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BACKGROUND: Prospective evaluation of optical coherence tomography (OCT) and OCT angiography (OCT-A) characteristics in different stages of papilledema in idiopathic intracranial hypertension (IIH). METHODS: In this prospective, observational study patients of IIH with papilledema were recruited and divided into 3 groups-early/established (Group 1), chronic (Group 2), and atrophic papilledema (Group 3). Peripapillary retinal nerve fiber layer (RNFL) and macular ganglion cell inner plexiform layer (GC-IPL) were recorded on OCT. Peripapillary and macular perfusion was documented at superficial retinal, deep retinal, and choriocapillary level using OCT-A. The investigations were repeated at 3 months. RESULTS: RNFL showed significant thinning in all groups on follow-up with the atrophic group showing maximum thinning ( P = 0.01-Group 3). GC-IPL was significantly reduced in all stages of papilledema at baseline compared with the controls. Thinnest GC-IPL was noted in the atrophic group (52.75 ± 7.44 µm; P = 0.00 in Group 3 vs controls) that showed further deterioration on follow-up. On Image J analysis, significant decrease was noted at various levels in the peripapillary and macular perfusion at baseline especially in the atrophic group which showed further deterioration noted on follow-up. The final visual acuity showed a statistically significant weak negative correlation with baseline RNFL (r = -0.306) and GC-IPL (r = -0.384) and moderately negative correlation with baseline superficial peripapillary retinal perfusion (r = -0.553). A significant negative correlation was seen between increasing grade of papilledema and superficial peripapillary retinal perfusion with both Image J and automated indices (r = -0.46; r = -0.61), respectively. CONCLUSIONS: GC-IPL may help identify early damage in papilledema even in the presence of thicker RNFL. Significant vascular changes can be observed on OCT-A that may help predict the final visual outcome in papilledema due to IIH.
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Papiledema , Pseudotumor Cerebral , Humanos , Papiledema/diagnóstico , Tomografia de Coerência Óptica/métodos , Células Ganglionares da Retina , Retina , AngiografiaRESUMO
The establishment of cardiac function in the developing embryo is essential to ensure blood flow and, therefore, growth and survival of the animal. The molecular mechanisms controlling normal cardiac rhythm remain to be fully elucidated. From a forward genetic screen, we identified a unique mutant, grime, that displayed a specific cardiac arrhythmia phenotype. We show that loss-of-function mutations in tmem161b are responsible for the phenotype, identifying Tmem161b as a regulator of cardiac rhythm in zebrafish. To examine the evolutionary conservation of this function, we generated knockout mice for Tmem161b. Tmem161b knockout mice are neonatal lethal and cardiomyocytes exhibit arrhythmic calcium oscillations. Mechanistically, we find that Tmem161b is expressed at the cell membrane of excitable cells and live imaging shows it is required for action potential repolarization in the developing heart. Electrophysiology on isolated cardiomyocytes demonstrates that Tmem161b is essential to inhibit Ca2+ and K+ currents in cardiomyocytes. Importantly, Tmem161b haploinsufficiency leads to cardiac rhythm phenotypes, implicating it as a candidate gene in heritable cardiac arrhythmia. Overall, these data describe Tmem161b as a highly conserved regulator of cardiac rhythm that functions to modulate ion channel activity in zebrafish and mice.
