Joint Hypermobility Syndrome and Membrane Proteins: A Comprehensive Review.

Ehlers-Danlos syndromes (EDSs) constitute a heterogeneous group of connective tissue disorders characterized by joint hypermobility, skin hyperextensibility, and tissue fragility. Asymptomatic EDSs, joint hypermobility without associated syndromes, EDSs, and hypermobility spectrum disorders are the commonest phenotypes associated with joint hypermobility. Joint hypermobility syndrome (JHS) is a connective tissue disorder characterized by extreme flexibility of the joints, along with pain and other symptoms. JHS can be a sign of a more serious underlying genetic condition, such as EDS, which affects the cartilage, bone, fat, and blood. The exact cause of JHS could be related to genetic changes in the proteins that add flexibility and strength to the joints, ligaments, and tendons, such as collagen. Membrane proteins are a class of proteins embedded in the cell membrane and play a crucial role in cell signaling, transport, and adhesion. Dysregulated membrane proteins have been implicated in a variety of diseases, including cancer, cardiovascular disease, and neurological disorders; recent studies have suggested that membrane proteins may also play a role in the pathogenesis of JHS. This article presents an exploration of the causative factors contributing to musculoskeletal pain in individuals with hypermobility, based on research findings. It aims to provide an understanding of JHS and its association with membrane proteins, addressing the clinical manifestations, pathogenesis, diagnosis, and management of JHS.

Approximating constant potential DFT with canonical DFT and electrostatic corrections.

The complexity of electrochemical interfaces has led to the development of several approximate density functional theory (DFT)-based schemes to study reaction thermodynamics and kinetics as a function of electrode potential. While fixed electrode potential conditions can be simulated with grand canonical ensemble DFT (GCE-DFT), various electrostatic corrections on canonical, constant charge DFT are often applied instead. In this work, we present a systematic derivation and analysis of the different electrostatic corrections on canonical DFT to understand their physical validity, implicit assumptions, and scope of applicability. Our work highlights the need to carefully address the suitability of a given model for the problem under study, especially if physical or chemical insight in addition to reaction energetics is sought. In particular, we analytically show that the different corrections cannot differentiate between electrostatic interactions and covalent or charge-transfer interactions. By numerically testing different models for CO2 adsorption on a single-atom catalyst as a function of the electrode potential, we further show that computed capacitances, dipole moments, and the obtained physical insight depend sensitively on the chosen approximation. These features limit the scope, generality, and physical insight of these corrective schemes despite their proven practicality for specific systems and energetics. Finally, we suggest guidelines for choosing different electrostatic corrections and propose the use of conceptual DFT to develop more general approximations for electrochemical interfaces and reactions using canonical DFT.

The Transcription of Flagella of Enteropathogenic Escherichia coli O127:H6 Is Activated in Response to Environmental and Nutritional Signals.

The flagella of enteropathogenic Escherichia coli (EPEC) O127:H6 E2348/69 mediate adherence to host proteins and epithelial cells. What environmental and nutritional signals trigger or down-regulate flagella expression in EPEC are largely unknown. In this study, we analyzed the influence of pH, oxygen tension, cationic and anionic salts (including bile salt), carbon and nitrogen sources, and catecholamines on the expression of the flagellin gene (fliC) of E2348/69. We found that sodium bicarbonate, which has been shown to induce the expression of type III secretion effectors, down-regulated flagella expression, explaining why E2348/69 shows reduced motility and flagellation when growing in Dulbecco's Minimal Essential Medium (DMEM). Further, growth under a 5% carbon dioxide atmosphere, in DMEM adjusted to pH 8.2, in M9 minimal medium supplemented with 80 mM glucose or sucrose, and in DMEM containing 150 mM sodium chloride, 0.1% sodium deoxycholate, or 30 µM epinephrine significantly enhanced fliC transcription to different levels in comparison to growth in DMEM alone. When EPEC was grown in the presence of HeLa cells or in supernatants of cultured HeLa cells, high levels (4-fold increase) of fliC transcription were detected in comparison to growth in DMEM alone. Our data suggest that nutritional and host signals that EPEC may encounter in the intestinal niche activate fliC expression in order to favor motility and host colonization.

Animal Model of Video-Assisted Cecum and Ileum Instrumentation for Equine Visceral Pain Study.

