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As the need for high-speed electronics continues to rise rapidly, printed wiring board (PWB) requirements become ever-more demanding. A typical PWB is fabricated by bonding dielectric films such as polyimide to electrically conductive copper foil such as rolled annealed (RA) copper and is expected to become thinner, flexible, durable, and compatible with high-frequency 5G performance. Polyimide films inherently feature a higher coefficient of thermal expansion (CTE) than copper foils; this mismatch causes residual thermal stresses. To attenuate the mismatch, silica nanoparticles may be used to reduce the CTE of PI. A nodulated copper surface can be used to enhance the Cu/PI adhesion by additional bonding mechanisms that could include a type of mechanical bonding, which is a focus of this study. In this investigation, a 90° peel test was used to measure the peel strength in copper/polyimide/copper laminates containing nodulated copper and polyimide reinforced with 0, 20, and 40 wt % silica nanoparticles. The influence of silica nanoparticles on the peel strength was quantitatively evaluated. Laminates incorporating polyimide films lacking silica nanoparticles had a â¼3.75× higher peel strength compared with laminates reinforced with 40% silica. Their failure surfaces were analyzed by using scanning electron microscopy (SEM), energy-dispersive X-ray analysis (EDX), and X-ray photoelectron spectroscopy to identify the mode of failure and to understand bonding mechanisms. The key bonding mechanism, mechanical interlocking, was achieved when the polyimide surrounded or engulfed the copper nodules when the laminate was created. Post-testing failure surface analysis revealed the presence of copper on the polyimide side and polyimide on the copper side, indicating mixed mode failure. An analytical model was developed to determine the impact of applied pressure, temperature, and time on the polyimide penetration and mechanical interlocking around the copper nodules. The model was validated by measuring the peel strength on another set of specimens fabricated using increased temperature and pressure that showed a 3× increase in peel strength compared to lower temperature/pressure processing conditions. This enhanced adhesion resulted from the lower polymer material viscosity at higher temperatures, which fosters deeper and more complete penetration around the copper nodules during processing at higher pressures for longer durations. The methodology of combining peel testing, viscosity and CTE measurement, SEM/EDX, surface chemical analysis, and penetration depth calculation developed herein enables the calculation of the desired processing parameters to enhance functionality and improve adhesion.
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OBJECTIVE: Global treatment guidelines recommend treatment with oral anticoagulants (OACs) for patients with non-valvular atrial fibrillation (NVAF) and an elevated stroke risk. However, not all patients with NVAF and an elevated stroke risk receive guideline-recommended therapy. A literature review and synthesis of observational studies were undertaken to identify the body of evidence on untreated and undertreated NVAF and the association with clinical and economic outcomes. METHODS: An extensive search (1/2010-4/2020) of MEDLINE, the Cochrane Library, conference proceedings, and health technology assessments (HTAs) was conducted. Studies must have evaluated rates of nontreatment or undertreatment in NVAF. Nontreatment was defined as absence of OACs (but with possible antiplatelet treatment), while undertreatment was defined as treatment with only antiplatelet agents. RESULTS: Sixteen studies met our inclusion criteria. Rates of nontreatment for patients with elevated stroke risk ranged from 2.0-51.1%, while rates of undertreatment ranged from 10.0-45.1%. The clinical benefits of anticoagulation were reported in the evaluated studies with reductions in stroke and mortality outcomes observed among patients treated with anticoagulants compared to untreated or undertreated patients. Adverse events associated with all bleeding types (i.e. hemorrhagic stroke, major bleeding or gastrointestinal hemorrhaging) were found to be higher for warfarin patients compared to untreated patients in real-world practice. Healthcare resource utilization was found to be lower among patients highly-adherent to warfarin compared to untreated patients. CONCLUSIONS: Rates of nontreatment and undertreatment among NVAF patients remain high and are associated with preventable cardiovascular events and death. Strategies to increase rates of treatment may improve clinical outcomes.
