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During 1992 and 1993, a bacterial disease occurred in a seawater Atlantic salmon Salmo salar farm, causing serious mortalities. The causative agent was subsequently named as Oceanivirga salmonicida, a member of the Leptotrichiaceae. Searches of 16S rRNA gene sequence databases have shown sequence similarities between O. salmonicida and uncultured bacterial clones from the digestive tracts of marine mammals. In the current study, oral samples were taken from stranded dolphins (common dolphin Delphinus delphis, striped dolphin Stenella coeruleoalba) and healthy harbour seals Phoca vitulina. A bacterium with growth characteristics consistent with O. salmonicida was isolated from a common dolphin. The isolate was confirmed as O. salmonicida, by comparisons to the type strain, using 16S rRNA gene, gyrB, groEL, and recA sequence analyses, average nucleotide identity analysis, and MALDI-TOF mass spectrometry. Metagenomic analysis indicated that the genus Oceanivirga represented a significant component of the oral bacterial microbiomes of the dolphins and seals. However, sequences consistent with O. salmonicida were only found in the dolphin samples. Analyses of marine mammal microbiome studies in the NCBI databases showed sequences consistent with O. salmonicida from the common dolphin, striped dolphin, bottlenose dolphin Tursiops truncatus, humpback whale Megaptera novaeangliae, and harbour seal. Sequences from marine environmental studies in the NCBI databases showed no sequences consistent with O. salmonicida. The findings suggest that several species of marine mammals are natural hosts of O. salmonicida.
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Caniformia , Salmo salar , Animais , Cetáceos , Fusobactérias , RNA Ribossômico 16SRESUMO
OBJECTIVE: The healthcare and social disruption caused by the COVID-19 pandemic could pose significant risk to patients with intrathecal pump (ITP) who may miss refill or replacement appointments. In some cases, this could be life-threatening. We designed and piloted a novel refill protocol to assess its efficacy and safety. MATERIALS AND METHODS: Screening of our ITP database for patients most at risk of harm was conducted. These patients were risk-assessed for COVID-19 infection and were enrolled in a protocol to optimize the safety and efficiency of their pump replacement or refill. RESULTS: Of note, 31 of 51 database patients were deemed to be high risk of ITP failure during the pandemic. Thirty patients were successfully refilled with only one patient refusing to leave their house for refill. There were no significant adverse outcomes. CONCLUSION: Our protocol offers a safe and efficient pathway for ITP management during a pandemic.
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COVID-19 , Atenção à Saúde , Bombas de Infusão Implantáveis , Injeções Espinhais , Adolescente , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , SARS-CoV-2 , Adulto JovemRESUMO
STUDY OBJECTIVE: Assessment of older emergency department (ED) patients with cognitive impairment is challenging because few tools exist that can be quickly administered by front-line practitioners. Our objective is to validate the Ottawa 3DY Scale, a 4-question screening tool for cognitive impairment, in older ED patients and compare its performance with that of the Animal Fluency Test. METHODS: We conducted a prospective cohort study in 2 EDs and enrolled a convenience sample of patients aged 75 years or older with no history of cognitive impairment. Eligible patients were assessed by geriatric emergency management nurses who administered the Mini-Mental State Examination, ordered with the Ottawa 3DY Scale questions first, followed by the Animal Fluency Test. Mini-Mental State Examination score less than 25 was our criterion standard for cognitive impairment. RESULTS: Study patients (N=238) had a mean age of 81.9 years and were 60.1% women, and 26.5% were admitted to the hospital. The Ottawa 3DY Scale and Mini-Mental State Examination were in agreement for 75.6% of cases, with a sensitivity of 93.8% (95% confidence interval [CI] 77.8% to 98.9%) and specificity of 72.8% (95% CI 66.1% to 78.7%). The Animal Fluency Test score less than 15 and Mini-Mental State Examination score were in agreement for 46.2% of cases, with sensitivity 90.6% (95% CI 73.8% to 97.5%) and specificity 39.3% (95% CI 32.7% to 46.4%). CONCLUSION: Both the Ottawa 3DY Scale and the Animal Fluency Test demonstrated excellent sensitivity versus the Mini-Mental State Examination; however, the Animal Fluency Test exhibited poor specificity. The Ottawa 3DY Scale is an effective tool to screen for cognitive impairment in older ED patients, and its use may facilitate improved care in this vulnerable population.
