RESUMEN
Drug development for ischemic stroke is challenging as evidenced by the paucity of therapeutics that have advanced beyond a phase III trial. There are many reasons for this lack of clinical translation including factors related to the experimental design of preclinical studies. Often overlooked in therapeutic development for ischemic stroke is the requirement of effective drug delivery to the brain, which is critical for neuroprotective efficacy of several small and large molecule drugs. Advancing central nervous system drug delivery technologies implies a need for detailed comprehension of the blood-brain barrier (BBB) and neurovascular unit. Such knowledge will permit the innate biology of the BBB/neurovascular unit to be leveraged for improved bench-to-bedside translation of novel stroke therapeutics. In this review, we will highlight key aspects of BBB/neurovascular unit pathophysiology and describe state-of-the-art approaches for optimization of central nervous system drug delivery (ie, passive diffusion, mechanical opening of the BBB, liposomes/nanoparticles, transcytosis, intranasal drug administration). Additionally, we will discuss how endogenous BBB transporters represent the next frontier of drug delivery strategies for stroke. Overall, this review will provide cutting edge perspective on how central nervous system drug delivery must be considered for the advancement of new stroke drugs toward human trials.
Asunto(s)
Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Humanos , Sistemas de Liberación de Medicamentos , Accidente Cerebrovascular/tratamiento farmacológico , Fármacos del Sistema Nervioso Central/farmacología , Barrera HematoencefálicaRESUMEN
The fishing and aquaculture industry is vital for global food security, yet viral diseases can result in mass fish die-off events. Determining the viromes of traditionally understudied species, such as fish, enhances our understanding of the global virosphere and the factors that influence virome composition and disease emergence. Very little is known about the viruses present in New Zealand's native fish species, including the shortfin eel (Anguilla australis) and the longfin eel (Anguilla dieffenbachii), both of which are fished culturally by Maori (the indigenous population of New Zealand) and commercially. Through a total RNA metatranscriptomic analysis of longfin and shortfin eels across three different geographic locations in the South Island of New Zealand, we aimed to determine whether viruses had jumped between the two eel species and whether eel virome composition was impacted by life stage, species, and geographic location. We identified nine viral species spanning eight different families, thereby enhancing our understanding of eel virus diversity in New Zealand and the host range of these viral families. Viruses of the family Flaviviridae (genus Hepacivirus) were widespread and found in both longfin and shortfin eels, indicative of cross-species transmission or virus-host co-divergence. Notably, both host specificity and geographic location appeared to influence eel virome composition, highlighting the complex interaction between viruses, hosts, and their ecosystems. This study broadens our understanding of viromes in aquatic hosts and highlights the importance of gaining baseline knowledge of fish viral abundance and diversity, particularly in aquatic species that are facing population declines.
Asunto(s)
Anguilla , Rhabdoviridae , Animales , Anguilla/virología , Ecosistema , Geografía , Nueva ZelandaRESUMEN
BACKGROUND: Drug discovery for stroke is challenging as indicated by poor clinical translatability. In contrast, HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase inhibitors (ie, statins) improve poststroke neurological outcomes. This property requires transport across the blood-brain barrier via an endogenous uptake transporter (ie, Oatp1a4 [organic anion transporting polypeptide 1a4]). Our goal was to study Oatp1a4 as a drug delivery mechanism because the blood-brain barrier cannot be assumed to be completely open for all drugs in ischemic stroke. METHODS: Male Sprague-Dawley rats (200-250 g) were subjected to middle cerebral artery occlusion (90 minutes) followed by reperfusion for up to 7 days. Atorvastatin (20 mg/kg, IV) was administered 2 hours following intraluminal suture removal. Involvement of Oatp-mediated transport was determined using fexofenadine (3.2 mg/kg, IV), a competitive Oatp inhibitor. Oatp1a4 transport activity was measured by in situ brain perfusion. Infarction volumes/brain edema ratios and neuronal nuclei expression were determined using 2,3,5-triphenyltetrazolium chloride-stained brain tissue slices and confocal microscopy, respectively. Poststroke functional outcomes were assessed via neurological deficit scores and rotarod analysis. RESULTS: At 2-hour post-middle cerebral artery occlusion, [3H]atorvastatin uptake was increased in ischemic brain tissue. A single dose of atorvastatin significantly reduced post-middle cerebral artery occlusion infarction volume, decreased brain edema ratio, increased caudoputamen neuronal nuclei expression, and improved functional neurological outcomes. All middle cerebral artery occlusion positive effects of atorvastatin were attenuated by fexofenadine coadministration (ie, an Oatp transport inhibitor). CONCLUSIONS: Our data demonstrate that neuroprotective effects of atorvastatin may require central nervous system delivery by Oatp-mediated transport at the blood-brain barrier, a mechanism that persists despite increased cerebrovascular permeability in ischemic stroke. These novel and translational findings support utility of blood-brain barrier transporters in drug delivery for neuroprotective agents.
