The impact of the English national health inequalities strategy on inequalities in mortality at age 65: a time-trend analysis.

BACKGROUND: During the 1997-2010 Labour government, several policies were implemented to narrow health inequalities as part of a national health inequalities strategy. Many of these policies are likely to have had a disproportionately large impact on people aged 65 and over. We aimed to understand the association between the health inequalities strategy period and inequalities in mortality at age 65-69. METHODS: We use population at risk and mortality data covering 1991-2019 to calculate mortality rate at age 65-69 at the Local Authority level. We use the 2019 Index of Multiple Deprivation to examine geographical inequalities. We employ segmented linear regression models with marginal spline terms for the strategy period and interact these with an indicator of deprivation to understand how inequalities changed before, during and after the strategy. The reporting of this study adheres to STROBE guidelines. RESULTS: Mortality rates in each deprivation quintile improved continuously throughout the period of study. Prior to the programme (1991-9) there was no significant change in absolute inequalities. However, during the strategy (2000-10) there was a significant decrease in absolute inequalities of -9.66 (-17.48 to -1.84). The period following the strategy (2011-19) was associated with a significant increase in absolute inequalities of 12.84 (6.60 to 19.08). Our results were robust to a range of sensitivity tests. CONCLUSION: The English health inequalities strategy was associated with a significant reduction in absolute inequality in mortality age 65-69. Future strategies to address inequalities in ageing populations may benefit from adopting a similar approach.

Socioeconomic inequalities in vaccine uptake: A global umbrella review.

This global umbrella review aimed to synthesise evidence of socioeconomic inequalities in the uptake of routine vaccinations and identify the mechanisms that may contribute to the association. To our knowledge, no attempt has been made to synthesise the global body of systematic reviews across a variety of vaccines, geographical locations, and measures of SES. The inclusion criteria were as follows: studies assessing vaccination uptake according to education, income, occupation/employment, and/or area-level deprivation; any country or universally recommended routine vaccination (according to the WHO); qualitative or quantitative reviews, published 2011-present. The searches were performed in eight databases. The screening process followed PRISMA-E guidelines, each stage was performed by one reviewer, and a 10% sample checked by a second for consistency. Included reviews underwent data extraction, quality appraisal (AMSTAR-2), and narrative synthesis according to country-context. After deduplication, 9,163 reports underwent title and abstract screening, leaving 119 full texts to be assessed for eligibility. Overall, 26 studies were included in the umbrella review. Evidence for lower uptake amongst disadvantaged SES individuals was found in all 26 reviews. However, 17 reviews showed mixed results, as inverse associations were also identified (lower uptake for advantaged SES, and/or higher uptake for disadvantaged SES). Those that explored high-income countries had a greater prevalence of mixed findings than those focusing on low/middle-income countries. The two most frequently cited mechanisms were vaccination knowledge, and confidence in vaccination or vaccination providers. These mechanisms were often understood by review authors as varying by level of education. We find socioeconomic differences in routine vaccination uptake, but the association did not always follow a gradient. Whilst education may be associated with uptake globally, our study indicates that its role varies by country-context. A limitation is the overlap of some primary studies across the included systematic reviews.

Targeting hedgehog-driven mechanisms of drug-resistant cancers.

Due to the cellular plasticity that is inherent to cancer, the acquisition of resistance to therapy remains one of the biggest obstacles to patient care. In many patients, the surviving cancer cell subpopulation goes on to proliferate or metastasize, often as the result of dramatically altered cell signaling and transcriptional pathways. A notable example is the Hedgehog (Hh) signaling pathway, which is a driver of several cancer subtypes and aberrantly activated in a wide range of malignancies in response to therapy. This review will summarize the field's current understanding of the many roles played by Hh signaling in drug resistance and will include topics such as non-canonical activation of Gli proteins, amplification of genes which promote tolerance to chemotherapy, the use of hedgehog-targeted drugs and tool compounds, and remaining gaps in our knowledge of the transcriptional mechanisms at play.

The impact of integrating bioscience and nursing subjects in a first-year nursing curriculum: A retrospective study.