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Arritmias Cardíacas/genética , Frequência Cardíaca/genética , Proteínas de Membrana/fisiologia , Mutação , Miócitos Cardíacos/metabolismo , Proteínas de Peixe-Zebra/fisiologia , Potenciais de Ação/genética , Animais , Animais Geneticamente Modificados , Arritmias Cardíacas/metabolismo , Arritmias Cardíacas/patologia , Sequência de Bases , Cálcio/metabolismo , Sequência Conservada , Modelos Animais de Doenças , Embrião de Mamíferos , Embrião não Mamífero , Regulação da Expressão Gênica no Desenvolvimento , Genes Letais , Coração/embriologia , Coração/fisiopatologia , Transporte de Íons , Proteínas de Membrana/genética , Camundongos , Camundongos Knockout , Miócitos Cardíacos/patologia , Organogênese/genética , Periodicidade , Potássio/metabolismo , Peixe-Zebra , Proteínas de Peixe-Zebra/genéticaRESUMO
High-risk neuroblastoma (NB) is challenging to treat with 5-year long-term survival in patients remaining below 50% and low chances of survival after tumor relapse or recurrence. Different strategies are being tested or under evaluation to destroy resistant tumors and improve survival outcomes in NB patients. Immunotherapy, which uses certain parts of a person's immune system to recognize or kill tumor cells, effectively improves patient outcomes in several types of cancer, including NB. One of the immunotherapy strategies is to block immune checkpoint signaling in tumors to increase tumor immunogenicity and anti-tumor immunity. Immune checkpoint proteins put brakes on immune cell functions to regulate immune activation, but this activity is exploited in tumors to evade immune surveillance and attack. Immune checkpoint proteins play an essential role in NB biology and immune escape mechanisms, which makes these tumors immunologically cold. Therapeutic strategies to block immune checkpoint signaling have shown promising outcomes in NB but only in a subset of patients. However, combining immune checkpoint blockade with other therapies, including conjugated antibody-based immunotherapy, radioimmunotherapy, tumor vaccines, or cellular therapies like modified T or natural killer (NK) cells, has shown encouraging results in enhancing anti-tumor immunity in the preclinical setting. An analysis of publicly available dataset using computational tools has unraveled the complexity of multiple cancer including NB. This review comprehensively summarizes the current information on immune checkpoint molecules, their biology, role in immune suppression and tumor development, and novel therapeutic approaches combining immune checkpoint inhibitors with other therapies to combat high-risk NB.
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Proteínas de Checkpoint Imunológico , Neuroblastoma , Humanos , Recidiva Local de Neoplasia , Neuroblastoma/terapia , Imunoterapia/métodos , Células Matadoras NaturaisRESUMO
Diagnostic criteria for dyslexia describe specific reading difficulties, and single-deficit models, including the phonological deficit theory, have prevailed. Children seeking diagnosis, however, do not always show phonological deficits, and may present with strengths and challenges beyond reading. Through extensive neurological, neuropsychological, and academic evaluation, we describe four children with visuospatial, socio-emotional, and attention impairments and spared phonology, alongside long-standing reading difficulties. Diffusion tensor imaging revealed white matter alterations in inferior longitudinal, uncinate, and superior longitudinal fasciculi versus neurotypical children. Findings emphasize that difficulties may extend beyond reading in dyslexia and underscore the value of deep phenotyping in learning disabilities.
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Dislexia , Substância Branca , Criança , Humanos , Imagem de Tensor de Difusão , Fonética , Dislexia/psicologia , LeituraRESUMO
OBJECTIVES: To study memories of ICU following discharge, their associations, and impact on mental health and quality of life in a low- and middle-income country. DESIGN: Prospective observational cohort; data on memories (pain, fear, nightmare, factual), clinical and demographic variables, anxiety-depression, posttraumatic stress symptoms, and quality of life were collected 0, 7, 14, 30, 90, and 180 days post discharge. Home visits for assessment minimized loss to follow-up. Linear mixed-models and regression analyses were used to estimate adjusted effects of memories controlling for age, sex, time, and severity of illness. SETTING: Twenty-five bedded ICU of a tertiary care center in East India. PATIENTS: Adult ICU survivors between January 2017 and July 2018 able to communicate their memories. INTERVENTIONS: Not applicable. MEASUREMENTS AND MAIN RESULTS: Final sample consisted of 322 patients who completed 180 days follow-up. Pain, fear, factual, and nightmare memories dropped from 85%, 56%, 55%, and 45% at discharge to less than or equal to 5% at 180 days. Patients with gaps in ICU memory had worse anxiety-depression, posttraumatic stress symptoms, and quality of life at all follow-up points. Sedation (odds ratio, 0.54; CI, 0.4-0.7), steroids (odds ratio, 0.47; CI, 0.3-0.8), benzodiazepines (odds ratio, 1.74; CI, 1-3.04), and mechanical ventilation (odds ratio, 0.43; CI, 0.2-0.8) were independently associated with gaps in memory. Non-ICU factor such as substance addiction (odds ratio, 5.38; CI, 2-14) was associated with memories affecting mental health and quality of life. CONCLUSIONS: Gaps in memory and various memory types were common after ICU admission, whose prevalence waned over time. Compared with nightmares and fearful memories, gaps in memories were most strongly associated with poor mental health and quality of life. Identifying patients with gaps in memories might be an objective way of planning interventions to improve their long-term outcomes.
