Innovative Staffing Solutions to Nursing Shortages in Acute Mental Health Inpatient Wards.

The aim of this pilot project was to investigate the perceived impact of a newly introduced therapeutic staffing model at Kent and Medway NHS and Social Care Partnership Trust (KMPT). Questionnaires were distributed to patients and staff across four wards and analysed for the purposes of getting a better understanding from patients and staff on how the model was working. Results indicate that the therapeutic staffing model was well received by patients, although staff perception was more mixed. Amongst patients, themes in staffing, therapeutic input and ward environment were identified. Amongst staff themes: shift patterns, ward duties/workload, and morale were identified. The new model appears promising, although there are some issues identified. Recommendations were made in terms of improving team cohesiveness, sense of value and professional identities.

Inferior Vena Cava Filter Retrieval Trends: A Single-Center Experience.

Recognition of the adverse events of inferior vena cava filters (VCFs) has prompted the Food and Drug Administration (FDA) to issue safety warnings (2010 and 2014), advocating for removal, once the risk of pulmonary embolism has abated. Despite an initial increase in retrieval rates, these remain low (25-30% at 1 year in 2014). We retrospectively investigated retrieval trends in adults with VCFs placed between 2015 and 2018 at a single institution. The rate of retrievable VCF removal accounting for the competing risk of death was the main outcome. There were 494 VCFs placed (305 retrievable). The cumulative incidence of retrieval remained low (21% at 1 year), even after the second FDA warning (2014). Patients who resumed anticoagulation (AC) at any time were more likely to have retrieval (hazard ratio [HR] = 3.6, p < 0.01) and had higher retrieval rates at every time point (31.4 vs. 7.6% at 1 year). Advanced age (HR = 0.98 per year, p = 0.004), stroke (HR = 0.28, p = 0.028), and active malignancy (HR = 0.42, p = 0.006) predicted nonretrieval. Device-related complications were infrequent (<1%) but thrombotic complications occurred early and were more common for nonretrieved VCFs (17 vs. 12%, p = 0.29). Revision of guidelines to recommend active surveillance for the ability to tolerate AC in the immediate postimplantation period may improve retrieval rates.

Gastrointestinal activity of Justicia spicigera Schltdl. in experimental models.

Justicia spicigera Schltdl. (Acanthaceae) is used for treatment of gastrointestinal illnesses therapy in traditional medicine. The objective of this study was to give evidence of the antinociceptive and spasmolytic effects of the J. spicigera ethanol extract (JS EtOH) using in in vivo and/or in vitro assays. The JS EtOH exerted regulatory effect on the motility and a partial relaxing response on the intestinal tissue. Furthermore, a significant abdominal antinociceptive response was obtained in mice, which was totally abolished in the presence of 5-HT1A receptor antagonist (WAY100635, 0.1 mg/kg, s.c.) and partially by blocking opioid receptors (NX, 1 mg/kg, i.p.), whereas the inhibition of the NO synthesis (L-NAME, 30 mg/kg, i.p.) facilitated antinociception of this extract. Kaempferitrin was isolated and identified as major secondary metabolite. These results support the analgesic and spasmolytic-like activity of J. spicigera aerial parts involving inhibitory neurotransmission reinforcing the potential of this medicinal plant for alleviating pain.

Antihypertensive and vasorelaxant mode of action of the ethanol-soluble extract from Tagetes lucida Cav. aerial parts and its main bioactive metabolites.

ETHNOPHARMACOLOGICAL RELEVANCE: Tagetes lucida Cav. commonly known as "yauhtli" or "pericón" is used in Mexican traditional medicine for the treatment of anxiety, depressant diseases, pain, hypertension, among others. AIM: To evaluate the antihypertensive and vasorelaxant modes of action of a crude ethanolic extract from T. lucida aerial parts and to isolate the bioactive compounds. MATERIALS AND METHODS: Ethanolic extract was tested in an in vivo assay in SHR rats by intragastric administration at 10 and 100 mg/kg dosages, to measure and to compare hemodynamic parameters like diastolic and systolic blood pressure and heart rate. Also, extract (3.03-1000 µg/ml), fractions (3.03-1000 µg/ml) and pure isolated compounds (1.75-550 µM) were evaluated on isolated aortic rings contracted with noradrenaline (0.1 µM) to determine their vasorelaxant effect and extract-mode of action. RESULTS: Ethanolic extract of T. lucida lowered systolic and diastolic blood pressure on SHR rats without heart rate modification (P > 0.05). Moreover, the extract showed concentration-dependent relaxant effect in a partially endothelium-dependent manner (P < 0.05), through NO/cGMP system activation and calcium channel blockade. 6,7,8-trimethoxycoumarin (1), 6,7-dimethoxycoumarin (2), and 7-methoxycoumarin (3) from T. lucida are the main bioactive compounds of the extract and showed significant vasorelaxant activity. CONCLUSIONS: Results provide evidence and endorsed the antihypertensive properties attributed to T. lucida in traditional medicine, which is produced by vasorelaxant effect mainly through multitarget NO/cGMP system activation and calcium channel blockade. Coumarin derivatives 1, 2 and 3 are the responsible of the vasorelaxant activity.

