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BACKGROUND AND OBJECTIVES: Few cadaveric studies have evaluated the dye spread with superficial parasternal intercostal plane (SPIP) blocks. In this study, we examined the dye spread of an ultrasound-guided SPIP block in a human cadaveric model with single and double injection techniques. METHODS: Seven single and four double ultrasound-guided SPIP blocks were performed in seven unembalmed human cadavers using an in-plane approach with the transducer oriented parasagitally 1 cm lateral to the sternum. For the single SPIP, 20 mL of 0.166% methylene blue was injected in the second or third intercostal space into the plane between the Pec major muscle and internal intercostal muscles. For the double SPIP, 10 mL of 0.166% methylene blue was injected in the SPIP at one intercostal space with an additional 10 mL injected in the SPIP two intercostal spaces caudally. The extent of dye spread was documented. RESULTS: For all SPIP injections, there was consistent mediolateral spread from the sternum to the mid-clavicular line, with many extending laterally to the anterior axillary line. There was craniocaudal spread to a median of 2 intercostal muscles with a single SPIP and 3 intercostal muscles with a double SPIP. There was a median spread to 1 intercostal nerve for the single SPIP and 1.5 intercostal nerves with the double SPIP. CONCLUSIONS: The SPIP block demonstrated limited spread in this cadaver study. A single injection of this block may be of limited value and multiple SPIP injections may be needed to have adequate spread for anterior thoracic procedures.
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Background: Fabry's disease, an X-linked lysosomal storage disorder, shares cardiac manifestations with hypertrophic cardiomyopathy (HCM). We underscore the importance of considering Fabry's disease as a differential diagnosis in HCM patients, highlighting genetic testing's role in cardiomyopathy evaluation. Case summary: Three male patients with left ventricular hypertrophy were initially diagnosed with HCM but were later found to have Fabry's disease through genetic testing. Atypical features such as renal dysfunction and conduction abnormalities raised suspicion. Genetic testing confirmed diagnosis, guiding tailored management. Discussion: Fabry's disease poses diagnostic challenges due to its resemblance to HCM. Genetic testing enables precise diagnosis and personalized management, especially in cases with atypical presentations. Early recognition and intervention, facilitated by genetic testing, can improve patient outcomes in Fabry's disease.
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Genetically heterogeneous UM-HET3 mice born in 2020 were used to test possible lifespan effects of alpha-ketoglutarate (AKG), 2,4-dinitrophenol (DNP), hydralazine (HYD), nebivolol (NEBI), 16α-hydroxyestriol (OH_Est), and sodium thiosulfate (THIO), and to evaluate the effects of canagliflozin (Cana) when started at 16 months of age. OH_Est produced a 15% increase (p = 0.0001) in median lifespan in males but led to a significant (7%) decline in female lifespan. Cana, started at 16 months, also led to a significant increase (14%, p = 0.004) in males and a significant decline (6%, p = 0.03) in females. Cana given to mice at 6 months led, as in our previous study, to an increase in male lifespan without any change in female lifespan, suggesting that this agent may lead to female-specific late-life harm. We found that blood levels of Cana were approximately 20-fold higher in aged females than in young males, suggesting a possible mechanism for the sex-specific disparities in its effects. NEBI was also found to produce a female-specific decline (4%, p = 0.03) in lifespan. None of the other tested drugs provided a lifespan benefit in either sex. These data bring to 7 the list of ITP-tested drugs that induce at least a 10% lifespan increase in one or both sexes, add a fourth drug with demonstrated mid-life benefits on lifespan, and provide a testable hypothesis that might explain the sexual dimorphism in lifespan effects of the SGLT2 inhibitor Cana.
