Tourism dependence and poverty alleviation thresholds in Chinese ethnic tourism.

Questions persist on the relationship between tourism dependence and economic growth in ethnic tourism areas. This study addresses such gaps by constructing a threshold regression model based on socio-economic data from 2006 to 2019 for nine sites in Enshi Prefecture of central China. ArcGIS and other open-source data were also used to visualize changing tourism resources in the region. Findings suggest that tourism dependence (the ratio of tourism-based GDP to overall GDP) significantly promotes economic growth in ethnic minority areas. However, the positive influence of tourism dependence on economic growth appears dynamic and non-linear - rising at first before falling when tourism dependence exceeded a threshold of 34%, with effects varying by site and year. Methods and findings make crucial theoretical contributions to understanding tourism dependence and poverty alleviation linkages. This paper also highlights the importance of political support and balanced investment in diverse industries to minimize decreasing returns beyond tourism dependence thresholds in destinations worldwide.

Politics of disease control in Africa and the critical role of global health diplomacy: A systematic review.

Background: Africa is facing the triple burden of communicable diseases, non-communicable diseases (NCDs), and nutritional disorders. Multilateral institutions, bilateral arrangements, and philanthropies have historically privileged economic development over health concerns. That focus has resulted in weak health systems and inadequate preparedness when there are outbreaks of diseases. This review aims to understand the politics of disease control in Africa and global health diplomacy's (GHD's) critical role. Methods: A literature review was done in Medline/PubMed, Web of Science, Scopus, Embase, and Google scholar search engines. Keywords included MeSH and common terms related to the topics: "Politics," "disease control," "epidemics/ endemics," and "global health diplomacy" in the "African" context. The resources also included reports of World Health Organization, United Nations and resolutions of the World Health Assembly (WHA). Results: African countries continue to struggle in their attempts to build health systems for disease control that are robust enough to tackle the frequent epidemics that plague the continent. The politics of disease control requires the crafting of cooperative partnerships to accommodate the divergent interests of multiple actors. Recent outbreaks of COVID-19 and Ebola had a significant impact on African economies. It is extremely important to prioritize health in the African development agendas. The African Union (AU) should leverage the momentum of the rise of GHD to (i) navigate the politics of global health governance in an interconnected world(ii) develop robust preparedness and disease response strategies to tackle emerging and reemerging disease epidemics in the region (iii) address the linkages between health and broader human security issues driven by climate change-induced food, water, and other insecurities (iv) mobilize resources and capacities to train health officials in the craft of diplomacy. Conclusion: The AU, Regional Economic Communities (RECs), and African Centres for Disease Control should harmonize their plans and strategies and align them towards a common goal that integrates health in African development agendas. The AU must innovatively harness the practice and tools of GHD towards developing the necessary partnerships with relevant actors in the global health arena to achieve the health targets of the Sustainable Development Goals.

Adjuvant therapy following oesophagectomy for adenocarcinoma in patients with a positive resection margin.

BACKGROUND: The role of adjuvant therapy in patients with oesophagogastric adenocarcinoma treated by neoadjuvant chemotherapy is contentious. In UK practice, surgical resection margin status is often used to classify patients for receiving adjuvant treatment. The aim of this study was to assess the survival benefit of adjuvant therapy in patients with positive (R1) resection margins. METHODS: Two prospectively collected UK institutional databases were combined to identify eligible patients. Adjusted Cox regression analyses were used to compare overall and recurrence-free survival according to adjuvant treatment. Recurrence patterns were assessed as a secondary outcome. Propensity score-matched analysis was also performed. RESULTS: Of 616 patients included in the combined database, 242 patients who had an R1 resection were included in the study. Of these, 112 patients (46·3 per cent) received adjuvant chemoradiotherapy, 46 (19·0 per cent) were treated with adjuvant chemotherapy and 84 (34·7 per cent) had no adjuvant treatment. In adjusted analysis, adjuvant chemoradiotherapy improved recurrence-free survival (hazard ratio (HR) 0·59, 95 per cent c.i. 0·38 to 0·94; P = 0·026), with a benefit in terms of both local (HR 0·48, 0·24 to 0·99; P = 0·047) and systemic (HR 0·56, 0·33 to 0·94; P = 0·027) recurrence. In analyses stratified by tumour response to neoadjuvant chemotherapy, non-responders (Mandard tumour regression grade 4-5) treated with adjuvant chemoradiotherapy had an overall survival benefit (HR 0·61, 0·38 to 0·97; P = 0·037). In propensity score-matched analysis, an overall survival benefit (HR 0·62, 0·39 to 0·98; P = 0·042) and recurrence-free survival benefit (HR 0·51, 0·30 to 0·87; P = 0·004) were observed for adjuvant chemoradiotherapy versus no adjuvant treatment. CONCLUSION: Adjuvant therapy may improve overall survival and recurrence-free survival after margin-positive resection. This pattern seems most pronounced with adjuvant chemoradiotherapy in non-responders to neoadjuvant chemotherapy.