CRISPR-Generated Nrf2a Loss- and Gain-of-Function Mutants Facilitate Mechanistic Analysis of Chemical Oxidative Stress-Mediated Toxicity in Zebrafish.

The transcription factor Nrf2a induces a cellular antioxidant response and provides protection against chemical-induced oxidative stress, as well as playing a critical role in development and disease. Zebrafish are a powerful model to study the role of Nrf2a in these processes but have been limited by reliance on transient gene knockdown techniques or mutants with only partial functional alteration. We developed several lines of zebrafish carrying different null (loss of function, LOF) or hyperactive (gain of function, GOF) mutations to facilitate our understanding of the Nrf2a pathway in protecting against oxidative stress. The mutants confirmed Nrf2a dependence for induction of the antioxidant genes gclc, gstp, prdx1, and gpx1a and identified a role for Nrf2a in the baseline expression of these genes, as well as for sod1. Specifically, the 4-fold induction of gstp by tert-butyl hydroperoxide (tBHP) in wild type fish was abolished in LOF mutants. In addition, baseline gstp expression in GOF mutants increased by 12.6-fold and in LOF mutants was 0.8-fold relative to wild type. Nrf2a LOF mutants showed increased sensitivity to the acute toxicity of cumene hydroperoxide (CHP) and tBHP throughout the first 4 days of development. Conversely, GOF mutants were less sensitive to CHP toxicity during the first 4 days of development and were protected against the toxicity of both hydroperoxides after 4 dpf. Neither gain nor loss of Nrf2a modulated the toxicity of R-(-)-carvone (CAR), despite the ability of this compound to potently induce Nrf2a-dependent antioxidant genes. Similar to other species, GOF zebrafish mutants exhibited significant growth and survival defects. In summary, these new genetic tools can be used to facilitate the identification of downstream gene targets of Nrf2a, better define the role of Nrf2a in the toxicity of environmental chemicals, and further the study of diseases involving altered Nrf2a function.

Development of a clinical risk score to diagnose concurrent bacterial infections in children with dengue

Background@#The clinical course of dengue can be adversely affected by bacterial coinfection. Because of this, clinical manifestations may be severe and may lead to morbidity and mortality. Little is known about this dual infection in the pediatric population. @*Objectives@#This study was conducted to evaluate the clinical characteristics and risk factors of patients with dengue infection and coinfection and subsequently develop a scoring system to diagnose bacterial coinfection in patients with dengue.@*Methods@#A prospective cross-sectional observational study was conducted among hospitalized pediatric patients with confirmed dengue infection between January 2019 to August 2019. Baseline characteristics, risk factors, clinical parameters, laboratory findings, management and outcomes were recorded. Cases with concurrent bacterial infections were further analyzed. A scoring system was created which assigned 1 point each for the following risk factors -age ≤9 years, fever >5 days, dengue severe, and 2 points for CRP >12 mg/l) @*Results@#A total of 154 pediatric dengue patients were enrolled with a mean age of 8.54 ± 4.15 years, and 99 patients (64%) had bacterial coinfection. Patients with coinfection were A total of 154 pediatric dengue patients were enrolled with a mean age of 8.54 ± 4.15 years, and 99 patients (%) had bacterial co-infection. Patients with coinfection were younger, have prolonged fever (>5 days), and were more frequently observed to have hypotension, tachycardia, desaturations and bleeding. Patients with coinfection also had higher white blood cell counts (>8 x109 cells/L), higher neutrophil counts (58.80 ± 18.42 % count), and elevated CRP (>12 mg/l) and procalcitonin (>4.01 ng/L). Utilizing the scoring system developed, a score of ≥3 had a sensitivity of 66.67% and specificity of 76.36%, in diagnosing concurrent bacterial infection in children with dengue. @*Conclusions@#Patients with dengue and bacterial coinfections were younger with comorbidities. They presented with significantly abnormal vital signs, physical examination findings, and elevated acute phase reactants. Using age ≤ 9 years, fever >5 days, dengue severe, and CRP >12mg/l, a scoring system was developed to diagnose bacterial coinfection in patients with dengue. A score of ≥3 can help diagnose patients with dengue and bacterial coinfection who will most likely need early empiric antimicrobial therapy.

