RESUMEN
PURPOSE: Considering the dynamic influence of environmental, social, economic, and political factors in the emergence and growth of the BRICS countries (Brazil, Russia, India, China, and South Africa) over the years and pre-existing differences, the adverse effects of air pollution on the health and well-being of the people have remained major areas of academic inquiry and policy interventions. The present study examines the global trend of deaths and Disability Adjusted Life Years (DALYs) attributable to air pollution with particular reference to the BRICS countries for the period 1990 to 2019. METHODS: This study has used the global burden of disease estimates by using different rounds of the Global Burden of Disease (GBD) study report published by the Institute of Health Metrics Evaluation. This study has calculated the cause of death and DALYs due to environmental risk factors (i.e. Air pollution). Data analysis has been done by using the standard formula for the calculation of death (mortality) rate and DALYs rate. Similarly, we calculated the age and gender-wise death and DALYs rate by using the appropriate numerator and denominator. RESULTS: The study discovered a significant shift in disease patterns over this period, as communicable diseases like respiratory infections and tuberculosis were replaced by non-communicable diseases such as ischemic heart disease (17.2 million), chronic obstructive pulmonary disease (14.59 million), and stroke (17.02 million) as the primary causes of air pollution-related deaths in 2019 at the global level. Additionally, the study identified a worrying increase in deaths linked to neonatal disorders and respiratory infections caused by ambient particulate matter pollution in South Africa, India, and Brazil. The impact of air pollution on public health is evident across different age groups and genders, with people aged 50-69 years, those aged 70 and above, and children under 5 years being more vulnerable. Furthermore, the male population is disproportionately affected by communicable and noncommunicable diseases caused by air pollution. CONCLUSION: The study highlights the need for policymakers to implement evidence-based interventions to tackle this global health problem. The interventions should aim to reduce the emerging crisis of non-communicable diseases related to air pollution, particularly among vulnerable age groups and the male population, ultimately improving public health outcomes.
RESUMEN
Aryldiazonium salts remain a staple in organic synthesis and are still prepared largely in accord with the protocol developed in the 19th century. Because of the favorable reactivity that often cannot be achieved with other aryl(pseudo)halides, diazonium chemistry continues to grow. Facile extrusion of dinitrogen contributes to the desired reactivity but is also reason for safety concerns. Explosions have occurred since the discovery of these reagents and still result in accidents. In this study, we report a diazonium chemistry paradigm shift based on nitrate reduction using thiosulfate or dihalocuprates as electron donors that avoids diazonium accumulation. Because nitrate reduction is rate-limiting, aryldiazoniums are produced as fleeting intermediates, which results in a safer and often more efficient deaminative halogenation in a single step from anilines.
RESUMEN
In the context of sustainable development, this study investigates the intricate dynamics among good governance, renewable energy investment, and green finance in BRICS nations. The aim of the study is to assess how green finance and governance effectiveness moderate the impact of renewable energy investment on CO2 emissions. Utilizing the Cross-Sectional Autoregressive Distributed Lag (CS-ARDL) model, a meticulous analysis spanning two decades was conducted to unravel the relationships among key variables and CO2 emissions. The findings underscore a nuanced interplay where renewable energy investments, synergized with robust governance and strategic green finance, significantly mitigate CO2 emissions, contributing to sustainable economic development. However, the study reveals non-linear relationships, highlighting the necessity for optimal allocation and strategic planning to maximize environmental benefits. In the short-run, a government effectiveness policy threshold that should be attained in order for renewable energy investment to reduce CO2 emissions is provided. In the long-run, the negative responsiveness of CO2 emissions to renewable energy investment is further consolidated by green finance. Moreover, enhancing renewable energy investment in the long run is positive for environmental sustainability. It follows that policy makers should tailor policies aimed at enhancing renewable energy investment in the long-run as well as complementing renewable energy investment with green finance in the long-run in order to ensure environmental sustainability by means of reducing CO2 emissions. Policymakers in BRICS nations are urged to strengthen governance structures, promote renewable energy investments, leverage green finance, foster public-private partnerships, adopt a holistic approach, and address non-linear effects to accelerate the transition to a low-carbon economy.