AIM: The aim of this study is to explore the effects of integrating bioscience and nursing units on academic achievement and perception in the first-year nursing curriculum. BACKGROUND: Nursing students have historically found biosciences difficult and struggle to relate it to nursing practice. In response, nursing and non-nursing academics have employed different teaching modes and integration strategies to enhance learning. Despite these efforts, substantial gaps still persist concerning the integration of biosciences within nursing curriculum and the effect of integration on student academic achievement and student perception. DESIGN: Retrospective descriptive. The setting was a large University in Victoria Australia with two undergraduate nursing campuses (metropolitan and non-metropolitan). METHOD: Student academic records and online evaluation surveys that were completed from 2014 to 2019 were examined. Students self-reported their experiences of the unit using a five-point Likert scale and two open-ended questions. Descriptive and inferential statistics were used to analyse the data. Content analysis was used to analyse the two open-response survey items. RESULTS: First-year student records from 2014 to 2016 (pre-integration) and 2017-2019 (post-integration) were examined. Student mean age was 24.5 years (SD 7.2) and 20.9 years (SD 4.8) pre-integration and post-integration respectively. There was a statistically significant decrease in student attrition from pre-integration (n=536, 29.9%) to post-integration (n=358, 20.2%) (p <0.001), and a significant improvement in students' mean academic scores post-integration in the first semester 61.9 (SD 15.9) and 67.0 (SD 14.9) respectively, confidence interval 3.9-6.2 (p <0.001). Student satisfaction with the units improved post-integration, from 77.8% to 85.8% (χ2 = 10.1076) (p=0.001). However, there was no significant difference in students' perception of feeling overwhelmed, and their self-reported ability to link theory to practice. CONCLUSION: Integrating bioscience and clinical nursing practice units in the first-year curriculum can help decrease student attrition rates, improve student academic results and increase student satisfaction which may lead to an overall improvement in student learning experiences.

Bioinformatics Screen Reveals Gli-Mediated Hedgehog Signaling as an Associated Pathway to Poor Immune Infiltration of Dedifferentiated Liposarcoma.

Liposarcomas are the most diagnosed soft tissue sarcoma, with most cases consisting of well-differentiated (WDLPS) or dedifferentiated (DDLPS) histological subtypes. While both tumor subtypes can have clinical recurrence due to incomplete resections, DDLPS often has worse prognosis due to a higher likelihood of metastasis compared to its well-differentiated counterpart. Unfortunately, targeted therapeutic interventions have lagged in sarcoma oncology, making the need for molecular targeted therapies a promising future area of research for this family of malignancies. In this work, previously published data were analyzed to identify differential pathways that may contribute to the dedifferentiation process in liposarcoma. Interestingly, Gli-mediated Hedgehog signaling appeared to be enriched in dedifferentiated adipose progenitor cells and DDLPS tumors, and coincidentally Gli1 is often co-amplified with MDM2 and CDK4, given its genomic proximity along chromosome 12q13-12q15. However, we find that Gli2, but not Gli1, is differentially expressed between WDLPS and DDLPS, with a noticeable co-expression signature between Gli2 and genes involved in ECM remodeling. Additionally, Gli2 co-expression had a noticeable transcriptional signature that could suggest Gli-mediated Hedgehog signaling as an associated pathway contributing to poor immune infiltration in these tumors.

Nanoparticle STING Agonist Reprograms the Bone Marrow to an Antitumor Phenotype and Protects Against Bone Destruction.

When breast cancer metastasizes to bone, treatment options are limited. Failure to treat bone metastases is thought to be due to therapy-resistant features of the bone marrow microenvironment. Using a murine model of bone metastatic mammary carcinoma, we demonstrate that systemic delivery of polymer nanoparticles loaded with cyclic dinucleotide (CDN) agonists of stimulator of interferon genes (STING) inhibited tumor growth and bone destruction after 7 days of treatment. Each dose of STING-activating nanoparticles trafficked to the bone marrow compartment and was retained within the tumor microenvironment for over 24 hours, enhancing antitumor immunity through proinflammatory cytokine production and early T-cell activation. While acquired resistance mechanisms, including increased levels of immunosuppressive cytokines and the infiltration of regulatory T cells, ultimately limited antitumor efficacy after 2 weeks of treatment, bone protective effects remained. Overall, these studies demonstrate that STING pathway activation, here enabled using a nanomedicine approach to enhance CDN delivery to bone metastatic sites, can reprogram the immune contexture of the bone marrow to an antitumor phenotype that inhibits bone colonization of metastatic breast cancer cells and protects from tumor-mediated bone destruction. Significance: Bone metastases are difficult to treat due to the inaccessibility of the bone marrow compartment and the immunosuppressive microenvironment that protects resident stem cells. Packaging a STING agonist into a nanoparticle that enables systemic administration and drug accumulation at tumor sites overcomes both barriers to stymie metastatic breast cancer growth.