Differential copper-induced death and regeneration of olfactory sensory neuron populations and neurobehavioral function in larval zebrafish.

Fish rely heavily on their sense of smell to maintain behaviors essential for survival, such as predator detection and avoidance, prey selection, social behavior, imprinting, and homing to natal streams and spawning sites. Due to its direct contact with the outside environment, the peripheral olfactory system of fish is particularly susceptible to dissolved contaminants. In particular, environmental exposures to copper (Cu) can cause a rapid loss of olfactory function. In this study, confocal imaging of double-transgenic zebrafish larvae with differentially labeled ciliated and microvillous olfactory sensory neurons (OSNs) were used to examine cell death and regeneration following Cu exposure. Changes in cell morphologies were observed at varying degrees within both ciliated and microvillous OSNs, including the presence of round dense cell bodies, cell loss and fragmentation, retraction or loss of axons, disorganized cell arrangements, and loss of cells and fluorescence signal intensity, which are all indicators of cell death after Cu exposure. A marked loss of ciliated OSNs relative to microvillous OSNs occurred after exposure to low Cu concentrations for 3 h, with some regeneration observed after 72 h. At higher Cu concentrations and 24-h exposures, ciliated and microvillous OSNs were damaged with increased severity of injury with longer Cu exposures. Interestingly, microvillous, but not ciliated OSNs, regenerated rapidly within the 72-h time period of recovery after death from Cu exposure, suggesting that microvillous OSNs may be replaced in lieu of ciliated OSNs. An increase in bromodeoxyuridine labeling was observed 24 h after Cu-induced OSN death, suggesting that increased proliferation of the olfactory stem cells replaced the damaged OSNs. Olfactory behavioral analyses supported our imaging studies and revealed both initial loss and restoration of olfactory function after Cu exposures. In summary, our studies indicate that following zebrafish OSN damage by Cu, regeneration of microvillous OSNs may occur exceeding ciliated OSNs, likely via increased proliferation of the cellular reservoir of neuronal OSC precursors. Transgenic zebrafish are a valuable tool to study metal olfactory injury and recovery and to characterize sensitive olfactory neuron populations in fish exposed to environmental pollutants.

Spasmolytic effect of aqueous extract of Tagetes erecta L. flowers is mediated through calcium channel blockade on the guinea-pig ileum.

This study provides pharmacological evidence on the spasmolytic activity of Tagetes erecta L. (marigold or cempasúchil) on the guinea-pig ileum and presents data on its mechanism of action. The relaxant effect on KCl contractions was more marked with aqueous (AqEx) than with ethanol extracts (EtEx) of T. erecta flowers (55.6 ±â€¯11.0 vs 21.1 ±â€¯4.4%, respectively). In addition, the aqueous extract antagonized contractions elicited by EFS, but not by acetylcholine (73.5 ±â€¯1.9 vs 14.5 ±â€¯5.3%, respectively). These effects were not diminished by hexamethonium or L-NAME, but this extract caused a rightward shift in the Ca2+ concentration-response curves like that of verapamil. Quercetin and rutin, two flavonoids present in this plant, also showed spasmolytic effects (95.7 ±â€¯2.8 and 27.9 ±â€¯7.1%, respectively). Interestingly, in tissues without spasmogens, the extract induced contractions superimposed on their spontaneous activity. These results support the traditional use of T. erecta as a spasmolytic in folk medicine and suggest mainly that quercetin could be partly responsible for this effect. The spasmolytic effect appears to involve voltage-gated calcium channels, but not the nitric oxide pathway or the release of neurotransmitters from enteric neurons. Nevertheless, this plant could produce colic or stomachache as adverse effects in clinical situations in which these symptoms are not originally present.