ANTECEDENTES: El papel del tratamiento adyuvante en pacientes con adenocarcinoma esofagogástrico tratados con quimioterapia neoadyuvante es polémico. En la práctica del Reino Unido, el estado del margen de resección quirúrgico se utiliza a menudo para identificar a los pacientes que reciben tratamiento adyuvante. El objetivo de este estudio fue evaluar el beneficio en la supervivencia del tratamiento adyuvante en pacientes con márgenes de resección positivos (R1). MÉTODOS: Se combinaron dos bases de datos de instituciones del Reino Unido que recogen información de forma prospectiva para identificar pacientes elegibles. Se utilizaron análisis de regresión de Cox ajustados para comparar la supervivencia global y la supervivencia libre de recidiva según el tratamiento adyuvante. Los patrones de recidiva se evaluaron como resultado secundario. También se realizó un análisis de emparejamiento por puntaje de propensión. RESULTADOS: De 616 pacientes incluidos en la base de datos combinada, se incluyeron en el estudio 242 pacientes con resección R1. De estos pacientes, 112 (46%) recibieron quimiorradioterapia adyuvante, 46 (19%) pacientes fueron tratados con quimioterapia adyuvante y 84 (35%) pacientes no recibieron ningún tratamiento. En el análisis ajustado, la quimiorradioterapia adyuvante mejoró la supervivencia libre de recidiva (cociente de riesgos instantáneos, hazard ratio, HR 0,59, i.c. del 95% 0,38-0,94; P = 0,026) con un beneficio tanto para la recidiva local (HR 0,48, i.c. del 95% 0,24-0,99; P = 0,047) como para la sistémica (HR 0,56, i.c. del 95% 0,33-0,94; P = 0,027). Cuando los pacientes se clasificaron según la respuesta tumoral a la quimioterapia neoadyuvante, los no respondedores (Mandard Grado 4/5) tratados con quimiorradioterapia adyuvante obtuvieron un beneficio en la supervivencia (HR 0,61, i.c. del 95% 0,38-0,97; P = 0,037). En el análisis por emparejamiento por puntaje de propensión, se observó un beneficio en la supervivencia global (HR 0,62, i.c. del 95% 0,39-0,98; P = 0,042) y en la supervivencia libre de recidiva (HR 0,51.i.c. del 95% 0,30-0,87; P = 0,004) con la quimiorradioterapia adyuvante frente a no recibir tratamiento adyuvante. CONCLUSIÓN: El tratamiento adyuvante puede mejorar la supervivencia global y la supervivencia libre de recidiva en pacientes con margen de resección positivo. Este patrón parece más pronunciado con la quimiorradioterapia adyuvante en pacientes que no responden a la quimioterapia.

Prediction of a positive circumferential resection margin at surgery following neoadjuvant chemotherapy for adenocarcinoma of the oesophagus.

Background: A positive circumferential resection margin (CRM) has been associated with higher rates of locoregional recurrence and worse survival in oesophageal cancer. The aim of this study was to establish if clinicopathological and radiological variables might predict CRM positivity in patients who received neoadjuvant chemotherapy before surgery for oesophageal adenocarcinoma. Methods: Multivariable analysis of clinicopathological and CT imaging characteristics considered potentially predictive of CRM was performed at initial staging and following neoadjuvant chemotherapy. Prediction models were constructed. The area under the curve (AUC) with 95% confidence intervals (c.i.) from 1000 bootstrapping was assessed. Results: A total of 223 patients were included in the study. Poor differentiation (odds ratio (OR) 2·84, 95 per cent c.i. 1·39 to 6·01) and advanced clinical tumour status (T3-4) (OR 2·93, 1·03 to 9·48) were independently associated with an increased CRM risk at diagnosis. CT-assessed lack of response (stable or progressive disease) following chemotherapy independently corresponded with an increased risk of CRM positivity (OR 3·38, 1·43 to 8·50). Additional CT evidence of local invasion and higher CT tumour volume (14 cm3) improved the performance of a prediction model, including all the above parameters, with an AUC (c-index) of 0·76 (0·67 to 0·83). Variables associated with significantly higher rates of locoregional recurrence were pN status (P = 0·020), lymphovascular invasion (P = 0·007) and poor response to chemotherapy (Mandard score 4-5) (P = 0·006). CRM positivity was associated with a higher locoregional recurrence rate, but this was not statistically significant (P = 0·092). Conclusion: The presence of advanced cT status, poor tumour differentiation, and CT-assessed lack of response to chemotherapy, higher tumour volume and local invasion can be used to identify patients at risk of a positive CRM following neoadjuvant chemotherapy.