Asunto(s)
Edema Encefálico , Accidente Cerebrovascular Isquémico , Fármacos Neuroprotectores , Transportadores de Anión Orgánico , Accidente Cerebrovascular , Ratas , Animales , Masculino , Atorvastatina/farmacología , Ratas Sprague-Dawley , Neuroprotección , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Accidente Cerebrovascular/tratamiento farmacológico , Fármacos Neuroprotectores/farmacología , Transportadores de Anión Orgánico/metabolismoRESUMEN
Our laboratory has shown that activation of transforming growth factor- ß (TGF- ß )/activin receptor-like kinase 1 (ALK1) signaling can increase protein expression and transport activity of organic anion transporting polypeptide 1a4 (Oatp1a4) at the blood-brain barrier (BBB). These results are relevant to treatment of ischemic stroke because Oatp transport substrates such as 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (i.e., statins) improve functional neurologic outcomes in patients. Advancement of our work requires determination if TGF- ß /ALK1 signaling alters Oatp1a4 functional expression differently across brain regions and if such disparities affect central nervous system (CNS) statin disposition. Therefore, we studied regulation of Oatp1a4 by the TGF- ß /ALK1 pathway, in vivo, in rat brain microvessels isolated from cerebral cortex, hippocampus, and cerebellum using the ALK1 agonist bone morphogenetic protein-9 (BMP-9) and the ALK1 inhibitor 4-[6-[4-(1-piperazinyl)phenyl]pyrazolo[1,5-a]pyrimidin-3-yl]quinoline dihydrochloride 193189. We showed that Oatp1a4 protein expression and brain distribution of three currently marketed statin drugs (i.e., atorvastatin, pravastatin, and rosuvastatin) were increased in cortex relative to hippocampus and cerebellum. Additionally, BMP-9 treatment enhanced Oatp-mediated statin transport in cortical tissue but not in hippocampus or cerebellum. Although brain drug delivery is also dependent upon efflux transporters, such as P-glycoprotein and/or Breast Cancer Resistance Protein, our data showed that administration of BMP-9 did not alter the relative contribution of these transporters to CNS disposition of statins. Overall, this study provides evidence for differential regulation of Oatp1a4 by TGF- ß /ALK1 signaling across brain regions, knowledge that is critical for development of therapeutic strategies to target Oatps at the BBB for CNS drug delivery. SIGNIFICANCE STATEMENT: Organic anion transporting polypeptides (Oatps) represent transporter targets for brain drug delivery. We have shown that Oatp1a4 statin uptake is higher in cortex versus hippocampus and cerebellum. Additionally, we report that the transforming growth factor- ß /activin receptor-like kinase 1 agonist bone morphogenetic protein-9 increases Oatp1a4 functional expression, but not efflux transporters P-glycoprotein and Breast Cancer Resistance Protein, in cortical brain microvessels. Overall, this study provides critical data that will advance treatment for neurological diseases where drug development has been challenging.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Neoplasias , Transportadores de Anión Orgánico , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/metabolismo , Receptores de Activinas/metabolismo , Animales , Barrera Hematoencefálica/metabolismo , Encéfalo/metabolismo , Coenzima A/metabolismo , Factor 2 de Diferenciación de Crecimiento/metabolismo , Inhibidores de Hidroximetilglutaril-CoA Reductasas/metabolismo , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Proteínas de Neoplasias/metabolismo , Neoplasias/metabolismo , Transportadores de Anión Orgánico/metabolismo , Oxidorreductasas/metabolismo , Ratas , Factor de Crecimiento Transformador beta/metabolismo , Factores de Crecimiento Transformadores/metabolismoRESUMEN