Neuropathic and inflammatory antinociceptive effects and electrocortical changes produced by Salvia divinorum in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Salvia divinorum is a medicinal plant traditionally used in hallucinogenic ethnopharmacological practices and for its analgesic and antinflammatory properties. Its active compounds include diterpenes known as salvinorins which act as potent κ opioid receptor agonists. AIM OF THE STUDY: Given its effects in acute animal models of pain, as well as its antinflammatory attributes, we decided to investigate the analgesic effects of an SD extract in neuropathic (sciatic loose nerve ligature) and inflammatory (intra plantar carrageenan) pain models in rats. We also determined in this study the electrocorticographic changes to correlate similar hallucinogenic state and behavior as those produced in humans. MATERIAL AND METHODS: Mechanical and thermonociceptive responses, plantar test and von Frey assay, respectively, were measured in adult Wistar rats 30min, 3h and 24h after the intraperitoneal administration of saline or an hydroponic SD extract. We also evaluated carbamazepine and celecoxib, as gold reference drugs, to compare its antinociceptive effects. RESULTS: Our results showed that administration of SD extract induced antialgesic effects in both neuropathic and inflammatory pain models. All those effects were blocked by nor-binaltorphimine (a Kappa opioid receptor antagonist). Moreover, it was observed an increase of the anterior power spectral density and a decrease in the posterior region as electrocorticographic changes. CONCLUSION: The present investigation give evidence that SD is capable to reduce algesic response associated to neuropathic and inflammatory nociception. This study support therapeutic alternatives for a disabling health problem due to the long term pain with high impact on population and personal and social implications.

Justicia spicigera Schltdl. and kaempferitrin as potential anticonvulsant natural products.

Justicia spicigera Schltdl. is a vegetal species traditionally used to control epilepsy, but scientific evidence is required to reinforce this activity. The aim of the study was to evaluate the anticonvulsant-like activity of J. spicigera aqueous extract (JsAE) and a bioactive compound. JsAE was assessed in a dose-response manner (30, 100 and 1000mg/kg, i.p.) using the pentylenetetrazol (PTZ)-induced seizures and maximal electroshock seizure (MES) test in mice in comparison to ethosuximide (ETX, reference drug 100mg/kg, i.p.) or phenytoin (25mg/kg, i.p.), respectively. Then a significant dosage (1000mg/kg, i.p.) was chosen to examine electrographic activity (EEG) in rats. Treatment groups were compared to the vehicle and ETX in the convulsive behavior alone or simultaneous to EEG after PTZ-induced seizures (80 or 35mg/kg, i.p., mice or rats). Kaempferitrin (a flavonoid of JsAE) and ETX were administered via intracerebroventricular (i.c.v, 4th ventricle, 1µg/µL) and tested in the presence of PTZ in rats. Results confirmed that JsAE delayed the onset of seizures and reduced frequency of tonic convulsion and mortality in mice. JsAE or kaempferitrin also decreased the EEG spikes frequency and amplitude in a similar manner than EXT in rats. In conclusion, these preliminary data give evidence of the potential of J. spicigera as possible anticonvulsant as recommended in folk medicine for treating epilepsy, where kaempferitrin is suggested as a partial responsible bioactive compound.

High levels of sarcospan are well tolerated and act as a sarcolemmal stabilizer to address skeletal muscle and pulmonary dysfunction in DMD.

Duchenne muscular dystrophy (DMD) is a genetic disorder that causes progressive muscle weakness, ultimately leading to early mortality in affected teenagers and young adults. Previous work from our lab has shown that a small transmembrane protein called sarcospan (SSPN) can enhance the recruitment of adhesion complex proteins to the cell surface. When human SSPN is expressed at three-fold levels in mdx mice, this increase in adhesion complex abundance improves muscle membrane stability, preventing many of the histopathological changes associated with DMD. However, expressing higher levels of human SSPN (ten-fold transgenic expression) causes a severe degenerative muscle phenotype in wild-type mice. Since SSPN-mediated stabilization of the sarcolemma represents a promising therapeutic strategy in DMD, it is important to determine whether SSPN can be introduced at high levels without toxicity. Here, we show that mouse SSPN (mSSPN) can be overexpressed at 30-fold levels in wild-type mice with no deleterious effects. In mdx mice, mSSPN overexpression improves dystrophic pathology and sarcolemmal stability. We show that these mice exhibit increased resistance to eccentric contraction-induced damage and reduced fatigue following exercise. mSSPN overexpression improved pulmonary function and reduced dystrophic histopathology in the diaphragm. Together, these results demonstrate that SSPN overexpression is well tolerated in mdx mice and improves sarcolemma defects that underlie skeletal muscle and pulmonary dysfunction in DMD.