Antecedentes: Un margen de resección circunferencial (circumferential resection margin, CRM) positivo se ha asociado con tasas más elevadas de recidiva locorregional y peor supervivencia en el cáncer de esófago. El objetivo de este estudio fue establecer si las variables clínico­patológicas y radiológicas podrían predecir la positividad del CRM en el adenocarcinoma de esófago tras quimioterapia neoadyuvante antes de la cirugía. Métodos: Se realizó un análisis multivariable de las características clínico­patológicas y de la tomografía computarizada (computed tomography, CT) que se consideraron potencialmente predictivas de CRM en la estadificación inicial y tras la quimioterapia neoadyuvante. Se construyeron modelos de predicción. Se evaluó el área bajo la curva (area under curve, AUC) con el i.c. del 95% a partir de 1.000 muestras bootstrap. Resultados: Se incluyeron 223 pacientes en el estudio. Una pobre diferenciación (razón de oportunidades, odds ratio, OR 2,84, i.c. del 95% 1,39­6,01) y un estadio clínico T avanzado (T3­4) (OR 2,93, i.c. del 95% 1,03­9,48) se asociaron de forma independiente con un riesgo aumentado de CRM en el diagnóstico. La falta de respuesta en la CT (estable o enfermedad en progresión) tras la quimioterapia se correspondía de forma independiente con un riesgo aumentado de CRM positivo (OR 3,38, i.c. del 95% 1,43­8,50). Además, la evidencia por CT de invasión local y un mayor volumen del tumor en CT (14 cm3) mejoraron el funcionamiento del modelo predictivo, incluyendo todos los parámetros previamente señalados; con AUC (índice c) de 0,76 (0,68­0,83). Las variables asociadas de forma significativa con tasas más elevadas de recidiva locorregional fueron el estado de los ganglios linfáticos patológicos (P = 0,002), la invasión linfovascular (P = 0,007) y la respuesta pobre a la quimioterapia (Mandard 4 y 5 (P = 0,006)). La positividad del CRM se asoció con una tasa de recidiva locorregional más elevada pero sin alcanzar significación estadística (P = 0,09). Conclusión: La presencia de un estadio clínico T avanzado, tumor pobremente diferenciado, falta de respuesta a la quimioterapia en la TC, mayor volumen del tumor en la TC e invasión local pueden ser utilizados para identificar pacientes en riesgo de un CRM positivo tras quimioterapia neoadyuvante.

Regional and global impacts of the 2007 Port-of-Spain Declaration on noncommunicable diseases

[ABSTRACT]. Objective. To assess how well Caribbean regional institutions (RIs) met their commitments from the 2007 Portof-Spain Summit (POSS) declaration on noncommunicable diseases (NCDs), and evaluate the POSS impact on the United Nations High-level Meeting (HLM) on NCDs in 2011 (2011 HLM), HLM NCD review in 2014 (2014 HLM), World Health Organization’s 2025 NCD targets (2025 WHO), and 2030 Sustainable Development Goals (SDGs) agreed upon in 2015. Methods. This study uses a method developed by the University of Toronto’s Global Governance Program to measure institutions’ compliance with commitments from a summit and the match with commitments from earlier summits. This approach was supplemented using data from published literature, primary documents, and semistructured key informant interviews to detail how and why Caribbean RIs met the 2007 POSS commitments, how the 2007 POSS commitments led to compliance, and how the 2007 POSS influenced international NCD commitments. Results. Caribbean RIs implemented the 2007 POSS commitments better when they had more public legitimacy, when their missions aligned with those commitments, and when more resources were available to them. Implementation constraints arose from multiple, sometimes competing, interests of the decision-making and national implementing bodies of the Caribbean Community (CARICOM). Internationally, the early, expanding efforts of the POSS pioneers had an initially important but subsequently diminishing impact on the HLMs. Conclusions. For the Caribbean region, the Caribbean Public Health Agency should be funded to lead strengthened Caribbean RIs in coordinated action on NCDs. At the international level, the United Nations should embed NCDs in a “whole-of-global-governance” approach, monitor implementation annually, foster transregional partnerships on NCD-related themes, engage civil society, and support regular regional and global summits to enhance implementation and improvement, aimed at future HLMs on NCDs, the 2025 WHO targets, and the SDG NCD targets.

[RESUMEN]. Objetivo. Evaluar el grado de cumplimiento de las instituciones regionales del Caribe con los compromisos adquiridos en la Declaración de la Cumbre de Puerto de España de 2007 sobre las enfermedades no transmisibles (ENT), y evaluar el impacto de esta Cumbre en la Reunión de Alto Nivel de las Naciones Unidas sobre las ENT de 2011, la Reunión de Revisión de 2014, las metas sobre ENT para 2025 de la Organización Mundial de la Salud (OMS), y los Objetivos de Desarrollo Sostenible 2030, acordados en 2015. Métodos. Este estudio utilizó un método desarrollado por el Programa de Gobernanza Global de la Universidad de Toronto para medir el cumplimiento de las instituciones con los compromisos de una cumbre y la compatibilidad con los compromisos de cumbres anteriores. Este enfoque se complementó con datos de la bibliografía, documentos primarios y entrevistas semiestructuradas con informantes clave para detallar cómo y por qué las instituciones regionales del Caribe cumplieron con los compromisos de la Cumbre de Puerto de España de 2007, cómo los compromisos de esta Cumbre llevaron a su cumplimiento, y cómo la Cumbre influyó en los compromisos internacionales relacionados con las ENT. Resultados. Las instituciones regionales del Caribe implementaron mejor los compromisos de la Cumbre de Puerto de España de 2007 cuando disponían de mayor legitimidad pública, cuando sus misiones se alineaban con esos compromisos y cuando disponían de más recursos para afrontarlos. Las restricciones en la implementación se relacionaron con la existencia de intereses múltiples –y a veces contrapuestos– de los organismos tomadores de decisiones y los organismos responsables de la implementación a nivel nacional en la Comunidad del Caribe (CARICOM). A nivel internacional, los primeros esfuerzos de expansión de los pioneros de la Cumbre de Puerto de España tuvieron un impacto importante al inicio de las reuniones de alto nivel, pero posteriormente este disminuyó. Conclusiones. En la región del Caribe, la Agencia de Salud Pública del Caribe (CARPHA) debe disponer de financiación para liderar a las instituciones regionales del Caribe en una acción coordinada contra las ENT. A nivel internacional, las Naciones Unidas deben integrar las ENT en un enfoque de “gobernanza global”, monitorear la implementación de manera anual, fomentar asociaciones transregionales en temas relacionados con las ENT, involucrar a la sociedad civil y apoyar la realización regular de cumbres regionales y mundiales para mejorar su implementación y mejora, con miras a futuras reuniones de alto nivel sobre ENT, las metas de la OMS 2025 y las metas para las ENT de los Objetivos de Desarrollo Sostenible 2030.

