The Role of Knowledge and Attitudes About Nonsteroidal Anti-inflammatory Drugs in Determining Treatment Use.

OBJECTIVE: The objective of this study was to evaluate how patient knowledge and beliefs regarding nonsteroidal anti-inflammatory drugs (NSAIDs) may influence the use of NSAIDs for osteoarthritis (OA). METHODS: Surveys of 334 adults with knee and/or hip OA were analyzed in this cross-sectional study. Familiarity with and perceptions of benefits/risks of NSAID use were measured to assess associations with the use of prescription and nonprescription oral NSAIDs. Multinomial logistic regression models were adjusted for sociodemographic and clinical variables. RESULTS: In this sample, 35.9% and 35.6% reported use of oral prescription and nonprescription-only NSAIDs, respectively. Hispanic participants, compared with non-Hispanic White participants, had lower perceived benefit (P = 0.005) and risk (P = 0.001) of prescription NSAIDs. The following were associated with prescription NSAID use instead of no NSAID use: having family/friends who used prescription (relative risk ratio [RRR] 3.91; 95% confidence interval [CI] 2.05-7.47) and over-the-counter (OTC) (RRR 3.10; 95% CI 1.65-5.83) NSAIDs for OA, understanding the consequences of using both prescription (RRR 3.50; 95% CI 1.79-6.86) and OTC (RRR 2.80; 95% CI 1.39-5.65) NSAIDs, higher perceived benefit of both prescription (RRR 2.51; 95% CI 1.71-3.66) and OTC (RRR 1.44; 95% CI 1.01-2.06) NSAIDs, and lower perceived risk of both types of NSAIDs (prescription: RRR 0.63 [95% CI 0.46-0.87]; OTC: RRR 0.53 [95% CI 0.37-0.75]). Similar results were found when we assessed the relationship between these variables and OTC NSAID use versus no oral NSAID use. CONCLUSION: Adults with knee and/or hip OA were more likely to use NSAIDs if they were more familiar with, had an increased perceived benefit of, and had a decreased perceived risk of these drugs. Patients' perceptions and beliefs about NSAIDs should be evaluated when considering them for treatment.

Social & psychological factors associated with oral analgesic use in knee osteoarthritis management.

OBJECTIVE: Determine modifiable social and psychological health factors that are associated with use of oral opioid and non-opioid medications for OA. METHODS: Patients were categorized based on use of the following oral medications: opioids (with/without other oral analgesic treatments), non-opioid analgesics, and no oral analgesic treatment. We used multinomial logistic regression models to estimate adjusted relative risk ratios (RRRs) of using an opioid or a non-opioid analgesic (vs. no oral analgesic treatment), comparing patients by levels of social support (Medical Outcomes Study scale), health literacy ("How confident are you filling out medical forms by yourself?"), and depressive symptoms (Patient Health Questionnaire-8). Models were adjusted for demographic and clinical characteristics. RESULTS: In this sample (mean age 64.2 years, 23.6% women), 30.6% (n = 110) reported taking opioid analgesics for OA, 54.2% (n = 195) reported non-opioid use, and 15.3% (n = 55) reported no oral analgesic use. Opioid users had lower mean social support scores (10.0 vs 10.5 vs 11.9, P = 0.007) and were more likely to have moderate-severe depressive symptoms (42.7% vs 24.1% vs 14.5%, P < 0.001). Health literacy did not differ by treatment group type. Having moderate-severe depression was associated with higher risk of opioid analgesic use compared to no oral analgesic use (RRR 2.96, 95%CI 1.08-8.07) when adjusted for sociodemographic and clinical factors. Neither social support nor health literacy was associated with opioid or non-opioid oral analgesic use in fully adjusted models. CONCLUSIONS: Knee OA patients with more severe depression symptoms, compared to those without, were more likely to report using opioid analgesics for OA.

Chondroitin Sulfate in Human Cutaneous Meissner and Pacinian Sensory Corpuscles.