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Avaliação de Resultados em Cuidados de Saúde/estatística & dados numéricos , Pacientes/psicologia , APACHE , Adulto , Idoso , Estudos de Coortes , Países em Desenvolvimento/estatística & dados numéricos , Feminino , Humanos , Índia , Unidades de Terapia Intensiva/organização & administração , Unidades de Terapia Intensiva/estatística & dados numéricos , Entrevistas como Assunto/métodos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde/métodos , Satisfação do Paciente , Pacientes/estatística & dados numéricos , Estudos Prospectivos , Pesquisa Qualitativa , Qualidade de Vida/psicologia , Estatísticas não ParamétricasRESUMO
BACKGROUND: Data on intensive care unit (ICU) related psychiatric morbidity from Low Middle-Income Countries are sparse. We studied the ICU related posttraumatic stress symptoms (PTSS), anxiety, and depression symptoms in a cohort of patients from Eastern India. METHODS: We included adults admitted more than 24 h to a mixed ICU. PTSS, anxiety, and depression symptoms were assessed by telephonic or face to face interviews by using the Impact of Events-r (IES-r) and Hospital anxiety and depression (HADS), respectively, at 0, 7,14, 30, 90 and 180 days from ICU discharge. The loss to follow up was minimal. Demographic, socioeconomic, quality of life (QOL), and critical care related variables were studied. RESULTS: Of 527 patients, 322 (59.4%) completed 6 months' follow up. The majority were male (60%), mechanically ventilated > 48 h (59.4%), mean age of 48 (+/- 16), mean acute physiology and chronic health evaluation II (APACHE II) at admission 9.4 (+/- 4.6), median length of stay 3 (2-28 days). The rates of ICU related clinical PTSS was < 1 and < 3% for anxiety/depression at any point of follow up. Data were analyzed by linear mixed (random effects) models. There was a significant drop in all scores and association with repeated measures over time. Poor QOL at discharge from the ICU showed significant association with PTSS, anxiety, and depression (ß = - 2.94, - 1.34, - 0.7 respectively) when corrected for gender and education levels. Younger age, greater severity of illness, and prior stressful life experiences predicted worse PTSS (ß = - 0.02, 0.08, 3.82, respectively). Benzodiazepines and lower sedation scores (better alertness) predicted lower depression symptoms. (ß = - 0.43, 0.37 respectively). CONCLUSION: ICU related psychiatric morbidity rates in our population are low compared with reported rates in the literature. Poor QOL at ICU discharge may predict worse long-term mental health outcomes. Further research on the impact of ICU and sociocultural factors on mental health outcomes in patients from different backgrounds is needed. The study was registered at CTRI/2017/07/008959.