Globally, stroke is a leading cause of death and long-term disability. Over the past decades, several efforts have attempted to discover new drugs or repurpose existing therapeutics to promote post-stroke neurological recovery. Preclinical stroke studies have reported successes in identifying novel neuroprotective agents; however, none of these compounds have advanced beyond a phase III clinical trial. One reason for these failures is the lack of consideration of blood-brain barrier (BBB) transport mechanisms that can enable these drugs to achieve efficacious concentrations in ischemic brain tissue. Despite the knowledge that drugs with neuroprotective properties (i.e., statins, memantine, metformin) are substrates for endogenous BBB transporters, preclinical stroke research has not extensively studied the role of transporters in central nervous system (CNS) drug delivery. Here, we review current knowledge on specific BBB uptake transporters (i.e., organic anion transporting polypeptides (OATPs in humans; Oatps in rodents); organic cation transporters (OCTs in humans; Octs in rodents) that can be targeted for improved neuroprotective drug delivery. Additionally, we provide state-of-the-art perspectives on how transporter pharmacology can be integrated into preclinical stroke research. Specifically, we discuss the utility of in vivo stroke models to transporter studies and considerations (i.e., species selection, co-morbid conditions) that will optimize the translational success of stroke pharmacotherapeutic experiments.
Asunto(s)
Barrera Hematoencefálica/metabolismo , Accidente Cerebrovascular Isquémico/metabolismo , Transportadores de Anión Orgánico/metabolismo , Proteínas de Transporte de Catión Orgánico/metabolismo , Animales , Modelos Animales de Enfermedad , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Accidente Cerebrovascular Isquémico/tratamiento farmacológico , Terapia Molecular Dirigida , Fármacos Neuroprotectores/farmacocinética , Fármacos Neuroprotectores/uso terapéuticoRESUMEN
BACKGROUND: Non-surgical multidisciplinary management is often the first pathway of care for patients with chronic low back pain (LBP). This study explores if patient characteristics recorded at the initial service examination have an association with a poor response to this pathway of care in an advanced practice physiotherapist-led tertiary service. METHODS: Two hundred and forty nine patients undergoing non-surgical multidisciplinary management for their LBP across 8 tertiary public hospitals in Queensland, Australia participated in this prospective longitudinal study. Generalised linear models (logistic family) examined the relationship between patient characteristics and a poor response at 6 months follow-up using a Global Rating of Change measure. RESULTS: Overall 79 of the 178 (44%) patients completing the Global Rating of Change measure (28.5% loss to follow-up) reported a poor outcome. Patient characteristics retained in the final model associated with a poor response included lower Formal Education Level (ie did not complete school) (Odds Ratio (OR (95% confidence interval)) (2.67 (1.17-6.09), p = 0.02) and higher self-reported back disability (measured with the Oswestry Disability Index) (OR 1.33 (1.01-1.77) per 10/100 point score increase, p = 0.046). CONCLUSIONS: A low level of formal education and high level of self-reported back disability may be associated with a poor response to non-surgical multidisciplinary management of LBP in tertiary care. Patients with these characteristics may need greater assistance with regard to their comprehension of health information, and judicious monitoring of their response to facilitate timely alternative care if no benefits are attained.
Asunto(s)
Dolor de la Región Lumbar , Fisioterapeutas , Australia/epidemiología , Evaluación de la Discapacidad , Humanos , Estudios Longitudinales , Dolor de la Región Lumbar/diagnóstico , Dolor de la Región Lumbar/epidemiología , Dolor de la Región Lumbar/terapia , Dimensión del Dolor , Estudios ProspectivosRESUMEN
Drug permeability across the blood-brain barrier (BBB) is an important concept in the development of therapeutic strategies to treat neurological diseases such as ischemic stroke. These mechanisms can be evaluated in detail using cultured brain microvascular endothelial cells or intact animals subjected to experimental stroke. Here, we describe state-of-the-art approaches to study BBB transport of therapeutics using our in vitro and in vivo approaches. These methodologies allow for precise determination of transporter kinetic properties for currently marketed therapeutics or for new chemical entities that are under development as stroke drugs.