Chondroitin sulfate is a glycosaminoglycan involved in maintaining the morphofunctional properties of the extracellular matrix in peripheral nerves, but its distribution in human sensory corpuscles is unknown despite the role of extracellular matrix in mechanotransduction and axonal guidance. In this study we used immunohistochemistry to analyze the distribution of chondroitin sulfate in human cutaneous Meissner and Pacinian corpuscles. Chondroitin sulfate expression was absent from Meissner corpuscles. In Pacinian corpuscles chondroitin sulfate was found associated to a CD34 positive endoneurial-related layer, interposed between the S100 protein positive inner core cells, and the vimentin positive inner core and outer core-capsule cells. Therefore, the intermediate CD34+/chondroitin sulfate+ intermediate layer present in Pacinian corpuscles isolates the neural segment of the corpuscles (axon and inner core) from the non-neural segments (outer core and capsule). These results suggest a role of chondroitin sulfate in the proper axonal growth and guidance, within the neuronal compartment of the Pacinian corpuscles during development and reinnervation, can be hypothesized. Moreover, a role of CS in mechanotransduction cannot be ruled out. Anat Rec, 302:325-331, 2019. © 2018 Wiley Periodicals, Inc.

Healthcare resource utilization and costs associated with long-term corticosteroid exposure in patients with systemic lupus erythematosus.

Objective To evaluate the association between exposure to oral corticosteroids and future healthcare resource utilization and costs for patients with systemic lupus erythematosus. Methods Adults diagnosed with systemic lupus erythematosus (index date) between 1 January 2008 and 30 June 2013 and naive to oral corticosteroids with continuous health plan enrollment for ≥6 months pre- and ≥5 years post-index were identified from a large health plan claims database. Per-patient monthly average daily dose of oral corticosteroids (prednisone or its equivalent) was calculated for the first 2 years post-index to categorize patients into four steroid exposure cohorts: low (≤5 mg/day), medium (6-20 mg/day), high (>20 mg/day) and no steroids. Differences in healthcare resource utilization and total healthcare costs during the third year post-index across corticosteroid exposure cohorts were modeled with adjustment for baseline characteristics. Results The study included 18,618 systemic lupus erythematosus patients (163 high dose, 1127 medium dose, 6717 low dose and 10,611 no steroids). Compared to low-dose corticosteroid users, high-dose corticosteroid users were more likely to have emergency room visits (39.3% vs. 29.7%; p = 0.0085) and to be hospitalized (21.5% vs. 12.3%; p = 0.0005). After adjustment for baseline characteristics, they also had significantly greater average annual total healthcare costs (US$60,366 vs. US$18,777; p < 0.0001). A 1 mg increase in corticosteroid average daily dose was associated with 1.07 times the average annual costs after adjusting for baseline characteristics ( p < 0.0001). Conclusion Long-term high-dose oral corticosteroid use was associated with significantly greater future healthcare resource utilization and costs. Judicious reduction in daily steroid dose may decrease the imminent economic burden associated with high-dose steroid use in systemic lupus erythematosus.

Natural history of pain and disability among African-Americans and Whites with or at risk for knee osteoarthritis: A longitudinal study.

OBJECTIVE: Compare knee pain and disability between African Americans (AAs) and Whites (WHs), with or at risk of knee osteoarthritis (KOA), over 9 years, and evaluate racial disparities in KOA-related symptoms across socioeconomic and clinical characteristics. DESIGN: Osteoarthritis Initiative (OAI) participants were evaluated annually over 9 years for pain and disability, assessed by the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and a numerical rating scale (NRS) for knee pain severity. Mean annual WOMAC pain, NRS pain, and WOMAC disability levels were estimated by race using mixed effects models, adjusted for age, sex, education, marital status, body mass index (BMI), depression, and baseline Kellgren-Lawrence grade score. Race-specific mean WOMAC pain scores were also estimated in analyses stratified by socioeconomic and clinical characteristics. RESULTS: AAs reported worse mean WOMAC pain compared to WHs at baseline (3.69 vs 2.20; P ≤ 0.0001) and over 9 years of follow-up, with similar disparities reflected in NRS pain severity and WOMAC disability. Radiographic severity did not account for the differences in pain and disability, as substantial and significant racial disparities were observed after stratification by Kellgren-Lawrence grade. Depression and low income exacerbated differences in WOMAC pain between AAs and WHs by a substantial and significant magnitude. CONCLUSIONS: Over 9 years of follow-up, AAs reported persistently greater KOA symptoms than WHs. Socioeconomically and clinically disadvantaged AAs reported the most pronounced disparities in pain and disability.