[RESUMO]. Objetivo. Avaliar o grau de cumprimento das instituições regionais do Caribe com os compromissos assumidos na Declaração do Cume de Porto da Espanha de 2007 sobre as doenças não transmissíveis (DNT), e avaliar o impacto deste Cume sobre a Reunião de Alto Nível das Nações Unidas sobre as DNT de 2011, a Reunião de Revisão de 2014, as metas sobre DNT para 2025 da Organização Mundial da Saúde (OMS) e os Objetivos de Desenvolvimento Sustentável 2030, concordados em 2015. Métodos. Este estudo utilizou um método desenvolvido pelo Programa de Governança Global da Universidade de Toronto para medir o cumprimento das instituições com os compromissos de um cume e a compatibilidade com os compromissos de cumes anteriores. Este enfoque foi complementado com dados da bibliografia, documentos primários e entrevistas semi-estruturadas com informantes chave para detalhar como e por que as instituições regionais do Caribe cumpriram os compromissos do Cume de Porto da Espanha de 2007, como os compromissos deste Cume levaram ao seu cumprimento, e como o Cume influiu nos compromissos internacionais relacionados com as DNT. Resultados. As instituições regionais do Caribe implementaram melhor os compromissos do Cume de Porto da Espanha de 2007 quando dispuserem de maior legitimidade pública, quando suas missões se alinhavam com esses compromissos e quando dispunham de mais recursos para confrontá-los. As restrições na implementação se relacionaram com à existência de interesses múltiplos–e às vezes contrapostos–dos organismos responsáveis pela tomada de decisão e or organismos responsáveis pela implementação no nível nacional na Comunidade do Caribe (CARICOM). No plano internacional, os primeiros esforços de expansão dos pioneiros do Cume de Porto da Espanha tiveram um impacto importante no início das reuniões de alto nível, mas posteriormente este diminuiu. Conclusões. Na região do Caribe, a Agência de Saúde Pública do Caribe (CARPHA) deve dispor de financiamento para liderar as instituições regionais do Caribe em uma ação coordenada contra as DNT. No plano internacional, as Nações Unidas devem integrar as DNT em um enfoque de "governança global", monitorar a implementação de maneira anual, promover associações transregionais em temas relacionados com as DNT, envolver a sociedade civil, e apoiar a realização regular de cumes regionais e mundiais para melhorar sua implementação e melhora com vistas a reuniões de alto nível futuras sobre DNT, as metas da OMS 2025 e as metas para as DNT dos Objetivos de Desenvolvimento Sustentável 2030.

Impact of incremental circumferential resection margin distance on overall survival and recurrence in oesophageal adenocarcinoma.

BACKGROUND: Previous analyses of the oesophageal circumferential resection margin (CRM) have focused on the prognostic validity of two different definitions of a positive CRM, that of the College of American Pathologists (tumour at margin) and that of the Royal College of Pathologists (tumour within 1 mm). This study aimed to analyse the validity of these definitions and explore the risk of recurrence and survival with incremental tumour distances from the CRM. METHODS: This cohort study included patients who underwent resection for adenocarcinoma of the oesophagus between 2000 and 2014. Kaplan-Meier and Cox regression analyses were performed to determine the hazard ratio (HR) with 95 per cent confidence intervals for recurrence and mortality in CRM increments: tumour at the cut margin, extending to within 0·1-0·9, 1·0-1·9, 2·0-4·9 mm, and 5·0 mm or more from the margin. RESULTS: A total of 444 patients were included in the study. Kaplan-Meier and unadjusted analyses showed a significant incremental improvement in overall survival (P < 0·001) and recurrence (P for trend < 0·001) rates with increasing distance from the CRM. Tumour distance of 2·0 mm or more remained a significant predictor of survival on multivariable analysis (HR for risk of death 0·66, 95 per cent c.i. 0·44 to 1·00). Multivariable analysis of overall survival demonstrated a significant difference between a positive and negative CRM with the Royal College of Pathologists' definition (HR 1·37, 1·01 to 1·85), but not with the College of American Pathologists' definition (HR 1·22, 0·90 to 1·65). CONCLUSION: This study demonstrated an incremental improvement in survival and recurrence rates with increasing tumour distance from the CRM.