Asunto(s)
Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Animales , Barrera Hematoencefálica , Células Endoteliales , Encéfalo , Accidente Cerebrovascular/tratamiento farmacológicoRESUMEN
The neurovascular unit (NVU) is an anatomical group of cells that establishes the blood-brain barrier (BBB) and coordinates cerebral blood flow in association with neuronal function. In cerebral gray matter, cellular constituents of the NVU include endothelial cells and associated pericytes, astrocytes, neurons, and microglia. Dysfunction of the NVU is a common feature of diseases that affect the CNS, such as ischemic stroke. High-level evaluation of these NVU changes requires the use of imaging modalities that can enable the visualization of various cell types under disease conditions. In this study, we applied our confocal microscopy strategy using commercially available labeling reagents to, for the first time, simultaneously investigate associations between endothelial cells, the vascular basal lamina, pericytes, microglia, astrocytes and/or astrocyte end-feet, and neurites in both healthy and ischemic brain tissue. This allowed us to demonstrate ischemia-induced astrocyte activation, neurite loss, and microglial migration toward blood vessels in a single confocal image. Furthermore, our labeling cocktail enabled a precise quantification of changes in neurites and astrocyte reactivity, thereby showing the relationship between different NVU cellular constituents in healthy and diseased brain tissue. The application of our imaging approach for the simultaneous visualization of multiple NVU cell types provides an enhanced understanding of NVU function and pathology, a state-of-the-art advancement that will facilitate the development of more effective treatment strategies for diseases of the CNS that exhibit neurovascular dysfunction, such as ischemic stroke.
Asunto(s)
Accidente Cerebrovascular Isquémico , Humanos , Accidente Cerebrovascular Isquémico/metabolismo , Células Endoteliales/fisiología , Encéfalo/patología , Barrera Hematoencefálica/patología , Astrocitos/metabolismoRESUMEN
Drug discovery and development for stroke is challenging as evidenced by few drugs that have advanced beyond a Phase III clinical trial. Memantine is a N-methyl-d-aspartate (NMDA) receptor antagonist that has been shown to be neuroprotective in various preclinical studies. We have identified an endogenous BBB uptake transport system for memantine: organic cation transporters 1 and 2 (Oct1/Oct2). Our goal was to evaluate Oct1/Oct2 as a required BBB mechanism for memantine neuroprotective effects. Male Sprague-Dawley rats (200-250 g) were subjected to middle cerebral artery occlusion (MCAO) for 90 min followed by reperfusion. Memantine (5 mg/kg, i.v.) was administered 2 h following intraluminal suture removal. Specificity of Oct-mediated transport was evaluated using cimetidine (15 mg/kg, i.v.), a competitive Oct1/Oct2 inhibitor. At 2 h post-MCAO, [3H]memantine uptake was increased in ischemic brain tissue. Cimetidine inhibited blood-to-brain uptake of [3H]memantine, which confirmed involvement of an Oct-mediated transport mechanism. Memantine reduced post-MCAO infarction and brain edema progression as well as improved neurological outcomes during post-stroke recovery. All positive effects of memantine were attenuated by co-administration of cimetidine, which demonstrates that Oct1/Oct2 transport is required for memantine to exert neuroprotective effects in ischemic stroke. Furthermore, Oct1/Oct2-mediated transport was shown to be the dominant mechanism for memantine brain uptake in the MCAO model despite a concurrent increase in paracellular "leak." These novel and translational findings provide mechanistic evidence for the critical role of BBB transporters in CNS delivery of stroke therapeutics, information that can help such drugs advance in clinical trials.