This study aimed to describe an animal model for studying equine visceral pain using minimally invasive and video-assisted cecum and ileum instrumentation. The access to the cecum and ileum was affected because of a previous typhlostomy. For video-assisted distention of the cecum and ileum, a distention device, which we developed using an endotracheal Rusch probe, was used, adapted, and coupled to a cuffometer to inflate and measure the pressure of the cuff attached to its distal portion. In a video-assisted manner, the distal portion of the device was introduced into the cecum and ileum, which contained the cuff in its distal portion, properly positioning it in the lumen. The cuff of the distension device was insufflated after the measurement of baseline physiological parameters of the animals and video-assisted confirmation of its right placement in the cecum and ileum lumen (M0). Was performed in one moment through two simultaneous cuff compressions and 1 minute of animal observation to evaluate the degree of abdominal discomfort manifestations (M1). To cease these stimuli, the cuff was deflated by disconnecting the extensor of the distension device attached to its proximal portion (M2). The procedure was easily performed in most cases. Slow and progressive insufflation allowed subjective adjustment of the intensity of the pain stimulus based on behavioral manifestations. Even with a low rate of complications, the model is feasible and reproducible for studies on visceral pain and the evaluation of analgesic effects.

Identification of potential inhibitors of SARS-CoV-2 S protein-ACE2 interaction by in silico drug repurposing.

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a new coronavirus discovered that appeared in Wuhan, China, in December 2019, causes COVID-19 disease which have resulted in cases similar to SARS-atypical pneumonia. As of March 1, 2021, Mexico had reached 2.11 million cases of COVID-19 and 189 thousand deaths; around 116 million cases and 2.57 million deaths are reported worldwide with new cases and increasing mortality every day. To date, there is no specific commercial treatment to control the infection. Repurpose drugs targeting the angiotensin-converting enzyme 2 (ACE2) receptor represents an alternative strategy to block the binding of SARS-CoV-2 protein S and forestall virus adhesion, internalization and replication in the host cell. Methods: Rigid molecular docking was performed using receptor binding domain of the S1 subunit of S protein (RBD S1)-ACE2 (PDB ID: 6VW1) interaction site and 1,283 drugs FDA approved and prescribed by the Mexican Public Health System. The results were analyzed by docking score, frequency of the drug in receptor site and the types of interactions at the binding site residues. Results: About 40 drugs were identified as a potential inhibitor of RBD S1-ACE2 interaction. Within the top-ranked drugs, we identified ipratropium, formoterol and fexofenadine, which stands out as they are used as therapies to treat chronic obstructive pulmonary disease, asthma and virtually any respiratory infection. Conclusions: Our results will serve as the basis for in vitro and in vivo studies to evaluate the potential use of those drugs to generate affordable and convenient therapies to treat COVID-19.

Polar amplification of Pliocene climate by elevated trace gas radiative forcing.

Warm periods in Earth's history offer opportunities to understand the dynamics of the Earth system under conditions that are similar to those expected in the near future. The Middle Pliocene warm period (MPWP), from 3.3 to 3.0 My B.P, is the most recent time when atmospheric CO2 levels were as high as today. However, climate model simulations of the Pliocene underestimate high-latitude warming that has been reconstructed from fossil pollen samples and other geological archives. One possible reason for this is that enhanced non-CO2 trace gas radiative forcing during the Pliocene, including from methane (CH4), has not been included in modeling. We use a suite of terrestrial biogeochemistry models forced with MPWP climate model simulations from four different climate models to produce a comprehensive reconstruction of the MPWP CH4 cycle, including uncertainty. We simulate an atmospheric CH4 mixing ratio of 1,000 to 1,200 ppbv, which in combination with estimates of radiative forcing from N2O and O3, contributes a non-CO2 radiative forcing of 0.9 [Formula: see text] (range 0.6 to 1.1), which is 43% (range 36 to 56%) of the CO2 radiative forcing used in MPWP climate simulations. This additional forcing would cause a global surface temperature increase of 0.6 to 1.0 °C, with amplified changes at high latitudes, improving agreement with geological evidence of Middle Pliocene climate. We conclude that natural trace gas feedbacks are critical for interpreting climate warmth during the Pliocene and potentially many other warm phases of the Cenezoic. These results also imply that using Pliocene CO2 and temperature reconstructions alone may lead to overestimates of the fast or Charney climate sensitivity.

Phenylbutyrate ameliorates prefrontal cortex, hippocampus, and nucleus accumbens neural atrophy as well as synaptophysin and GFAP stress in aging mice.

