Inter- and intra-observer reliability of thoracic limb circumference measurement methods in sound dogs.

Objective: The primary objectives of this study are to (1) compare the inter- and intra-observer reliability of thoracic limb circumference measurement methods in sound dogs, and (2) determine the most reliable thoracic limb positioning and location on the thoracic limb for performing circumferential measurements. Methods: Thoracic limbs of 10 apparently sound dogs (20 limbs) were blindly and independently measured by 3 observers. Triplicate measurements were performed with dogs in lateral recumbency at 50 and 70% brachial (Br) length (length between the greater tubercle and lateral humoral epicondyle) and 25% ABr length (length between the lateral humeral epicondyle and ulnar styloid process), both with the elbow extended and at an approximate weight-bearing (WB) angle. Intra-class correlation coefficients (ICC) with a 95% confidence interval (CI) were used for data analysis with a p < 0.05 being significant. Results: All measures had significantly good to excellent intra- (ICC 0.836-0.994, p < 0.001) and inter-observer reliability (ICC 0.834-0.996, p < 0.001). Inter-observer reliability was excellent at 25% ABr extended and WB positions, and at 50% Br WB position, with a wider confidence interval at the latter location. Intra-observer reliability was excellent across all observers for 25% ABr extended and WB, and 50% Br WB positions, also with a wider confidence interval at the latter location. Conclusion: Circumferential measurement of the canine thoracic limb was most reliable at 25% ABr length with the elbow either in an extended or WB position.

Parallel cortical-brainstem pathways to attentional analgesia.

Pain demands attention, yet pain can be reduced by focusing attention elsewhere. The neural processes involved in this robust psychophysical phenomenon, attentional analgesia, are still being defined. Our previous fMRI study linked activity in the brainstem triad of locus coeruleus (LC), rostral ventromedial medulla (RVM) and periaqueductal grey (PAG) with attentional analgesia. Here we identify and model the functional interactions between these regions and the cortex in healthy human subjects (n = 57), who received painful thermal stimuli whilst simultaneously performing a visual attention task. RVM activity encoded pain intensity while contralateral LC activity correlated with attentional analgesia. Psycho-Physiological Interaction analysis and Dynamic Causal Modelling identified two parallel paths between forebrain and brainstem. These connections are modulated by attentional demand: a bidirectional anterior cingulate cortex (ACC) - right-LC loop, and a top-down influence of task on ACC-PAG-RVM. By recruiting discrete brainstem circuits, the ACC is able to modulate nociceptive input to reduce pain in situations of conflicting attentional demand.

Resolving the Brainstem Contributions to Attentional Analgesia.

Previous human imaging studies manipulating attention or expectancy have identified the periaqueductal gray (PAG) as a key brainstem structure implicated in endogenous analgesia. However, animal studies indicate that PAG analgesia is mediated largely via caudal brainstem structures, such as the rostral ventromedial medulla (RVM) and locus coeruleus (LC). To identify their involvement in endogenous analgesia, we used brainstem optimized, whole-brain imaging to record responses to concurrent thermal stimulation (left forearm) and visual attention tasks of titrated difficulty in 20 healthy subjects. The PAG, LC, and RVM were anatomically discriminated using a probabilistic atlas. Pain ratings disclosed the anticipated analgesic interaction between task difficulty and pain intensity (p < 0.001). Main effects of noxious thermal stimulation were observed across several brain regions, including operculoinsular, primary somatosensory, and cingulate cortices, whereas hard task difficulty was represented in anterior insular, parietal, and prefrontal cortices. Permutation testing within the brainstem nuclei revealed the following: main effects of task in dorsal PAG and right LC; and main effect of temperature in RVM and a task × temperature interaction in right LC. Intrasubject regression revealed a distributed network of supratentorial brain regions and the RVM whose activity was linearly related to pain intensity. Intersubject analgesia scores correlated to activity within a distinct region of the RVM alone. These results identify distinct roles for a brainstem triumvirate in attentional analgesia: with the PAG activated by attentional load; specific RVM regions showing pronociceptive and antinociceptive processes (in line with previous animal studies); and the LC showing lateralized activity during conflicting attentional demands.SIGNIFICANCE STATEMENT Attention modulates pain intensity, and human studies have identified roles for a network of forebrain structures plus the periaqueductal gray (PAG). Animal data indicate that the PAG acts via caudal brainstem structures to control nociception. We investigated this issue within an attentional analgesia paradigm with brainstem-optimized fMRI and analysis using a probabilistic brainstem atlas. We find pain intensity encoding in several forebrain structures, including the insula and attentional activation of the PAG. Discrete regions of the rostral ventromedial medulla bidirectionally influence pain perception, and locus coeruleus activity mirrors the interaction between attention and nociception. This approach has enabled the resolution of contributions from a hub of key brainstem structures to endogenous analgesia.