Asunto(s)
Dióxido de Carbono , Energía Renovable , Desarrollo Sostenible , Inversiones en Salud , Desarrollo Económico , Conservación de los Recursos NaturalesRESUMEN
OBJECTIVES: To describe the prevalence of anaemia among currently married women with high-risk fertility behaviour (HRFB) based on age, parity and birth spacing indicators. DESIGN: Cross-sectional study. SETTINGS AND PARTICIPANTS: Fifth round of the National Family Health Survey (NFHS) was conducted in India (2019-2021) and included a nationally representative sample of 724, 115 women in the reproductive age group (15-49). Our analysis focused exclusively on married women who had given birth in the preceding 5 years. PRIMARY AND SECONDARY OUTCOME MEASURES: The prevalence of anaemia with HRFB was the primary outcome, and the likelihood of having anaemia due to HRFB was the secondary outcome. DATA AND METHODS: Secondary data analysis of the NFHS-5 (2019-2021) datasets was done using a weighted analysis to determine anaemia prevalence in different HRFB categories. Bivariate analysis was done using the χ2 test, and multiple binary logistic regression analyses were done to estimate the odds of having anaemia due to HRFB after adjusting for known confounders. A p value <0.05 was reported as statistically significant. RESULTS: The final analysis comprised 145,468 women, of whom 59.1% had anaemia. About 53.1% of women depicted 'No risk' fertility behaviour, and 34.6% and 12.3% had single and multiple HRFB. Women with 'no-risk,' single and multiple HRFB had anaemia prevalence rates of 58.1%, 59.4% and 63.1%, respectively. Women with 'Single risk' had an 18% higher likelihood (1.18; 1.13-1.22) of having anaemia after controlling for confounding variables, compared with the HRFB category with 'No risk.' Women with 'Multiple risks' showed a 6% higher likelihood (adjusted OR 1.06; 95% CI 1.03 to 1.08). CONCLUSIONS: Anaemia remains a prevalent issue in India, and HRFB is observed as a significant contributing factor. This vulnerable group can be targeted through multiple interventions and further our efforts to realise our anaemia-related goals.
Asunto(s)
Anemia , Historia Reproductiva , Embarazo , Humanos , Femenino , Estudios Transversales , Prevalencia , Análisis de Datos Secundarios , Anemia/epidemiología , Fertilidad , Encuestas Epidemiológicas , India/epidemiologíaRESUMEN
BACKGROUND: The Central Government of India introduced the National Health Mission (NHM) in 2005 to improve health outcomes by enhancing publicly financed (government) health expenditure and health infrastructure at the state level. This study aims to examine the effects of the state-level heterogeneity in publicly financed spending on health services on major health outcomes such as life expectancy, infant mortality rate, child mortality rate, the incidence of malaria, and immunization coverage (i.e., BCG, Polio, Measles, and Tetanus). METHODS: This study investigates the relationships between publicly financed health expenditure and health outcomes by controlling income and infrastructure levels across 28 Indian States from 2005 to 2016. Along with all states, the empirical analysis has also been carried out for high-focus and non-high-focus states as per the NHM fund flow criteria. It has applied panel fixed-effects and random effects model wherever required based on the Hausman test. RESULTS: The empirical results show that publicly financed health expenditure reduces infant mortality, child mortality, and malaria cases. At the same time, it improves life expectancy and immunization coverage in India. It also finds that the relationship between publicly financed health expenditure and health outcomes is weak, especially in the high-focus states. CONCLUSIONS: Given the healthcare need for achieving desirable health outcomes, Indian States should enhance publicly financed expenditure on health services. This study augments essential guidance for implementing public health policies in developing countries.