Regional and global impacts of the 2007 Port-of-Spain Declaration on noncommunicable diseases.

OBJECTIVE: To assess how well Caribbean regional institutions (RIs) met their commitments from the 2007 Port-of-Spain Summit (POSS) declaration on noncommunicable diseases (NCDs), and evaluate the POSS impact on the United Nations High-level Meeting (HLM) on NCDs in 2011 (2011 HLM), HLM NCD review in 2014 (2014 HLM), World Health Organization's 2025 NCD targets (2025 WHO), and 2030 Sustainable Development Goals (SDGs) agreed upon in 2015. METHODS: This study uses a method developed by the University of Toronto's Global Governance Program to measure institutions' compliance with commitments from a summit and the match with commitments from earlier summits. This approach was supplemented using data from published literature, primary documents, and semistructured key informant interviews to detail how and why Caribbean RIs met the 2007 POSS commitments, how the 2007 POSS commitments led to compliance, and how the 2007 POSS influenced international NCD commitments. RESULTS: Caribbean RIs implemented the 2007 POSS commitments better when they had more public legitimacy, when their missions aligned with those commitments, and when more resources were available to them. Implementation constraints arose from multiple, sometimes competing, interests of the decision-making and national implementing bodies of the Caribbean Community (CARICOM). Internationally, the early, expanding efforts of the POSS pioneers had an initially important but subsequently diminishing impact on the HLMs. CONCLUSIONS: For the Caribbean region, the Caribbean Public Health Agency should be funded to lead strengthened Caribbean RIs in coordinated action on NCDs. At the international level, the United Nations should embed NCDs in a "whole-of-global-governance" approach, monitor implementation annually, foster transregional partnerships on NCD-related themes, engage civil society, and support regular regional and global summits to enhance implementation and improvement, aimed at future HLMs on NCDs, the 2025 WHO targets, and the SDG NCD targets.

Patterns of recurrence in oesophageal cancer following oesophagectomy in the era of neoadjuvant chemotherapy.

BACKGROUND: Tumour recurrence following oesophagectomy for oesophageal cancer is common despite neoadjuvant treatment. Understanding patterns of recurrence and risk factors associated with locoregional and systemic recurrence might influence future treatment strategies. METHODS: This was a cohort study involving patients undergoing resection for adenocarcinoma or squamous cell carcinoma of the oesophagus between 2000 and 2014. Clinicopathological factors associated with locoregional and systemic recurrence were analysed using multivariable logistic regression to determine odds ratios (ORs) and 95 per cent confidence intervals. RESULTS: Some 698 patients were identified. Lymphovascular invasion (OR 2·09, 95 per cent c.i. 1·18 to 3·71) and preoperative stenting (OR 3·70, 1·34 to 10·23) were independent risk factors for isolated locoregional recurrence. Pathological nodal disease in patients with pT1-2 (pN1: OR 2·72, 1·35 to 5·48; pN2-3: OR 5·00, 2·35 to 10·66) or pT3-4 (pN1: OR 3·03, 1·51 to 6·07; pN2-3: OR 5·75, 3·15 to 10·49) disease predisposed to systemic recurrence. Poor or no response to chemotherapy was also an independent risk factor for isolated systemic recurrence (OR 1·85, 1·05 to 3·26). A positive resection margin (R1 resection) was not associated with a significantly increased risk of isolated locoregional recurrence (OR 1·37, 0·81 to 2·33). CONCLUSION: These findings confirm that oesophageal adenocarcinoma is frequently a systemic disease. Understanding the key predictors of local and systemic recurrence may facilitate the tailoring of oncological therapies to the individual patient.

Enoxaparin venous thromboembolism prophylaxis in bariatric surgery: A best evidence topic.

A best evidence topic in surgery was written according to a structured protocol. The question addressed was: which is the best regimen of enoxaparin thromboprophylaxis for patients undergoing bariatric surgery? One hundred and twenty-five papers were identified using the reported literature search, of which four represented the best evidence to answer the clinical question. The authors, country and date of publication, patient groups, relevant outcomes and results of these papers were tabulated. All four studies are non-randomized cohort studies examining venous thromboembolism rates and major postoperative bleeding following varying regimens of Enoxaparin thromboprophylaxis. There is no level 1 evidence which significantly favors any particular thromboprophylaxis regimen. There is some evidence that extended duration of treatment of ten days after discharge significantly reduces the incidence of VTE compared to in-hospital treatment only, and that a higher incidence of post-operative bleeding occurs with a regimen that includes a pre-operative dose of Enoxaparin. With regard to dosage, for in-hospital treatment the higher dosage of 40 mg twice daily as opposed to 30 mg seems to significantly reduce the incidence of VTE without significantly affecting bleeding rate.