Octopus bimaculoides' arm recruitment and use during visually evoked prey capture.

Octopus' limb hyper-redundancy complicates traditional motor control system theory due to its extensive sensory inputs, subsequent decision-making, and arm coordination. Octopuses are thought to reduce flexibility control complexity by relying on highly stereotypical motor primitives (e.g., reaching1,2,3,4 and crawling5) and multi-level processes to coordinate movement,6,7 utilizing extensive peripheral nervous system (PNS) processing.2,8,9 Division of labor along the anterior-posterior axis10 and limb specialization of the four anterior arms in T-maze food retrieval11 further simplify control. However, specific arm recruitment and coordination during visually guided reaching behavior remains poorly understood. Here, we investigated visually evoked Octopus bimaculoides' prey capture capabilities12,13 by eliciting and examining prey-specific arm recruitment. When striking crabs, octopuses preferred synchronous arm recruitment, while sequential arm recruitment with a characteristic swaying movement is employed for shrimp. Such behavioral selection aligns with specific prey escape strategies and the octopus' flexible arm biomechanical constraints. Although side bias existed, we found significant bilateral symmetry, with one side being functionally a mirror of the other rather than anterior arm use being functionally equal and differing to posterior arm use. Among arms, the second limb is unequivocally dominant for goal-directed monocularly driven prey capture. Although the eight arms share gross anatomy and are considered equipotential,10,14 such arm use for specific actions could reflect subtle evolutionary adaptations. Finally, we quantitatively show, corroborating earlier observations,10,15 that octopuses employ a dimension reduction strategy by actively deciding to recruit adjacent arms over other available arms during either sequential or synchronous visually evoked prey attack.

Horizontal integration of bioscience and nursing in first-year nursing curricula: A systematic review.

OBJECTIVES: To systematically identify, appraise and summarise available evidence related to the horizontal integration of bioscience and nursing in first-year nursing curricula; to examine students', nurses' and academics' perceptions of the integration and provide recommendations for future curriculum development, practice and research priorities. DESIGN: A systematic review. DATA SOURCES: An online search of Ovid Medline, Ovid Emcare, CINAHL, Embase Classic + and Embase, ERIC, A+Education, Scopus (Elsevier) and Google Scholar was conducted between July and September 2021. A manual search of the reference list of included articles was also undertaken. REVIEW METHODS: This systematic review followed The PRISMA Statement. The study selection process was managed using the Covidence software platform and quality was assessed using JBI Critical appraisal tools and Mixed Methods Appraisal tools. A narrative synthesis of included studies was undertaken. RESULTS: Six articles were identified which met the inclusion criteria. The study population included students, academics and registered nurses. Four studies used clinical scenarios as a method of horizontally integrating bioscience and nursing content. The integration outcomes were measured by student understanding and learning, satisfaction and motivation. Students', nurses' and academics' perceptions of integration challenges were: i) depth of bioscience content; ii) structure of bioscience content; and iii) knowledge and experience. CONCLUSIONS: This systematic review did not identify a wide range of methods to integrate bioscience in first year nursing curricula. The use of clinical scenarios increased student understanding and learning. However, teaching academics needed to be cognizant of both nursing and bioscience to achieve the required depth of bioscience content and demonstrate integration of bioscience in nursing practice. There is a need for further investigations of methods of horizontal integration of bioscience and nursing in the first-year nursing curricula.

Distress Tolerance and Emotion Regulation as Potential Mediators Between Secondary Traumatic Stress and Maladaptive Coping.