RESUMEN
INTRODUCTION: The world is experiencing the Coronavirus pandemic and the aftermath consequences leading to lockdown and travel restrictions. The pandemic has brought a far-reaching impact on various sectors, including the economic, and health sectors. Therefore, this study analyses the possible impact of the COVID-19 pandemic on the disruption - in accessing family planning measures i.e. contraception facilities; and in seeking help from women organizations for health services. METHODS: This study has used the COVID-19 health services disruption survey-2020 and data was obtained from the Institute of Health Metrics and Evaluation. This survey was conducted in 76 countries using the smartphone-based premise data collection platform. Respondents were individual members of the general population ages 15-49 years who were identified as women. Data were collected from 12,354 respondents. Our data analysis has been done on both aggregate samples as well as region-wise samples (i.e. Africa, Asia, Europe, and Latin America & the Caribbean) to assess the change in levels of service delivery in both pre-COVID and post-COVID periods. RESULTS: Descriptive statistics results shows that two particular reasons - unable to access due to lockdown restrictions (5.4%), and fear of being infected with COVID-19 (9.7%) were reported as mostly impacting the access to contraception facilities due to lockdown restriction. Further, the logit regression using socio-economic and demographic variables suggests that geographical location (rural), and poor financial status turned out negative and significant, showing higher odds of facing difficulty than the reference category for the aggregate sample. The region-wise analysis suggests that Europe and Asia are the regions with the highest percentage of respondents reporting unavailability of services during COVID-19. CONCLUSION: The study concludes that pandemic-related emergencies affect the health care system, especially women-related health care services. The implication of our study indicates the requirement of a supply chain strategy for managing health care demand during emerging situations. So, the disruptions and bottlenecks in health care facilities should be addressed by various governments through appropriate policies and interventions.
Asunto(s)
COVID-19 , Pandemias , Femenino , Humanos , Adolescente , Adulto Joven , Adulto , Persona de Mediana Edad , Países en Desarrollo , COVID-19/epidemiología , Control de Enfermedades Transmisibles , Servicios de Planificación Familiar , Anticoncepción , Servicios de Salud , Salud de la Mujer , Encuestas y CuestionariosRESUMEN
Purpose: [18F]F-AraG is a radiolabeled nucleoside analog that shows relative specificity for activated T cells. The aim of this study was to investigate the biodistribution of [18F]F-AraG in healthy volunteers and assess the preliminary safety and radiation dosimetry. Methods: Six healthy subjects (three female and three male) between the ages of 24 and 60 participated in the study. Each subject received a bolus venous injection of [18F]F-AraG (dose range: 244.2-329.3 MBq) prior to four consecutive PET/MR whole-body scans. Blood samples were collected at regular intervals and vital signs monitored before and after tracer administration. Regions of interest were delineated for multiple organs, and the area under the time-activity curves was calculated for each organ and used to derive time-integrated activity coefficient (TIAC). TIACs were input for absorbed dose and effective dose calculations using OLINDA. Results: PET/MR examination was well tolerated, and no adverse effects to the administration of [18F]F-AraG were noted by the study participants. The biodistribution was generally reflective of the expression and activity profiles of the enzymes involved in [18F]F-AraG's cellular accumulation, mitochondrial kinase dGK, and SAMHD1. The highest uptake was observed in the kidneys and liver, while the brain, lung, bone marrow, and muscle showed low tracer uptake. The estimated effective dose for [18F]F-AraG was 0.0162 mSv/MBq (0.0167 mSv/MBq for females and 0.0157 mSv/MBq for males). Conclusion: Biodistribution of [18F]F-AraG in healthy volunteers was consistent with its association with mitochondrial metabolism. PET/MR [18F]F-AraG imaging was well tolerated, with a radiation dosimetry profile similar to other commonly used [18F]-labeled tracers. [18F]F-AraG's connection with mitochondrial biogenesis and favorable biodistribution characteristics make it an attractive tracer with a variety of potential applications.
Asunto(s)
Tomografía de Emisión de Positrones , Radiofármacos , Adulto , Femenino , Voluntarios Sanos , Humanos , Masculino , Persona de Mediana Edad , Tomografía de Emisión de Positrones/métodos , Radiometría/métodos , Distribución Tisular , Adulto JovenRESUMEN
BACKGROUND: India is one of the fastest-growing developing economies associated with many socio-demographic challenges that include a high density of population, growing urbanization, and poor road infrastructure. These challenges might lead to the cause of injury, especially transport related. Therefore, we aim to analyze the burden of Transport Injury (TI) and associated risk factors in India using the required data from 1990 to 2019. METHODS: This study has used the latest Global Burden of Disease Study (GBD) 2019 data set and estimated TI-related incidence rate, mortality (death) rate, and Disability-Adjusted Life Years (DALYs) lost for India over the period from 1990 to 2019. The latest round of GBD survey-2019 provides information about 369 diseases and injuries and 87 risk factors across age groups and gender. RESULTS: Around 25% of the death rate of all ages was caused due to TI in 2019, significantly higher than in 1990 (20%). However, between 1990 and 2019, the DALYs rate per 100,000 people due to TI decreased slightly by 1.6% for all ages and both gender while more reduction has been observed in under 5- and 5-14-years age groups. On the contrary, the incidence rate and DALYs rate had increased substantially in the age group above 50 years which could be a serious issue for the safety of aging people. By analyzing the sub-cause of TI, we found that motorcyclist road injuries and pedestrian road injuries have been major causes of deaths in India during the last three decades. Further, we have found four risk factors associated with environmental change, occupational hazard, behavioral risk, and metabolic risk that cause TI injuries. CONCLUSIONS: TI-related disease burden has not been reduced over the years in India despite improvements in road infrastructure and digital technology. Improvement in transport policies; awareness about traffic rules and laws among citizens, and improvement in governance in the road & transport sector could change the behavioral risk factors of TI and reduce population unwanted death and suffering.