Acid-sensing ion channels and transient-receptor potential ion channels in zebrafish taste buds.

Sensory information from the environment is required for life and survival, and it is detected by specialized cells which together make up the sensory system. The fish sensory system includes specialized organs that are able to detect mechanical and chemical stimuli. In particular, taste buds are small organs located on the tongue in terrestrial vertebrates that function in the perception of taste. In fish, taste buds occur on the lips, the flanks, and the caudal (tail) fins of some species and on the barbels of others. In fish taste receptor cells, different classes of ion channels have been detected which, like in mammals, presumably participate in the detection and/or transduction of chemical gustatory signals. However, since some of these ion channels are involved in the detection of additional sensory modalities, it can be hypothesized that taste cells sense stimuli other than those specific for taste. This mini-review summarizes current knowledge on the presence of transient-receptor potential (TRP) and acid-sensing (ASIC) ion channels in the taste buds of teleosts, especially adult zebrafish. Up to now ASIC4, TRPC2, TRPA1, TRPV1 and TRPV4 ion channels have been found in the sensory cells, while ASIC2 was detected in the nerves supplying the taste buds.

Neuralgia del trigémino: estudio funcional mediante tensor de difusión de alta densidad como herramienta diagnóstica / Trigeminal Neuralgia: functional study using high density diffusion tensor imaging as a diagnostic tool

Objetivo: El objetivo del presente artículo es demostrar la alteración de la fracción de anisotropía (FA) en la neuralgia esencial del trigémino (NET). Materiales y métodos: Se evaluaron 10 pacientes con diagnóstico de neuralgia esencial del trigémino mediante secuencias de tensor de difusión de alta densidad e imágenes anatómicas 3D en un resonador de alto campo 3 Tesla. En todos los casos se localizaron los nervios. Las imágenes obtenidas se posprocesaron para realizar la tractografía y medir la FA en 20 nervios. Resultados: Se correlacionaron los hallazgos patológicos entre la medición de la FA y la clínica de los pacientes. De los 10 casos, 6 presentaron compresión neurovascular de lado con neuralgia y un valor de FA descendido con respecto al contralateral en rango normal; mientras que 2 mostraron compresión neurovascular bilateral, pero solo descenso del valor de FA del lado afectado clínicamente. En los otros 2 pacientes no se determinó compresión neurovascular, aunque en el lado con manifestación clínica neurálgica la FA se encontraba descendida. Conclusión: La realización de la difusión anisotrópica de alta densidad y la medición de la FA pueden ser una herramienta en la evaluación de la neuralgia esencial del trigémino, ya que es un método reproducible y seguro que permite estudiar la función del nervio.

Objective: The objective of this article is to demonstrate the alteration of the anisotropy factor (FA) in essential trigeminal neuralgia. Materials and methods: Ten patients with essential trigeminal neuralgia were studied with sequences of high density diffusion tensor and anatomic 3D images with a high-field 3 Tesla resonator. The nerves were located in all cases studied. The obtained images were post-processed to perform tractography and FA was measured in 20 nerves. Results: There was correlation of pathological findings between measuring FA and clinical presentation of the patients. Six of the ten patients studied with neurovascular compression at the neuralgia side had decreased FA values compared to contralateral normal range. Two of the ten patients showed bilateral neurovascular compression, but only abnormal values of FA were found at the clinically affected side. In the remaining two patients no neurovascular compression was determined; however the FA was lower at the clinical manifestation neuralgic side. Conclusión: The performing of high density anisotropic diffusion and the measurement of the FA may be useful in the evaluation of Trigeminal neuralgia, since it is a safe and reproducible method that allows the study of nerve function.