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Transtornos Cognitivos/diagnóstico , Enfermagem em Emergência , Programas de Rastreamento/métodos , Idoso , Idoso de 80 Anos ou mais , Serviço Hospitalar de Emergência , Feminino , Humanos , Masculino , Ontário , Estudos Prospectivos , Sensibilidade e EspecificidadeRESUMO
As part of the European Union Marine Strategy Framework Directive (MSFD), member states are required to address noise pollution in the marine environment under Descriptor 11. This study aimed to provide a practical desk-based application of Descriptor 11 assessment, focusing on the main contributors of ocean noise pollution in Irish waters, seismic surveying and shipping. To highlight specific geographical areas subject to elevated levels of noise pollution, the proportion of days over a calendar year that seismic air guns were operational was calculated and the vessel density per 50-km(2) grids was determined across Ireland's exclusive economic zone (EEZ). Additionally, cetacean sighting data were used to determine the degree of spatial overlap between areas of elevated noise pollution and areas of cetacean abundance.
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Ruído , Água , Animais , Cetáceos/fisiologia , Geografia , Irlanda , Navios , Inquéritos e QuestionáriosRESUMO
The Shannon Estuary on the west coast of Ireland is one of Europe's premier deepwater berths catering for ships up to 200,000 deadweight tonnage. It is also Ireland's only designated candidate special area of conservation for bottlenose dolphins under the EU Habitats Directive. Long-term static acoustic monitoring was carried out at a number of intensive shipping sites. In 2012, noise monitoring took place over a 6-month period (at 1 site) as part of Ireland's requirements under the Marine Strategy Framework Directive (MSFD). This is the first assessment of the potential effect of vessel traffic on the behavior of this discrete dolphin population.
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Golfinho Nariz-de-Garrafa/fisiologia , Conservação dos Recursos Naturais , Estuários , Ruído , Água do Mar , Animais , Monitoramento Ambiental , Geografia , Irlanda , PressãoRESUMO
Sperm whales spatially segregate by sex and social behavior as they mature. In the North Atlantic, male whales move to higher latitudes as far as Svalbard at 80° N, while females and young whales typically remain around lower latitudes below 40-45° N. The Azores, Madeira, and the Canary Islands constitute important nursery grounds for female and young sperm whales. Irish waters represent a midpoint for this species' spatial segregation in the Northeast Atlantic, where the species occurs along the submarine canyon systems to the west of the country. Historically, just male whales were thought to be found in this region between 51 and 55° N, but one adult female was caught by commercial whalers in 1910, and a 5.49 m calf was found stranded in 1916. Between 1995 and 2023, 10 female sperm whales have been stranded around the coast of Ireland. Eight of these whales have been stranded since 2013, and there has been at least one stranding per year between 2019 and 2023. Four of these strandings have occurred in Donegal in the northwest of Ireland, indicating the presence of female whales along the continental shelf off this region. Two females were stranded within a day of each other and were found in similar states of decomposition in February 2022, indicating that they may have been part of the same group rather than being lone vagrant individuals. Sperm whale calves and juveniles were also sighted in Irish waters in 2001, 2004, and 2010 in the Rockall Trough, along the Porcupine Bank and Goban Spur, where between 1 and 3 individuals were observed on four occasions while one calf live stranded in 2004. These records indicate a historical presence of female and young sperm whales in this region but that an apparent increase in occurrence has taken place over the past decade.