Asunto(s)
Renta , Tuberculosis , Humanos , Pobreza , Tuberculosis/epidemiología , Tuberculosis/prevención & controlRESUMEN
BACKGROUND: Rising healthcare costs and poor access to health services have become a significant concern for policy-makers; therefore, efforts must be made to generate fiscal space through alternative revenue measures in resource-poor economies. This study attempts to identify possible sources of fiscal space for health in India across political regimes. METHODS: The study followed a descriptive approach to examine the political commitment towards health sector development by estimating the trend of growth in fiscal space indicators over the political regimes from 1998-1999 to 2021-2022 using a dummy variable regression model. RESULTS: We found four possible sources of fiscal space for health, which include (1) raising domestic revenue mobilization, (2) generating alternative revenue collection mechanisms, (3) prioritizing health through expenditure management and (4) effective utilization of central transfer. Fiscal space measures such as goods and services tax reform, collection of health-specific tax, higher excise duty on tobacco products, cooking gas subsidies to poor people, tax administration reform and direct beneficiary transfer of health services could be alternative revenue mobilization channels for fiscal space for health. CONCLUSION: The study reveals that the central government has a political commitment to generating revenue through various fiscal policy reforms. Health has been prioritized over the period, but there is less evidence of health-related political commitment for an increased share of health expenditure to total budgetary allocation. During the last 2 years, however, the health budget has been prioritized due to the COVID-19 pandemic crisis despite slower economic growth in India. This study will be a policy document for fiscal space analysis from a political-economic perspective, and the role of the ministry of finance can be assessed through administrative data and documents.
Asunto(s)
COVID-19 , Pandemias , Gobierno Federal , Gastos en Salud , Humanos , IndiaRESUMEN
Climate change resulting from a rapid increase in greenhouse gas (GHG) emissions is adversely affecting humanity. If the GHG emission continues to rise at the current pace, humanity will face severe consequences and reverse all the progress made. This paper, therefore, uses relevant data from 14 developing countries in Asia from 1990 to 2018 to examine the potential impact of environmental innovation on CO2 emissions by controlling globalization, urbanization, and economic growth. The number of environmental-related technology patents is used as a measure of environmental innovation. We employed a panel long-run regression model - FMOLS, PCSE, and FGLS to estimate the elasticity of CO2 emissions. For causal association among variables, we used Dumitrescu-Hurlin Granger causality tests. Our results show that renewable energy consumption and globalization have a significant impact in reducing CO2 emissions, while environmental technology innovations play a meager role in reducing emissions and only when economic growth support those type of investment. Furthermore, we found urbanization, oil consumption, and economic growth is detrimental to the environment, which is also evident in past studies. Therefore, countries should invest in renewable energy and environmental innovation aligned with the growth to reduce GHG emissions.
Asunto(s)
Dióxido de Carbono , Gases de Efecto Invernadero , Dióxido de Carbono/análisis , Desarrollo Económico , Gases de Efecto Invernadero/análisis , Energía Renovable , UrbanizaciónRESUMEN
BACKGROUND: This study aims to measure the burden of diarrhea in India and analyze the trend of mortality associated with it for the past 30 years. We also intend to find the prevailing etiology and risk factors associated with diarrheal mortality in India. METHODS: The study has used the latest round of Global Burden of Disease (GBD) study-2019. GBD data is available across age groups and gender-wise over the period from 1990 to 2019. The study has identified 13 etiologies for the cause of diarrhea deaths and 20 risk factors to analyze the burden of disease. RESULTS: Our study shows, childhood diarrhea has declined over the years significantly, yet contributes to a larger share of DALYs associated with the disease. Among all the death cases of Diarrhea, in 2019, the most prevalent disease-causing pathogen is found to be Campylobacter. But Adenovirus is the major contributor to childhood diarrheal deaths. Though the burden of diarrhea is declining over the period, still there is a need to progress the interventions to prevent and control diarrhea rapidly to avoid the huge number of deaths and disabilities experienced in India. CONCLUSIONS: Consumption of safe and clean water, proper sanitation facility in every household, required nutrition intake by mother and child, safe breastfeeding and stool disposal practices and careful case management, rotavirus vaccination are some of the effective interventions to be implemented all over the country. Further, evidence-based policies should be made and implemented to sustain diarrhea prevention programs.