Rectal temperature changes and oxygen toxicity in dogs treated in a monoplace chamber.

Hyperbaric oxygen treatments are increasingly administered to pet dogs, using veterinary-specific monoplace chambers. The basic physiologic responses, chamber performance and oxygen toxicity rates have not yet been evaluated in dogs in a clinical setting. As a result, a series of consecutive 45-minute, 2-atmospheres absolute (atm abs) hyperbaric treatments with 100% oxygen were evaluated in a veterinary rehabilitation center (n = 285). 65 dogs with a mean body weight of 21 ± 15 kg (1.4-71 kg) were treated with an average of four sessions each. The mean rectal temperature of canine patients decreased 0.07 degrees C (0.1 degrees F) during treatments (p = 0.04). Intra-chamber temperature and humidity both increased: +1.0 degrees C (1.7 degrees F, p < 0.0001) and +5.7% (p < 0.0001), respectively. The mean maximal oxygen concentration measured before depressurization of the veterinary-specific commercial chamber was 98.0 ± 0.9%. No strong correlations (r > 0.75) were identified between body weights, body condition scores, maximal oxygen concentrations, starting or ending rectal temperature, chamber humidity and chamber temperature. Oxygen toxicity was not observed during the observational period. Patients were most commonly treated for intervertebral disc disease (n = 16 dogs) and extensive traumatic wounds (n = 10 dogs), which represented a large number of the total study sessions (19% and 16%, respectively).

O acesso da classe média à estratégia de saúde da família em contexto de expansão da atenção primária à saúde no município do Rio de Janeiro / The middle class of access to family health strategy in the context of expansion of primary health care in the municipality of Rio de Janeiro

O acesso é um dos atributos essenciais da Atenção Primária à Saúde (APS) e as desigualdades para a sua obtenção vem sendo amplamente estudadas na literatura nacional e internacional. A criação do Sistema Único de Saúde (SUS) operacionalizou o princípio da universalidade de modo que a saúde se tornou um direito de todos. Historicamente, foi possível perceber que a forma de organização do SUS dentro de uma perspectiva da APS focalizada e seletiva, acabou direcionando esses serviços às classes sociais mais baixas o que impulsionou a classe média para a adesão ao subsistema privado e esvaziou o princípio da universalidade. O presente estudo apresenta como objetivo geral analisar o acesso da classe média à Estratégia de Saúde da Família (ESF) em contexto de expansão da Atenção Primária à Saúde no município do Rio de Janeiro. Trata-se de estudo quantiqualitativo, realizado em um Centro Municipal de Saúde tipo B, localizado na Zona Sul do município do Rio de Janeiro. A etapa quantitativa se deu através da análise documental do Consolidado das Fichas de Cadastramento da Família e Cidadão da Unidade de Saúde e a etapa qualitativa ocorreu através de entrevista semiestruturada realizada com uma amostra de usuários cadastrados considerados de classe média. Os resultados revelam um perfil de famílias de classe média bem heterogêneo, com maioria de indivíduos brancos, de boa escolaridade, apresentando ocupações compatíveis com a sua formação, boas condições de moradia e renda e com grandes chances de convênio com o subsistema privado. As estratégias de expansão da Atenção Primária na cidade carioca parecem ter aproximado a classe média da ESF. Os sujeitos vocalizam suas demandas na expectativa de tornar o uso do serviço mais ágil e resolutivo, o que proporcionará uma APS com mais qualidade, condição importante para a manutenção deste segmento social na ESF.