Recent reports on brain aging suggest that oxidative stress and inflammatory processes contribute to aging. Interestingly, sodium phenylbutyrate (PBA) is an inhibitor of histone deacetylase, which has anti-inflammatory properties. Several reports have suggested the effect of PBA on learning and memory processes, however there are no studies of the effect of this inhibitor of histone deacetylase on aging. Consequently, in the present study, the effect of PBA was studied in 18-month-old mice. The animals were administered PBA for 2 months after locomotor activity treatment and Morris water maze tests were performed. The Golgi-Cox staining technique and immunohistochemistry for glial fibrillary acidic protein (GFAP) and synaptophysin were performed for the morphological procedures. The administration of PBA improves learning and memory according to the Morris water maze test compared to vehicle-treated animals, which had unchanged locomotor activity. Using Golgi-Cox staining, dendritic length and the number of dendritic spines were measured in limbic regions, such as the nucleus accumbens (NAcc), prefrontal cortex (PFC) layer 3, and the CA1 of the dorsal hippocampus. In addition, PBA increased the number of dendritic spines in the PFC, NAcc, and CA1 subregions of the hippocampus with an increase in dendritic length only in the CA1 region. Moreover, PBA reduced the levels of the GFAP and increased the levels of synaptophysin in the studied regions. Thus, PBA can be a useful pharmacological tool to prevent or delay synaptic plasticity damage and cognitive impairment caused by age.

Interactions of ions across carbon nanotubes.

The interactions between a pair of Li+ ions across a semiconducting (8,0)CNT and a conducting (5,5)CNT has been investigated by density functional theory. The direct Coulomb interaction between the ions is almost completely screened. The band structure of the CNTs is not affected by the Li+ ions, but the Fermi level is raised to accommodate the extra electrons. Because of the unique band structure of CNTs this results in an effective attraction between the ions, which is greater for the (8,0)CNT. In contrast, a Cl- ion inside a CNT forms a chemical bond which modifies the band structure. Again, the electrostatic field of the ion is almost completely screened outside of the tube. Nevertheless, the adsorption of a Li+ ion outside is favored by a Cl- ion inside. This apparent attraction is mainly caused by a lowering of the work function of the CNT by the presence of the Cl-.

Identification of two arylimides as cholinesterase inhibitors and testing of propranolol addition on impaired rat memory.

Alzheimer's disease (AD) is clearly linked to the decline of acetylcholine (ACh) effects in the brain. These effects are regulated by the hydrolytic action of acetylcholinesterase (AChE). Therefore, a central palliative treatment of AD is the administration of AChE inhibitors although additional mechanisms are currently described and tested for generating advantageous therapeutic strategies. In this work, we tested new arylamides and arylimides as potential inhibitors of AChE using in silico tools. Then, these compounds were tested in vitro, and two selected compounds, C7 and C8, as well as propranolol showed inhibition of AChE. In addition, they demonstrated an advantageous acute toxicity profile compared to that of galantamine as a reference AChE inhibitor. in vivo evaluation of memory performance enhancement was performed in an animal model of cognitive disturbance with each of these compounds and propranolol individually as well as each compound combined with propranolol. Memory improvement was observed in each case, but without a significant additive effect with the combinations.

Experimentally Induced Open Pneumothorax in Horses.

The objective of this study was to evaluate clinical and cardiovascular parameters and pleural and intra-abdominal pressures of horses after experimentally induced unilateral open pneumothorax. Prospective, experimental study-animals: seven healthy adult horses, 4 females and 3 males. Left hemithorax thoracotomy was carried out to create an open pneumothorax for 60 minutes. Pleural pressure (Ppl) was directly obtained at the midpoint of the left eighth intercostal space before thoracotomy. Esophageal pressure (Pes), arterial blood gas analysis, left ventricular function, and ultrasonographic assessment of pneumothorax extent/resolution were performed at the baseline, and 5, 10, 15, 30, 45, and 60 minutes after thoracotomy, and on the first, second, third, fifth, and seventh days postoperatively. Intra-abdominal pressure was only recorded while the pneumothorax was present. There was moderate correlation (Spearman's rs = 0.404; R2 = 0.8; P < .00001; Bland-Altman bias = -2.59; s.d. = 2.11) between Pes and Ppl. Esophageal pressure increased (P < .05) after open pneumothorax until the fifth day postoperatively. Partial pressure of oxygen in arterial blood reduced (P < .05) until the third day postoperatively when it returned to the baseline. No significant variations in PaCO2, pH in arterial blood, and in left ventricular function were appreciated. The extent of the pneumothorax was assessed by thoracic ultrasonography. Esophageal pressure, in association with blood gas analysis and thoracic ultrasonography, could be used to aid diagnosis of pneumothorax in horses. Horses tolerate open pneumothorax, with minimum cardiovascular impairment, even without aspiration of free air from within pleural space to restore thoracic wall integrity.