Anxiolytic and sedative-like effects of flavonoids from Tilia Americana var. Mexicana: GABAergic and serotonergic participation / Efecto ansiolítico y sedante de flavonoides de Tilia Americana var. Mexicana: participación GABAérgica y serotonérgica

Abstract: INTRODUCTION: The inflorescences of Tilia americana var. mexicana are used as an infusion in Mexican traditional medicine due to their tranquilizing effects; however, pharmacological and phytochemical studies of the leaves are lacking. OBJECTIVE: In this research, the anxiolytic and sedative-like efficacy of the Tilia americana var. mexicana leaves was compared to that obtained with its inflorescences and flavonoids therein identified, as well as the possible mechanism of action. METHODS: The sorted and dried inflorescences and leaves were macerated subsequently in hexane, ethyl acetate and methanol. The methanol extracts were qualitative- and quantitative-analyzed by HPLC, using commercial flavonoids standards selected on the basis of their previously reported presence in Tilia species. The pharmacological activity was evaluated in CD-1 mice in the tests: open-field, elevated plus-maze, hole-board, and the sodium pentobarbital-induced sleep potentiation test. In regard to the mechanism of action, participation of benzodiazepine and 5-HT1A serotonin receptors was tested with the respective antagonists: flumazenil and WAY100635. RESULTS: The presence of quercetin, rutin and isoquercitrin was confirmed in the extracts of the inflorescences and leaves. The anxiolytic-like effects were the same between the two organs, which were inhibited in the presence of flumazenil and WAY100635. DISCUSSION AND CONCLUSION: Our results provide evidence that the extracts of the leaves of T. americana var. mexicana are as efficacious as the inflorescences to produce anxiolytic and sedative-like effects, where flavonoids like quercetin, rutin and isoquercitrin are partially responsible for these activities by the involvement of GABA/BDZ and 5HT1A serotonergic receptors.

Resumen: INTRODUCCIÓN: En la medicina tradicional mexicana, la infusión de inflorescencias de Tilia americana var. mexicana es utilizada por sus efectos tranquilizantes; sin embargo, los estudios farmacológicos y fitoquímicos de sus hojas son deficientes. OBJETIVO: En esta investigación, la eficacia ansiolítico-sedante de las hojas de T. americana var. mexicana se comparó con la obtenida con las inflorescencias y los flavonoides previamente identificados; se analizó además el posible mecanismo de acción. MÉTODOS: Inflorescencias y hojas separadas y secas se maceraron sucesivamente en hexano, acetato de etilo y metanol. Los extractos metanólicos se analizaron cualitativa y cuantitativamente por HPLC usando estándares comerciales de flavonoides previamente reportados en especies de Tilia. La actividad farmacológica se evaluó en ratones CD-1 en las pruebas de campo abierto, cruz elevada, tablero con orificios y la prueba de potenciación de hipnosis inducida por pentobarbital sódico. Respecto al mecanismo de acción, la participación de los receptores de benzodiazepinas y 5-HT1A de serotonina se examinó utilizando los antagonistas flumazenil y WAY100635, respectivamente. RESULTADOS: La presencia de quercetina, rutina e isoquercitrina se confirmó en los extractos de inflorescencias y hojas, donde se confirmó el efecto como ansiolítico, el cual fue inhibido en la presencia de flumazenil y WAY100635. DISCUSIÓN Y CONCLUSIÓN: Nuestros resultados dan evidencia de que las hojas de T. americana var. mexicana son tan eficaces como las inflorescencias para producir efectos ansiolítico-sedantes, donde los flavonoides quercetina, rutina e isoquercitrina son responsables parciales y se involucra la participación de los receptores GABA/BDZ y 5HT1A de serotonina.

Neuroprotective effects of Tilia americana var. mexicana on damage induced by cerebral ischaemia in mice.

Tilia americana var. mexicana (T. americana) is a plant widely used in Mexico for its medicinal properties on the central nervous system. In the present study, we designed a protocol to investigate the neuroprotective effects of non-polar and polar extracts of T. americana on damage induced by cerebral ischaemia in mice. Vehicle or extracts were administered immediately after ischaemia. Functional neurological deficit, survival percentage and infarct area were determined in each experimental group. Results showed that groups treated with non-polar or polar extracts of T. americana had increased survival rate, improved neurological deficits and diminished the infarct area in relation to the ischaemic group. In conclusion, this study confirms the neuroprotective activity of T. americana, suggests a possible synergism between non-polar and polar constituents and supports its potential as a useful aid in the clinical management of stroke.

