RESUMO
BACKGROUND: Neuropeptide Y (NPY) Y2 receptor (Y2) antagonist BIIE0246 can both inhibit and facilitate nociception. The authors hypothesized that Y2 function depends on inflammation or nerve injury status. METHODS: The authors implemented a battery of behavioral tests in mice of both sexes that received (1) no injury; (2) an incision model of postoperative pain; (3) a spared nerve injury model of neuropathic pain; and (4) a latent sensitization model of chronic postsurgical pain. In addition to Y2 gene expression assays, spinal Y2 G-protein coupling was studied with guanosine-5'-O-(3-[35S]thio)triphosphate ([35S]GTPγS) binding assays. RESULTS: The authors report that intrathecal BIIE0246 increased mechanical and cold hypersensitivity, produced behavioral signs of spontaneous nociception and itch, and produced conditioned place aversion and preference in normal, uninjured mice. BIIE0246 did not change heat hypersensitivity or motor coordination. Conditional (sensory neuron-specific) Y2 deletion prevented BIIE0246-induced mechanical and cold hypersensitivity, nocifensive behaviors, and aversion. Both conditional deletion and pharmacologic blockade of Y2 reduced mechanical and thermal hypersensitivity after incision or nerve injury. SNI did not change the sensitivity of Y2 G-protein coupling with the Y2 agonist peptide YY (3-36) (PYY3-36), but increased the population of Y2 that effectively coupled G-proteins. Intrathecal PYY3-36 failed to reduce spared nerve injury- or incision-induced hypersensitivity in C57BL/6N mice. Incision did not change Npy2r gene expression in dorsal root ganglion. CONCLUSIONS: The authors conclude that Y2 at central terminals of primary afferent neurons provides tonic inhibition of mechanical and cold nociception and itch. This switches to the promotion of mechanical and thermal hyperalgesia in models of acute and chronic postsurgical and neuropathic pain, perhaps due to an increase in the population of Y2 that effectively couples to G-proteins. These results support the development of Y2 antagonists for the treatment of chronic postsurgical and neuropathic pain.
Assuntos
Hiperalgesia , Neuralgia , Nociceptividade , Dor Pós-Operatória , Prurido , Receptores de Neuropeptídeo Y , Células Receptoras Sensoriais , Animais , Receptores de Neuropeptídeo Y/antagonistas & inibidores , Receptores de Neuropeptídeo Y/metabolismo , Prurido/metabolismo , Camundongos , Neuralgia/metabolismo , Masculino , Nociceptividade/efeitos dos fármacos , Nociceptividade/fisiologia , Células Receptoras Sensoriais/efeitos dos fármacos , Células Receptoras Sensoriais/metabolismo , Feminino , Dor Pós-Operatória/metabolismo , Hiperalgesia/metabolismo , Camundongos Endogâmicos C57BL , Arginina/análogos & derivados , BenzazepinasRESUMO
Pharmacological agents directed to either opioid receptors or peroxisome proliferator-activated receptor gamma (PPARγ) at peripheral tissues reduce behavioral signs of persistent pain. Both receptors are expressed in muscle tissue, but the contribution of PPARγ activation to muscle pain and its modulation by opioid receptors remains unknown. To address this question, we first tested whether the endogenous PPARγ ligand 15d-PGJ2 would decrease mechanical hyperalgesia induced by carrageenan administration into the gastrocnemius muscle of rats. Next, we used receptor antagonists to determine whether the antihyperalgesic effect of 15-deoxyΔ-12,14-prostaglandin J2 (15d-PGJ2) was PPARγ- or opioid receptor-dependent. Three hours after carrageenan, muscle hyperalgesia was quantified with the Randall-Selitto test. 15d-PGJ2 prevented carrageenan-induced muscle hyperalgesia in a dose-dependent manner. The antihyperalgesic effect of 15d-PGJ2 was dose-dependently inhibited by either the PPARγ antagonist, 2-chloro-5-nitro-N-phenylbenzamide, or by the opioid receptor antagonist, naloxone. We conclude that 15d-PGJ2 targets PPARγ and opioid receptors to prevent muscle hyperalgesia. We suggest that local PPARγ receptors are important pharmacological targets for inflammatory muscle pain.