Access is one of the essential attributes of the Primary Health Care (PHC) and the inequalities for its attainment have been widely studied in the international and national literature. The creation of the Sistema Único de Saude (Unified Health System) enabled the universal coverage principle in a way that health became a right to everyone. Historically it become possible to perceive that the SUS form of organization in a focused and selective Primary Health Care perspective resulted in directing these services to the less fortunate social classes what motivated the middle class to adhere to the private subsystem and emptied the universal coverage principle. The current study aims to analyze the access of the middle class to the Family Health Strategy (FHS) in the Primary Health Care expansion context in the city of Rio de Janeiro. This is a quantitative and qualitative study carried out in a City Health Centre Type B located in the noble area, called South Zone, in the city of Rio de Janeiro. The quantitative phase occurred through documental analysis of Consolidated Registration Forms of a Family and Citizens Health Center and the qualitative phase occurred through semi structured interviews made with a group of registered users considered middle class. The results reveal a heterogeneous middle class family profile with majority of white skinned individuals, highly educated, presenting jobs compatible with their education, good living conditions and income and with great chances of accessing the private subsystem. The Primary Health Care expansion strategy in the carioca (from Rio de Janeiro) city seems to have approximated the middle class to the FHS. The subjects express their demands with expectations to make the service use more agile and incisive, what would provide a PHC with more quality, important condition for this social segment´s maintenance in the FHS.

Comparison of computerized image analysis with traditional semiquantitative scoring of Perls' Prussian Blue stained hepatic iron deposition.

Image analysis is now routinely employed as a tool in toxicologic pathology to help quantitate end points of efficacy and safety. It is regarded as a proficient and a sensitive technique to generate numerical data that can be easily interrogated for statistical evaluation. Traditional semiquantitative pathology scoring on the other hand is sometimes regarded as less accurate due to the limitations of the scoring systems employed and the day-to-day variations often noted between pathologists. We therefore decided to generate an optimized histochemical staining and image analysis protocol to compare the accuracy of semiquantitative scoring with computerized image analysis. In order to achieve this, we describe a standardized protocol for staining and image analysis that eliminates or minimizes as many sources of error as possible. The results of this experiment demonstrate that despite consistent variations in scoring between two independent pathologists, correlation with image analysis data of 0.91 to 0.95 (Spearman's Rho test) was achieved. These data indicate that either image analysis or traditional semiquantitative scoring can generate accurate data. As a result of this, it appears that it is equally safe to employ either method dependent upon the complexity and the practicality of the task at hand provided that the experimental conditions are rigorously optimized and rigidly adhered to.

Pharmacological activation of the pyruvate dehydrogenase complex reduces statin-mediated upregulation of FOXO gene targets and protects against statin myopathy in rodents.

We previously reported that statin myopathy is associated with impaired carbohydrate (CHO) oxidation in fast-twitch rodent skeletal muscle, which we hypothesised occurred as a result of forkhead box protein O1 (FOXO1) mediated upregulation of pyruvate dehydrogenase kinase-4 (PDK4) gene transcription. Upregulation of FOXO gene targets known to regulate proteasomal and lysosomal muscle protein breakdown was also evident. We hypothesised that increasing CHO oxidation in vivo, using the pyruvate dehydrogenase complex (PDC) activator, dichloroacetate (DCA), would blunt activation of FOXO gene targets and reduce statin myopathy. Female Wistar Hanover rats were dosed daily for 12 days (oral gavage) with either vehicle (control, 0.5% w/v hydroxypropyl-methylcellulose 0.1% w/v polysorbate-80; n = 9), 88 mg( )kg(-1) day(-1) simvastatin (n = 8), 88 mg( )kg(-1) day(-1) simvastatin + 30 mg kg(-1) day(-1) DCA (n = 9) or 88 mg kg(-1) day(-1) simvastatin + 40 mg kg(-1) day(-1) DCA (n = 9). Compared with control, simvastatin reduced body mass gain and food intake, increased muscle fibre necrosis, plasma creatine kinase levels, muscle PDK4, muscle atrophy F-box (MAFbx) and cathepsin-L mRNA expression, increased PDK4 protein expression, and proteasome and cathepsin-L activity, and reduced muscle PDC activity. Simvastatin with DCA maintained body mass gain and food intake, abrogated the myopathy, decreased muscle PDK4 mRNA and protein, MAFbx and cathepsin-L mRNA, increased activity of PDC and reduced proteasome activity compared with simvastatin. PDC activation abolished statin myopathy in rodent skeletal muscle, which occurred at least in part via inhibition of FOXO-mediated transcription of genes regulating muscle CHO utilisation and protein breakdown.