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Fibrilación Atrial , Accidente Cerebrovascular , Administración Oral , Anticoagulantes/efectos adversos , Fibrilación Atrial/complicaciones , Fibrilación Atrial/tratamiento farmacológico , Humanos , Accidente Cerebrovascular/tratamiento farmacológico , Accidente Cerebrovascular/etiología , Accidente Cerebrovascular/prevención & control , Warfarina/uso terapéuticoRESUMEN
BACKGROUND: Despite treatment guidelines recommending the use of oral anticoagulants (OACs) for patients with non-valvular atrial fibrillation (NVAF) and moderate to high risk of stroke (CHA2DS2-VASc score ≥1), many patients remain untreated. A study conducted among Medicare beneficiaries with AF and a CHA2DS2-VASc score of ≥2 found that 51% of patients were not prescribed an OAC despite being eligible for treatment. When left untreated, NVAF poses an enormous burden to society, as stroke events are estimated to cost the US healthcare system about $34 billion each year in both direct medical costs and indirect productivity losses. This research explored the short-term clinical implications and budget impact (BI) of increasing OAC use among Medicare beneficiaries with NVAF. METHODS: A decision-analytic model was developed from the payer and societal perspectives to estimate the impact of increasing treatment rates among Medicare-eligible NVAF patients with a moderate-to-high risk of stroke over 1 year. Results of the model compared (1) a base case scenario using literature-derived rates of OAC use, and (2) a hypothetical scenario assuming an absolute 5% increase in overall OAC use. Clinical outcomes included the incremental annual number of ischemic stroke, hemorrhagic stroke, and gastrointestinal bleeding events, and stroke-related deaths. Economic outcomes included incremental annual and per-member per-month (PMPM) direct medical costs for the payer perspective and the incremental sum of annual direct medical and indirect costs from productivity loss and caregiver burden for the societal perspective. RESULTS: In total, 1.95 million Medicare patients with NVAF were estimated to be treated with OACs in the base case (3.8% of beneficiaries). In the hypothetical scenario analysis, nearly 200,000 more patients were treated resulting in 3,705 fewer ischemic strokes, 14 fewer gastrointestinal bleeds, 141 more hemorrhagic strokes, and 175 fewer deaths. The total incremental BI was $399.16 million ($0.65 PMPM) from the payer perspective and $377.10 million from the societal perspective due to indirect cost savings ($22.06 million). CONCLUSION: Our findings suggest that increased overall OAC use has a positive clinical benefit on the annual number of ischemic stroke events and deaths avoided in the Medicare population, while maintaining a modest increase in the overall BI to the Medicare system.
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Fibrilación Atrial , Accidente Cerebrovascular , Administración Oral , Anciano , Anticoagulantes/uso terapéutico , Fibrilación Atrial/tratamiento farmacológico , Ahorro de Costo , Humanos , Medicare , Accidente Cerebrovascular/tratamiento farmacológico , Accidente Cerebrovascular/epidemiología , Accidente Cerebrovascular/prevención & control , Estados Unidos/epidemiologíaRESUMEN
INTRODUCTION: Detection of atrial fibrillation (AF) is required to initiate oral anticoagulation (OAC) after cryptogenic stroke (CS). However, paroxysmal AF can be difficult to diagnose with short term cardiac monitoring. Taking an Australian payer perspective, we evaluated whether long-term continuous monitoring for 3 years with an insertable cardiac monitor (ICM) is cost-effective for preventing recurrent stroke in patients with CS. METHODS: A lifetime Markov model was developed to simulate the follow-up of patients, comparing long-term continuous monitoring with an ICM to monitoring by conventional care. We used a linked evidence approach to estimate the rates of recurrent stroke when AF detection leads to initiation of OAC, as detected using ICM during the lifetime of the device or as detected using usual care. All diagnostic and patient management costs were modeled. Other model inputs were determined by literature review. Probabilistic sensitivity analysis (PSA) was undertaken to explore the effect of parameter uncertainty according to CHADS2 score and OAC treatment effect. RESULTS: In the base-case analysis, the model predicted an incremental cost-effectiveness ratio (ICER) of A$29 570 per quality-adjusted life year (QALY). Among CHADS2 subgroups analyses, the ICER ranged from A$26 342/QALY (CHADS2 = 6) to A$42 967/QALY (CHADS2 = 2). PSA suggested that the probabilities of ICM strategy being cost-effective were 53.4% and 78.7%, at thresholds of $30 000 (highly cost-effective) and $50 000 per QALY (cost-effective), respectively. CONCLUSIONS: Long-term continuous monitoring with an ICM is a cost-effective intervention to prevent recurrent stroke in patients following CS in the Australian context.
