies.

Batroxase, a new metalloproteinase from B. atrox snake venom with strong fibrinolytic activity.

The structures and functional activities of metalloproteinases from snake venoms have been widely studied because of the importance of these molecules in envenomation. Batroxase, which is a metalloproteinase isolated from Bothrops atrox (Pará) snake venom, was obtained by gel filtration and anion exchange chromatography. The enzyme is a single protein chain composed of 202 amino acid residues with a molecular mass of 22.9 kDa, as determined by mass spectrometry analysis, showing an isoelectric point of 7.5. The primary sequence analysis indicates that the proteinase contains a zinc ligand motif (HELGHNLGISH) and a sequence C164 I165M166 motif that is associated with a "Met-turn" structure. The protein lacks N-glycosylation sites and contains seven half cystine residues, six of which are conserved as pairs to form disulfide bridges. The three-dimensional structure of Batroxase was modeled based on the crystal structure of BmooMPα-I from Bothrops moojeni. The model revealed that the zinc binding site has a high structural similarity to the binding site of other metalloproteinases. Batroxase presented weak hemorrhagic activity, with a MHD of 10 µg, and was able to hydrolyze extracellular matrix components, such as type IV collagen and fibronectin. The toxin cleaves both α and ß-chains of the fibrinogen molecule, and it can be inhibited by EDTA, EGTA and ß-mercaptoethanol. Batroxase was able to dissolve fibrin clots independently of plasminogen activation. These results demonstrate that Batroxase is a zinc-dependent hemorrhagic metalloproteinase with fibrin(ogen)olytic and thrombolytic activity.

Hypolipemic and antioxidant activities from Tamarindus indica L. pulp fruit extract in hypercholesterolemic hamsters.

Dietary modifications may significantly reduce cardiovascular disease (CVD) risk factors, including cholesterol and atherosclerosis. The present study addressed the effects of the crude extract from the pulp fruit of Tamarindus indica L. on lipid serum levels and early atherosclerotic lesions in hypercholesterolemic hamsters in vivo, and the extract's antioxidant action, in vitro. Animals were fed on either chow or atherogenic diet during 10 weeks and concomitantly received either water or T. indica L. extract for drinking. Treatment of hypercholesterolemic hamsters with the T. indica pulp fruit extract (5%) led to a decrease in the levels of serum total cholesterol (50%), non-HDL cholesterol (73%) and triglyceride (60%), and to an increase of high-density lipoprotein (HDL) cholesterol levels (61%). In vitro, the extract presented radical scavenging ability, as assessed by the 2,2-diphenyl-1-picrylhydrazyl (DPPH) and superoxide radicals assays, and led to decreased lipid peroxidation in serum, as assessed by the thiobarbituric acid reactive substances (TBARS) assay. In vivo, the extract improved the efficiency of the antioxidant defense system, as assessed by the superoxide dismutase, catalase and glutathione peroxidase activities. Together these results indicate the potential of tamarind extracts in diminishing the risk of atherosclerosis development in humans.

Biochemical and histopathological alterations induced in rats by Tityus serrulatus scorpion venom and its major neurotoxin tityustoxin-I.

Intravenous injection into the rat of sublethal doses of Tityus serrulatus scorpion venom (100 micrograms protein/kg) or its major neurotoxin tityustoxin-I (TsTX-I, 20 micrograms/kg) caused, 30-180 min after injection, statistically significant increases in the serum levels of aspartate aminotransferase, amylase, creatine kinase and lactate dehydrogenase, as well as hyperglycemia, a high level of plasma free fatty acids and a low level of liver glycogen. The in vitro serum levels of the above enzymes did not change. For alanine aminotransferase, gamma-glutamyl transferase and alkaline phosphatase, neither in vitro nor in vivo alterations were observed. The whole venom and TsTX-I caused hepatic congestion with hemolysis and hydropic degeneration. Other histological lesions included edema and congestion with subpleural hemorrhage in the lungs, hypertrophy of fibers with degeneration areas in the heart, and congestion and hemorrhage in the kidneys. In the salivary glands, alterations to the acini and ductules were visible. In the adrenal glands no morphological alterations could be detected at the studied doses. The results suggest that the in vivo enzymatic and histopathological alterations are due to tissue lesions evoked by the whole venom and TsTX-I. An indirect effect, however, induced by stimulation of acetylcholine and catecholamine release in the postganglionic nerve terminals, cannot be excluded.

[Quality of the Early Cervical Cancer Detection Program in the State of Nuevo León]. / Calidad del Programa de Detección Oportuna de Cáncer Cervicouterino en el estado de Nuevo León.

OBJECTIVE: To determine the quality of the Early Cervical Cancer Detection Program in the state of Nuevo León. MATERIAL AND METHODS: A random selection of 4791 cytologic reports were analyzed, emitted by the State Ministry of Health, the University Hospital and the Mexican Institute for Social Security early cervical cancer detection modules. Pap tests of women with hysterectomy, current pregnancy, menopause or positive result were excluded. Quality was measured with previously defined standards. Analysis included, besides univariate statistics, tests of significance for proportions and means. RESULTS: The quality of the program was fairly satisfactory at the level of the State. The quality of the sampling procedure was low; 39.9% of the tests contained endocervical cells. Quality of coverage was low; 15.6% were women 25+years with first time Pap test. Quality of opportunity was high; 8.5 +/- 7 weekdays between the date of the pap smear and the interpretation date. CONCLUSIONS: Strategies are needed to increase the impact of the state program, such as improving the sampling procedure and the coverage quality levels.