A UK panel consensus on the initiation of aripiprazole for the treatment of bipolar mania.

OBJECTIVE: The objective of this consensus paper is to provide practical guidance on why and how aripiprazole, with its distinct pharmacological and side effect profile, should be used for treatment of acute bipolar mania. METHODS: An advisory panel of UK healthcare professionals, with extensive experience of prescribing aripiprazole for acute bipolar mania, met to discuss its use in this setting. RESULTS: The panel agreed that aripiprazole is effective in treating bipolar mania when prescribed and dosed appropriately, in both the short and long term, as monotherapy or in combination with a mood stabilizer. Unlike other atypical agents, aripiprazole has antimanic effects that are not associated with sedation, which is beneficial for patients, particularly in the long term. If rapid tranquillization is required when initiating aripiprazole in acutely disturbed patients, short-term coprescription of a benzodiazepine is recommended. Most side effects associated with aripiprazole occur within the first 1-3 weeks and are usually transient and easily treatable. Aripiprazole poses low risk of metabolic side effects, sexual dysfunction, and anhedonia, which can facilitate treatment adherence and help improve clinical outcomes. CONCLUSIONS: Aripiprazole is an effective first-line treatment for acute bipolar mania with a favorable safety/tolerability profile.

Acute generalised exanthematous pustulosis following intravitreal Ranibizumab.

Acute generalised exanthematous pustulosis, or AGEP, is a well documented cutaneous drug reaction. It typically occurs within 48 hours of oral antibiotics, but can be caused by other medications and, occasionally, after viral infections. We present a case of AGEP following intravitreal injection of Ranibizumab, a monoclonal antibody vascular endothelial growth factor inhibitor.

Ulcerated tophaceous gout.

Gout is often considered a disease of an excessive lifestyle, a 'malady of kings'. Today, more than 1% of the European and US populations are afflicted with gout, although ulceration over gout tophi remains uncommon. We describe four cases of ulceration associated with gout tophi to highlight the clinical presentation, complications and a management strategy.

Comparison between analgesic effects of buprenorphine, carprofen, and buprenorphine with carprofen for canine ovariohysterectomy.

OBJECTIVE: To compare the analgesic effects of buprenorphine, carprofen, and their combination in dogs undergoing ovariohysterectomy. STUDY DESIGN: Prospective, randomized blinded clinical study. ANIMALS: 60 dogs. METHODS: Treatments were buprenorphine 0.02 mg kg(-1), intramuscularly (IM) (group B); carprofen 4 mg kg(-1), subcutaneously (SC) (group C); or a combination of both (group CB). Anesthesia was induced with propofol and maintained with isoflurane. A Dynamic Interactive Visual Analog Scale (DIVAS, 0-100 mm) and the Glasgow Composite Pain Scale (GCMPS, 0-24) were used to evaluate comfort and sedation at baseline, 2, 4, 6, and 24 hours after extubation. Rescue analgesia was provided with buprenorphine (0.02 mg kg(-1)). Wound swelling measurements (WM) and a visual inflammation score (VIS) of the incision were made after surgery and 2, 4, 6, and 24 hours later. p < 0.05 was considered significant. RESULTS: Group C required more propofol (5.0 +/- 1.4 mg kg(-1)) compared with B (3.3 +/- 1.1 mg kg(-1)) and CB (3.2 +/- 0.7 mg kg(-1)); respectively, p = 0.0002 and 0.0001. Rescue analgesia was required in nine dogs. B had a higher GCMPS and DIVAS III score at 6 hours (2.6 +/- 2.5) and (23 +/- 22.5 mm) compared with C (1.0 +/- 1.3, 6 +/- 7.3 mm) and CB (1.5 +/- 1.4, 8 +/- 10.7 mm); respectively, p = 0.02 and 0.006. Group C had a lower sedation score at 2 hours (43 +/- 23.6 mm) compared with B (68 +/- 32.1 mm) and BC (69 +/- 22.1 mm); respectively, p = 0.03 and 0.004. Group B had a higher WM score at 2 hours (3 +/- 0.8 mm) compared with C (2 +/- 0.6 mm) p = 0.01 and at 6 hours (3 +/- 1 mm) compared with C (2 +/- 0.8 mm) and CB (2 +/- 0.8 mm); respectively, p = 0.01 and 0.008. VIS was not different between groups. CONCLUSION AND CLINICAL RELEVANCE: All treatments provided satisfactory analgesia for the first 6 hours and at 24 hours. C and CB pain score and WS were superior to B at 6 hours. No superior analgesic effect was noted when the drugs were combined.