The extant literature has illustrated that protective service workers experience negative repercussions associated with their job (including the development of secondary traumatic stress; STS) and may utilize maladaptive coping mechanisms. Developing an improved understanding of factors that might explain the relationship between STS and the utilization of maladaptive coping mechanisms is warranted. This study sought to examine emotion regulation and distress tolerance as potential mediators between STS and the utilization of maladaptive coping mechanisms. Participants were 152 elder protective service workers and 105 child protective service workers who completed an online survey of self-report measures of emotion regulation, distress tolerance, STS, and coping behaviors. A parallel multiple mediator model was analyzed using structural equation modeling (SEM) to examine the hypothesis that distress tolerance and emotion regulation would mediate the relationship between STS and the utilization of maladaptive coping. Our hypothesis was partially supported as the effect of STS on maladaptive coping was mediated by emotion regulation but not by distress tolerance. The results from this study have both prevention and intervention implications. From a prevention perspective, efforts could be directed at teaching emotion regulation skills to those at risk for developing STS as a mechanism for decreasing the probability of denial, substance use, behavioral disengagement, and self-blame that may occur as a consequence of STS. From an intervention perspective, some of the negative sequelae of exposure to STS may be averted by teaching EPS and CPS workers who present with STS symptoms, emotion regulation skills.

Zika Virus Infection of Pregnant Ifnar1-/- Mice Triggers Strain-Specific Differences in Fetal Outcomes.

Zika virus (ZIKV) is a flavivirus that causes a constellation of adverse fetal outcomes collectively termed congenital Zika syndrome (CZS). However, not all pregnancies exposed to ZIKV result in an infant with apparent defects. During the 2015 to 2016 American outbreak of ZIKV, CZS rates varied by geographic location. The underlying mechanisms responsible for this heterogeneity in outcomes have not been well defined. Therefore, we sought to characterize and compare the pathogenic potential of multiple Asian-/American-lineage ZIKV strains in an established Ifnar1-/- pregnant mouse model. Here, we show significant differences in the rate of fetal demise following maternal inoculation with ZIKV strains from Puerto Rico, Panama, Mexico, Brazil, and Cambodia. Rates of fetal demise broadly correlated with maternal viremia but were independent of fetus and placenta virus titer, indicating that additional underlying factors contribute to fetal outcome. Our results, in concert with those from other studies, suggest that subtle differences in ZIKV strains may have important phenotypic impacts. With ZIKV now endemic in the Americas, greater emphasis needs to be placed on elucidating and understanding the underlying mechanisms that contribute to fetal outcome. IMPORTANCE Zika virus (ZIKV) transmission has been reported in 87 countries and territories around the globe. ZIKV infection during pregnancy is associated with adverse fetal outcomes, including birth defects, microcephaly, neurological complications, and even spontaneous abortion. Rates of adverse fetal outcomes vary between regions, and not every pregnancy exposed to ZIKV results in birth defects. Not much is known about how or if the infecting ZIKV strain is linked to fetal outcomes. Our research provides evidence of phenotypic heterogeneity between Asian-/American-lineage ZIKV strains and provides insight into the underlying causes of adverse fetal outcomes. Understanding ZIKV strain-dependent pathogenic potential during pregnancy and elucidating underlying causes of diverse clinical sequelae observed during human infections is critical to understanding ZIKV on a global scale.

Minority Participation in Randomized Controlled Trials for Prolonged Exposure Therapy: A Systematic Review of the Literature.

Per the most recent census, non-Latinx White individuals comprise the majority of the U.S. population (76.6%); Latinx individuals make up 18.3% of the total U.S. population, followed by African Americans (13.4%) and Asians (5.9%). Given the high prevalence rates of posttraumatic stress disorder (PTSD) observed across many ethnoracial minority groups in the United States, the fact that PTSD presentation may vary across culture, and the National Institute of Health's mandates for the inclusion of women and minorities in clinical outcome research, the aim of the present systematic review was to examine minority inclusion in clinical outcome research for PTSD. Our review focused exclusively on one empirically supported treatment: prolonged exposure therapy (PE); we identified 38 studies that met the inclusion criteria. Apart from African Americans, who were overrepresented in 21 studies (inclusion rate range: 13.5%-73.9%), ethnoracial minority inclusion in RCTs examining PE was low. More specifically, across included studies that reported ethnoracial minority data, 58.9% of participants were White, 31.1% were African American, 4.9% were Latinx, 0.6% were Asian American or Pacific Islander, and 4.7% reported race as "other." Inclusion rates for ethnoracial minorities appeared to increase across time, and recruitment strategies did not appear to be associated with increased ethnoracial minority participation in RCTs for PE.