Assuntos
Hiperalgesia/metabolismo , Fatores Imunológicos/farmacologia , Músculo Esquelético/efeitos dos fármacos , Mialgia/metabolismo , PPAR gama/efeitos dos fármacos , Prostaglandina D2/análogos & derivados , Anilidas/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Carragenina/toxicidade , Hiperalgesia/induzido quimicamente , Músculo Esquelético/metabolismo , Mialgia/induzido quimicamente , Naloxona/farmacologia , Antagonistas de Entorpecentes/farmacologia , PPAR gama/antagonistas & inibidores , Prostaglandina D2/farmacologia , RatosRESUMO
BACKGROUND: In 2017, the FDA approved the adjuvanted recombinant zoster vaccine (RZV) for the prevention of herpes zoster (HZ) in immunocompetent adults aged 50 years and older. RZV joined zoster vaccine live (ZVL) as U.S.-marketed vaccines against HZ. The Advisory Committee on Immunization Practices preferentially recommended use of RZV over ZVL. In order to inform population-based decision makers (PBDMs) about the incremental clinical and economic impact of RZV adoption, budget impact (BI) models may be used. Populating such models with national data can inform PBDMs about the incremental value of RZV adoption nationally; however, heterogeneity across health plans requires the inclusion of plan-specific data to ensure the relevance of modeling outcomes for plan-specific decision makers. OBJECTIVE: To investigate the clinical and economic outcomes associated with the adoption of RZV in nationally representative populations with commercial and Medicare coverage and to demonstrate the effect of the heterogeneity of health plans using real-world data from a large, integrated delivery network (IDN). METHODS: We used a publicly available BI model. The model accounts for national and IDN-collected population characteristics (size, age distribution) and epidemiological data (incidence of HZ and complications, HZ recurrence rate), vaccine characteristics from randomized controlled trials and observational studies (efficacy, waning, second dose compliance for RZV, adverse event rate), national costs (vaccine, direct medical for HZ, complications, and vaccine adverse events), and current and anticipated vaccine coverage. We assessed incremental clinical (HZ cases and complications) and economic (per-member-per-month [PMPM] costs) impact at 5-year to 15-year time horizons, comparing scenarios where RZV is solely implemented with one where only ZVL is utilized. RESULTS: Following the adoption of RZV, the incremental HZ cases avoided over 5 and 15 years were estimated to be 1,800 and 15,000 for a commercial plan, 3,800 and 21,000 for a Medicare plan, and 8,600 and 71,000 for a specific IDN. The incremental PMPM budget impact over the same time horizons was estimated to be $0.42 and $0.31, respectively, for a commercial plan, $0.35 and $0.10 for a Medicare plan, and $0.39 and $0.25 for a specific IDN. The differences in results across plans resulted from the population age distribution, the vaccine copay (applied in the Medicare scenario only), the vaccine coverage in the plan, and other plan-specific factors affecting disease epidemiology and costs per case of HZ. CONCLUSIONS: Model projections indicated that RZV adoption avoided HZ cases and related complications, with the PMPM budget impact dependent on plan-specific factors. As health gains increased over time, the incremental costs incurred were found to decrease as the shorter-term costs of adopting the new vaccine were increasingly offset by the longer-term benefits of vaccination. DISCLOSURES: GlaxoSmithKline Biologicals SA funded this study (GSK study identifier: HO-17-18378) and was involved in all stages of study conduct, including analysis of the data. GlaxoSmithKline Biologicals SA also paid all costs associated with the development and publication of this manuscript. Patterson, Van Oorschot, and Curran are employees of the GSK group of companies and hold shares in the GSK group of companies. Herring, Carrico, and Zhang are employees of RTI Health Solutions, which received funding via a contractual agreement with the GSK group of companies to perform the work contributing to this research. Ackerson, Bruxvoort, Sy, and Tseng are employees of Kaiser Permanente Southern California, which was contracted by the GSK group of companies for the conduct of this study and were members of the KPSC study team. Ackerson, Bruxvoort, Sy, and Tseng report research contracts with the following pharmaceutical companies unrelated to this study: Dynavax (Ackerson, Bruxvoort, and Sy); the GSK group of companies (Ackerson, Bruxvoort, Sy, and Tseng); Novavax (Ackerson, Sy, and Tseng); and Seqirus (Ackerson, Bruxvoort, Sy, and Tseng). Tseng reports having served as a paid consultant for the GSK group of companies. The authors declare no other financial and nonfinancial relationships and activities. Findings from this study were presented at AMCP Nexus 2019; October 29-November 1, 2019; National Harbor, MD.