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We address the dilemma faced by oncologists in administering preventative measures to "at risk" patients diagnosed with atypical and nonatypical hyperplasias due to lack of any molecular means of risk stratification and identifying high-risk subjects. Our study purpose is to investigate a four marker risk signature, MMP-1, CEACAM6, HYAL1, and HEC1, using 440 hyperplastic tissues for identifying high-risk subjects who will benefit from preventative therapies. We assayed the markers by IHC and combined their expression levels to obtain a composite value from 0-10, which we called a "Cancer Risk Score." We demonstrate that the four marker-based risk scores predict subsequent cancer development with an accuracy of 91% and 86% for atypical and nonatypical subjects, respectively. We have established a correlation between risk scores and cancer rates by stratifying the samples into low risk (score ≤ 0.5); intermediate risk (score ≤ 5.4), and high risk (score >5.4) groups using Kaplan-Meier survival analysis. We have evaluated cancer rates at 5, 10, and 15 years. Our results show that the average cancer rates in the first 5 years among low- and intermediate-risk groups were 2% and 15%, respectively. Among high-risk group, the average cancer rates at 5 years were 73% and 34% for atypical and nonatypical subjects, respectively. The molecular risk stratification described here assesses a patient's tumor biology-based risk level as low, intermediate, or high and for making informed treatment decisions. The outcomes of our study in conjunction with the available prophylactic measures could prevent approximately 20%-25% of sporadic breast cancers.
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Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/patología , Carcinoma Ductal de Mama/patología , Carcinoma Lobular/patología , Hiperplasia/patología , Medición de Riesgo/métodos , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/metabolismo , Carcinoma Ductal de Mama/epidemiología , Carcinoma Ductal de Mama/metabolismo , Carcinoma Lobular/epidemiología , Carcinoma Lobular/metabolismo , Estudios de Casos y Controles , Femenino , Estudios de Seguimiento , Humanos , Hiperplasia/epidemiología , Hiperplasia/metabolismo , Incidencia , Persona de Mediana Edad , Pronóstico , Factores de Riesgo , Estados Unidos/epidemiologíaRESUMEN
AIMS: The goal of this study was to assess the cost-effectiveness of mechanical thrombectomy (MT) for acute ischemic stroke (AIS) from an Australian payer perspective. METHODS: This study used a Markov model that employed a life-time time horizon, modeling patients from symptom onset of stroke until end of life. Clinical efficacy and safety data were taken from an individual patient level data (IPD) meta-analysis of clinical studies. The treatment effect of MT compared to usual care was measured by changes in modified Rankin Score (mRS). Post-treatment mRS scores were used to determine short- and long-term stroke care costs. Treatment costs were modeled, with health state utility values determined by literature review. All analyses were conducted using Microsoft Excel. RESULTS: In comparison to usual care, MT is associated with higher costs ($10,666 per patient) and additional quality-adjusted life years (QALYs) (0.8281 per patient), resulting in an incremental cost per QALY of $12,880. Sensitivity analyses demonstrated the reliability of the base case results across a range of assumptions. The higher cost associated with MT is, to an extent, offset by the cost savings resulting from lower stroke care costs due to improved patient outcomes. The life-time cost savings in terms of stroke care costs are estimated to be more than $8,000 per patient for patients who had received MT in combination with usual care. LIMITATIONS: Stroke care costs based on patient disability/functional level were not available and were derived. As a consequence, long-term care costs for patients with poorer outcomes may be under-estimated. Patient outcomes at 90 days were extrapolated to a lifetime horizon, but this approach was supported by long-term evidence on stroke survival. CONCLUSIONS: Mechanical thrombectomy is a cost-effective treatment option for AIS, with clinical benefits translating to short- and long-term cost benefits. This analysis supports rapid update of stroke care pathways to incorporate this therapy as a treatment option.