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Canagliflozina , Longevidade , Tiossulfatos , Animais , Canagliflozina/farmacologia , Masculino , Feminino , Tiossulfatos/farmacologia , Longevidade/efeitos dos fármacos , Camundongos , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Fatores SexuaisRESUMO
Myeloproliferative neoplasms (MPNs) are associated with substantial healthcare resource use and productivity loss. This retrospective cohort analysis used disability leave and medical claims data to measure direct and indirect healthcare costs associated with MPNs. The analysis included 173 patients with myelofibrosis (MF), 4477 with polycythemia vera (PV), 6061 with essential thrombocythemia (ET), and matched controls (n = 519, n = 13,431, and n = 18,183, respectively). Total healthcare costs were significantly higher for cases versus controls in each cohort (mean cost difference: MF, $67,456; PV, $10,970; ET, $22,279). Cases were more likely than controls to take disability leave and incurred higher disability-related costs. Among subgroups with thrombotic events, direct and indirect costs were higher for cases versus controls. Thrombotic events substantially increased direct costs and disability leave for patients with PV or ET compared with the full PV or ET cohorts. These findings demonstrate increased economic burden for patients with MPNs.
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Efeitos Psicossociais da Doença , Custos de Cuidados de Saúde , Transtornos Mieloproliferativos , Humanos , Masculino , Feminino , Transtornos Mieloproliferativos/economia , Transtornos Mieloproliferativos/diagnóstico , Transtornos Mieloproliferativos/terapia , Transtornos Mieloproliferativos/epidemiologia , Custos de Cuidados de Saúde/estatística & dados numéricos , Pessoa de Meia-Idade , Idoso , Estudos Retrospectivos , Adulto , Estudos de Casos e Controles , Idoso de 80 Anos ou maisRESUMO
The National Institute on Aging Interventions Testing Program (ITP) has so far identified 12 compounds that extend the lifespan of genetically heterogeneous mice using the log-rank test. However, the log-rank test is relatively insensitive to any compound that does not uniformly reduce mortality across the lifespan. This test may thus miss compounds that only reduce mortality before midlife, for example, a plausible outcome if a compound only mitigates risk factors before midlife or if its efficacy is reduced at later ages. We therefore reanalyzed all data collected by the ITP from 2004-2022 using the Gehan test, which is more sensitive to mortality differences earlier in the life course and does not assume a uniformly reduced mortality hazard across the lifespan. The Gehan test identified 5 additional compounds, metformin, enalapril, 17-dimethylaminoethylamino-17-demethoxygeldanamycin hydrochloride (17-DMAG), caffeic acid phenethyl ester (CAPE), and green tea extract (GTE), which significantly increased survival but were previously missed by the log-rank test. Three (metformin, enalapril, and 17-DMAG) were only effective in males and two (CAPE and GTE) were only effective in females. In addition, 1,3-butanediol, which by log-rank analysis increased survival in females but not males, increased survival in males by the Gehan test. These results suggest that statistical tests sensitive to non-uniformity of drug efficacy across the lifespan should be included in the standard statistical testing protocol to minimize overlooking geroprotective interventions.
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Ácidos Cafeicos , Enalapril , Longevidade , Metformina , Extratos Vegetais , Chá , Animais , Metformina/farmacologia , Camundongos , Feminino , Extratos Vegetais/farmacologia , Masculino , Enalapril/farmacologia , Longevidade/efeitos dos fármacos , Ácidos Cafeicos/farmacologia , Álcool Feniletílico/análogos & derivados , Álcool Feniletílico/farmacologia , Estados Unidos , Lactamas Macrocíclicas/farmacologia , Benzoquinonas/farmacologiaRESUMO
Controllable and reproducible animal models of aneurysmal subarachnoid hemorrhage (SAH) are crucial for the systematic study of the pathophysiology and treatment of this debilitating condition. Despite the variety of animal models of SAH currently available, attempts to translate promising therapeutic strategies from preclinical studies to humans have largely failed. This failure is likely due, at least in part, to poor replication of pathology and disabilities in these preclinical models, especially the long-term neurocognitive deficits that drive poor quality of life / return to work in SAH survivors. Therefore, there is an unmet need to develop experimental models that reliably replicate the long-term clinical ramifications of SAH - especially in mice where genetic manipulations are straightforward and readily available. To address this need, we developed a standardized mouse model of SAH that reproducibly produced significant and trackable long-term neurobehavioral deficits. SAH was induced by performing double blood injections into the prechiasmatic cistern - a simple modification to the well-characterized single prechiasmatic injection mouse model of SAH. Following SAH, mice recapitulated key characteristics of SAH patients including long-term cognitive impairment as observed by a battery of behavioral testing and delayed pathophysiologic processes assayed by neuroinflammatory markers. We believe that this new SAH mouse model will be an ideal paradigm for investigating the complex pathophysiology of SAH and identifying novel druggable therapeutic targets for treating SAH-associated long-term neurocognitive deficits in patients.