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Irish waters are under increasing pressure from anthropogenic sources including the development of offshore renewable energy, vessel traffic and fishing activity. Spatial planning requires robust datasets on species distribution and the identification of important habitats to inform the planning process. Despite limited survey effort, long-term citizen science data on whale presence are available and provide an opportunity to fill information gaps. Using presence-only data as well as a variety of environmental variables, we constructed seasonal ensemble species distribution models based on five different algorithms for minke whales, fin whales, humpback whales, sei whales, and blue whales. The models predicted that the coastal waters off the south and west of Ireland are particularly suitable for minke, fin and humpback whales. Offshore waters in the Porcupine Seabight area were identified as a relevant habitat for fin whales, sei whales and blue whales. We combined model outputs with data on maritime traffic, fishing activity and offshore wind farms to measure the exposure of all the species to these pressures, identifying areas of concern. This study serves as a baseline for the species presence in Irish waters over the last two decades to help develop appropriate marine spatial plans in the future.
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Conservação dos Recursos Naturais , Ecossistema , Animais , Irlanda , Monitoramento Ambiental , Baleias/fisiologia , Balaenoptera/fisiologia , Jubarte/fisiologia , Baleia Comum/fisiologia , Pesqueiros/estatística & dados numéricosRESUMO
Animal songs can change within and between populations as the result of different evolutionary processes. When these processes include cultural transmission, the social learning of information or behaviours from conspecifics, songs can undergo rapid evolutions because cultural novelties can emerge more frequently than genetic mutations. Understanding these song variations over large temporal and spatial scales can provide insights into the patterns, drivers and limits of song evolution that can ultimately inform on the species' capacity to adapt to rapidly changing acoustic environments. Here, we analysed changes in fin whale (Balaenoptera physalus) songs recorded over two decades across the central and eastern North Atlantic Ocean. We document a rapid replacement of song INIs (inter-note intervals) over just four singing seasons, that co-occurred with hybrid songs (with both INIs), and a clear geographic gradient in the occurrence of different song INIs during the transition period. We also found gradual changes in INIs and note frequencies over more than a decade with fin whales adopting song changes. These results provide evidence of vocal learning in fin whales and reveal patterns of song evolution that raise questions on the limits of song variation in this species.
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Baleia Comum , Animais , Acústica , Oceano Atlântico , Mutação , Estações do AnoRESUMO
Parallel evolution provides strong evidence of adaptation by natural selection due to local environmental variation. Yet, the chronology, and mode of the process of parallel evolution remains debated. Here, we harness the temporal resolution of paleogenomics to address these long-standing questions, by comparing genomes originating from the mid-Holocene (8610-5626 years before present, BP) to contemporary pairs of coastal-pelagic ecotypes of bottlenose dolphin. We find that the affinity of ancient samples to coastal populations increases as the age of the samples decreases. We assess the youngest genome (5626 years BP) at sites previously inferred to be under parallel selection to coastal habitats and find it contained coastal-associated genotypes. Thus, coastal-associated variants rose to detectable frequencies close to the emergence of coastal habitat. Admixture graph analyses reveal a reticulate evolutionary history between pelagic and coastal populations, sharing standing genetic variation that facilitated rapid adaptation to newly emerged coastal habitats.
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Golfinho Nariz-de-Garrafa , Genética Populacional , Animais , Genômica , Paleontologia , Golfinho Nariz-de-Garrafa/genética , EcossistemaRESUMO
Studying repeated adaptation can provide insights into the mechanisms allowing species to adapt to novel environments. Here, we investigate repeated evolution driven by habitat specialization in the common bottlenose dolphin. Parapatric pelagic and coastal ecotypes of common bottlenose dolphins have repeatedly formed across the oceans. Analyzing whole genomes of 57 individuals, we find that ecotype evolution involved a complex reticulated evolutionary history. We find parallel linked selection acted upon ancient alleles in geographically distant coastal populations, which were present as standing genetic variation in the pelagic populations. Candidate loci evolving under parallel linked selection were found in ancient tracts, suggesting recurrent bouts of selection through time. Therefore, despite the constraints of small effective population size and long generation time on the efficacy of selection, repeated adaptation in long-lived social species can be driven by a combination of ecological opportunities and selection acting on ancestral standing genetic variation.