Experience with risperidone long-acting injection: results of a naturalistic observation study.

Typical antipsychotics are effective in the management of schizophrenia, but are associated with troublesome adverse effects which may lead to treatment discontinuation and relapse. Long-acting depot formulations of these drugs improve patient compliance, but do not reduce the incidence of adverse effects. There is evidence to suggest that newer atypical antipsychotic drugs have a reduced propensity to induce movement disorders and are associated with a modest reduction in relapse rates. The introduction of risperidone long-acting injection (RLAI) provided clinicians with the first long-acting formulation of an atypical antipsychotic. Objective. The aim of this study was to investigate the outcomes of patients from an acute mental health trust who received RLAI during the 18-month period following its licensing in the UK in order to examine measures of clinical effectiveness, and reasons for treatment discontinuation. Methods. Data were collected retrospectively from medical notes. Results. Fifty-nine patients were included in the study, and at the time of data collection 32 (54%) had discontinued treatment. The most common reason for discontinuation was lack of effectiveness, although all of the patients who discontinued due to lack of response were treatment resistant. RLAI appeared to be well tolerated, with only 12% of patients discontinuing due to adverse effects. Thirty-eight percent of the patients treated with RLAI showed a good response as measured by discharge from inpatient setting, and of the 22 outpatients at time of data collection, five had one re-hospitalisation during the study period. Conclusion. This study concludes that RLAI appears to be well tolerated, and shows some effectiveness in the treatment of schizophrenia, but may not be effective for patients who are treatment resistant.

Effect of lidocaine on the minimum alveolar concentration of isoflurane in dogs.

OBJECTIVE: To determine the influence of a low-dose constant rate infusion (LCRI; 50 microg kg(-1) minute(-1)) and high-dose CRI (HCRI; 200 microg kg(-1) minute(-1)) lidocaine infusion on the minimum alveolar concentration (MAC) of isoflurane (I) in dogs. STUDY DESIGN: Prospective experimental study. ANIMALS: Ten mongrel dogs (four females, six males), weighing 20-26.3 kg. METHODS: Dogs were anesthetized with I in oxygen and their lungs mechanically ventilated. Baseline MAC was determined using mechanical or electrical stimuli. Lidocaine (2 mg kg(-1) IV) was administered over 3 minutes, followed by the LCRI and MAC determination commenced 30 minutes later. Once MAC was determined following LCRI, the lidocaine infusion was stopped for 30 minutes. A second bolus of lidocaine (2 mg kg(-1), IV) was administered, followed by the HCRI and MAC re-determined. Concentrations of lidocaine and its metabolites were measured at end-tidal I concentrations immediately above and below MAC. Heart rates and blood pressures were measured. RESULTS: Minimum alveolar concentration of I was 1.34 +/- 0.11 (%; mean +/- SD) for both types of stimulus. The LCRI significantly reduced MAC to 1.09 +/- 0.13 (18.7% reduction) and HCRI to 0.76 +/- 0.10 (43.3% reduction). Plasma concentrations (ng mL(-1), median; value below and above MAC, respectively) for LCRI were: lidocaine, 1465 and 1537; glycinexylidide (GX), 111 and 181; monoethylglycinexylidide (MEGX), 180 and 471 and for HCRI were: lidocaine, 4350 and 4691; GX, 784 and 862; MEGX, 714 and 710. Blood pressure was significantly increased at 30 minutes after high dose infusion. CONCLUSION AND CLINICAL RELEVANCE: Lidocaine infusions reduced the MAC of I in a dose-dependent manner and did not induce clinically significant changes on heart rate or blood pressure.

Design and synthesis of peptidomimetic protein farnesyltransferase inhibitors as anti-Trypanosoma brucei agents.