Asunto(s)
Accidente Cerebrovascular Isquémico , Fármacos Neuroprotectores , Accidente Cerebrovascular , Animales , Barrera Hematoencefálica/metabolismo , Cationes , Cimetidina/farmacología , Cimetidina/uso terapéutico , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Masculino , Memantina/farmacología , Memantina/uso terapéutico , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Proteínas de Transporte de Catión Orgánico/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores de N-Metil-D-Aspartato , Accidente Cerebrovascular/tratamiento farmacológicoRESUMEN
The consumption of acetaminophen (APAP) can induce neurological changes in human subjects; however, effects of APAP on blood-brain barrier (BBB) integrity are unknown. BBB changes by APAP can have profound consequences for brain delivery of co-administered drugs. To study APAP effects, female Sprague-Dawley rats (12-16 weeks old) were administered vehicle (i.e., 100% dimethyl sulfoxide (DMSO), intraperitoneally (i.p.)) or APAP (80 mg/kg or 500 mg/kg in DMSO, i.p.; equivalent to a 900 mg or 5600 mg daily dose for a 70 kg human subject). BBB permeability was measured via in situ brain perfusion using [14C]sucrose and [3H]codeine, an opioid analgesic drug that is co-administered with APAP (i.e., Tylenol #3). Localization and protein expression of tight junction proteins (i.e., claudin-5, occludin, ZO-1) were studied in rat brain microvessels using Western blot analysis and confocal microscopy, respectively. Paracellular [14C]sucrose "leak" and brain [3H]codeine accumulation were significantly enhanced in rats treated with 500 mg/kg APAP only. Additionally, claudin-5 localization and protein expression were altered in brain microvessels isolated from rats administered 500 mg/kg APAP. Our novel and translational data show that BBB integrity is altered following a single high APAP dose, results that are relevant to patients abusing or misusing APAP and/or APAP/opioid combination products.
RESUMEN
Ischemic stroke is the 5th leading cause of death in the United States. Despite significant improvements in reperfusion therapies, stroke patients still suffer from debilitating neurocognitive deficits. This indicates an essential need to develop novel stroke treatment paradigms. Endogenous uptake transporters expressed at the blood-brain barrier (BBB) provide an excellent opportunity to advance stroke therapy via optimization of small molecule neuroprotective drug delivery to the brain. Examples of such uptake transporters include organic anion transporting polypeptides (OATPs in humans; Oatps in rodents) and organic cation transporters (OCTs in humans; Octs in rodents). Of particular note, small molecule drugs that have neuroprotective properties are known substrates for these transporters and include 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (i.e., statins) for OATPs/Oatps and 1-amino-3,5-dimethyladamantane (i.e., memantine) for OCTs/Octs. Here, we review current knowledge on specific BBB transporters that can be targeted for improvement of ischemic stroke treatment and provide state-of-the-art perspectives on the rationale for considering BBB transport properties during discovery/development of stroke therapeutics.
RESUMEN
Opioid-exposed infants display a wide and variable range of dysregulated neurobehavioral functioning, but the regulatory difficulties experienced by these infants outside the defined clusters of neonatal abstinence syndrome (NAS) have not been well described and may have implications for the infant's developmental course. This study describes the neurobehavioral functioning of neonates prenatally exposed to methadone, using the NICU Network Neurobehavioral Scale (NNNS), and explores the relationships between maternal factors and infant functioning. The relationship between NNNS measures, NAS severity, and need for pharmacotherapy for NAS was also evaluated. Infants who required pharmacologic treatment for NAS showed more dysregulated behavior and signs of stress and abstinence as indicated by NNNS scores, but NNNS scores were not significantly correlated with maternal methadone dose. The determination of the range of the methadone-exposed infant's neurobehavioral repertoire could guide the optimal treatment of all such infants, particularly those requiring only nonpharmacologic care.
Asunto(s)
Exposición Materna , Metadona/efectos adversos , Síndrome de Abstinencia Neonatal/patología , Efectos Tardíos de la Exposición Prenatal/fisiopatología , Análisis de Varianza , Femenino , Humanos , Recién Nacido , Letargia/inducido químicamente , Movimiento/efectos de los fármacos , Hipertonía Muscular/inducido químicamente , Hipotonía Muscular/inducido químicamente , Embarazo , Reflejo Anormal/efectos de los fármacos , Estrés Fisiológico/efectos de los fármacosRESUMEN
Desmoplakin (DP) is an obligate component of desmosomal cell-cell junctions that links the adhesion plaque to the cytoskeletal intermediate filament network. While a central role for DP in maintaining the structure and stability of the desmosome is well established, recent work has indicated that DP's functions may extend beyond cell-cell adhesion. In our study, we show that loss of DP results in a significant increase in cellular migration, as measured by scratch wound assays, Transwell migration assays, and invasion assays. Loss of DP causes dramatic changes in actin cytoskeleton morphology, including enhanced protrusiveness, and an increase in filopodia length and number. Interestingly, these changes are also observed in single cells, indicating that control of actin morphology is a cell-cell adhesion-independent function of DP. An investigation of cellular signaling pathways uncovered aberrant Rac and p38 mitogen-activated protein kinase (MAPK) activity in DP knockdown cells, restoration of which is sufficient to rescue DP-dependent changes in both cell migration and actin cytoskeleton morphology. Taken together, these data highlight a previously uncharacterized role for the desmosomal cytolinker DP in coordinating cellular migration via p38 MAPK and Rac signaling.