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Accidente Cerebrovascular/cirugía , Trombectomía/economía , Trombectomía/métodos , Australia , Análisis Costo-Beneficio , Femenino , Recursos en Salud/economía , Recursos en Salud/estadística & datos numéricos , Servicios de Salud/economía , Servicios de Salud/estadística & datos numéricos , Humanos , Masculino , Cadenas de Markov , Modelos Econométricos , Calidad de Vida , Años de Vida Ajustados por Calidad de Vida , Reproducibilidad de los ResultadosRESUMEN
Periocular necrotizing fasciitis is a rare, but potentially blinding, or even fatal disease. The authors report a case of a 44-year-old man who presented with quiescent bilateral periocular and facial necrotizing fasciitis. The patient was treated with antibiotics and surgical debridement, followed by negative-pressure wound therapy (NPWT), until the wound bed was thought to be healthy enough to support bilateral upper eyelid full-thickness skin grafts. NPWT appeared to decrease local edema; speed reperfusion and granulation tissue formation; and served to stabilize the skin grafts against the wound bed, while not causing any ocular complications. NPWT can be a safe and effective adjunct treatment for periocular necrotizing fasciitis.
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This review describes the evolving role of oral hormone therapy (HT) for treating menopausal symptoms and preventing osteoporosis, focusing on conjugated estrogens/bazedoxifene (CE/BZA). Estrogens alleviate hot flushes and prevent bone loss associated with menopause. In nonhysterectomized women, a progestin should be added to estrogens to reduce the risk of endometrial cancer. Use of HT declined since the Women's Health Initiative (WHI) studies showed that HT does not prevent coronary heart disease (CHD) and that conjugated estrogens/medroxyprogesterone acetate increased the risk of invasive breast cancer after nearly 5 years of use. However, re-analyses of the WHI data suggest that some risks (eg, CHD, all-cause mortality) may be reduced when HT is initiated in women <60 years of age and <10 years since menopause, compared with later. CE/BZA is the first menopausal HT without a progestogen for nonhysterectomized women. Instead, BZA, a selective estrogen receptor modulator, in combination with CE, protects against estrogenic effects on uterine and breast tissue. Data from 5 large, randomized clinical trials show that CE/BZA reduces hot flush frequency/severity, prevents bone loss, reduces bone turnover, improves the vaginal maturation index and ease of lubrication, and improves some measures of sleep and menopause-specific quality of life. In studies of up to 2 years, there was no increase in endometrial hyperplasia, vaginal bleeding, breast density, or breast pain/tenderness compared with placebo. Venous thromboembolism and stroke are risks of all estrogen-based therapies. The choice of HT should be individualized, with consideration of the risk/benefit profile and tolerability of therapy, as well as patient preferences.