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Bio-accumulation of persistent organic pollutants including polychlorinated biphenyls (PCBs), brominated flame retardants and organochlorine pesticides continue to be of major concern for marine apex predators such as killer whales. The concentrations of 16 polychlorinated biphenyls, 7 poly-brominated diphenyl ethers (PBDEs), 1 poly-brominated biphenyl (PBB) and a range of 19 organochlorine compounds (OCs) was investigated in blubber samples from a mother-foetus pair, an adult female and an adult male killer whale stranded in Ireland between 2010 and 2017. Concentrations ranged from 1.5â¯mg/kg to 49.3â¯mg/kg lipid weight and 0.04-1.2â¯mg/kg lipid weight for Σ16PCBs and Σ7PBDEs respectively. Concentrations of organochlorine compounds were also investigated in the male killer whale; a Σ19OC concentration of 49.4â¯mg/kg lipid weight was recorded. This study shows high levels of persistent organic pollutants occur in this species of whales stranded in Ireland.
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Monitoramento Ambiental , Poluentes Químicos da Água/metabolismo , Orca/metabolismo , Animais , Feminino , Feto , Éteres Difenil Halogenados/metabolismo , Irlanda , Masculino , Bifenilos Policlorados/metabolismoRESUMO
TNF-alpha is a pleitropic cytokine that expresses both pro- and anti-inflammatory activity and transgenic mice expressing human tumor necrosis factor-alpha (TNF-alpha) exhibit a progressive polyarthritis that models rheumatoid arthritis (RA). One of the common comorbidities of RA is anemia of chronic disease (ACD). The purpose of these experiments was to study the changes in the bone marrow and peripheral blood that accompany polyarthritis in TNF-alpha transgenic mice in an effort to better understand the pathogenesis of myelodysplasia and ACD. Polychromatic cytometry, hematology and serum cytokine analysis were used to study the pathogenesis of ACD in human TNF-alpha transgenic mice. Our hematological evaluation revealed a mild, compensated, microcytic hypochromic anemia, and monocytosis. In the bone marrow, we observed alterations in cell kinetics, decreased relative expression of transferrin receptor and increased apoptosis and cell death in several late precursor cell populations. Although significant levels of human TNF-alpha were found in the serum, neither change in serum murine erythropoietin nor any significant difference observed in serum levels of murine IL-beta, IL-5, IL-6, IL-10, IL-12(p70), IL-17, TNF-alpha, IFNgamma, GM-CSF, MIP-1alphaJE, MCP-5 was observed. Tg197 mice develop a compensated, microcytic, hypochromic anemia, and a functional iron deficiency by 9 weeks of age. Changes in peripheral blood are reflected in alterations in cell kinetics, transferrin receptor expression and markedly increased apoptosis and cell death in the bone marrow indicating that TNF-alpha may contribute to myelodysplasia in ACD. Moreover, since human TNF-alpha can interact only with murine TNFR1, our data suggest that TNFR1 may play an important role in the development of ACD.