Beta-blockers and salbutamol limited emotional memory disturbance and damage induced by orchiectomy in the rat hippocampus.

AIM: To evaluate the therapeutic potential of ligands of beta-adrenoceptors in cognitive disorders. Testosterone and adrenergic pathways are involved in hippocampal and emotional memory. Moreover, is strongly suggested that androgen diminishing in aging is involved in cognitive deficit, as well as beta-adrenoceptors, particularly beta2-adrenoceptor, participate in the adrenergic modulation of memory. In this regard, some animal models of memory disruption have shown improved performance after beta-drug administration. MATERIAL AND METHODS: In this work, we evaluated the effects of agonists (isoproterenol and salbutamol) and antagonists (propranolol and carvedilol) on beta-adrenoceptors in orchiectomized rats, as well as their effects in the performance on avoidance task and damage in hippocampal neurons by immunohistochemistry assays. KEY FINDINGS: Surprisingly, we found that both antagonists and salbutamol (but not isoproterenol) modulate the effects of hormone deprivation, improving memory and decreasing neuronal death and amyloid-beta related changes in some regions (particularly CA1-3 and dentate gyrus) of rat hippocampus. SIGNIFICANCE: Two ß-antagonists and one ß2-agonist modulated the effects of hormone deprivation on memory and damage in brain. The mechanisms of signaling of these drugs for beneficial effects remain unclear, even if used ß-ARs ligands share a weak activity on ß-arrestin/ERK-pathway activation which can be involved in these effects as we proposed in this manuscript. Our observations could be useful for understanding effects suggested of adrenergic drugs to modulate emotional memory. But also, our results could be related to other pathologies involving neuronal death and Aß accumulation.

Liver X Receptor-Binding DNA Motif Associated With Atherosclerosis-Specific DNA Methylation Profiles of Alu Elements and Neighboring CpG Islands.

BACKGROUND: The signals that determine atherosclerosis-specific DNA methylation profiles are only partially known. We previously identified a 29-bp DNA motif (differential methylation motif [DMM]) proximal to CpG islands (CGIs) that undergo demethylation in advanced human atheromas. Those data hinted that the DMM docks modifiers of DNA methylation and transcription. METHODS AND RESULTS: We sought to functionally characterize the DMM. We showed that the DMM overlaps with the RNA polymerase III-binding B box of Alu short interspersed nuclear elements and contains a DR2 nuclear receptor response element. Pointing to a possible functional role for an Alu DMM, CGIs proximal (<100 bp) to near-intact DMM-harboring Alu are significantly less methylated relative to CGIs proximal to degenerate DMM-harboring Alu or to DMM-devoid mammalian-wide interspersed repeat short interspersed nuclear elements in human arteries. As for DMM-binding factors, LXRB (liver X receptor ß) binds the DMM in a DR2-dependent fashion, and LXR (liver X receptor) agonists induce significant hypermethylation of the bulk of Alu in THP-1 cells. Furthermore, we describe 3 intergenic long noncoding RNAs that harbor a DMM, are under transcriptional control by LXR agonists, and are differentially expressed between normal and atherosclerotic human aortas. Notably, CGIs adjacent to those long noncoding RNAs tend to be hypomethylated in symptomatic relative to stable human atheromas. CONCLUSIONS: Collectively, the data suggest that a DMM is associated with 2 distinct methylation states: relatively low methylation of in cis CGIs and Alu element hypermethylation. Based on the known atheroprotective role of LXRs, we propose that LXR agonist-induced Alu hypermethylation, a landmark of atherosclerosis, is a compensatory rather than proatherogenic response.