On the basis of the structure of the CVIM tetrapeptide substrate of mammalian protein farnesyltransferase, a series of imidazole-containing peptidomimetics was designed and synthesized, and their inhibition activity against Trypanosoma brucei protein farnesyltransferase (TbPFT) was evaluated. Peptidomimetics where the 5-position of the imidazole ring was linked to the hydrophobic scaffold showed over 70% inhibition activity at 50 nM in the enzyme assay, whereas the corresponding C-4 regioisomers were less potent. The ester prodrug 23 was found to be a potent inhibitor against cultured Trypanosoma brucei brucei and Trypanosoma brucei rhodesiense cells with ED(50) values of 0.025 and 0.0026 microM, respectively. Furthermore, introducing a second imidazole group into 23 led to 31, which showed the highest inhibition activity against the parasite with an ED(50) of 0.0015 microM. The potency of the TbPFT inhibitors and the cytotoxicity of the corresponding esters to T. brucei cells were shown to be highly correlated. These studies validate TbPFT as a target for the development of novel therapeutics against African sleeping sickness.

Validation of several types of noxious stimuli for use in determining the minimum alveolar concentration for inhalation anesthetics in dogs and rabbits.

OBJECTIVE: To compare 3 types of noxious stimuli applied to various anatomic areas of anesthetized dogs and rabbits for determination of the minimum alveolar concentration (MAC). ANIMALS: 10 dogs and 10 rabbits. PROCEDURE: Dogs were anesthetized with isoflurane and halothane in a randomized order. Rabbits were anesthetized with isoflurane. The MAC was determined by skin incision on the lateral aspect of the chest; clamping of the tail, paw of the forelimb, and paw of the hind limb; and application of electrical current to the oral mucosa (dogs only), forelimb, and hind limb. The MAC was the end-tidal concentration midway between the value permitting and preventing purposeful movement in response to noxious stimuli. RESULTS: In dogs, mean +/- SEM MAC for isoflurane was 1.27 +/- 0.05% for clamping stimuli, 1.36 +/- 0.04% for oral electrical stimulation, 1.35 +/- 0.04% for electrical stimulation to the limbs, and 1.01 +/- 0.07% for surgical incision. The MAC for halothane was 0.97 +/- 0.03% for tail clamping, 0.96 +/- 0.03% for clamping of the limbs, 1.04 +/- 0.03% for electrical stimulation, and 0.75 +/- 0.06% for surgical incision. In rabbits, MAC for isoflurane was 2.08 +/- 0.02% for clamping stimuli, 2.04 +/- 0.02% for electrical stimulation, and 0.90 +/- 0.02% for surgical incision. The MAC for surgical incision was significantly lower than values for the other methods in both species. CONCLUSIONS AND CLINICAL RELEVANCE: Use of electrical current and clamping techniques resulted in similar MAC values. Surgical incision underestimated MAC values in dogs and rabbits.

Transition metal complexes of buparvaquone as potent new antimalarial agents. 1. Synthesis, X-ray crystal-structures, electrochemistry and antimalarial activity against Plasmodium falciparum.

New Cu(II), Ni(II), Co(II), Fe(II), and Mn(II) metal complexes of buparvaquone [3-trans(4-tert.-butylcyclohexyl)methyl-2-hydroxy-1,4-naphthoquione] (L1H) have been synthesized and characterized using IR, electron paramagnetic resonance (EPR) spectroscopy, microanalytical methods and single crystal X-ray diffraction methods. The single crystal structures were determined for ligand L1H [space group P-1 with a=6.2072(14) A, b=10.379 (2) A, c=13.840 (3) A, V=878.7(3) A(3), Z=2, D(calcd.)=1.234 mg/m(3)] and copper complex [Cu(L1)(2)(C(2)H(5)OH)(2)] C1 [space group I2/a with a=17.149(14) A, b=9.4492(8) A, c=26.946(3) A, V=4335.3(7)A(3), Z=4, D(calcd.)=1.233 mg/m(3)]. All the metal complexes along with the parent ligand have been studied for their electrochemical properties using cyclic voltammetric techniques. The compounds were tested for their in vitro antimalarial activity against Plasmodium falciparum strains. A correlation between the antimalarial activity and the redox property of these complexes is presented. The copper complex C1 exhibits significantly higher growth inhibitory activity both in vitro and in vivo than the parent ligand.