Asunto(s)
Movimiento Celular/fisiología , Desmoplaquinas/metabolismo , Transducción de Señal/fisiología , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Proteínas de Unión al GTP rho/metabolismo , Citoesqueleto de Actina/metabolismo , Amidas/farmacología , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Desmoplaquinas/genética , Técnicas de Silenciamiento del Gen , Humanos , Filamentos Intermedios/metabolismo , Piridinas/farmacología , Pironas/farmacología , Quinolinas/farmacología , ARN Interferente Pequeño/metabolismo , Transducción de Señal/efectos de los fármacos , Zearalenona/análogos & derivados , Zearalenona/farmacología , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidores , Proteínas Quinasas p38 Activadas por Mitógenos/genética , Proteínas de Unión al GTP rho/antagonistas & inhibidoresRESUMEN
PURPOSE: To compare speech intelligibility in the presence of a 10-Hz square-wave noise masker in younger and older listeners and to relate performance to recovery from forward masking. METHOD: The signal-to-noise ratio required to achieve 50% sentence identification in the presence of a 10-Hz square-wave noise masker was obtained for each of the 8 younger/older listener pairs. Listeners were matched according to their quiet thresholds for frequencies from 600 to 4800 Hz in octave steps. Forward masking was also measured in 2 younger/older threshold-matched groups for signal delays of 2-40 ms. RESULTS: Older listeners typically required a significantly higher signal-to-noise ratio than younger listeners to achieve 50% correct sentence recognition. This effect may be understood in terms of increased forward-masked thresholds throughout the range of signal delays corresponding to the silent intervals in the modulated noise (e.g., <50 ms). CONCLUSIONS: Significant differences were observed between older and younger listeners on measures of both speech intelligibility in a modulated background and forward masking over a range of signal delays (0-40 ms). Age-related susceptibility to forward masking at relatively short delays may reflect a deficit in processing at a fairly central level (e.g., broader temporal windows or less efficient processing).
Asunto(s)
Envejecimiento/fisiología , Enmascaramiento Perceptual/fisiología , Presbiacusia/fisiopatología , Percepción del Habla/fisiología , Estimulación Acústica , Adulto , Anciano , Umbral Auditivo/fisiología , Humanos , Persona de Mediana Edad , RuidoRESUMEN
OBJECTIVE: To estimate the prevalence of overweight and obesity in a population comprised of patients seen at two local primary care clinics and to evaluate the management of this epidemic in a primary care setting. METHODS: Patient medical charts from two urban community clinics in Louisville, Kentucky, were reviewed to determine how the diagnosis of overweight and obesity was assessed and treated. RESULTS: The estimated prevalence of obesity in this population was 40.2% as compared to the national statistics of 30.5%. Despite the higher percentage of obesity, less advice regarding weight loss was given to the patient group under study (30.5%) compared to national survey estimates (42% advised to lose weight and 34% counseled on physical activity). CONCLUSIONS: Data presented here suggest that patients within this Kentucky urban primary care community have not received adequate obesity advice from their physician. Obesity is a growing concern and must be addressed by increasing awareness.