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Two online experiments evaluated the relationship between long-term stress, as measured with the Perceived Stress Scale-10, and the Renewal Effect. In the first experiment renewal was assessed with a behavioral suppression task in a science-fiction based video game. Participants learned to suppress mouse clicking during a signal for an upcoming attack to avoid losing points. The signal was first paired with an attack in Context A and extinguished in Context B and tested back in Context A. The contexts were different space galaxies where the gameplay took place. Experiment 2 used a food/illness predictive-learning paradigm. Two food items were paired with stomachache in one restaurant (A) and extinguished in Context B prior to testing in both contexts without feedback. Positive correlations were obtained between renewal and stress in each experiment. Unlike acute stress (Drexler et al., 2017), long term stress was associated with greater renewal. The effects of stress, both chronic and punctual, on renewal are discussed.
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Estresse Psicológico , Estresse Psicológico/psicologia , Masculino , Feminino , Humanos , Adulto Jovem , Extinção Psicológica/fisiologia , Adulto , AdolescenteRESUMO
Natural and anthropogenic disturbances have led to rapid declines in the amount and quality of available habitat in many ecosystems. Many studies have focused on how habitat loss has affected the composition and configuration of habitats, but there have been fewer studies that investigate how this loss affects ecosystem function. We investigated how a large-scale seagrass die-off altered the distribution of energetic resources of three seagrass-associated consumers with varied resource use patterns. Using long-term benthic habitat monitoring data and resource use data from Bayesian stable isotope mixing models, we generated energetic resource landscapes (E-scapes) annually between 2007 and 2019. E-scapes link the resources being used by a consumer to the habitats that produce those resources to calculate a habitat resource index as a measurement of energetic quality of the landscape. Overall, our results revealed that following the die-off there was a reduction in trophic function across all species in areas affected by the die-off event, but the response was species-specific and dependent on resource use and recovery patterns. This study highlights how habitat loss can lead to changes in ecosystem function. Incorporating changes in ecosystem function into models of habitat loss could improve understanding of how species will respond to future change.
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Biodiversidade , Ecossistema , Teorema de BayesRESUMO
Evidence that life-extending interventions are not uniformly effective across the lifespan calls for an analytic tool that can estimate age-specific treatment effects on mortality hazards. Here we report such a tool, applying it to mouse data from 42 agents tested in the NIA Interventions Testing Program. This tool identified agents that either reduced (22) or increased (16) mortality hazards or did both (6), all with marked variation in the duration of efficacy and magnitude of effect size. Only 7 reduced mortality hazards after the 90% mortality, when the burden of senescence is greatest. Sex differences were apparent in all parameters. This new analytic tool complements the commonly used log-rank test. It detects more potential life-extending candidates (22 versus 10) and indicates when during the life course they are effective. It also uncovers adverse effects. Most importantly, it identifies agents that specifically reduce mortality hazards during the senescent phase of life.