Comparison of continuous intravenous infusion of tramadol and tramadol-lidocaine-ketamine in the sevoflurane requirement in dogs / Comparação da infusão continua intravenosa de tramadol e de tramadol-lidocaína-cetamina no requerimento de sevofluorano em cães

The objective of this study was to compare the influence of continuous intravenous infusion of tramadol alone, or tramadol combined with lidocaine and ketamine, on minimum alveolar concentration of sevoflurane (MACsevo) of dogs undergoing an ovariohysterectomy (OHE). We used 28 healthy dogs of various breeds and age, randomly divided into two groups according to the infusion given: TRA (tramadol alone) or TLK (tramadol, lidocaine and ketamine). The patients were premedicated with acepromazine and midazolam, and then anesthesia was induced with propofol and maintained with sevoflurane. Fifteen minutes after induction, the patients received their loading dose of treatment. Then, the continuous infusion was then set to 1.3mg/kg/hour of tramadol with or without 3mg/kg/hour of lidocaine and 0.6mg/kg/hour of ketamine, diluted in a 500mL bag of saline solution at an infusion rate of 10mL/kg/hour. The Dixon method was chosen to determine the MACsevo and a skin incision was used as a noxious stimulus. An unpaired Student's t-test was used to identify statistically significant differences between the treatments. These differences were considered significant when p<0.05. The MACsevo of the TRA group was 1.22±0.15 vol% and the MACsevo of the TLK group was 0.85±0.22 vol%. We conclude that TLK infusion decreased the MACsevo by 30.22% compared to tramadol alone, demonstrating that the combination of drugs was effective in reducing MACsevo in dogs.(AU)

O objetivo deste estudo foi comparar a influência da infusão contínua intravenosa do tramadol isolado e associado com lidocaína e cetamina, na concentração alveolar mínima de sevofluorano (CAMsevo) em cadelas submetidas à ovariosalpingohisterectomia. Foram utilizados 28 animais saudáveis de várias raças e idades, divididos aleatoriamente em dois grupos de acordo com a infusão adminstrada: TRA (tramadol) ou TLK (tramadol, lidocaína e cetamina). A medicação pré-anestésica foi realizada com acepromazina e midazolam, em seguida, a anestesia foi induzida com propofol e mantida com sevofluorano. Quinze minutos após a indução, os pacientes receberam um bolus do tratamento, com a infusão continua iniciada logo em seguida, sendo 1,3mg/kg/hora de tramadol, associado ou não a 3mg/kg/hora de lidocaína e 0,6mg/kg/hora de cetamina, diluidos em uma bolsa de solução salina de 500mL a uma taxa de infusão taxa de 10ml/kg/hora. O método de Dixon foi escolhido para determinar a MACsevo e a incisão na pele foi utilizada como o estímulo nocivo. O teste t de Student não pareado foi utilizado para identificar diferenças estatisticamente significativas entre os tratamentos. Estas diferenças foram consideradas significativas quando p<0,05. A CAMsevo do grupo TRA foi de 1,22±0,15vol% e a CAMsevo do grupo TLK foi de 0,85±0,22vol%. Conclui-se que a infusão de TLK diminuiu a CAMsevo em 30,22% em relação ao tramadol isolado, o que demonstra que a combinação de agentes analgésicos foi eficaz na redução do requerimento de sevofluorano em cães.(AU)

Not all boronic acids with a five-membered cycle induce tremor, neuronal damage and decreased dopamine.

Several striatal toxins can be used to induce motor disruption. One example is MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), whose toxicity is accepted as a murine model of parkinsonism. Recently, 3-Thienylboronic acid (3TB) was found to produce motor disruption and biased neuronal damage to basal ganglia in mice. The aim of this study was to examine the toxic effects of four boronic acids with a close structural relationship to 3TB (all having a five-membered cycle), as well as boric acid and 3TB. These boron-containing compounds were compared to MPTP regarding brain access, morphological disruption of the CNS, and behavioral manifestations of such disruption. Data was collected through acute toxicity evaluations, motor behavior tests, necropsies, determination of neuronal survival by immunohistochemistry, Raman spectroscopic analysis of brain tissue, and HPLC measurement of dopamine in substantia nigra and striatum tissue. Each compound showed a distinct profile for motor disruption. For example, motor activity was not disrupted by boric acid, but was decreased by two boronic acids (caused by a sedative effect). 3TB, 2-Thienyl and 2-furanyl boronic acid gave rise to shaking behavior. The various manifestations generated by these compounds can be linked, in part, to different levels of dopamine (measured by HPLC) and degrees of neuronal damage in the basal ganglia and cerebellum. Clearly, motor disruption is not induced by all boronic acids with a five-membered cycle as substituent. Possible explanations are given for the diverse chemico-morphological changes and degrees of disruption of the motor system, considering the role of boron and the structure-toxicity relationship.