Central losartan attenuates increases in arterial pressure and expression of FosB/ΔFosB along the autonomic axis associated with chronic intermittent hypoxia.

Chronic intermittent hypoxia (CIH) increases mean arterial pressure (MAP) and FosB/ΔFosB staining in central autonomic nuclei. To test the role of the brain renin-angiotensin system (RAS) in CIH hypertension, rats were implanted with intracerebroventricular (icv) cannulae delivering losartan (1 µg/h) or vehicle (VEH) via miniosmotic pumps and telemetry devices for arterial pressure recording. A third group was given the same dose of losartan subcutaneously (sc). Two groups of losartan-treated rats served as normoxic controls. Rats were exposed to CIH or normoxia for 7 days and then euthanized for immunohistochemistry. Intracerebroventricular losartan attenuated CIH-induced increases in arterial pressure during CIH exposure (0800-1600 during the light phase) on days 1, 6, and 7 and each day during the normoxic dark phase. FosB/ΔFosB staining in the organum vasculosum of the lamina terminalis (OVLT), median preoptic nucleus (MnPO), paraventricular nucleus of the hypothalamus (PVN), the rostral ventrolateral medulla (RVLM), and the nucleus of the solitary tract (NTS) was decreased in icv losartan-treated rats. Subcutaneous losartan also reduced CIH hypertension during the last 2 days of CIH and produced bradycardia prior to the effect on blood pressure. Following sc losartan, FosB/ΔFosB staining was reduced only in the OVLT, MnPO, PVN, and NTS. These data indicate that the central and peripheral RAS contribute to CIH-induced hypertension and transcriptional activation of autonomic nuclei and that the contribution of the central RAS is greater during the normoxic dark phase of CIH hypertension.

Cardiac cyclic nucleotide phosphodiesterases: function, regulation, and therapeutic prospects.

The second messengers cAMP and cGMP exist in multiple discrete compartments and regulate a variety of biological processes in the heart. The cyclic nucleotide phosphodiesterases, by catalyzing the hydrolysis of cAMP and cGMP, play crucial roles in controlling the amplitude, duration, and compartmentalization of cyclic nucleotide signaling. Over 60 phosphodiesterase isoforms, grouped into 11 families, have been discovered to date. In the heart, both cAMP- and cGMP-hydrolyzing phosphodiesterases play important roles in physiology and pathology. At least 7 of the 11 phosphodiesterase family members appear to be expressed in the myocardium, and evidence supports phosphodiesterase involvement in regulation of many processes important for normal cardiac function including pacemaking and contractility, as well as many pathological processes including remodeling and myocyte apoptosis. Pharmacological inhibitors for a number of phosphodiesterase families have also been used clinically or preclinically to treat several types of cardiovascular disease. In addition, phosphodiesterase inhibitors are also being considered for treatment of many forms of disease outside the cardiovascular system, raising the possibility of cardiovascular side effects of such agents. This review will discuss the roles of phosphodiesterases in the heart, in terms of expression patterns, regulation, and involvement in physiological and pathological functions. Additionally, the cardiac effects of various phosphodiesterase inhibitors, both potentially beneficial and detrimental, will be discussed.

An Essential role for DeltaFosB in the median preoptic nucleus in the sustained hypertensive effects of chronic intermittent hypoxia.

One of the main clinical features of obstructive sleep apnea is sustained hypertension and elevated sympathetic activity during waking hours. Chronic intermittent hypoxia (CIH), animal model of the hypoxemia associated with obstructive sleep apnea, produces a similar sustained increase in blood pressure. This study determined the role of ΔFosB in the median preoptic nucleus (MnPO) in the sustained increase in mean arterial pressure associated with CIH. Rats were injected in the MnPO with viral vectors that expressed green fluorescent protein alone or green fluorescent protein plus a dominant-negative construct that inhibits the transcriptional effects of ΔFosB. In green fluorescent protein-injected rats and uninjected controls, 7-day exposure to CIH increased mean arterial pressure by 7 to 10 mm Hg during both intermittent hypoxia exposure and normoxia. Dominant-negative inhibition of MnPO ΔFosB did not affect changes in mean arterial pressure during intermittent hypoxia exposure but significantly reduced the sustained component of the blood pressure response to CIH during the normoxic dark phase. Inhibition of MnPO ΔFosB reduced the FosB/ΔFosB staining in the paraventricular nucleus and rostral ventrolateral medulla but not the nucleus of the solitary tract. PCR array analysis identified 6 activator protein 1-regulated genes expressed in the MnPO that were increased by CIH exposure, ace, ace2, nos1, nos3, prdx2, and map3k3. Dominant-negative inhibition of ΔFosB in the MnPO blocked increased expression of each of these genes in rats exposed to CIH except for Prdx2. ΔFosB may mediate transcriptional activity in MnPO necessary for sustained CIH hypertension, suggesting that neural adaptations may contribute to diurnal hypertension in obstructive sleep apnea.

Chronic intermittent hypoxia increases blood pressure and expression of FosB/DeltaFosB in central autonomic regions.