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Over the last few decades, measurements of light stable isotope ratios have been increasingly used to answer questions across physiology, biology, ecology, and archaeology. The vast majority analyse carbon (δ13C) and nitrogen (δ15N) stable isotopes as the 'default' isotopes, omitting sulfur (δ34S) due to time, cost, or perceived lack of benefits and instrumentation capabilities. Using just carbon and nitrogen isotopic ratios can produce results that are inconclusive, uncertain, or in the worst cases, even misleading, especially for scientists that are new to the use and interpretation of stable isotope data. Using sulfur isotope values more regularly has the potential to mitigate these issues, especially given recent advancements that have lowered measurement barriers. Here we provide a review documenting case studies with real-world data, re-analysing different biological topics (i.e. niche, physiology, diet, movement and bioarchaeology) with and without sulfur isotopes to highlight the various strengths of this stable isotope for various applications. We also include a preliminary meta-analysis of the trophic discrimination factor (TDF) for sulfur isotopes, which suggest small (mean -0.4 ± 1.7 SD) but taxa-dependent mean trophic discrimination. Each case study demonstrates how the exclusion of sulfur comes at the detriment of the results, often leading to very different outputs, or missing valuable discoveries entirely. Given that studies relying on carbon and nitrogen stable isotopes currently underpin most of our understanding of various ecological processes, this has concerning implications. Collectively, these examples strongly suggest that researchers planning to use carbon and nitrogen stable isotopes for their research should incorporate sulfur where possible, and that the new 'default' isotope systems for aquatic science should now be carbon, nitrogen, and sulfur.
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Carbono , Nitrogênio , Isótopos de Carbono , Isótopos de Nitrogênio , Isótopos de EnxofreRESUMO
Two experiments observed an effect consistent with a latent-inhibition (LI) effect in humans that (a) did not depend on masking or instruction-generated expectations and (b) suggested that the effect results from a change in processing of the predictive cue. Participants viewed a video of a superhero character flying through three different contexts past a different stimulus in each context. In conditioning, The superhero flew past a target cue that was either Novel (Group No Exposure), had been preexposed in the Same context as where conditioning was occurring (Group Same), or was preexposed in a Different context (Group Different). Each time the superhero flew past the target cue his Hands Glowed (outcome). On test (E1), an image of the superhero flying in the context with normal Hands and the target cue was present. Participants were asked if anything was missing. Experiment 2 tested participants with the superhero present and his Hands Glowing to test outcome-cue associations (Test 1) or just the superhero in the context (Test 2, counterbalanced) to assess contextual associations. In E1 fewer people in Group Same reported the outcome missing than Group No Exposure or Group Different. In E2 fewer people in Group Same reported the target cue missing when presented with the outcome than in the other groups, a result inconsistent with interference accounts of LI. When presented only with contextual cues, reports of the stimulus missing showed that the context was associated with the stimuli presented within it. Results are discussed with respect to theories and demonstrations of human LI. (PsycInfo Database Record (c) 2024 APA, all rights reserved).
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Sinais (Psicologia) , Memória , Humanos , Inibição PsicológicaRESUMO
OBJECTIVE: This study investigates the impact of primary care utilisation of a symptom-based head and neck cancer risk calculator (Head and Neck Cancer Risk Calculator version 2) in the post-coronavirus disease 2019 period on the number of primary care referrals and cancer diagnoses. METHODS: The number of referrals from April 2019 to August 2019 and from April 2020 to July 2020 (pre-calculator) was compared with the number from the period January 2021 to August 2022 (post-calculator) using the chi-square test. The patients' characteristics, referral urgency, triage outcome, Head and Neck Cancer Risk Calculator version 2 score and cancer diagnosis were recorded. RESULTS: In total, 1110 referrals from the pre-calculator period were compared with 1559 from the post-calculator period. Patient characteristics were comparable for both cohorts. More patients were referred on the cancer pathway in the post-calculator cohort (pre-calculator patients 51.1 per cent vs post-calculator 64.0 per cent). The cancer diagnosis rate increased from 2.7 per cent in the pre-calculator cohort to 3.3 per cent in the post-calculator cohort. A lower rate of cancer diagnosis in the non-cancer pathway occurred in the cohort managed using the Head and Neck Cancer Risk Calculator version 2 (10 per cent vs 23 per cent, p = 0.10). CONCLUSION: Head and Neck Cancer Risk Calculator version 2 demonstrated high sensitivity in cancer diagnosis. Further studies are required to improve the predictive strength of the calculator.