Assuntos
Vacina contra Herpes Zoster/administração & dosagem , Herpes Zoster/prevenção & controle , Vacinação/economia , Orçamentos , Análise Custo-Benefício , Herpes Zoster/economia , Vacina contra Herpes Zoster/economia , Humanos , Pessoa de Meia-Idade , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Tempo , Estados Unidos , Vacinas SintéticasRESUMO
Understanding how climate change will shape species distributions in the future requires a functional understanding of the demographic responses of animals to their environment. For birds, most of our knowledge of how climate influences population vital rates stems from research in temperate environments, even though most of Earth's avian diversity is concentrated in the tropics. We evaluated effects of Southern Oscillation Index (SOI) and local temperature and rainfall at multiple temporal scales on sex-specific survival of a resident tropical bird, the rufous-and-white wren Thryophilus rufalbus, studied over 15 years in the dry forests of northwestern Costa Rica. We found that annual apparent survival of males was 8% higher than females, more variable over time, and responded more strongly to environmental variation than female survival, which did not vary strongly with SOI or local weather. For males, mean and maximum local temperatures were better predictors of survival than either rainfall or SOI, with high temperatures during the dry season and early wet season negatively influencing survival. These results suggest that, even for species adapted to hot environments, further temperature increases may threaten the persistence of local populations in the absence of distributional shifts.
Assuntos
Mudança Climática , Temperatura Alta/efeitos adversos , Longevidade , Aves Canoras/fisiologia , Animais , Costa Rica , El Niño Oscilação Sul , Feminino , Masculino , Estações do Ano , Clima TropicalRESUMO
STUDY DESIGN: Patellar tendon reflexes were elicited among patients who had had a unilateral total knee replacement, those planned for unilateral total knee replacement, and a cohort of controlled patients. Patellar tendon reflex (PTR) response was measured with surface electromyography. OBJECTIVE: The aim of this study was to determine if total knee arthroplasty significantly alters the PTR. SUMMARY OF BACKGROUND DATA: As part of the clinical evaluation of the spine, extremity reflexes are provoked. Reflex variation between right and left extremities can be a pathological finding in disease of the spine. It has been noted that in patients who have undergone total knee arthroplasty (TKA), the PTR is diminished on the operative side compared with the contralateral nonoperative side. PTR is part of the clinical exam when evaluating a patient for lumbar radiculopathy. METHODS: The right and left patellar tendon reflex intensities were measured by quadriceps surface electromyography in 3 groups of patients. Group 1 consisted of 21 patients with unilateral TKA who were at least 6 months postoperative. Group 2 consisted of 18 patients with unilateral severe knee arthritis indicated for TKA. Group 3, serving as the control group, included 20 patients with no evidence of knee arthritis in either knee. The average reflex response for each group was recorded and comparisons were then made between each group. RESULTS: Patients who have undergone unilateral TKA have a PTR on average of 55.1% of their contralateral uninvolved side. This is statistically significant when compared with reflexes in patients who are planned for unilateral total knee arthroplasty, 96.03% (Pâ=â0.001) and when compared with patients without evidence for knee arthritis, 102.2% (Pâ<â0.001). CONCLUSION: The results of this case control study show that TKAs do significantly diminish PTRs when compared with a contralateral uninvolved knee in the same patient. LEVEL OF EVIDENCE: 3.