Chronic intermittent hypoxia (CIH) models repetitive bouts of arterial hypoxemia that occur in humans suffering from obstructive sleep apnea. CIH has been linked to persistent activation of arterial chemoreceptors and the renin-angiotensin system, which have been linked to chronic elevations of sympathetic nerve activity (SNA) and mean arterial pressure (MAP). Because Fos and FosB are transcription factors involved in activator protein (AP)-1 driven central nervous system neuronal adaptations, this study determined if CIH causes increased Fos or FosB staining in brain regions that regulate SNA and autonomic function. Male Sprague Dawley rats were instrumented with telemetry transmitters for continuous recording of MAP and heart rate (HR). Rats were exposed to continuous normoxia (CON) or to CIH for 8 h/day for 7 days. CIH increased MAP by 7-10 mmHg without persistently affecting HR. A separate group of rats was killed 1 day after 7 days of CIH for immunohistochemistry. CIH did not increase Fos staining in any brain region examined. Staining for FosB/ΔFosB was increased in the organum vasculosum of the lamina terminalis (CON: 9 ± 1; CIH: 34 ± 3 cells/section), subfornical organ (CON: 7 ± 2; CIH: 31 ± 3), median preoptic nucleus (CON 15 ± 1; CIH: 38 ± 3), nucleus of the solitary tract (CON: 9 ± 2; CIH: 28 ± 4), A5 (CON: 3 ± 1; CIH: 10 ± 1), and rostral ventrolateral medulla (CON: 5 ± 1; CIH: 17 ± 2). In the paraventricular nucleus, FosB/ΔFosB staining was located mainly in the dorsal and medial parvocellular subnuclei. CIH did not increase FosB/ΔFosB staining in caudal ventrolateral medulla or supraoptic nucleus. These data indicate that CIH induces an increase in FosB/ΔFosB in autonomic nuclei and suggest that AP-1 transcriptional regulation may contribute to stable adaptive changes that support chronically elevated SNA.

Long-term caloric restriction reduces metabolic rate and heart rate under cool and thermoneutral conditions in FBNF1 rats.

The long-term metabolic and cardiovascular responses to caloric restriction (CR) are poorly understood. We examined the responses to one year of CR in FBNF1 rats housed in cool (COOL; T(a)=15 °C) or thermoneutral (TMN; T(a)=30 °C) conditions. Rats were acclimated to COOL or TMN for 2 months, instrumented for cardiovascular telemetry and studied in calorimeters. Baseline caloric intake, oxygen consumption (VO(2)), mean arterial blood pressure (MAP), and heart rate (HR) were determined prior to assignment to ad lib (AL) or CR groups (30-40% CR) within each T(a) (n = 8). Groups of rats were studied after 10 weeks CR, one year CR, and after 4 days of re-feeding. Both 10 weeks and one year of CR reduced HR and VO(2) irrespective of T(a). Evaluation of the relationship between metabolic organ mass (liver, heart, brain, and kidney mass) and energy expenditure revealed a clear shift induced by CR to reduce expenditure per unit metabolic mass in both COOL and TMN groups. Re-feeding resulted in prompt elevations of HR and VO(2) to levels observed in control rats. These findings are consistent with the hypothesis that long term CR produces sustained reductions in metabolic rate and heart rate in rats.

The Alabama Drug Discovery Alliance: a collaborative partnership to facilitate academic drug discovery.

The Alabama Drug Discovery Alliance is a collaboration between the University of Alabama at Birmingham and Southern Research Institute that aims to support the discovery and development of therapeutic molecules that address an unmet medical need. The alliance builds on the expertise present at both institutions and has the dedicated commitment of their respective technology transfer and intellectual property offices to guide any commercial opportunities that may arise from the supported efforts. Although most projects involve high throughput screening, projects at any stage in the drug discovery and development pathway are eligible for support. Irrespective of the target and stage of any project, well-functioning interdisciplinary teams are crucial to a project's progress. These teams consist of investigators with a wide variety of expertise from both institutions to contribute to the program's success.

Acceleration of cortical thinning in familial Alzheimer's disease.

BACKGROUND: MRI in presymptomatic autosomal dominant Alzheimer's disease mutation carriers (MC) provides an opportunity to detect changes that pre-date symptoms or clinical diagnosis. We used automated cortical thickness (CTh) measurement to compare the grey matter of such a group with cognitively normal controls. METHODS: 9 presymptomatic mutation carriers (4 PSEN1, 5 APP) and 25 healthy, age and sex-matched controls underwent longitudinal volumetric MRI brain imaging. CTh measurement was performed across the whole brain using a validated, automated technique. Four regions of interest (ROI) (entorhinal cortex (ERC), parahippocampal gyrus (PHG), posterior cingulate cortex and precuneus) and two control regions (paracentral and pericalcarine) were selected on the basis of imaging data in existing Alzheimer's disease (AD) literature. Linear mixed models were used to describe normal ageing in controls and the extent to which mean CTh in cases differed from controls according to time since clinical diagnosis, adjusting for normal ageing. RESULTS: An accelerating decline in CTh was observed across all ROI in the MC group. No such decline was demonstrated in the control regions for the MC group. Relative to controls, and adjusting for normal ageing, there was evidence (p=0.05, one-sided test) of lower CTh in the posterior cingulate up to 1.8 years prior to diagnosis and in the precuneus up to 4.1 years prior to diagnosis in the MC group. DISCUSSION: Automated CTh analysis is a relatively practical, rapid and effective technique for assessing subtle structural change in AD. There is evidence that cortical thickness is reduced in mutation carriers a number of years prior to clinical diagnosis.