Scope of Lipid Nanoparticles in Neuroscience: Impact on the Treatment of Neurodegenerative Diseases.

BACKGROUND: Lipid nanoparticles have been studied mainly as a means of transporting and releasing drugs. A special emphasis has been placed on designing nanoparticles that improve the delivery of drugs with targets in the central nervous system. METHODS: The biomedical literature was searched for basic and clinical studies. The recent applications are described and related with their bioactivities. RESULTS: The current review compiles data on the components and features of lipid nanoparticle systems as well as the necessary conditions for their selective action. As an example of their application, we present data from preclinical and clinical studies on lipid nanoparticles used as potent and efficient agents in the diagnosis and treatment of some neurodegenerative maladies, including Parkinson's disease. CONCLUSION: Current evidence supports the application of lipid nanoparticles for designing drugs carriers for neurodegenerative diseases. Also, we have gathered data that suggests a role of drug-free lipid nanoparticles as neuroprotective or preventive agents during neurodegenerative processes.

Associations between whole peripheral blood fatty acids and DNA methylation in humans.

Fatty acids (FA) modify DNA methylation in vitro, but limited information is available on whether corresponding associations exist in vivo and reflect any short-term effect of the diet. Associations between global DNA methylation and FAs were sought in blood from lactating infants (LI; n = 49) and adult males (AMM; n = 12) equally distributed across the three conventional BMI classes. AMM provided multiple samples at 2-hour intervals during 8 hours after either a single Western diet-representative meal (post-prandial samples) or no meal (fasting samples). Lipid/glucose profile, HDAC4 promoter and PDK4 5'UTR methylation were determined in AMM. Multiple regression analysis revealed that global (in LI) and both global and PDK4-specific DNA methylation (in AMM) were positively associated with eicosapentaenoic and arachidonic acid. HDAC4 methylation was inversely associated with arachidonic acid post-prandially in AMM. Global DNA methylation did not show any defined within-day pattern that would suggest a short-term response to the diet. Nonetheless, global DNA methylation was higher in normal weight subjects both post-prandially and in fasting and coincided with higher polyunsaturated relative to monounsaturated and saturated FAs. We show for the first time strong associations of DNA methylation with specific FAs in two human cohorts of distinct age, diet and postnatal development stage.

Nuclear reprogramming and its role in vascular smooth muscle cells.

In general terms, "nuclear reprogramming" refers to a change in gene expression profile that results in a significant switch in cellular phenotype. Nuclear reprogramming was first addressed by pioneering studies of cell differentiation during embryonic development. In recent years, nuclear reprogramming has been studied in great detail in the context of experimentally controlled dedifferentiation and transdifferentiation of mammalian cells for therapeutic purposes. In this review, we present a perspective on nuclear reprogramming in the context of spontaneous, pathophysiological phenotypic switch of vascular cells occurring in the atherosclerotic lesion. In particular, we focus on the current knowledge of epigenetic mechanisms participating in the extraordinary flexibility of the gene expression profile of vascular smooth muscle cells and other cell types participating in atherogenesis. Understanding how epigenetic changes participate in vascular cell plasticity may lead to effective therapies based on the remodelling of the vascular architecture.

Clinical implications of recent insights into the structural biology of beta2 adrenoceptors.

Analysis of the crystal structure of beta-2 adrenoceptors (ß2ARs) is providing new insights into the functioning of this receptor and perhaps of G-protein coupled receptors (GPCRs) as a whole. This class of receptors represents the target of at least a third of the drugs on the market and plays an essential role in the study of therapetic drug-response. Among GPCRs, the ß2AR is the best understood in terms of function, expression and activation. Regarding the interaction of ß2ARs with a specific ligand, polymorphisms, conformational changes and stereoselectivity are important factors. Agonist affinity for ß2ARs is influenced by the polymorphisms of these receptors, which in some cases appear to affect susceptibility to disorders. Conformational changes that take place upon the approach of a given ligand, as well as the stereoselectivity of this class of receptors can modify the intrinsic activity of ß2ARs (and certainly of other receptors as well). Hence, a deepening understanding of these factors can provide new data on affinity and specifically the key residues involved in recognition of ß2AR agonists. The deepening the understanding of the factors involved in ligand affinity for ß2ARs will assist in the development of ß2AR agonists that are more selective and potent, and that have longer term action. Not only are ß2AR agonists employed as therapeutic agents, but also in diagnosis. Currently, the main clinical application of targeting human ß2ARs is to treat asthma with bronchodilators. However, they are also used to treat other maladies in their acute or chronic forms, including heart conditions, metabolic disorders and muscle wasting. This review shows the scope and the possible future clinical implications of data from structures of ß2ARs.