Asunto(s)
Carga Global de Enfermedades , Saneamiento , Niño , Diarrea/etiología , Humanos , India/epidemiología , Lactante , Factores de RiesgoRESUMEN
BACKGROUND: In the last few years, there has been a worldwide commitment to protect the vulnerable individuals from higher financial risk through out-of-pocket (OOP) health expenditure. This study examines the influence of disability and socio-demographic factors on households' health financial risks in Uganda. METHODS: We used nationally representative cross-sectional data from the Uganda Demographic and Health Survey (UDHS) collected in 2016 by the Uganda Bureau of Statistics (UBOS) in Uganda. We measured financial risk (households' health expenditure) by money paid for health care services. We estimated the "probit" model to investigate the effect of disability on health financial risk. RESULTS: A total of 19,305 households were included in this study. Almost 32% of households paid money for health care services access, among which 32% paid through out-of-pocket. Almost 41% of household heads were affected by disability. The majority (73%) of families went to the public sector for health care services. The mean age was 45 years (SD ± 15). We find that disability is significantly associated with the household financial risk (p < 0.01). The private sector's choice for health care services is likely to positively affect the financial risk compared to the public sector (p < 0.01). The wealthier the household was, the more money paid for health service was (p < 0.01). CONCLUSION: Our results indicated that disability and household socio-demographic characteristics were associated with health financial risk in Uganda. Identifying families with disability and experiencing difficult living conditions constitute an entry point for health authorities to enhance health coverage progress in low and middle-income countries.
Asunto(s)
Composición Familiar , Pobreza , Estudios Transversales , Gastos en Salud , Humanos , Persona de Mediana Edad , UgandaRESUMEN
AIM: An enormous presence and their identified role as stress managers, antibiotic resistance, persistence, and biofilm formation is the reason why the research on Toxin-Antitoxin (TA) loci is getting more and more emphasis. These set of genes consist of poison (Toxin) and its antidote (Antitoxin) expressing in an operon where the toxin inhibits the cellular process and antitoxin which can be a protein or non-coding RNA, rescues the toxin. Most recent progress in genomics and in silico studies have revealed new TA families, and types of TA on bacterial chromosome. However, there is almost no or very little is known about the TA in H. pylori. Therefore, this study aims to identify the TA genes in human pathogen using a comprehensive in silico approach. METHODOLOGY: Here, we have collected the genome-wide data of TA in H. pylori 26695 using TASmania, a new TA database. Further, entire TA dataset was validated with several other databases available for TA, operon analysis and experimental data available. KEY FINDINGS: The study revealed the presence of 80 putative TA genes in H. pylori and highlighted their similarity as well as uniqueness in comparison to other three known TA carrying human pathogens. SIGNIFICANCE: The present study indicates the presence of a large number of TA genes in H. pylori which make biofilm and goes into persistence. Hence, our innovative approach unlocks the prospect for characterizing these putative TA genes and their role as stress managers.