Combined amylin-leptin treatment lowers blood pressure and adiposity in lean and obese rats.

OBJECTIVE: To examine the cardiovascular effects of combined amylin (AMN) and leptin (LEP) treatment in lean and obese rats. RESEARCH DESIGN: Rats were instrumented for telemetry and given LEP (300 µg kg(-1) day(-1)), AMN (100 µg kg(-1) day(-1)), AMN+LEP or vehicle (VEH; 0.9% normal saline) via a subcutaneous mini-osmotic pump for 7 days. The VEH group was subdivided into ad libitum fed and pair-fed to the amount of food AMN+LEP animals ate daily. Rats were housed in metabolic chambers for analysis of cardiovascular physiology and metabolism. SUBJECTS: Male Fisher 344 × Brown Norway (FBNF1; Harlan; age=3-5 months; n=72) rats were placed on standard rodent chow (LEAN, n=41) or moderately high-fat diet (OBESE; n=31) to produce obesity. RESULTS: AMN+LEP potently reduced food intake (LEAN: 57% OBESE: 59%) and abdominal fat mass (LEAN: 56% OBESE: 41%). Pair-fed rats displayed bradycardia and metabolic suppression. In contrast, AMN+LEP increased heart rate and oxygen consumption above levels in LEP or AMN-treated rats. LEP reduced blood pressure in both lean and obese rats but AMN had no effect. LEP-induced reductions in blood pressure were not altered by AMN+LEP treatment. Thus, AMN+LEP treatment decreased food intake, body fat and blood pressure in lean and obese rats. CONCLUSION: We conclude that the potent anti-adiposity actions of AMN+LEP are due in part to prevention of the bradycardia and metabolic suppression typically observed with negative energy balance. Furthermore, the hypotensive actions of peripheral LEP treatment are observable in spite of the potent AMN+LEP activation of anorexic and thermogenic mechanisms in the central nervous system.

Dehydration followed by sham rehydration contributes to reduced neuronal activation in vasopressinergic supraoptic neurons after water deprivation.

This experiment tested the role of oropharyngeal and gastric afferents on hypothalamic activation in dehydrated rats instrumented with gastric fistulas and allowed to drink water or isotonic saline compared with euhydrated controls (CON). Rats were water-deprived for 48 h (48 WD) or 46 h WD with 2 h rehydration with water (46+W) or isotonic saline (46+S). 46+W and 46+S rats were given water with fistulas open (46+WO/46+SO, sham) or closed (46+WC/46+SC). Compared with CON, water deprivation increased and water rehydration decreased plasma osmolality, while sham rehydration had no effect. Water deprivation increased c-Fos staining in the lamina terminalis. However, none of the sham or rehydration treatments normalized c-Fos staining in the lamina terminalis. Analysis of AVP and c-Fos-positive neurons in the supraoptic nucleus (SON) revealed reduced colocalization in 46+WO and 46+SC rats compared with 48 WD and 46+SO rats. However, 46+WO and 46+SC rats had higher c-Fos staining in the SON than 46+WC or CON rats. Examination of c-Fos in the perinuclear zone (PNZ) revealed that sham and rehydrated rats had increased c-Fos staining to CON, while 48 WD and 46+SO rats had little or no c-Fos staining in this region. Thus, preabsorptive reflexes contribute to the regulation of AVP neurons in a manner independent of c-Fos expression in the lamina terminalis. Further, this reflex pathway may include inhibitory interneurons in the PNZ region surrounding the SON.

Short-term physiological hyperleptinemia decreases arterial blood pressure.

We examined the possibility that chronic, low-dose peripheral leptin infusion would inhibit food intake but not increase blood pressure. Male Fisher Brown Norway (FBNF1) and Sprague-Dawley (SD) rats were instrumented for cardiovascular telemetry, housed in metabolic chambers, and given leptin (LEP: 600 microg/kg/day) or vehicle (SAL: 10 microl/h) via a subcutaneous osmotic pump for seven days. Leptin infusion increased plasma leptin levels to about 40 ng/ml, decreased food intake by 25-35% and stimulated lipolysis in both strains of rats. Leptin infusion for one week decreased mean arterial pressure from baseline. The reduction developed slowly, was generally about 3 to 7 mm Hg, and observed in both strains. The peripheral, hypotensive effect of chronic leptin in FBNF1 rats was prevented by blockade of nitric oxide production with L-NAME treatment. These results indicate that peripheral leptin treatment, at a level which inhibits food intake and induces lipolysis, produces nitric oxide-dependent decreases in blood pressure.