An Economic Evaluation of Voretigene Neparvovec for the Treatment of Biallelic RPE65-Mediated Inherited Retinal Dystrophies in the UK.

INTRODUCTION: Voretigene neparvovec (VN) is a gene therapy and the first approved pharmacological treatment for biallelic RPE65-mediated inherited retinal dystrophies (IRD), a rare condition that starts in early life and causes vision to progressively deteriorate towards complete blindness. In a phase III trial, treatment with VN significantly improved functional vision and visual function, and in October 2019 the National Institute for Health and Care Excellence (NICE) Highly Specialised Technologies (HST) process recommended VN for patients in England and Wales. We assessed the cost-effectiveness of VN compared with best supportive care (BSC) in individuals with biallelic RPE65-mediated IRD in the UK. METHODS: A Markov model was developed to estimate the incremental cost per quality-adjusted life-year (QALY) gained for VN compared with BSC, from the perspective of the UK National Health Service and Personal Social Services. Phase III trial data were used to inform transition probabilities up to year 1, after which the treatment effect was assumed to be maintained for 40 years, followed by a decline in vision. A bespoke elicitation exercise involving clinical experts, patients and carers was conducted to estimate utility values for each model health state. RESULTS: At list price, VN is associated with incremental costs of £612,404 and incremental QALYs of 6.4, resulting in an incremental cost-effectiveness ratio (ICER) of £95,072 per QALY gained. Voretigene neparvovec is associated with a significant undiscounted QALY gain (20.5) and is therefore eligible for additional QALY weighting under the NICE HST process; an ICER of up to £205,000 per QALY gained could be considered cost-effective under this framework. CONCLUSION: The results of the model show VN to be a cost-effective use of healthcare resources in the UK at list price. The availability of a commercial discount in the UK (as considered in the NICE appraisal) means that in reality the ICER will be even lower. Plain language summary available for this article.

Intravitreal Ranibizumab for the Treatment of Visual Impairment Due to Choroidal Neovascularization Associated with Rare Diseases: Cost-Effectiveness in the UK.

INTRODUCTION: This study sought to determine the cost-effectiveness of intravitreal ranibizumab compared with best supportive care (BSC; considered to be no active treatment) for the treatment of visual impairment due to choroidal neovascularization (CNV) associated with causes other than neovascular age-related macular degeneration (nAMD) and pathologic myopia (PM) in a UK setting. METHODS: An individual patient-level simulation model was developed to estimate the lifetime costs and quality-adjusted life years (QALYs) of ranibizumab vs. BSC. Regression analyses, performed on patient-level data collected within the pivotal phase III MINERVA trial, modelled visual acuity (VA) progression while patients remained on treatment. Patient utilities were modelled as a function of VA in both eyes and resource use estimates were based on trial data or the literature. Costs were evaluated from the perspective of the UK National Health Service and personal social services, with future costs and health outcomes discounted at 3.5% per annum. Sensitivity and scenario analyses were conducted. RESULTS: The incremental cost-effectiveness ratio for intravitreal ranibizumab was £1363 per QALY compared to BSC and was associated with an incremental benefit of 1.06 QALYs and an incremental cost of £1444 per patient. Drug and administration costs of intravitreal ranibizumab were offset by the prevention of the development of blindness and its associated costs, while the increase in benefits was driven by a reduction in mortality risk and an improved health-related quality of life attributed to an improvement in VA. The findings were robust to a range of sensitivity analyses and ranibizumab consistently remained cost-effective at a willingness-to-pay threshold of £20,000-30,000 per QALY gained for all sensitivity analyses. CONCLUSION: Intravitreal ranibizumab is a highly cost-effective intervention for the treatment of CNV due to causes other than nAMD and PM as it delivers substantial QALY gains to patients while making cost savings vs. BSC. FUNDING: Novartis Pharmaceuticals UK Ltd.