Asunto(s)
Antitoxinas/genética , Toxinas Bacterianas/genética , Regulación Bacteriana de la Expresión Génica , Genoma Bacteriano , Helicobacter pylori/genética , Operón , Sistemas Toxina-Antitoxina/genética , Genómica/métodos , HumanosRESUMEN
Immunotherapy is becoming the mainstay for treatment of a variety of malignancies, but only a subset of patients responds to treatment. Tumor-infiltrating CD8-positive (CD8+) T lymphocytes play a central role in antitumor immune responses. Noninvasive imaging of CD8+ T cells may provide new insights into the mechanisms of immunotherapy and potentially predict treatment response. We are studying the safety and utility of 89Zr-IAB22M2C, a radiolabeled minibody against CD8+ T cells, for targeted imaging of CD8+ T cells in patients with cancer. Methods: The initial dose escalation phase of this first-in-humans prospective study included 6 patients (melanoma, 1; lung, 4; hepatocellular carcinoma, 1). Patients received approximately 111 MBq (3 mCi) of 89Zr-IAB22M2C (at minibody mass doses of 0.2, 0.5, 1.0, 1.5, 5, or 10 mg) as a single dose, followed by PET/CT scans at approximately 1-2, 6-8, 24, 48, and 96-144 h after injection. Biodistribution in normal organs, lymph nodes, and lesions was evaluated. In addition, serum samples were obtained at approximately 5, 30, and 60 min and later at the times of imaging. Patients were monitored for safety during infusion and up to the last imaging time point. Results:89Zr-IAB22M2C infusion was well tolerated, with no immediate or delayed side effects observed after injection. Serum clearance was typically biexponential and dependent on the mass of minibody administered. Areas under the serum time-activity curve, normalized to administered activity, ranged from 1.3 h/L for 0.2 mg to 8.9 h/L for 10 mg. Biodistribution was dependent on the minibody mass administered. The highest uptake was always in spleen, followed by bone marrow. Liver uptake was more pronounced with higher minibody masses. Kidney uptake was typically low. Prominent uptake was seen in multiple normal lymph nodes as early as 2 h after injection, peaking by 24-48 h after injection. Uptake in tumor lesions was seen on imaging as early as 2 h after injection, with most 89Zr-IAB22M2C-positive lesions detectable by 24 h. Lesions were visualized early in patients receiving treatment, with SUV ranging from 5.85 to 22.8 in 6 target lesions. Conclusion:89Zr-IAB22M2C imaging is safe and has favorable kinetics for early imaging. Biodistribution suggests successful targeting of CD8+ T-cell-rich tissues. The observed targeting of tumor lesions suggests this may be informative for CD8+ T-cell accumulation within tumors. Further evaluation is under way.
Asunto(s)
Antígenos CD8/inmunología , Inmunoconjugados/química , Inmunoconjugados/farmacocinética , Neoplasias/diagnóstico por imagen , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Radioisótopos , Circonio , Adulto , Anciano , Anciano de 80 o más Años , Transporte Biológico , Femenino , Humanos , Inmunoconjugados/sangre , Inmunoconjugados/metabolismo , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Neoplasias/metabolismo , Neoplasias/patología , Distribución TisularRESUMEN
BACKGROUND: Health financing is a major challenge in low-and middle-income counties (LMICs) for achieving Universal Health Coverage (UHC). Past studies have argued that the budgetary allocation on health financing depends on macro-fiscal policies of an economy such as sustained economic growth and higher revenue mobilization. While the global financial crisis of late 2008 observed a shortage of financial resources in richer countries and adversely affected the health sector. Therefore, this study has examined the impact of macro-fiscal policies on health financing by adopting socioeconomic factors in 85 LMICs for the period 2000 to 2013. METHODS: The study has employed the panel System Generalized Method of Moment model that captures the endogeneity problem in the regression estimation by adopting appropriate instrumental variables. RESULTS: The elasticity of public health expenditure (PHE) with respect to macro-fiscal factors varies across LMICs. Tax revenue shows a positive and statistically significant relationship with PHE in full sample, pre-global financial crisis, middle-income, and coefficient value varies from 0.040 to 0.141%. Fiscal deficit and debt services payment shows a negative effect on PHE in full sample, as well as sub-samples and coefficient value, varies from 0.001 to 0.032%. Aging and per capita income show an expected positive relationship with PHE in LIMI countries. CONCLUSIONS: Favorable macro-fiscal policies would necessarily raise finance for the health sector development but the prioritization of health budget allocation during the crisis period depends on the nature of tax revenue mobilization and demand for health services. Therefore, the generation of health-specific revenues and effective usage of health budget would probably accelerate the progress towards the achievement of UHC.