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Centros Comunitarios de Salud/normas , Consejo/estadística & datos numéricos , Obesidad/diagnóstico , Obesidad/prevención & control , Atención Primaria de Salud/normas , Adulto , Anciano , Competencia Clínica , Femenino , Humanos , Kentucky/epidemiología , Masculino , Auditoría Médica , Persona de Mediana Edad , Obesidad/epidemiología , Educación del Paciente como Asunto , Prevalencia , Factores de RiesgoRESUMEN
Adverse effects associated with synthetic cannabinoid use include agitation, psychosis, seizures and cardiovascular effects, all which may result in a lethal outcome. We report the collection of data from 25 medical examiner and coroner cases where the presence of synthetic cannabinoids was analytically determined. Participating offices provided case history, investigative and relevant autopsy findings and toxicology results along with the cause and manner of death determination. This information, with the agency and cause and manner of death determinations blinded, was sent to participants. Participants offered their opinions regarding the likely contribution of the toxicology findings to cause and manner of death. The results show that some deaths are being attributed to synthetic cannabinoids, with the highest risk areas being behavioral toxicity resulting in excited delirium, trauma or accidents and as contributing factors in subjects with pre-existing cardiopulmonary disease. While insufficient information exists to correlate blood synthetic cannabinoid concentrations to effect, in the absence of other reasonable causes, the drugs should be considered as a cause or contributory cause of death based on history and circumstances with supporting toxicological data.
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Cannabinoides/efectos adversos , Drogas de Diseño/efectos adversos , Trastornos Relacionados con Sustancias/complicaciones , Trastornos Relacionados con Sustancias/mortalidad , Adolescente , Adulto , Causas de Muerte , Médicos Forenses , Delirio/inducido químicamente , Femenino , Patologia Forense , Toxicología Forense , Cardiopatías/mortalidad , Humanos , Masculino , Persona de Mediana Edad , Estados Unidos/epidemiología , Heridas y Lesiones/mortalidad , Adulto JovenRESUMEN
Cochlear compression in normal-hearing listeners was estimated at octave frequencies from 250 to 4000 Hz using a forward-masking paradigm. Temporal masking curves (TMCs) for a 10-dB SL signal were obtained with two maskers -- one equal in frequency to the signal and another an octave below the signal. The ratio of the slope of the off-frequency function to that of the mid-level portion of the on-frequency function was computed as an estimate of the amount of compression at each frequency. Compression was less frequency selective at low frequencies, so an average of the off-frequency slopes at high frequencies (1000, 2000, and 4000 Hz) was used in computing the ratio for each signal frequency. Results indicated strong compression (approximately 0.15-0.30) at all frequencies using the averaged off-frequency slopes, indicating little difference in compression across frequencies. Distortion product otoacoustic emission (DPOAE) input-output (I-O) functions were obtained for each subject at 1000, 2000, and 4000 Hz. The slopes of the DPOAE I-O functions and the psychophysical growth rates were similar to one another, reinforcing the assumption that the forward-masking procedure is providing an estimate of cochlear compression, at least at frequencies from 1000 to 4000 Hz.
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Percepción Auditiva/fisiología , Cóclea/fisiología , Emisiones Otoacústicas Espontáneas/fisiología , Enmascaramiento Perceptual/fisiología , Pruebas de Impedancia Acústica , Estimulación Acústica , Adulto , Análisis de Varianza , Umbral Auditivo/fisiología , Membrana Basilar/fisiología , Células Ciliadas Auditivas/fisiología , Humanos , Psicoacústica , Análisis de RegresiónRESUMEN
Objetivo: Comparar la eficacia de la inmovilización nocturna de la muñeca con una férula cubital en ángulo neutro junto con la aplicación de ultrasonido en pacientes con síndrome del túnel carpiano leve y moderado. Materiales y Métodos: Entre octubre de 2007 y marzo de 2010, se incluyó a pacientes >18 años con síndrome del túnel carpiano confirmado por electromiografía en un hospital de Buenos Aires. Se realizó una aleatorización estratificada, con bloques permutados aleatorios, y apareamiento por sexo y edad. Los pacientes fueron asignados al grupo experimental (GE) o al grupo de control (GC). Ambos grupos recibieron ultrasonido de 1 MHz pulsante por 15 min, 3 veces por semana, durante 6 semanas. Los pacientes del GE, además, utilizaron una férula nocturna. Se evaluaron el dolor y la parestesia con la escala analógica visual de 100 mm, la PSFS y el test de Moberg, al comenzar, a las 3 semanas y, al finalizar, a las 6 semanas, y durante el seguimiento, al mes, y a los 3 y 6 meses, con evaluador a ciego. Resultados: Se analizó a 32 pacientes del GC y a 33 del GE. Al finalizar el tratamiento, todas las variables habían mejorado en ambos grupos, con diferencia de medias estadísticamente significativa para el dolor a favor del GE a las 3 semanas de tratamiento 1,64 (IC95% 0,38-2,91; p = 0,012), pero sin diferencia clínica significativa. No se informaron efectos adversos. Conclusión: El tratamiento con una férula nocturna y ultrasonido no es superior al ultrasonido solo en pacientes con STC. Nivel de Evidencia; II