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Anemia Hipocrômica/patologia , Artrite/patologia , Citocinas/sangue , Síndromes Mielodisplásicas/patologia , Fator de Necrose Tumoral alfa/fisiologia , Anemia Hipocrômica/metabolismo , Animais , Apoptose/fisiologia , Artrite/metabolismo , Medula Óssea/metabolismo , Morte Celular/fisiologia , Doença Crônica , Humanos , Cápsula Articular/metabolismo , Cápsula Articular/patologia , Camundongos , Camundongos Transgênicos , Síndromes Mielodisplásicas/metabolismo , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Fator de Necrose Tumoral alfa/genéticaRESUMO
INTRODUCTION: It has been shown that a vast majority of injured patients who seek treatment in emergency departments are seen and released. The events resulting in the individuals seeking treatment may have been preventable and some of the time spent in an emergency department could be used for injury prevention (IP) education. This study sought to determine current IP practices of registered nurses working in an emergency department, to discover whether or not they believed IP was important, and to identify perceived obstacles for incorporating IP education into clinical practice. METHODS: A convenience sample of 150 registered nurses working in the emergency departments of an adult level 1 trauma centre in Ontario, Canada was used. A descriptive survey composed of 10 questions was used. Data analysis was completed using SPSS Version 11.0. RESULTS: Findings suggest current IP strategies are varied, and implemented inconsistently. Evidence indicates educating patients about IP is an important part of the emergency nurse role. However, time, education, and resources were recognized obstacles to implementation. DISCUSSION: A better understanding of registered nurses' current IP practices will guide the development and implementation of a future adult focused injury prevention program for ED patients.
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Enfermagem em Emergência/métodos , Enfermeiros Clínicos , Educação de Pacientes como Assunto/métodos , Ferimentos e Lesões/prevenção & controle , Adulto , Serviço Hospitalar de Emergência/organização & administração , Feminino , Pesquisas sobre Atenção à Saúde , Humanos , Masculino , Papel do Profissional de Enfermagem , Relações Enfermeiro-Paciente , Ontário , Prevenção Primária/educação , Probabilidade , Estudos de Amostragem , Sensibilidade e Especificidade , Centros de Traumatologia/normas , Centros de Traumatologia/tendênciasRESUMO
Little is known of the spatio-temporal occurrence of beaked whales off western Ireland, limiting the ability of Regulators to implement appropriate management and conservation measures. To address this knowledge gap, static acoustic monitoring was carried out using eight fixed bottom-mounted autonomous acoustic recorders: four from May to December 2015 on Ireland's northern slope and four from March to November 2016 on the western and southern slopes. Recorders ran for 205 to 230 days, resulting in 4.09 TB of data sampled at 250 kHz which could capture beaked whale acoustic signals. Zero-crossing-based automated detectors identified beaked whale clicks. A sample of detections was manually validated to evaluate and optimize detector performance. Analysis confirmed the occurrence of Sowerby's and Cuvier's beaked whales and Northern bottlenose whales. Northern bottlenose whale clicks occurred in late summer and autumn, but were too few to allow further analysis. Cuvier's and Sowerby's clicks occurred at all stations throughout the monitoring period. There was a significant effect of month and station (latitude) on the mean daily number of click detections for both species. Cuvier's clicks were more abundant at lower latitudes while Sowerby's were greater at higher latitudes, particularly in the spring, suggesting a spatial segregation between species, possibly driven by prey preference. Cuvier's occurrence increased in late autumn 2015 off northwest Porcupine Bank, a region of higher relative occurrence for each species. Seismic airgun shots, with daily sound exposure levels as high as 175 dB re 1 µPa2·s, did not appear to impact the mean daily number of Cuvier's or Sowerby's beaked whale click detections. This work provides insight into the significance of Irish waters for beaked whales and highlights the importance of using acoustics for beaked whale monitoring.