RESUMEN
BACKGROUND: The cystine/glutamate antiporter (xc-) has been implicated in several neurological disorders and, specifically, in multiple sclerosis (MS) as a mediator of glutamate excitotoxicity and proinflammatory immune responses. We aimed to evaluate an xc-specific positron emission tomography (PET) radiotracer, (4S)-4-(3-[18F]fluoropropyl)-L-glutamate ([18F]FSPG), for its ability to allow non-invasive monitoring of xc- activity in a mouse model of MS. METHODS: Experimental autoimmune encephalomyelitis (EAE) was induced in C57BL/6 mice by subcutaneous injection of myelin oligodendrocyte glycoprotein (MOG35-55) peptide in complete Freund's adjuvant (CFA) followed by pertussis toxin. Control mice received CFA emulsion and pertussis toxin without MOG peptide, while a separate cohort of naïve mice received no treatment. PET studies were performed to investigate the kinetics and distribution of [18F]FSPG in naïve, control, pre-symptomatic, and symptomatic EAE mice, compared to 18F-fluorodeoxyglucose ([18F]FDG). After final PET scans, each mouse was perfused and radioactivity in dissected tissues was measured using a gamma counter. Central nervous system (CNS) tissues were further analyzed using ex vivo autoradiography or western blot. [18F]FSPG uptake in human monocytes, and T cells pre- and post-activation was investigated in vitro. RESULTS: [18F]FSPG was found to be more sensitive than [18F]FDG at detecting pathological changes in the spinal cord and brain of EAE mice. Even before clinical signs of disease, a small but significant increase in [18F]FSPG signal was observed in the spinal cord of EAE mice compared to controls. This increase in PET signal became more pronounced in symptomatic EAE mice and was confirmed by ex vivo biodistribution and autoradiography. Likewise, in the brain of symptomatic EAE mice, [18F]FSPG uptake was significantly higher than controls, with the largest changes observed in the cerebellum. Western blot analyses of CNS tissues revealed a significant correlation between light chain of xc- (xCT) protein levels, the subunit of xc- credited with its transporter activity, and [18F]FSPG-PET signal. In vitro [18F]FSPG uptake studies suggest that both activated monocytes and T cells contribute to the observed in vivo PET signal. CONCLUSION: These data highlight the promise of [18F]FSPG-PET as a technique to provide insights into neuroimmune interactions in MS and the in vivo role of xc- in the development and progression of this disease, thus warranting further investigation.
Asunto(s)
Sistemas de Transporte de Aminoácidos Acídicos/metabolismo , Encefalomielitis Autoinmune Experimental/diagnóstico por imagen , Encefalomielitis Autoinmune Experimental/metabolismo , Radioisótopos de Flúor/metabolismo , Glutamatos/metabolismo , Tomografía de Emisión de Positrones/métodos , Animales , Células Cultivadas , Fluorodesoxiglucosa F18/metabolismo , Humanos , Leucocitos Mononucleares/metabolismo , Ratones , Ratones Endogámicos C57BL , Esclerosis Múltiple/diagnóstico por imagen , Esclerosis Múltiple/metabolismoRESUMEN
The ability to locate nerve injury and ensuing neuroinflammation would have tremendous clinical value for improving both the diagnosis and subsequent management of patients suffering from pain, weakness, and other neurologic phenomena associated with peripheral nerve injury. Although several non-invasive techniques exist for assessing the clinical manifestations and morphological aspects of nerve injury, they often fail to provide accurate diagnoses due to limited specificity and/or sensitivity. Herein, we describe a new imaging strategy for visualizing a molecular biomarker of nerve injury/neuroinflammation, i.e., the sigma-1 receptor (S1R), in a rat model of nerve injury and neuropathic pain. The two-fold higher increase of S1Rs was shown in the injured compared to the uninjured nerve by Western blotting analyses. With our novel S1R-selective radioligand, [18F]FTC-146 (6-(3-[18F]fluoropropyl)-3-(2-(azepan-1-yl)ethyl)benzo[d]thiazol-2(3H)-one), and positron emission tomography-magnetic resonance imaging (PET/MRI), we could accurately locate the site of nerve injury created in the rat model. We verified the accuracy of this technique by ex vivo autoradiography and immunostaining, which demonstrated a strong correlation between accumulation of [18F]FTC-146 and S1R staining. Finally, pain relief could also be achieved by blocking S1Rs in the neuroma with local administration of non-radioactive [19F]FTC-146. In summary, [18F]FTC-146 S1R PET/MR imaging has the potential to impact how we diagnose, manage and treat patients with nerve injury, and thus warrants further investigation.