Assuntos
Transtornos de Estresse Pós-Traumáticos , Adulto , Ansiedade/epidemiologia , Estudos de Coortes , Cuidados Críticos , Depressão/epidemiologia , Países em Desenvolvimento , Humanos , Índia/epidemiologia , Unidades de Terapia Intensiva , Estudos Longitudinais , Masculino , Alta do Paciente , Qualidade de Vida , Transtornos de Estresse Pós-Traumáticos/epidemiologia , Sobreviventes , Centros de Atenção TerciáriaRESUMO
Chemotherapy is a double-edged sword. It is anticancer because of its cytotoxicity. Paradoxically, by increasing chemoresistance and cancer metastasis, it is also procancer. However, the underlying mechanisms for chemotherapy-induced procancer activities are not well understood. Here we describe the ability of paclitaxel (PTX), a frontline chemotherapeutic agent, to exacerbate metastasis in mouse models of breast cancer. We demonstrate that, despite the apparent benefit of reducing tumor size, PTX increased the circulating tumor cells in the blood and enhanced the metastatic burden at the lung. At the primary tumor, PTX increased the abundance of the tumor microenvironment of metastasis, a landmark microanatomical structure at the microvasculature where cancer cells enter the blood stream. At the metastatic lung, PTX improved the tissue microenvironment (the "soil") for cancer cells (the "seeds") to thrive; these changes include increased inflammatory monocytes and reduced cytotoxicity. Importantly, these changes in the primary tumor and the metastatic lung were all dependent on Atf3, a stress-inducible gene, in the noncancer host cells. Together, our data provide mechanistic insights into the procancer effect of chemotherapy, explaining its paradox in the context of the seed-and-soil theory. Analyses of public datasets suggest that our data may have relevance to human cancers. Thus, ATF3 in the host cells links a chemotherapeutic agent-a stressor-to immune modulation and cancer metastasis. Dampening the effect of ATF3 may improve the efficacy of chemotherapy.
Assuntos
Fator 3 Ativador da Transcrição/metabolismo , Antineoplásicos/efeitos adversos , Neoplasias da Mama/metabolismo , Paclitaxel/efeitos adversos , Fator 3 Ativador da Transcrição/genética , Animais , Antineoplásicos/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Neoplasias da Mama/fisiopatologia , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundário , Camundongos , Metástase Neoplásica , Paclitaxel/administração & dosagem , Estresse Fisiológico/efeitos dos fármacosRESUMO
BACKGROUND: The HIV perinatal transmission in India even after interventions is still high. The anti-retroviral therapy failure rate and the risk of HIV vertical transmission to infants from women with failed treatment during pregnancy also largely remains unevaluated. METHODS: This is a prospective, observational and follow-up study of 18 months to determine the association of ART failure in pregnant women and the subsequent risk of HIV transmission to their infants. A total of 81 mothers were evaluated for ART success/failure by analysing their viral loads. RESULTS: Analyses revealed that a high percentage (19.75%) of women on ART had high viral loads, while the overall HIV transmission rate to the infants was 8.64%. The rate of transmission from women with high viral load was significantly high compared to women with low viral load (37.5% vs. 1.54%; p = 0.0015). CD4 level was not associated with HIV transmission. However, CD4 levels in women, who had successful or failed ART, were significantly different (p = 0.0031). Factors such as mother's age, baby's sex and weight as well as delivery mode were not associated with HIV transmission, however, breastfeeding and viral loads were found to be independently associated with HIV transmission to the neonates. CONCLUSIONS: This study highlights that a significant proportion of women on ART had impaired viral load control. The rate of HIV transmission to infants was also significantly high among these women. This warrants viral load monitoring of HIV infected women to reduce the overall transmission to the infants.