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Terapia de Reemplazo de Estrógeno/métodos , Estrógenos Conjugados (USP)/uso terapéutico , Indoles/uso terapéutico , Menopausia/efectos de los fármacos , Moduladores Selectivos de los Receptores de Estrógeno/uso terapéutico , Factores de Edad , Remodelación Ósea/efectos de los fármacos , Neoplasias de la Mama/inducido químicamente , Enfermedades Cardiovasculares/inducido químicamente , Vías de Administración de Medicamentos , Combinación de Medicamentos , Hiperplasia Endometrial/inducido químicamente , Terapia de Reemplazo de Estrógeno/efectos adversos , Estrógenos Conjugados (USP)/administración & dosificación , Estrógenos Conjugados (USP)/efectos adversos , Femenino , Sofocos/tratamiento farmacológico , Humanos , Indoles/administración & dosificación , Indoles/efectos adversos , Osteoporosis Posmenopáusica/prevención & control , Calidad de Vida , Ensayos Clínicos Controlados Aleatorios como Asunto , Moduladores Selectivos de los Receptores de Estrógeno/administración & dosificación , Moduladores Selectivos de los Receptores de Estrógeno/efectos adversos , Trastornos del Sueño-Vigilia/tratamiento farmacológico , Factores de Tiempo , Vagina/metabolismoRESUMEN
Smokers develop metastatic prostate cancer more frequently than nonsmokers, suggesting that a tobacco-derived factor is driving metastatic progression. To identify smoking-induced alterations in human prostate cancer, we analyzed gene and protein expression patterns in tumors collected from current, past, and never smokers. By this route, we elucidated a distinct pattern of molecular alterations characterized by an immune and inflammation signature in tumors from current smokers that were either attenuated or absent in past and never smokers. Specifically, this signature included elevated immunoglobulin expression by tumor-infiltrating B cells, NF-κB activation, and increased chemokine expression. In an alternate approach to characterize smoking-induced oncogenic alterations, we also explored the effects of nicotine in human prostate cancer cells and prostate cancer-prone TRAMP mice. These investigations showed that nicotine increased glutamine consumption and invasiveness of cancer cells in vitro and accelerated metastatic progression in tumor-bearing TRAMP mice. Overall, our findings suggest that nicotine is sufficient to induce a phenotype resembling the epidemiology of smoking-associated prostate cancer progression, illuminating a novel candidate driver underlying metastatic prostate cancer in current smokers.
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Inflamación/metabolismo , Neoplasias de la Próstata/inmunología , Fumar/efectos adversos , Transcriptoma , Animales , Línea Celular Tumoral , Núcleo Celular/metabolismo , Humanos , Inmunoglobulinas/genética , Interleucina-8/sangre , Masculino , Ratones , FN-kappa B/metabolismo , Invasividad Neoplásica , Metástasis de la Neoplasia , Nicotina/farmacología , Neoplasias de la Próstata/etiología , Neoplasias de la Próstata/patología , Proteínas Proto-Oncogénicas c-akt/metabolismoRESUMEN
The electrophoretic deposition (EPD) method was used to deposit polyethylenimine (PEI) functionalized multiwall carbon nanotube (CNT) films onto the surface of individual S-2 glass fibers. By varying the processing parameters of EPD following Hamaker's equation, the thickness of the CNT film was controlled over a wide range from 200 nm to 2 µm. The films exhibited low electrical resistance, providing evidence of coating uniformity and consolidation. The effect of the CNT coating on fiber matrix interfacial properties was investigated through microdroplet experiments. Changes in interfacial properties due to application of CNT coatings onto the fiber surface with and without a CNT-modified matrix were studied. A glass fiber with a 2 µm thick CNT coating and the unmodified epoxy matrix showed the highest increase (58%) in interfacial shear strength (IFSS) compared to the baseline. The increase in the IFSS was proportional to CNT film thickness. Failure analysis of the microdroplet specimens indicated higher IFSS was related to fracture morphologies with higher levels of surface roughness. EPD enables the thickness of the CNT coating to be adjusted, facilitating control of fiber/matrix interfacial resistivity. The electrical sensitivity provides the opportunity to fabricate a new class of sizing with tailored interfacial properties and the ability to detect damage initiation.