Objective: To compare the effectiveness of night wrist immobilization using an ulnar splint in neutral angle versus the use of ultrasound (US) in patients with Carpal Tunnel Syndrome (CTS). Materials and Methods: Study population included over 18 years of age that were treated for electromyography-confirmed CTS between October 2007 and March 2010 at a Buenos Aires hospital. A sex- and age-stratified randomization was performed by using randomly permuted blocks, allocating patients into the experimental group (EG) and control group (CG). Pulsed US therapy was administered for 15 minutes to all patients three times a week for six weeks at a frequency of 1 MHz. In addition, EG patients were also prescribed night splint. Pain and paresthesia were evaluated using a 100mm Visual Analogue Scale (VAS), the Patient Specific Functional Scale (PSFS), and the Moberg pickup test (MPUT) at baseline, at 3 and 6 weeks, and at 3 and 6 months after treatment institution by a blinded investigator. Results: Study population consisted of 85 cases (65 patients) that were randomly allocated to CG (n=42) or EG (n=43). Improvement of all the variables was observed at the end of treatment in both groups, with a 1.64 (95% CI: 0.38-2.91, P=0.012) statistically significant difference in means for pain in favor of the EG at 3 weeks of treatment, but without a significant clinical difference. No adverse effects were observed. Conclusion: The effectiveness of combined night splint and US therapy is not superior to the US alone treatment in CTS patients. Level of Evidence; II
Asunto(s)
Adulto , Persona de Mediana Edad , Terapia por Ultrasonido , Síndrome del Túnel Carpiano , FerulaRESUMEN
Previous research has shown that separate information sources, activated closely together in time, can induce errors suggestive of memory blends. In Experiment 1, homophones were used to induce such memory errors. In a study task, participants made relatedness judgments to word pairs that included homophones (e.g., PAWS-BEAR). During this task, one group (study-similar) maintained memory loads with words that were orthographically similar to the presented homophones (e.g., JAWS). Another group (test-similar) maintained memory loads similar to those obtained for the study homophone's alternate spelling (e.g., CAUSE). A third group maintained no memory load during the task. In a surprise recognition test, participants were presented both previously viewed homophones (PAWS) and non-presented alternate spellings (PAUSE). We hypothesized that partially activated alternate spellings, in conjunction with the orthographically similar memory words, would result in the creation of blended memories. The results followed suit: The test-similar condition produced significantly elevated false alarms, relative to both the study-similar and the no-load conditions. Experiment 2 replicated these results while including memory loads to control for potential orthographic confusions. The findings are discussed in terms of multiple, episodic memories later activated as single, blended memories.
Asunto(s)
Memoria , Fonética , Percepción del Habla , Humanos , Reconocimiento en Psicología , VocabularioRESUMEN
There is accumulating evidence that pregnancy is accompanied by hyporesponsivity to physical, cognitive, and psychological challenges. This study evaluates whether observed autonomic blunting extends to conditions designed to decrease arousal. Physiological and psychological responsivity to an 18-min guided imagery relaxation protocol in healthy pregnant women during the 32nd week of gestation (n=54) and non-pregnant women (n=28) was measured. Data collection included heart period (HP), respiratory sinus arrhythmia (RSA), tonic and phasic measures of skin conductance (SCL and NS-SCR), respiratory period (RP), and self-reported psychological relaxation. As expected, responses to the manipulation included increased HP, RSA, and RP and decreased SCL and NS-SCR, followed by post-manipulation recovery. However, responsivity was attenuated for all physiological measures except RP in pregnant women, despite no difference in self-reported psychological relaxation. Findings support non-specific blunting of physiological responsivity during pregnancy.