Influence of age, gender, and race on nitric oxide release over acupuncture points-meridians.

This study examined the influence of age, gender and race on nitric oxide (NO) release over acupuncture points, meridian without acupoint, and non-meridian regions of the Pericardium (PC) and Bladder (BL) meridian as well as aging on LU meridian in 61 healthy subjects. Biocapture tubes were attached to the skin surface, and total nitrite and nitrate was biocaptured and quantified using chemiluminescence. In elder ages compared to adults, NO levels over the ventral forearm were significantly decreased over LU on radial regions but not altered over PC on medial regions. Conversely, NO content was elevated over BL regions only in overweight/obesity of elder ages. NO levels over PC regions were marginally elevated in overweight/obese males compared to females but did not alter between races. These results suggest a selective reduction of NO release over LU meridian with aging, which is consistent with a progressive decline in lung function and increase in chronic respiratory disease in elder ages. Increased NO levels along the BL meridian in older obese subjects may reflect a modified NO level along somatic-bladder pathway for counteracting bladder dysfunctions with aging. Both of them support somatic-organ connections in the meridian system associated with potential pathophysiological changes with aging.

Tramadol and Tramadol+Caffeine Synergism in the Rat Formalin Test Are Mediated by Central Opioid and Serotonergic Mechanisms.

Different analgesic combinations with caffeine have shown this drug to be capable of increasing the analgesic effect. Many combinations with nonsteroidal anti-inflammatory drugs (NSAIDs) have been carried out, but, in regard to opioids, only combinations with morphine and tramadol have been reported. The antinociceptive synergism mechanism of these combinations is not well understood. The purpose of the present study was to determine the participation of spinal and supraspinal opioidergic and serotonergic systems in the synergic effect of the tramadol+caffeine combination in the rat formalin test. At the supraspinal level, the opioid antagonist, naloxone, completely reversed the effect of the drug combination, whereas ketanserin, a 5-HT2 receptor antagonist, inhibited the effect by 60%; however, ondansetron, a 5-HT3 receptor antagonist, did not alter the combination effect. When the antagonists were intrathecally administered, there was a significant reduction in all tramadol-caffeine combination effects. With respect to tramadol alone, there was significant participation of the opioid system at the supraspinal level, whereas it was the serotonergic system that participated at the spinal level by means of the two receptors studied. In conclusion, the tramadol+caffeine combination synergically activated the opioid and serotonergic systems at the supraspinal level, as well as at the spinal level, to produce the antinociception.

Synaptojanin 1 is required for endolysosomal trafficking of synaptic proteins in cone photoreceptor inner segments.

Highly polarized cells such as photoreceptors require precise and efficient strategies for establishing and maintaining the proper subcellular distribution of proteins. The signals and molecular machinery that regulate trafficking and sorting of synaptic proteins within cone inner segments is mostly unknown. In this study, we show that the polyphosphoinositide phosphatase Synaptojanin 1 (SynJ1) is critical for this process. We used transgenic markers for trafficking pathways, electron microscopy, and immunocytochemistry to characterize trafficking defects in cones of the zebrafish mutant, nrc(a14) , which is deficient in phosphoinositide phosphatase, SynJ1. The outer segments and connecting cilia of nrc(a14) cone photoreceptors are normal, but RibeyeB and VAMP2/synaptobrevin, which normally localize to the synapse, accumulate in the nrc(a14) inner segment. The structure of the Endoplasmic Reticulum in nrc(a14) mutant cones is normal. Golgi develop normally, but later become disordered. Large vesicular structures accumulate within nrc(a14) cone photoreceptor inner segments, particularly after prolonged incubation in darkness. Cone inner segments of nrc (a14) mutants also have enlarged acidic vesicles, abnormal late endosomes, and a disruption in autophagy. This last pathway also appears exacerbated by darkness. Taken altogether, these findings show that SynJ1 is required in cones for normal endolysosomal trafficking of synaptic proteins.

Ursolic acid from Agastache mexicana aerial parts produces antinociceptive activity involving TRPV1 receptors, cGMP and a serotonergic synergism.