Neuralgia del trigémino: estudio funcional mediante tensor de difusión de alta densidad como herramienta diagnóstica

Objetivo: El objetivo del presente artículo es demostrar la alteración de la fracción de anisotropía (FA) en la neuralgia esencial del trigémino (NET). Materiales y métodos: Se evaluaron 10 pacientes con diagnóstico de neuralgia esencial del trigémino mediante secuencias de tensor de difusión de alta densidad e imágenes anatómicas 3D en un resonador de alto campo 3 Tesla. En todos los casos se localizaron los nervios. Las imágenes obtenidas se posprocesaron para realizar la tractografía y medir la FA en 20 nervios. Resultados: Se correlacionaron los hallazgos patológicos entre la medición de la FA y la clínica de los pacientes. De los 10 casos, 6 presentaron compresión neurovascular de lado con neuralgia y un valor de FA descendido con respecto al contralateral en rango normal; mientras que 2 mostraron compresión neurovascular bilateral, pero solo descenso del valor de FA del lado afectado clínicamente. En los otros 2 pacientes no se determinó compresión neurovascular, aunque en el lado con manifestación clínica neurálgica la FA se encontraba descendida. Conclusión: La realización de la difusión anisotrópica de alta densidad y la medición de la FA pueden ser una herramienta en la evaluación de la neuralgia esencial del trigémino, ya que es un método reproducible y seguro que permite estudiar la función del nervio.(AU)

Objective: The objective of this article is to demonstrate the alteration of the anisotropy factor (FA) in essential trigeminal neuralgia. Materials and methods: Ten patients with essential trigeminal neuralgia were studied with sequences of high density diffusion tensor and anatomic 3D images with a high-field 3 Tesla resonator. The nerves were located in all cases studied. The obtained images were post-processed to perform tractography and FA was measured in 20 nerves. Results: There was correlation of pathological findings between measuring FA and clinical presentation of the patients. Six of the ten patients studied with neurovascular compression at the neuralgia side had decreased FA values compared to contralateral normal range. Two of the ten patients showed bilateral neurovascular compression, but only abnormal values of FA were found at the clinically affected side. In the remaining two patients no neurovascular compression was determined; however the FA was lower at the clinical manifestation neuralgic side. Conclusión: The performing of high density anisotropic diffusion and the measurement of the FA may be useful in the evaluation of Trigeminal neuralgia, since it is a safe and reproducible method that allows the study of nerve function.(AU)

Acid-sensing ion channels (ASICs) 2 and 4.2 are expressed in the retina of the adult zebrafish.

Acid-sensing ion channels (ASICs) are H(+)-gated, voltage-insensitive cation channels involved in synaptic transmission, mechanosensation and nociception. Different ASICs have been detected in the retina of mammals but it is not known whether they are expressed in adult zebrafish, a commonly used animal model to study the retina in both normal and pathological conditions. We study the expression and distribution of ASIC2 and ASIC4 in the retina of adult zebrafish and its regulation by light using PCR, in situ hybridization, western blot and immunohistochemistry. We detected mRNA encoding zASIC2 and zASIC4.2 but not zASIC4.1. ASIC2, at the mRNA or protein level, was detected in the outer nuclear layer, the outer plexiform layer, the inner plexiform layer, the retinal ganglion cell layer and the optic nerve. ASIC4 was expressed in the photoreceptors layer and to a lesser extent in the retinal ganglion cell layer. Furthermore, the expression of both ASIC2 and ASIC4.2 was down-regulated by light and darkness. These results are the first demonstration that ASIC2 and ASIC4 are expressed in the adult zebrafish retina and suggest that zebrafish could be used as a model organism for studying retinal pathologies involving ASICs.

Acid-sensing ion channel 2 (ASIC2) is selectively localized in the cilia of the non-sensory olfactory epithelium of adult zebrafish.

Ionic channels play key roles in the sensory cells, such as transducing specific stimuli into electrical signals. The acid-sensing ion channel (ASIC) family is voltage-insensitive, amiloride-sensitive, proton-gated cation channels involved in several sensory functions. ASIC2, in particular, has a dual function as mechano- and chemo-sensor. In this study, we explored the possible role of zebrafish ASIC2 in olfaction. RT-PCR, Western blot, chromogenic in situ hybridization and immunohistochemistry, as well as ultrastructural analysis, were performed on the olfactory rosette of adult zebrafish. ASIC2 mRNA and protein were detected in homogenates of olfactory rosettes. Specific ASIC2 hybridization was observed in the luminal pole of the non-sensory epithelium, especially in the cilia basal bodies, and immunoreactivity for ASIC2 was restricted to the cilia of the non-sensory cells where it was co-localized with the cilia marker tubulin. ASIC2 expression was always absent in the olfactory cells. These findings demonstrate for the first time the expression of ASIC2 in the olfactory epithelium of adult zebrafish and suggest that it is not involved in olfaction. Since the cilium sense and transduce mechanical and chemical stimuli, ASIC2 expression in this location might be related to detection of aquatic environment pH variations or to detection of water movement through the nasal cavity.