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Cardiac-related clinical practice guidelines have become an integral part of the practice of cardiology. Unfortunately, these guidelines are often long, complex, and difficult for practicing cardiologists to use. Guidelines should be condensed and their format upgraded, so that the key messages are easier to comprehend and can be applied more readily by those involved in patient care. After presenting the historical background and describing the guideline structure, we make several recommendations to make clinical practice guidelines more user-friendly for clinical cardiologists. Our most important recommendations are that the clinical cardiology guidelines should focus exclusively on (1) class I recommendations with established benefits that are supported by randomized clinical trials and (2) class III recommendations for diagnostic or therapeutic approaches in which quality studies show no benefit or possible harm. Class II recommendations are not evidence based but reflect expert opinions related to published clinical studies, with potential for personal bias by members of the guideline committee. Class II recommendations should be published separately as "Expert Consensus Statements" or "Task Force Committee Opinions," so that both majority and minority expert opinions can be presented in a less dogmatic form than the way these recommendations currently appear in clinical practice guidelines.
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Cardiología/normas , Guías de Práctica Clínica como Asunto/normas , Mejoramiento de la Calidad , HumanosRESUMEN
OBJECTIVE: A hemisplit turndown tibialis anterior muscle flap is described for coverage of distal leg wounds with preservation of active extensor function for open wounds of the distal ankle is presented. This is a new flap not previously described and is another local option for coverage of selected distal leg wounds. METHODS: A description of the operative procedure and a clinical successful example is presented. RESULTS: The split hemitibialis anterior turndown muscle flap was successful and preserved function of the muscle and tendon. CONCLUSIONS: This is another option for coverage of difficult wounds of the lower extremity without sacrifice of function of the donor muscle.
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INTRODUCTION: U.S. smoking prevalence has been declining over the last several decades. During this time, the population has also experienced changes in its demographic composition, as Americans are living longer and becoming increasingly racially and ethnically diverse. Since smoking rates vary across age and race/ethnicity groups, demographics alone could contribute to changes in smoking prevalence among the general population. We examined the effect of changing age and race/ethnicity distributions on total smoking prevalence from 1980 to 2010. METHODS: Using the National Health Interview Survey weighting scheme, we applied the distribution of smokers across age and race/ethnicity categories for the years 1980 and 2010 to the distribution of adults in those categories for both years. The total number of smokers was summed to determine resulting smoking prevalence. RESULTS: The combined effect of aging and the changing racial/ethnic composition of the U.S. population has contributed 2.1% points to the decline in smoking prevalence. If the age and racial/ethnic demographic composition had not changed since 1980, smoking prevalence would have been 21.3% in 2010 (with rounding)--statistically significantly higher than the reported 19.3%. Of the 3 demographic factors we considered (age, race, and ethnicity), ethnicity--specifically the rising share of Hispanics in the population--is the most important contributor to declines in smoking. CONCLUSIONS: Our changing demographics have had an impact on smoking prevalence over the last 3 decades. Future declines in smoking may be driven even more by the aging of the population and increasing racial and ethnic diversity.
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Vigilancia de la Población , Fumar/etnología , Fumar/epidemiología , Adolescente , Adulto , Distribución por Edad , Anciano , Anciano de 80 o más Años , Demografía , Etnicidad/estadística & datos numéricos , Femenino , Hispánicos o Latinos/estadística & datos numéricos , Humanos , Masculino , Persona de Mediana Edad , Prevalencia , Grupos Raciales/estadística & datos numéricos , Estados Unidos/epidemiología , Adulto JovenRESUMEN
Phospholipid remodeling involves phospholipase activity to remove acyl chains and acyltransferases to replace acyl chains. We here describe the characterization of a lysophospholipid acyltransferase in the opportunistic fungal pathogen, Candida albicans. Expression of this gene, C.a. LPT1, complemented the lysophospholipid acyltransferase defect in Saccharomyces cerevisiae strains lacking the homologous LPT1 gene. In vitro, lysophospholipid acyltransferase activity in these strains showed acyl-CoA substrate specificity, as measured by apparent Vmax/Km ratios, to be linolenoyl-CoA>oleoyl-CoA>linoleoyl-CoA>stearoyl-CoA. To address the physiological importance of C.a. LPT1, homozygous deletion strains were generated. Lysophospholipid acyltransferase activity with amine containing lysophospholipids was dramatically reduced while lysophosphatidylinositol and lysophosphatidic acid esterification was not significantly lowered. However, C.a. LPT1 over-expression yielded an increased amount of lysophosphatidic acyltransferase activity, suggesting a role in de novo phospholipid synthesis. LPT1 deletion strains showed slightly slowed growth in standard liquid media but no phenotype in media containing three antifungals that target sterols. To assess the role of C.a. Lpt1 in phospholipid remodeling, an in vivo, pulse-chase assay utilizing polysorbitan palmitate and mass spectrometry was developed. Cellular phospholipid composition became atypical with the provision of palmitate and gradually returned to the typical distribution when palmitate was removed. Deletion of C.a. LPT1 showed a modest yet significant effect on remodeling under these conditions.