Agastache mexicana is a plant that has long been used in large demands in Mexican folk medicine to treat anxiety, insomnia and pain, among others affections. Chromatographic technique was used to identify ursolic acid (UA), 130.7 mg/g and 20.3 mg/g, as an antinociceptive active compound identified in ethyl acetate and methanol extracts of A. mexicana aerial parts, respectively. Temporal course curves of the antinociceptive response demonstrated a dose-dependent and significant activity of UA (1 to 100 mg/kg, i.p.) with an ED50=2 mg/kg in comparison to the efficacy of diclofenac (1 or 30 to 100 mg/kg, i.p.), a non-steroidal anti-inflammatory drug, with an ED50=11.56 mg/kg. The antinociceptive response consisted in the reduction of abdominal constrictions induced with 1% acetic acid in mice. Similarly, UA at 2 mg/kg produced significant antinociception in the intracolonic administration of 0.3% capsaicin (a TRPV1 agonist) in mice. It has been reported the inhibition produced by UA on the calcium-flux induced by capsaicin on TRPV1 receptor suggesting the antagonistic activity of this receptor. Finally, an ED50=44 mg/kg was calculated in the neurogenic and inflammatory nociception induced in the formalin test in rats. The antinociceptive response of UA in the formalin test was not modified in presence of naloxone, flumazenil or L-arginine. Nevertheless, it was reverted in presence of 1-H-(1,2,4)-oxadiazolo(4,2-a)quinoxalin-1-one (ODQ, an inhibitor of soluble guanylyl cyclase) and increased in presence of N(G)-L-nitro-arginine methyl ester (L-NAME, inhibitor of nitric oxide synthase), theophylline (inhibitor of phosphodiesterase) and WAY100635 (an antagonist of 5-HT1A receptors). Current results provide evidence that the antinociceptive response of A. mexicana depends in part on the presence of UA. Moreover, this triterpene may exerts its antinociceptive effect mediated by the presence of cGMP and an additive synergism with 5HT1A receptors, but also an antagonistic activity towards TRPV1 receptors may be involved.

Endogenous opioids participation in the effect of Rosmarinus officinalis L. in the visceral, inflammatory and gout arthritis nociception in rodents / Participación de los opioides endógenos en el efecto de Rosmarinus officinalis L. en la nocicepción visceral, inflamatoria y artritis gotosa en roedores

The aim of this study was to investigate the endogenous opioid participation in the antinociceptive effect of R. officinalis aerial parts in experimental models of visceral, inflammatory and gout arthritis nociception. Acid-acetic induced writhing and formalin tests as well as the pain-induced functional impairment model in the rat (PIFIR) assay were studied. Antinociceptive doses of R. officinalis via oral, alone and in presence of an opioid antagonist were evaluated in comparison to the reference analgesic drug tramadol (31.6 and 50mg/kg i.p., in mice and rats, respectively). The antinociceptive effect of R. officinalis at a 300mg/kg dosage was significantly reverted in presence of 1.0mg/ kg s.c. of naloxone in writhing and formalin tests. Concerning PIFIR model, significant antinociceptive response produced for 1000 and 3000mg/kg was not inhibited in presence of 1.0 or 3.16mg/kg, s.c. of naloxone. In the antinociceptive effect of tramadol, naloxone produced partial inhibition in all models tested. These results suggest that antinociceptive and anti-inflammatory activities of R. officinalis aerial parts involve endogenous opioids, but activation of these mediators depends on the experimental model and the physiological process of the induced nociception.

El objetivo de este estudio fue investigar la participación de los opioides endógenos en el efecto antinociceptivo producido por un extracto preparado con las partes aéreas de Rosmarinus officinalis en modelos experimentales de nocicepción visceral, inflamatoria y tipo artritis gotosa. Para la inducción de nocicepción visceral e inflamatoria se utilizaron los modelos de estiramiento abdominal "writhing" y de formalina intraplantar al 1 %, respectivamente, en ratones. A su vez, para la nocicepción de tipo artritis gotosa se utilizó el modelo de disfunción inducida por ácido úrico al 20% intraarticular en ratas conocido como PIFIR (por sus siglas en inglés). Dosis antinociceptivas de R. officinalis vía oral se evaluaron solas y en presencia del antagonista de opioides endógenos naloxona. Adicionalmente, dicho efecto se comparó con el fármaco analgésico de referencia tramadol (31.6 y 50mg/kg i.p., en ratones y ratas, respectivamente). El efecto antinociceptivo de R. officinalis significativo en la dosis de 300mg/kg se revirtió en presencia de 1mg/kg s.c. de naloxona en las pruebas de estiramiento abdominal y formalina. En cuanto al modelo PIFIR, la respuesta antinociceptiva producida por 1000 y 3000mg/kg no se inhibió en presencia de 1 o 3.16mg/kg, s.c. de naloxona. En el efecto de tramadol, opioide atípico, la naloxona produjo inhibición parcial de la respuesta antinociceptiva en todos los modelos probados. Los resultados sugieren que la actividad antinociceptiva producida por el extracto de las partes aéreas de R. officinalis involucra al sistema de opioides endógenos, pero la presencia de estos mediadores depende del tipo de estímulo y del proceso fisiológico involucrado en la nocicepción inducida.