Assuntos
Artroplastia do Joelho/efeitos adversos , Região Lombossacral/fisiopatologia , Ligamento Patelar/fisiopatologia , Radiculopatia/fisiopatologia , Idoso , Eletromiografia , Feminino , Humanos , Joelho/fisiologia , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/fisiologiaRESUMO
Salivary gland myoepithelial carcinoma (MC) or malignant myoepithelioma is a rare entity. MC usually presents as a slow-growing painless mass arising in the parotid gland, but may involve other salivary glands. This tumour may be particularly locally aggressive, but its clinical and biological features are not yet fully understood. MC may arise from pre-existing benign lesions, such as pleomorphic adenomas or benign myoepitheliomas, or may arise de novo. It usually affects patients over 50 years old, with no gender preference. Because it is often asymptomatic, the presentation and diagnosis can be delayed by months, even years. The current WHO classification considers MC to be an intermediate- to high-grade malignancy. Other published data suggest it is likely to be a high-grade neoplasm, consistent with its aggressive behaviour. Its epidemiology, histopathological features, immunohistochemical profile, clinical behaviour and optimal management are not well understood. Following review of the current literature we aim to address these.
Assuntos
Carcinoma , Mioepitelioma , Neoplasias das Glândulas Salivares , HumanosRESUMO
The prevalence of intestinal parasites in young Quichua children was assessed in 20 rural communities in the highlands of Ecuador in August 2005. The caregivers of 293 children aged 12-60 months were interviewed about the status of child health, household socioeconomic and environmental factors, and water-use practices and were requested to collect a faecal sample from the study child. Two hundred three (69.3%) of the 293 children provided faecal samples that were tested for parasites. The overall prevalences of infection for specific agents were Entamoeba histolytica or dispar 57.1%, Ascaris lumbricoides 35.5%, Entamoeba coli 34.0%, Giardia intestinalis (lamblia) 21.1%, Hymenolepis nana 11.3%, Cryptosporidium parvum 8.9%, Chilomastix mesnili 1.7%, Hymenolepis diminuta 1.0%, Strongyloides stercoralis 0.7%, and Trichuris trichiura 0.5%. The prevalence of parasites increased with age. Water storage, water treatment, consistent latrine-use, and participation in a community-based clean water project were not strongly associated with the prevalence of intestinal parasites, although having dirt floors was a risk factor for infection with E. histolytica or dispar and G. intestinalis.
Assuntos
Fezes/parasitologia , Enteropatias Parasitárias/epidemiologia , Água/parasitologia , Fatores Etários , Criança , Pré-Escolar , Equador/epidemiologia , Feminino , Humanos , Higiene , Lactente , Enteropatias Parasitárias/diagnóstico , Enteropatias Parasitárias/transmissão , Masculino , Prevalência , Fatores de Risco , Saúde da População Rural , Fatores SocioeconômicosRESUMO
After sensitization to ovalbumin (Ova) by inhalation of nebulized antigen, BALB/c mice respond with an early rise in IgE but not in IgG anti-Ova antibody production. Our purpose here was to analyze the repertoire of T cells that may contribute to regulating this IgE response. Initial study of Ova-reactive T-cell hybridomas showed that they selectively express the T-cell receptor variable beta-chain (V beta) elements 2, 8.1/8.2, and 14. The frequency of T cells bearing these V beta elements in local draining lymph nodes of the airways and lungs (peribronchial-draining lymph nodes) after Ova inhalation was examined. Local sensitization increased the proportion of V beta 8.1/8.2 T cells in the peribronchial-draining lymph nodes, whereas expression of V beta 2 or V beta 14 was similar in sensitized and nonsensitized animals. In the presence of increased antigen concentrations, V beta 8 and V beta 2 T cells were equally reactive to Ova when cell proliferation was assayed. Coculture of Ova-selected V beta 8 T cells from peribronchial-draining lymph nodes and spleens of sensitized animals with primed splenic B cells increased IgE but not IgG production. The V beta 8 increase in IgE production was related to an increase in numbers of IgE-secreting B cells. In contrast, coculture of Ova-selected V beta 2 T cells with sensitized B cells had no stimulatory effect on either IgE or IgG production. Further, addition of V beta 2 cells to V beta 8 cells inhibited the V beta 8-induced augmentation of IgE production. These data indicate that T cells expressing different T cell receptors or, perhaps, different V beta elements may play different roles in IgE production in sensitized mice.