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1-Acilglicerofosfocolina O-Aciltransferasa/genética , Candida albicans/enzimología , Membrana Celular/metabolismo , Lisofosfolípidos/metabolismo , 1-Acilglicerofosfocolina O-Aciltransferasa/biosíntesis , 1-Acilglicerofosfocolina O-Aciltransferasa/metabolismo , Acilcoenzima A/metabolismo , Membrana Celular/química , Membrana Celular/enzimología , Regulación Fúngica de la Expresión Génica , Lisofosfolípidos/biosíntesis , Saccharomyces cerevisiae/enzimología , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Especificidad por SustratoRESUMEN
Calcium (Ca(2+))/calmodulin (CaM)-dependent kinase II (CaMKII) activity plays a fundamental role in learning and memory. A key feature of CaMKII in memory formation is its ability to be regulated by autophosphorylation, which switches its activity on and off during synaptic plasticity. The synaptic scaffolding protein CASK (calcium (Ca(2+))/calmodulin (CaM) associated serine kinase) is also important for learning and memory, as mutations in CASK result in intellectual disability and neurological defects in humans. We show that in Drosophila larvae, CASK interacts with CaMKII to control neuronal growth and calcium signaling. Furthermore, deletion of the CaMK-like and L27 domains of CASK (CASK ß null) or expression of overactive CaMKII (T287D) produced similar effects on synaptic growth and Ca(2+) signaling. CASK overexpression rescues the effects of CaMKII overactivity, consistent with the notion that CASK and CaMKII act in a common pathway that controls these neuronal processes. The reduction in Ca(2+) signaling observed in the CASK ß null mutant caused a decrease in vesicle trafficking at synapses. In addition, the decrease in Ca(2+) signaling in CASK mutants was associated with an increase in Ether-à-go-go (EAG) potassium (K(+)) channel localization to synapses. Reducing EAG restored the decrease in Ca(2+) signaling observed in CASK mutants to the level of wildtype, suggesting that CASK regulates Ca(2+) signaling via EAG. CASK knockdown reduced both appetitive associative learning and odor evoked Ca(2+) responses in Drosophila mushroom bodies, which are the learning centers of Drosophila. Expression of human CASK in Drosophila rescued the effect of CASK deletion on the activity state of CaMKII, suggesting that human CASK may also regulate CaMKII autophosphorylation.
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An increasing number of academic senior physicians are approaching their potential retirement in good health with accumulated clinical and research experience that can be a valuable asset to an academic institution. Considering the need to let the next generation ascend to leadership roles, when and how should a medical career be brought to a close? We explore the roles for academic medical faculty as they move into their senior years and approach various retirement options. The individual and institutional considerations require a frank dialogue among the interested parties to optimize the benefits while minimizing the risks for both. In the United States there is no fixed age for retirement as there is in Europe, but European physicians are initiating changes. What is certain is that careful planning, innovative thinking, and the incorporation of new patterns of medical practice are all part of this complex transition and timing of senior academic physicians into retirement.