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Acústica , Processamento de Sinais Assistido por Computador , Análise Espaço-Temporal , Vocalização Animal/fisiologia , Baleias/fisiologia , Acústica/instrumentação , Animais , Oceano Atlântico , Ritmo Circadiano/fisiologia , Geografia , Irlanda , Fatores de Tempo , Análise de OndaletasRESUMO
PURPOSE/AIMS: The purpose of this study was to examine the management of patient's neuropathic pain with capsaicin 8% in a nurse-led clinic when administered by 1 registered advanced nurse practitioner without physician supervision. DESIGN: A longitudinal, single-group, descriptive research design was used to assess pain scores and quality of life 3 times over 3 months after treatment. METHODS: Patients with a diagnosis of neuropathic pain were assessed and treated with capsaicin 8% by 1 advanced nurse practitioner with prescriptive authority in a nurse-led clinic. Pain scores were collected at baseline, and self-assessed pain, activity level, and quality of life were assessed at 1 week, 4 weeks, and 3 months after treatment. Twenty-four patients were recruited, and data were analyzed using Friedman's test. In post hoc analysis, Wilcoxon signed-rank test was used with Bonferroni correction. RESULTS: Pain scores differed from pretreatment to posttreatment at each of the 3 time points, at rest (χ3 = 20.54, P = .001) and on movement (χ3 = 23.644, P = .001), and remained significant after Bonferroni correction. Overall, 62.5% (n = 15) of patients achieved at least a 30% reduction in self-reported pain at rest from pretreatment to 3 months, and 54% (n = 13) achieved the same reduction in pain on movement. Most improvements in patient's quality of life occurred between 1 and 4 weeks. Patient satisfaction was high, with 83% stating that they would be happy to have the treatment repeated. CONCLUSION: Single-dose capsaicin 8% decreased neuropathic pain after being administered in an outpatient setting by an experienced registered advanced nurse practitioner. Further multicenter research led by advanced nurse practitioners is needed to support high-quality, safe treatment of neuropathic pain with high-concentration capsaicin in nurse-led chronic pain clinics.
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Prática Avançada de Enfermagem , Capsaicina/uso terapêutico , Neuralgia/tratamento farmacológico , Neuralgia/enfermagem , Manejo da Dor/enfermagem , Adulto , Idoso , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Medição da Dor , Relações Médico-Enfermeiro , Padrões de Prática em Enfermagem , Qualidade de Vida , Resultado do Tratamento , Adulto JovemRESUMO
When mammals strand, they present a unique opportunity to obtain insights into their ecology. In May 2013, three True's beaked whales (two adult females and a female calf) stranded on the north and west coasts of Ireland and the contents of their stomachs and intestines were analysed for anthropogenic debris. A method for identifying microplastics ingested by larger marine organisms was developed. Microplastics were identified throughout the digestive tract of the single whale that was examined for the presence of microplastics. The two adult females had macroplastic items in their stomachs. Food remains recovered from the adult whales consisted of mesopelagic fish (Benthosema glaciale, Nansenia spp., Chauliodius sloani) and cephalopods, although trophic transfer has been discussed, it was not possible to ascertain whether prey were the source of microplastics. This is the first study to directly identify microplastics <5 mm in a cetacean species.
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Monitoramento Ambiental , Conteúdo Gastrointestinal , Plásticos/análise , Poluentes da Água/análise , Baleias , Animais , Mergulho , Feminino , IrlandaRESUMO
The family practitioner plays an important role in the prevention, diagnosis, and early management of chronic pain. He/she is generally the first to be consulted, the one most familiar with the patients and their medical history, and is likely the first to be alerted in case of inadequate pain control or safety and tolerability issues. The family practitioner should therefore be at the center of the multidisciplinary team involved in a patient's pain management. The most frequent indications associated with chronic pain in family practice are of musculoskeletal origin, and the pain is often multimechanistic. Fixed-dose combination analgesics combine compounds with different mechanisms of action; their broader analgesic spectrum and potentially synergistic analgesic efficacy and improved benefit/risk ratio might thus be useful. A pain specialist meeting held in November 2010 agreed that the fixed-dose combination tramadol/paracetamol might be a useful pharmacological option for chronic pain management in family practice. The combination is effective in a variety of pain conditions with generally good tolerability. Particularly in elderly patients, it might be considered as an alternative to conventional analgesics such as NSAIDs, which should be used rarely with caution in this population.