ASIC2 is present in human mechanosensory neurons of the dorsal root ganglia and in mechanoreceptors of the glabrous skin.

Mechanosensory neurons lead to the central nervous system touch, vibration and pressure sensation. They project to the periphery and form different kinds of mechanoreceptors. The manner in which they sense mechanical signals is still not fully understood, but electrophysiological experiments have suggested that this may occur through the activation of ion channels that gate in response to mechanical stimuli. The acid-sensing ion channels (ASICs), especially ASIC2, may function as mechanosensors or are required for mechanosensation, and they are expressed in both mechanosensory neurons and mechanoreceptors. Here, we have used double immunohistochemistry for ASIC2 together with neuronal and glial markers associated with laser confocal microscopy and image analysis, to investigate the distribution of ASIC2 in human lumbar dorsal root ganglia, as well as in mechanoreceptors of the hand and foot glabrous skin. In lumbar dorsal root ganglia, ASIC2 immunoreactive neurons were almost all intermediate or large sized (mean diameter ≥20-70 µm), and no ASIC2 was detected in the satellite glial. ASIC2-positive axons were observed in Merkel cell-neurite complexes, Meissner and Pacinian corpuscles, all of them regarded as low-threshold mechanoreceptors. Moreover, a variable percent of Meissner (8 %) and Pacinian corpuscles (27 %) also displayed ASIC2 immunoreactivity in the Schwann-related cells. These results demonstrate the distribution of ASIC2 in the human cutaneous mechanosensory system and suggest the involvement of ASIC2 in mechanosensation.

Calcium-activated potassium channel SK1 is widely expressed in the peripheral nervous system and sensory organs of adult zebrafish.

Sensory cells contain ion channels involved in the organ-specific transduction mechanisms that convert different types of stimuli into electric energy. Here we focus on small-conductance calcium-activated potassium channel 1 (SK1) which plays an important role in all excitable cells acting as feedback regulators in after-hyperpolarization. This study was undertaken to analyze the pattern of expression of SK1 in the zebrafish peripheral nervous system and sensory organs using RT-PRC, Westernblot and immunohistochemistry. Expression of SK1 mRNA was observed at all developmental stages analyzed (from 10 to 100 days post fertilization, dpf), and the antibody used identified a protein with a molecular weight of 70kDa, at 100dpf (regarded to be adult). Cell expressing SK1 in adult animals were neurons of dorsal root and cranial nerve sensory ganglia, sympathetic neurons, sensory cells in neuromasts of the lateral line system and taste buds, crypt olfactory neurons and photoreceptors. Present results report for the first time the expression and the distribution of SK1 in the peripheral nervous system and sensory organs of adult zebrafish, and may contribute to set zebrafish as an interesting experimental model for calcium-activated potassium channels research. Moreover these findings are of potential interest because the potential role of SK as targets for the treatment of neurological diseases and sensory disorders.

Acid-sensing ion channels (ASICs) in the taste buds of adult zebrafish.

In detecting chemical properties of food, different molecules and ion channels are involved including members of the acid-sensing ion channels (ASICs) family. Consistently ASICs are present in sensory cells of taste buds of mammals. In the present study the presence of ASICs (ASIC1, ASIC2, ASIC3 and ASIC4) was investigated in the taste buds of adult zebrafish (zASICs) using Western blot and immunohistochemistry. zASIC1 and zASIC3 were regularly absent from taste buds, whereas faint zASIC2 and robust zASIC4 immunoreactivities were detected in sensory cells. Moreover, zASIC2 also immunolabelled nerves supplying taste buds. The present results demonstrate for the first time the presence of zASICs in taste buds of teleosts, with different patterns to that occurring in mammals, probably due to the function of taste buds in aquatic environment and feeding. Nevertheless, the role of zASICs in taste remains to be demonstrated.