Changing pattern of agitated impaired mental status in patients with advanced cancer: association with cognitive monitoring, hydration, and opioid rotation.

In late 1990, it became standard practice at the palliative care unit of the Edmonton General Hospital to regularly administer the Mini-Mental State Questionnaire (MMSQ) and to undertake opioid rotation and hydration upon detection of cognitive failure. We retrospectively reviewed the charts of 117 and 162 patients admitted in 1988-1989 and 1991-1992, respectively, to assess the impact of these maneuvers on the prevalence of agitated impaired mental status (IMS). All patients underwent regular cognitive assessment in 1991-1992 versus none in 1988-1989. Seventy-three percent of patients received hydration in the second period versus 32% in the first (P < 0.01). The frequency of opioid rotation was also greater in the second period (41% versus 21%, P < 0.001). The incidence of agitated IMS decreased from 26% in 1988-1989 to 10% in 1991-1992 (P < 0.001). This was reflected by a lower mean dose of the major drug used to treat this condition, haloperidol (3.6 +/- 2.4 versus 5.6 +/- 3.8 mg/day, P < 0.01), and less frequent use of other neuroleptics and benzodiazepines (0.12 versus 0.38 prescriptions per patient, P < 0.01) in the second period. Our data suggest that routine cognitive monitoring, opioid rotation, and hydration may reduce the incidence of agitated IMS in terminal cancer patients.

Circannual variation in the incidence of uterine cervix cancer.

The impact of uterine cervix cancer (UCC) can be greatly reduced by regular vaginal examination and other preventive measures. With this aim, UCC screening programs had been developed and applied for several years in Mexico and elsewhere. One point still to be considered in such preventive programs is the possible circannual pattern in the morbidity or mortality of UCC. With the aim of identifying a possible circannual pattern of variation in the incidence of UCC, we analyzed the monthly totals of positive detected cases of UCC in the state of Nuevo León (Mexico) between 1978 and 1987. For eliminating bias due to the seasonal variation in the number of preventive check-ups, data were first expressed in percentage of tests done in the same month. The least-squares fit of a 1-year cosine curve to the data reveals a statistically significant circannual pattern (p = 0.013), with a maximum of relative incidence detected in February. Results indicate UCC incidence higher than the yearly average during the winter, with secondary peaks in August and November. This pattern of variation is similar if one considers separately for analysis the relative incidence of type III, IV, or V UCC (relating to cases suggesting, highly suggesting, or concluding a malignant alteration, respectively). For evaluating the cost-effectiveness of the UCC screening campaign providing these data, the monthly totals of screening check-ups done over the same period were also analyzed. Results reveal a statistically significant circannual rhythm (p < 0.001), with a maximum detected in June.(ABSTRACT TRUNCATED AT 250 WORDS)

Epidemiologia de los tumores de ovario. / Epidemiology of ovarian tumors

Se efectuo un analisis epidemiologico de 522 casos de tumores de ovario atendidos en un periodo de ocho anos. Su frecuencia fue del 1.8 por ciento. El 86.4 por ciento fueron benignos y predominaron en la cuarta decada de la vida; los malignos, (13.6 por ciento) prevalecieron en la quinta y sexta decada. El dolor en hipogastrio y la hemorragia uterina anormal, fueron los sintomas mas frecuentes.De acuerdo a la estirpe histologica el mayor porcentaje fue para los de origen epitelial (70.l por ciento); de estos los mas frecuentes fueron cistadenoma seroso (45.9 por ciento) y cistadenocarcinoma seroso (4.7 por ciento)

La historia clinica como un instrumento de evaluacion de la aptitud clinica.Comparacion entre su ejecucion y su elaboracion escrita. / The clinical history as an instrument to evaluate the clinical capacity

Se compara el desempeno de 26 medicos en las diversas actividades que componen la deteccion de los problemas clinicos. Los aspectos evaluados incluian: a) cantidad y calidad del interrogatorio; b) cantidad y calidad de la exploracion fisica; c) actitudes del medico; d) cantidad y calidad de la descripcion de los datos clinicos y e) reconocimiento del problema y generacion de hipotesis diagnosticas. Se llamara ejecucion de la historia clinica a lo referente a los puntos a y b y elaboracion a lo relativo a d y e. Solo los aspectos de cantidad entre si y de calidad entre si mostraron correlacion estadisticamente significativa, lo comun fue no encontrar correlacion entre las actividades evaluadas. Se concluye que la ejecucion y la elaboracion de la historia clinica no son equivalentes y por lo tanto insubstituible una por otra para fines evaluativos. La no correlacion entre la mayoria de las actividades expresa que el dominio de las capacidades clinicas por parte de los medicos se desarrolla en forma desigual