Asunto(s)
Imagen por Resonancia Magnética/métodos , Neuralgia/diagnóstico por imagen , Neuralgia/patología , Nervios Periféricos/diagnóstico por imagen , Nervios Periféricos/patología , Tomografía de Emisión de Positrones/métodos , Receptores sigma/análisis , Animales , Azepinas/administración & dosificación , Benzotiazoles/administración & dosificación , Modelos Animales de Enfermedad , Radioisótopos de Flúor/administración & dosificación , Marcaje Isotópico , Masculino , Neuroma/complicaciones , Ratas Sprague-Dawley , Receptor Sigma-1RESUMEN
PURPOSE: Sigma-1 receptors (S1Rs) play an important role in many neurological disorders. Simultaneous positron emission tomography (PET)/magnetic resonance imaging (MRI) with S1R radioligands may provide valuable information for diagnosing and guiding treatment for these diseases. Our previously reported S1R radioligand, [18F]FTC-146, demonstrated high affinity for the S1R (K i = 0.0025 nM) and excellent selectivity for the S1R over the sigma-2 receptor (S2Rs; K i = 364 nM) across several species (from mouse to non-human primate). Herein, we report the clinical-grade radiochemistry filed with exploratory Investigational New Drug (eIND) and first-in-human PET/MRI evaluation of [18F]FTC-146. PROCEDURES: [18F]FTC-146 is prepared via a direct [18F] fluoride nucleophilic radiolabeling reaction and formulated in 0.9 % NaCl containing no more than 10 % ethanol through sterile filtration. Quality control (QC) was performed based on USP 823 before doses were released for clinical use. The safety and whole body biodistribution of [18F]FTC-146 were evaluated using a simultaneous PET/MR scanner in two representative healthy human subjects. RESULTS: [18F]FTC-146 was synthesized with a radiochemical yield of 3.3 ± 0.7 % and specific radioactivity of 8.3 ± 3.3 Ci/µmol (n = 10, decay corrected to EOB). Both radiochemical and chemical purities were >95 %; the prepared doses were stable for 4 h at ambient temperature. All QC test results met specified clinical criteria. The in vivo PET/MRI investigations showed that [18F]FTC-146 rapidly crossed the blood brain barrier and accumulated in S1R-rich regions of the brain. There were also radioactivity distributed in the peripheral organs, i.e., the lungs, spleen, pancreas, and thyroid. Furthermore, insignificant uptake of [18F]FTC-146 was observed in cortical bone and muscle. CONCLUSION: A reliable and automated radiosynthesis for providing routine clinical-grade [18F]FTC-146 for human studies was established in a modified GE TRACERlab FXFN. PET/MRI demonstrated the initial tracer biodistribution in humans, and clinical studies investigating different S1R-related diseases are in progress.
Asunto(s)
Azepinas/química , Azepinas/síntesis química , Benzotiazoles/química , Benzotiazoles/síntesis química , Imagen por Resonancia Magnética , Tomografía de Emisión de Positrones , Adulto , Azepinas/farmacocinética , Benzotiazoles/farmacocinética , Femenino , Humanos , Masculino , Distribución TisularRESUMEN
Molecular and cellular imaging of neuropathic pain, utilizing the myriad of receptors and inflammatory mediators involved in nociceptive activity, is a promising approach toward objectively identifying peripheral pain generators. Neuropathic conditions arise from injured and inflamed nerves, which have been shown to elaborate several molecular and cellular elements that give rise to the neuropathic phenotype and can be exploited for imaging purposes. As such, in vivo approaches to image neuropathic pain mechanisms include imaging voltage-gated sodium channels with radiolabeled saxitoxin, calcium signaling with manganese-enhanced magnetic resonance imaging, and inflammatory changes and nerve metabolism with (18)F-fluorodeoxyglucose. Imaging approaches exploiting other mediators of nociceptive activity, such as substance P (neurokinin-1) receptor, sigma-1 receptor, and macrophages, have shown promising early advances in animal models. By combining the sensitivity and specificity of molecular imaging with the high anatomical, spatial and contrast resolution afforded by computed tomography and MRI, radiologists can potentially identify sites of nerve injury or neuroinflammation that are implicated as peripheral pain drivers with greater accuracy and confidence. In addition to guiding therapy, these approaches will aid in new drug designs for analgesia and more individualized treatment options.