Butyrate decreases its own oxidation in colorectal cancer cells through inhibition of histone deacetylases.

Colorectal cancer is characterized by an increase in the utilization of glucose and a diminishment in the oxidation of butyrate, which is a short chain fatty acid. In colorectal cancer cells, butyrate inhibits histone deacetylases to increase the expression of genes that slow the cell cycle and induce apoptosis. Understanding the mechanisms that contribute to the metabolic shift away from butyrate oxidation in cancer cells is important in in understanding the beneficial effects of the molecule toward colorectal cancer. Here, we demonstrate that butyrate decreased its own oxidation in cancerous colonocytes. Butyrate lowered the expression of short chain acyl-CoA dehydrogenase, an enzyme that mediates the oxidation of short-chain fatty acids. Butyrate does not alter short chain acyl-CoA dehydrogenase levels in non-cancerous colonocytes. Trichostatin A, a structurally unrelated inhibitor of histone deacetylases, and propionate also decreased the level of short chain acyl-CoA dehydrogenase, which alluded to inhibition of histone deacetylases as a part of the mechanism. Knockdown of histone deacetylase isoform 1, but not isoform 2 or 3, inhibited the ability of butyrate to decrease short chain acyl-CoA dehydrogenase expression. This work identifies a mechanism by which butyrate selective targets colorectal cancer cells to reduce its own metabolism.

Clinical Efficacy and Safety of Current Interventions for Choroidal Neovascularization Associated with Rare Diseases: A Systematic Literature Review.

INTRODUCTION: The aim of this systematic literature review was to evaluate the efficacy and safety of interventions for the treatment of choroidal neovascularization (CNV) secondary to etiologies other than age-related macular degeneration and pathologic myopia. METHODS: Relevant randomized controlled trials (RCTs) and prospective observational studies were identified by searching MEDLINE, MEDLINE In-Process, EMBASE, and CENTRAL. RESULTS: The search identified 5 RCTs; no relevant observational studies were identified. The studies differed in terms of underlying cause of CNV, patient numbers (n = 9-178), follow-up time (2-36 months) and quality assessment. In the largest RCT (n = 178 across a range of rare CNV etiologies), intravitreal ranibizumab showed superior efficacy versus sham from baseline to month 2 [mean best-corrected visual acuity (BCVA): + 9.5 vs. - 0.4 letters; p < 0.001]; the gain was maintained up to month 12. In the treatment of CNV secondary to presumed ocular histoplasmosis syndrome (POHS), both intravitreal ranibizumab and photodynamic therapy (PDT) showed significant improvement from baseline BCVA over the 12-month period (n = 9); however, all patients in the PDT group required rescue ranibizumab therapy. Unlicensed intravitreal bevacizumab was associated with a statistically significant improvement in BCVA compared to PDT at 12 months (p < 0.001) in patients with CNV secondary to multifocal choroiditis (n = 27). The use of steroids before PDT showed better BCVA outcomes than PDT alone (p < 0.05) in patients with idiopathic CNV (n = 20). Argon green laser therapy showed limited efficacy in patients with CNV secondary to OHS (n = 134). CONCLUSION: There is evidence from a relatively large, good-quality study to support the use of intravitreal ranibizumab for the treatment of CNV secondary to rare diseases. However, the limited number of RCTs for this indication and differences in study characteristics between RCTs mean that there is uncertainty regarding comparative clinical effectiveness of interventions. RCTs with an active comparator are required to fully establish the comparative effectiveness of treatments for CNV secondary to rare diseases. FUNDING: Novartis Pharmaceuticals UK Ltd, Surrey, UK.

Characterization of the Pro-Inflammatory Cytokine IL-1ß on Butyrate Oxidation in Colorectal Cancer Cells.