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Centros Médicos Académicos , Docentes Médicos , Médicos , Investigadores , Jubilación , Centros Médicos Académicos/organización & administración , Adulto , Factores de Edad , Anciano , Movilidad Laboral , Competencia Clínica , Cognición , Europa (Continente) , Docentes Médicos/organización & administración , Humanos , Liderazgo , Persona de Mediana Edad , Médicos/organización & administración , Médicos/psicología , Investigadores/organización & administración , Investigadores/psicología , Desarrollo de Personal , Factores de Tiempo , Estados Unidos , Recursos HumanosRESUMEN
Ca(2+)/CaM serine/threonine kinase II (CaMKII) is a central molecule in mechanisms of synaptic plasticity and memory. A vital feature of CaMKII in plasticity is its ability to switch to a calcium (Ca(2+)) independent constitutively active state after autophosphorylation at threonine 287 (T287). A second pair of sites, T306 T307 in the calmodulin (CaM) binding region once autophosphorylated, prevent subsequent CaM binding and inactivates the kinase during synaptic plasticity and memory. Recently a synaptic molecule called Ca(2+)/CaM-dependent serine protein kinase (CASK) has been shown to control both sets of CaMKII autophosphorylation events and hence is well poised to be a key regulator of memory. We show deletion of full length CASK or just its CaMK-like and L27 domains disrupts middle-term memory (MTM) and long-term memory (LTM), with CASK function in the α'/ß' subset of mushroom body neurons being required for memory. Likewise directly changing the levels of CaMKII autophosphorylation in these neurons removed MTM and LTM. The requirement of CASK and CaMKII autophosphorylation was not developmental as their manipulation just in the adult α'/ß' neurons was sufficient to remove memory. Overexpression of CASK or CaMKII in the α'/ß' neurons also occluded MTM and LTM. Overexpression of either Drosophila or human CASK in the α'/ß' neurons of the CASK mutant completely rescued memory, confirming that CASK signaling in α'/ß' neurons is necessary and sufficient for Drosophila memory formation and that the neuronal function of CASK is conserved between Drosophila and human. At the cellular level CaMKII overexpression in the α'/ß' neurons increased activity dependent Ca(2+) responses while reduction of CaMKII decreased it. Likewise reducing CASK or directly expressing a phosphomimetic CaMKII T287D transgene in the α'/ß' similarly decreased Ca(2+) signaling. Our results are consistent with CASK regulating CaMKII autophosphorylation in a pathway required for memory formation that involves activity dependent changes in Ca(2+) signaling in the α'/ß' neurons.
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Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/fisiología , Guanilato-Quinasas/fisiología , Memoria/fisiología , Cuerpos Pedunculados/fisiología , Neuronas/fisiología , Animales , Animales Modificados Genéticamente , Drosophila , HumanosRESUMEN
Diffusion as a bonding mechanism for ultrasonic consolidation of metals is widely debated due to the short weld times and low processing temperatures. To quantify interdiffusion coefficients, X-ray energy dispersive spectroscopy (XEDS) line-scans were performed across an Al-Cu interface using the Scanning Electron Microscope (SEM) with accelerating voltages ranging from 6 to 22 KeV in increments of 2 KeV and a step size of 0.05 microns. Higher accelerating voltages resulted in broader concentration profiles, indicating higher apparent interdiffusion coefficients when scanned at the same location of the same sample. This error due to the interaction volume interference was quantified using Monte Carlo simulations. It was found that an accelerating voltage of 22 KeV and diffusion distance less than 5 microns resulted in at least 50% error. Even at a smaller accelerating voltage of 6 KeV, the percent error in calculation of the interdiffusion coefficient for a diffusion distance of 0.5 microns is expected to be 15-20%. An approximate diffusion distance and apparent interdiffusion coefficient for ultrasonically consolidated Al-Cu were 0.503 microns and 0.013 um(2) /s, respectively. In this study, a methodology is presented that allows one to estimate the error in the calculation of an interdiffusion coefficient from the accelerating voltage used and the diffusion distance measured by the SEM XEDS at that accelerating voltage.