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This commentary concerns our recent report that prepubertal castration rescued the shorter lifespan of males, using the first mouse line that robustly shows the same shorter longevity with a similar age-variable mortality disadvantage as human males. This model provides a unique opportunity for research to uncover the basis for this clinically important sex difference in aging. Researchers can now identify the hormones involved, the duration of exposure required, and, most important, the cellular and molecular targets, with the ultimate goal of developing therapeutic interventions to enhance health and reduce mortality without castration-compromising reproductive function.
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Resiliência Psicológica , Humanos , Masculino , Feminino , Camundongos , Animais , Envelhecimento , Longevidade , CastraçãoRESUMO
In genetically heterogeneous (UM-HET3) mice produced by the CByB6F1 × C3D2F1 cross, the Nrf2 activator astaxanthin (Asta) extended the median male lifespan by 12% (p = 0.003, log-rank test), while meclizine (Mec), an mTORC1 inhibitor, extended the male lifespan by 8% (p = 0.03). Asta was fed at 1840 ± 520 (9) ppm and Mec at 544 ± 48 (9) ppm, stated as mean ± SE (n) of independent diet preparations. Both were started at 12 months of age. The 90th percentile lifespan for both treatments was extended in absolute value by 6% in males, but neither was significant by the Wang-Allison test. Five other new agents were also tested as follows: fisetin, SG1002 (hydrogen sulfide donor), dimethyl fumarate, mycophenolic acid, and 4-phenylbutyrate. None of these increased lifespan significantly at the dose and method of administration tested in either sex. Amounts of dimethyl fumarate in the diet averaged 35% of the target dose, which may explain the absence of lifespan effects. Body weight was not significantly affected in males by any of the test agents. Late life weights were lower in females fed Asta and Mec, but lifespan was not significantly affected in these females. The male-specific lifespan benefits from Asta and Mec may provide insights into sex-specific aspects of aging.
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Flavonóis , Sulfeto de Hidrogênio , Longevidade , Fenilbutiratos , Feminino , Camundongos , Masculino , Animais , Meclizina/farmacologia , Sulfeto de Hidrogênio/farmacologia , Fumarato de Dimetilo/farmacologia , Ácido Micofenólico/farmacologia , XantofilasRESUMO
Both excessive alcohol consumption and exposure to high levels of arsenic can lead to neurodegeneration, especially in the hippocampus. Co-exposure to arsenic and alcohol can occur because an individual with an Alcohol Use Disorder (AUD) is exposed to arsenic in their drinking water or food or because of arsenic found directly in alcoholic beverages. This study aims to determine if co-exposure to alcohol and arsenic leads to worse outcomes in neurodegeneration and associated mechanisms that could lead to cell death. To study this, mice were exposed to a 10-day gavage model of alcohol-induced neurodegeneration with varying doses of arsenic (0, 0.005, 2.5, or 10 mg/kg). The following were examined after the last dose of ethanol: (1) microglia activation assessed via immunohistochemical detection of Iba-1, (2) reactive oxygen and nitrogen species (ROS/RNS) using a colorimetric assay, (3) neurodegeneration using Fluoro-Jade® C staining (FJC), and 4) arsenic absorption using ICP-MS. After exposure, there was an additive effect of the highest dose of arsenic (10 mg/kg) in the dentate gyrus of alcohol-induced FJC+ cells. This additional cell loss may have been due to the observed increase in microglial reactivity or increased arsenic absorption following co-exposure to ethanol and arsenic. The data also showed that arsenic caused an increase in CYP2E1 expression and ROS/RNS production in the hippocampus which could have independently contributed to increased neurodegeneration. Altogether, these findings suggest a potential cyclical impact of co-exposure to arsenic and ethanol as ethanol increases arsenic absorption but arsenic also enhances alcohol's deleterious effects in the CNS.