TRPV4 in the sensory organs of adult zebrafish.

TRPV4 is a nonselective cation channel that belongs to the vanilloid (V) subfamily of transient receptor potential (TRP) ion channels. While TRP channels have been found to be involved in sensing temperature, light, pressure, and chemical stimuli, TPRV4 is believed to be primarily a mechanosensor although it can also respond to warm temperatures, acidic pH, and several chemical compounds. In zebrafish, the expression of trpv4 has been studied during embryonic development, whereas its pattern of TPRV4 expression during the adult life has not been thoroughly analyzed. In this study, the occurrence of TRPV4 was addressed in the zebrafish sensory organs at the mRNA (RT-PCR) and protein (Westernblot) levels. Once the occurrence of TRPV4 was demonstrated, the TRPV4 positive cells were identified by using immunohistochemistry. TPRV4 was detected in mantle and sensory cells of neuromasts, in a subpopulation of hair sensory cells in the macula and in the cristae ampullaris of the inner ear, in sensory cells in the taste buds, in crypt neurons and ciliated sensory neurons of the olfactory epithelium, and in cells of the retina. These results demonstrate the presence of TRPV4 in all sensory organs of adult zebrafish and are consistent with the multiple physiological functions suspected for TRPV4 in mammals (mechanosensation, hearing, and temperature sensing), but furthermore suggest potential roles in olfaction and vision in zebrafish.

Effect of cyclooxygenase-2 inhibitor (celecoxib) on the infarcted heart in situ.

Several attempts have been made to replace aspirin with compounds without gastric toxicity; a cyclooxygenase-2 (COX-2) inhibitor, celecoxib, and a nitric oxide-aspirin, NCX-4016, have been developed for this purpose. This paper compares effects of celecoxib, NCX-4016 and aspirin on production of prostacyclin (PGI2) and thromboxane A2 (TXA2) and activation of the inducible form of nitric oxide synthase (iNOS) in infarcted heart in situ. Aspirin was most effective in reducing myocardial PGI2 synthesis and formation of TXA2. Myocardial effects of celecoxib resemble those of NCX-4016, although the two compounds have different modes of action.

The effect of aspirin and two nitric oxide donors on the infarcted heart in situ.

Nitric oxide (NO) donors are heterogeneous substances which release NO, a biologically active compound. NO released by nitric oxide donors has important effects on the circulation by causing vasodilation, diminishing myocardial contractile force, inhibiting platelet aggregation, and counteracting the effects of thromboxane A2. In the infarcted heart, activation of the inducible form of nitric oxide synthase (iNOS) and the formation of prostacyclin and thromboxane A2 by cyclooxygenase (COX) were increased. Myocardial infarction also resulted in increased myocardial NO production. Aspirin (acetylsalicylic acid. ASA) at low concentration (35 mg/kg/day) fails to change iNOS production, in contrast to higher dose (150 mg/kg/day) which, as previously shown, inhibits iNOS activity. ASA at all doses also suppresses myocardial prostanoid formation because of inhibition of COX. Recently, two NO donors have been synthesized: NCX 4016 and Diethylenetriamine/NO (DETA/NO). NCX 4016 combines an NO-releasing moiety with a carboxylic residue via an esteric bond. We describe here that NCX 4016 (65 mg/kg/day) increased prostacyclin and thromboxane A2 production in the infarcted heart muscle, overcoming the inhibitory effects of ASA. As a result of nitric oxide release, oxidation products of NO (NO2- and NO3-; NOx) in arterial blood rose following administration of NCX 4016. On oral administration, NCX 4016 did not change systemic arterial pressure. The effects of a single NO donor, DETA/NO (1.0 mg/kg/day) on the infarcted heart were also investigated On intravenous administration, the compound increased NO concentration in arterial blood slightly but to a lesser degree than NCX 4016. Like NCX 4016, it raised myocardial production of prostacyclin and thromboxane A2 in the infarcted heart. However, it caused a severe fall in blood pressure. These findings demonstrate that newly-synthesized NO donors release nitric oxide in situ and increase myocardial production of prostanoids. NCX 4016 has therapeutic potential because it can be orally administered, lacks hypotensive effects, increases blood levels of nitric oxide and myocardial prostacyclin production.