Effects of butorphanol on the minimum anesthetic concentration for sevoflurane in guineafowl (Numida meleagris).

OBJECTIVE: To determine the minimum anesthetic concentration (MAC) for sevoflurane and measure the dose and temporal effects of butorphanol on the MAC for sevoflurane in guineafowl. ANIMALS: 10 healthy adult guineafowl (Numida meleagris). PROCEDURES: Each bird was anesthetized with sevoflurane, and a standard bracketing method was used to measure the MAC in response to a noxious electrical stimulus. Subsequently, conditions were adjusted so that each bird was anesthetized with sevoflurane at a fraction of its respective MAC (eg, 0.7 times the MAC for that bird). Butorphanol tartrate (2 mg/kg, IV) was administered, and a noxious stimulus was applied every 15 minutes until the bird moved in response. The reduction in MAC was estimated with logistic regression by use of a standard quantal method. After an interval of ≥ 1 week, the MAC reduction experiment was repeated with an increased butorphanol dosage (4 mg/kg). RESULTS: Individual mean ± SE MAC for sevoflurane was 2.9 ± 0.1%. At 15 minutes after administration of 2 mg of butorphanol/kg, estimated reduction in the MAC for sevoflurane was 9 ± 3%. At 15 and 30 minutes after administration of 4 mg of butorphanol/kg, estimated reduction in the MAC for sevoflurane was 21 ± 4% and 11 ± 8%, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: In guineafowl, the MAC for sevoflurane was similar to values reported for other species. Increasing the butorphanol dosage decreased the MAC for sevoflurane, but the effect was small and of short duration for dosages up to 4 mg/kg.

Ovário-histerectomia vídeo-assistida com único portal em cadelas: estudo retrospectivo de 20 casos / Single-port video-assisted ovariohysterectomy in bitches: retrospective study of 20 cases

O objetivo do presente estudo foi avaliar retrospectivamente as 20 primeiras ovário-histerectomias vídeo-assistidas com único portal (SPVA-OSH), realizadas por um cirurgião não proficiente nessa técnica. Vinte cadelas foram submetidas à laparoscopia para SPVA-OSH, com o auxílio de um endoscópio de 10mm, com canal de trabalho de 5mm, inserido por um trocarte, posicionado na região pré-púbica, e coagulação bipolar. O tempo cirúrgico médio foi de 22,95±5,17 minutos. Os cinco primeiros procedimentos consumiram mais tempo cirúrgico do que os demais. A abordagem aos pedículos ovarianos direito e esquerdo foram as etapas que apresentaram maior tempo de execução. Houve complicação leve ou moderada em seis (30 por cento) das 20 cadelas operadas. As complicações foram: hemorragia leve ou moderada em um dos pedículos ovarianos em quatro (20 por cento) cadelas e hemorragia grave, devido à punção do baço com agulha de Veress em dois (10 por cento) animais. A SPVA-OSH foi realizada em cadelas por um cirurgião no início da curva de aprendizado, sem complicações maiores.

The aim of the present study was to evaluate retrospectively the first 20 cases of single-port video-assisted ovariohysterectomy (SPVA-OSH) performed by an inexperienced surgeon. Twenty bitches submitted to SPVA-OSH were assessed. A 10mm operative rigid endoscope with one 5 mm working channel and bipolar coagulation was used. The trocar was positioned in the prepubic area of the abdomen. Surgical time and complication rates were assessed descriptively. Mean surgical time was of 22.95±5.17 minutes. Mild or moderate complications were present in six (30 percent) out of 20 bitches that were operated. The first five surgical procedures spent more time to be performed than the others. The longest transoperative momentum time of execution was spent in the approach to the left and right ovarian pedicles. The complications were: mild or moderate hemorrhage from one of the ovarian pedicles in four bitches (20 percent) and severe hemorrhage due to accidental puncture of the spleen with Veress needle in two animals (10 percent). SPVA-OSH was performed in bitches by an inexperienced surgeon, without severe complications.