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Delayed cerebral ischemia (DCI) is an important contributor to poor outcomes in aneurysmal subarachnoid hemorrhage (SAH) patients. We previously showed that volatile anesthetics such as isoflurane, sevoflurane and desflurane provided robust protection against SAH-induced DCI, but the impact of a more commonly used intravenous anesthetic agent, propofol, is not known. The goal of our current study is to examine the neurovascular protective effects of propofol on SAH-induced DCI. Twelve-week-old male wild-type mice were utilized for the study. Mice underwent endovascular perforation SAH or sham surgery followed one hour later by propofol infusion through the internal jugular vein (2 mg/kg/min continuous intravenous infusion). Large artery vasospasm was assessed three days after SAH. Neurological outcome assessment was performed at baseline and then daily until animal sacrifice. Statistical analysis was performed via one-way ANOVA and two-way repeated measures ANOVA followed by the Newman-Keuls multiple comparison test with significance set at p < 0.05. Intravenous propofol did not provide any protection against large artery vasospasm or sensory-motor neurological deficits induced by SAH. Our data show that propofol did not afford significant protection against SAH-induced DCI. These results are consistent with recent clinical studies that suggest that the neurovascular protection afforded by anesthetic conditioning is critically dependent on the class of anesthetic agent.
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B cells contribute to multiple aspects of autoimmune disorders, and B cell-targeting therapies, including B cell depletion, have been proven to be efficacious in treatment of multiple autoimmune diseases. However, the development of novel therapies targeting B cells with higher efficacy and a nondepleting mechanism of action is highly desirable. Here we describe a nondepleting, high-affinity anti-human CD19 antibody LY3541860 that exhibits potent B cell inhibitory activities. LY3541860 inhibits B cell activation, proliferation, and differentiation of primary human B cells with high potency. LY3541860 also inhibits human B cell activities in vivo in humanized mice. Similarly, our potent anti-mCD19 antibody also demonstrates improved efficacy over CD20 B cell depletion therapy in multiple B cell-dependent autoimmune disease models. Our data indicate that anti-CD19 antibody is a highly potent B cell inhibitor that may have potential to demonstrate improved efficacy over currently available B cell-targeting therapies in treatment of autoimmune conditions without causing B cell depletion.
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Doenças Autoimunes , Linfócitos B , Camundongos , Animais , Antígenos CD19 , Doenças Autoimunes/tratamento farmacológicoRESUMO
Background Recent evidence implicates inflammation as a key driver in delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage (SAH). Inducible nitric oxide synthase (iNOS) is one of the known major mediators of inflammation. We previously showed that an inhalational anesthetic, isoflurane, provides strong protection against delayed cerebral ischemia after SAH. Our current study aims to define the role of iNOS in isoflurane conditioning-induced protection against delayed cerebral ischemia in a mouse model of SAH. Methods and Results The experiments used 10- to 14-week-old male wild-type (C57BL/6) and iNOS global knockout mice. Anesthetic conditioning was initiated 1 hour after SAH with isoflurane 2% for 1 hour. Isoflurane-induced changes in iNOS expression were measured. N-(3-(aminomethyl) benzyl) acetamidine, a highly selective iNOS inhibitor, was injected intraperitoneally immediately after SAH and then daily. Vasospasm, microvessel thrombosis, and neurological assessment was performed. Data were analyzed by 1-way ANOVA and 2-way repeated measures ANOVA followed by Student Newman Keuls comparison test. Statistical significance was set at P<0.05. Isoflurane conditioning downregulated iNOS expression in naïve and SAH mice. N-(3-(aminomethyl) benzyl) acetamidine attenuated large artery vasospasm and microvessel thrombosis and improved neurological deficits in wild-type animals. iNOS knockout mice were significantly resistant to vasospasm, microvessel thrombosis, and neurological deficits induced by SAH. Combining isoflurane with N-(3-(aminomethyl) benzyl) acetamidine did not offer extra protection, nor did treating iNOS knockout mice with isoflurane. Conclusions Isoflurane conditioning-induced delayed cerebral ischemia protection appears to be mediated by downregulating iNOS. iNOS is a potential therapeutic target to improve outcomes after SAH.