Computerized left ventricular regional ejection fraction analysis for detection of ischemic coronary artery disease with multidetector CT angiography.

Regional ejection fraction (REF) provides important functional information of the left ventricular regional myocardium. We aimed to test the diagnostic accuracy of computerized REF analysis for detecting the ischemia and significant stenosis with multidetector CT angiography (MDCT). This is a retrospective study including 155 patients who underwent MDCT scans for evaluation of coronary artery disease. Among them, 83 patients also underwent SPECT imaging and invasive coronary angiography (ICA). Two groups of patients were defined: Control group with 0 coronary artery calcium and normal global and regional ventricular function, and comparison group. REF measurement was performed on all patients using computerized software. Control group REF measurements will be used as reference standard (mean-2SD REF/mean global ejection fraction) to define abnormal REF. The sensitivity, specificity, positive and negative predictive value of REF in detecting perfusion defects (fixed and reversible) was 73, 80, 75 and 79 % respectively, in a patient based analysis of comparison group. The diagnostic accuracy of REF in predicting significant stenosis (>50 %) on ICA compared with SPECT was 72 versus 61 % and 85 versus 79 % in patient and vessel based analysis of comparison group, respectively. ROC curve analysis showed REF to be a better predictor of perfusion defects on SPECT compared with significant stenosis (>50 %) alone or stenosis combined with REF (P < 0.05). The computerized assessment of REF analysis is comparable to SPECT in predicting ischemia and a better predictor of significant stenosis than SPECT. This study also provides reference standard to define abnormal values.

Anti-ulcer activity of Cyrtocarpa procera analogous to that of Amphipterygium adstringens, both assayed on the experimental gastric injury in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: The bark of Amphipterygium adstringens (Aa) is commonly mixed or adulterated with the bark of Cyrtocarpa procera (Cp) and sold in Mexican markets. Aa is a well known species in Mexico used as decoction to relieve ulcers. Scientific reports reinforcing the anti-ulcer activity of Aa have been previously described, but those describing the anti-ulcer properties of Cp as a substitute for Aa in folk medicine are scarce. AIM OF THE STUDY: To investigate anatomical and phytochemical differences between these species, as well as to assess the anti-ulcer effect of Cp extracts in comparison to the Aa extracts. MATERIAL AND METHODS: Anatomical micro-technique and physical and spectroscopic data were used to analyze differences between Cp and Aa. Regard to the pharmacological activity, it was assessed by using the ethanol-induced gastric damage model in rats. RESULTS: Whereas the bark anatomy of Aa was characterized by vertical canals in the periderm and the rare occurrence of fibers in its phloem, a periderm without vertical canals and abundant fibers in the phloem were distinctive features of Cp. Phytochemical analysis allowed the identification of tirucallane, masticadienonic and 3α-hydroxymasticadienonic acids as major components in Aa, while ß-amyrin and ß-sitosterol were obtained from Cp. Gastric lesions observed in the control group decreased in the presence of 100mg/kg of hexane, ethyl acetate and methanol extracts from the normal or regenerated bark of Cp, thus resembling the anti-ulcer effect of Aa. Nevertheless, major anti-ulcer potency was observed with the most active methanol extract from Cp obtained from normal [the effective dose fifty ED(50)=45.54 mg/kg] or regenerated (ED(50)=36.68 mg/kg) bark in comparison to Aa (ED(50)=115.64 mg/kg). CONCLUSION: Chemical and anatomical differences were found between these species, but since the anti-ulcer activity of Cp is similar to that shown by Aa our results reinforce the use of both species for the relief of gastric ulcer in folk medicine.