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Managing pain from chronic conditions, such as, but not limited to, osteoarthritis and rheumatoid arthritis, requires the clinician to balance the need for effective analgesia against safety risks associated with analgesic agents. Osteoarthritis and rheumatoid arthritis pain is incompletely understood but involves both nociceptive and non-nociceptive mechanisms, including neuropathic mechanisms. Prevailing guidelines for arthritis-related pain do not differentiate between nociceptive and non-nociceptive pain, sometimes leading to recommendations that do not fully address the nature of pain. NSAIDs are effective in treating the nociceptive arthritis-related pain. However, safety concerns of NSAIDs may cause clinicians to undertreat arthritis-related pain. In this context, combination therapy may be more appropriate to manage the different pain mechanisms involved. A panel convened in November 2010 found that among the currently recommended analgesic products for arthritis-related pain, fixed-low-dose combination products hold promise for pain control because such products allow lower doses of individual agents resulting in decreased toxicity and acceptable efficacy due to synergy between the individual drugs. Better evidence and recommendations are required to improve treatment of chronic arthritis-related pain.
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Pain is the most common reason patients seek medical attention and pain relief has been put forward as an ethical obligation of clinicians and a fundamental human right. However, pain management is challenging because the pathophysiology of pain is complex and not completely understood. Widely used analgesics such as nonsteroidal anti-inflammatory drugs (NSAIDs) and paracetamol (acetaminophen) have been associated with adverse events. Adverse event rates are of concern, especially in long-term treatment or at high doses. Paracetamol and NSAIDs are available by prescription, over the counter, and in combination preparations. Patients may be unaware of the risk associated with high dosages or long-term use of paracetamol and NSAIDs. Clinicians should encourage patients to disclose all medications they take in a "do ask, do tell" approach that includes patient education about the risks and benefits of common pain relievers. The ideal pain reliever would have few risks and enhanced analgesic efficacy. Fixed-dose combination analgesics with two or more agents may offer additive or synergistic benefits to treat the multiple mechanisms of pain. Therefore, pain may be effectively treated while toxicity is reduced due to lower doses. One recent fixed-dose combination analgesic product combines tramadol, a centrally acting weak opioid analgesic, with low-dose paracetamol. Evidence-based guidelines recognize the potential value of combination analgesics in specific situations. The current guideline-based paradigm for pain treatment recommends NSAIDs for ongoing use with analgesics such as opioids to manage flares. However, the treatment model should evolve how to use low-dose combination products to manage pain with occasional use of NSAIDs for flares to avoid long-term and high-dose treatment with these analgesics. A next step in pain management guidelines should be targeted therapy when possible, or low-dose combination therapy or both, to achieve maximal efficacy with minimal toxicity.
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PURPOSE: Originally approved for three times/week dosing, recombinant human erythropoietin (rhEPO) is now often used at weekly intervals. We have studied rhEPO in mice to better understand why the extended dosing interval retains efficacy. METHODS: C57Bl/6 mice received a single sc. dose of rhEPO (3,000 IU/kg). Bone marrow and blood were collected at 8 h and 1, 2, 5 and 7 days. Staining for TER-119 and CD71, pulse labeling with bromodeoxyuridine, annexin-V binding and vital staining with 7-aminoactinomycin D: were used cell cycle and apoptosis in erythroblasts by four color flow cytometry. RESULTS: A wave of proliferation and/or maturation progressed through all erythroblasts, resulting in the emigration of immature reticulocytes into the periphery. An increase in the fraction of erythroblasts in S and G2M was found, but suppression of apoptosis was not. CONCLUSIONS: Most of the effects of rhEPO occurred 48 h after dosing, when the concentration of rhEPO was less than 1% of Cmax, suggesting that the processes set in motion by rhEPO can continue after rhEPO concentrations fall. Our observation of apoptosis in erythroblasts even when rhEPO concentrations were high suggests that regulatory mechanisms which down-regulate erythropoiesis are also engaged.