Cancer, in part, is driven, by alterations in cellular metabolism that promote cell survival and cell proliferation. Identifying factors that influence this shift in cellular metabolism in cancer cells is important. Interleukin-1ß (IL-1ß) is a pro-inflammatory cytokine that has been reported to be elevated in colorectal cancer patients. While much is known toward the effect of dietary nutrients on regulating inflammation and the inflammatory response, which includes cytokines such as IL-1ß, far less is understood how cytokines impact nutrient fate to alter cancer cell metabolism. Butyrate, a nutrient derived from the fermentation of dietary fiber in the colon, is the preferential exogenous energetic substrate used by non-cancerous colonocytes, but is used less efficiently by colorectal cancer cells. To test whether IL-1ß alters colonocyte energy metabolism, we measured butyrate oxidation in HCT116 colorectal cancer cells with and without IL-1ß. We hypothesize that IL-1ß will push cancerous colonocytes away from the utilization and oxidation of butyrate. In this study, we demonstrate that pretreatment of colorectal cancer cells with IL-1ß diminished butyrate oxidation and NADH levels. This effect was blocked with the interleukin receptor antagonist A (IL-1RA). Moreover, IL-1ß suppressed basal mitochondrial respiration and lowered the mitochondrial spare capacity. By using inhibitors to block downstream targets of the interleukin-1 receptor pathway, we show that p38 is required for the IL-1ß-mediated decrease in butyrate oxidation. These data provide insight into the metabolic effects induced by IL-1ß in colorectal cancer, and identify relevant targets that may be exploited to block the effects of this cytokine. J. Cell. Biochem. 118: 1614-1621, 2017. © 2016 Wiley Periodicals, Inc.

Cellular Metabolism and Dose Reveal Carnitine-Dependent and -Independent Mechanisms of Butyrate Oxidation in Colorectal Cancer Cells.

Dietary fiber has been suggested to suppress colorectal cancer development, although the mechanisms contributing to this beneficial effect remain elusive. Butyrate, a fermentation product of fiber, has been shown to have anti-proliferative and pro-apoptotic effects on colorectal cancer cells. The metabolic fate of butyrate in the cell is important in determining whether, it acts as an HDAC inhibitor or is consumed as a short-chain fatty acid. Non-cancerous colonocytes utilize butyrate as the primary energy source whereas cancerous colonocytes increase glucose utilization through the Warburg effect. In this study, we show that butyrate oxidation is decreased in cancerous colonocytes compared to non-cancerous colonocytes. We demonstrate that colorectal cancer cells utilize both a carnitine-dependent and carnitine-independent mechanism that contributes to butyrate oxidation. The carnitine-dependent mechanism is contingent on butyrate concentration. Knockdown of CPT1A in colorectal cancer cells abolishes butyrate oxidation. In terms of selectivity, the carnitine-dependent mechanism only regulated butyrate oxidation, as acetate and propionate oxidation were carnitine-independent. Carnitine decreased the action of butyrate as an HDAC inhibitor and suppressed induction of H3 acetylation by butyrate in colorectal cancer cells. Thus, diminished oxidation of butyrate is associated with decreased HDAC inhibition and histone acetylation. In relation to the mechanism, we find that dichloroacetate, which decreases phosphorylation of pyruvate dehydrogenase, increased butyrate oxidation and that this effect was carnitine-dependent. In conclusion, these data suggest that colorectal cancer cells decrease butyrate oxidation through inhibition of pyruvate dehydrogenase, which is carnitine-dependent, and provide insight into why butyrate shows selective effects toward colorectal cancer cells. J. Cell. Physiol. 231: 1804-1813, 2016. © 2015 Wiley Periodicals, Inc.

Using prolonged exposure therapy to treat posttraumatic stress disorder a latina female with a complex trauma history

Hispanics experience more severe and higher rates of PTSD than other ethnic groups. Despite the higher prevalence and more severe symptom presentation, few researchers have focused on the treatment of PTSD with Hispanics despite that the manner in which the disorder manifests may be related to ethnicity. We present the case of a 31 year-old Hispanic female who presented with PTSD. Prolonged Exposure (PE) Therapy was used to successfully treat the client. A number of factors were considered over the course of treatment including language, relevant Hispanic cultural factors, and the client’s undocumented status. From this case study we can deduce that 1) PE can be effectively used with Hispanics; 2) treatment should be provided in the client’s preferred language; 3) assessment should integrate cultural considerations; and 4) factors or characteristics that are related to culture may surface and the clinician should address these factors or characteristics as needed (AU)

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