Assuntos
Terapia Antirretroviral de Alta Atividade/métodos , Infecções por HIV/tratamento farmacológico , Infecções por HIV/transmissão , Transmissão Vertical de Doenças Infecciosas/prevenção & controle , Complicações Infecciosas na Gravidez/tratamento farmacológico , Adulto , Aleitamento Materno , Feminino , Seguimentos , Infecções por HIV/epidemiologia , Infecções por HIV/imunologia , Soropositividade para HIV/transmissão , Humanos , Índia/epidemiologia , Lactente , Recém-Nascido , Mães , Gravidez , Complicações Infecciosas na Gravidez/imunologia , Gestantes , Estudos Prospectivos , Falha de Tratamento , Carga ViralRESUMO
BACKGROUND: Chronic obstructive pulmonary disease (COPD) is associated with a two-to-five fold increase in the risk of coronary artery disease independent of shared risk factors. This association is hypothesized to be mediated by systemic inflammation but this link has not been established. METHODS: We included 300 participants enrolled in the SPIROMICS cohort, 75 each of lifetime non-smokers, smokers without airflow obstruction, mild-moderate COPD, and severe-very severe COPD. We quantified emphysema and airway disease on computed tomography, characterized visual emphysema subtypes (centrilobular and paraseptal) and airway disease, and used the Weston visual score to quantify coronary artery calcification (CAC). We used the Sobel test to determine whether markers of systemic inflammation mediated a link between spirometric and radiographic features of COPD and CAC. RESULTS: FEV1/FVC but not quantitative emphysema or airway wall thickening was associated with CAC (p = 0.036), after adjustment for demographics, diabetes mellitus, hypertension, statin use, and CT scanner type. To explain this discordance, we examined visual subtypes of emphysema and airway disease, and found that centrilobular emphysema but not paraseptal emphysema or bronchial thickening was independently associated with CAC (p = 0.019). MMP3, VCAM1, CXCL5 and CXCL9 mediated 8, 8, 7 and 16% of the association between FEV1/FVC and CAC, respectively. Similar biomarkers partially mediated the association between centrilobular emphysema and CAC. CONCLUSIONS: The association between airflow obstruction and coronary calcification is driven primarily by the centrilobular subtype of emphysema, and is linked through bioactive molecules implicated in the pathogenesis of atherosclerosis. TRIAL REGISTRATION: ClinicalTrials.gov: Identifier: NCT01969344 .
Assuntos
Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/fisiopatologia , Enfisema Pulmonar/sangue , Enfisema Pulmonar/fisiopatologia , Calcificação Vascular/sangue , Calcificação Vascular/fisiopatologia , Idoso , Biomarcadores/sangue , Estudos de Coortes , Doença da Artéria Coronariana/diagnóstico , Feminino , Humanos , Mediadores da Inflamação/sangue , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde/métodos , Doença Pulmonar Obstrutiva Crônica/sangue , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Enfisema Pulmonar/diagnóstico , Fumar/sangue , Fumar/fisiopatologia , Calcificação Vascular/diagnóstico , Capacidade Vital/fisiologiaRESUMO
The original version of this article unfortunately contained a mistake. Ambika Devi K was not listed among the authors. The corrected authorship is given below.
RESUMO
Dual orexin receptor antagonists (DORAs), or orexin 1 (OX1) and orexin 2 (OX2) receptor antagonists, have demonstrated clinical utility for the treatment of insomnia. Medicinal chemistry efforts focused on the reduction of bioactivation potential of diazepane amide 1 through the modification of the Western heterocycle resulted in the discovery of suvorexant, a DORA recently approved by the FDA for the treatment of insomnia. A second strategy towards reducing bioactivation risk is presented herein through the exploration of monocyclic quinazoline isosteres, namely substituted pyrimidines. These studies afforded potent DORAs with significantly reduced bioactivation risk and efficacy in rodent sleep models. Surprisingly, side products from the chemistry used to produce these DORAs yielded isomeric pyrimidine-containing diazepane amides possessing selective OX2R antagonist (2-SORA) profiles. Additional exploration of these isomeric pyrimidines uncovered potent 2-SORA diazepane amides with sleep efficacy in mouse EEG studies.
Assuntos
Descoberta de Drogas , Antagonistas dos Receptores de Orexina/farmacologia , Receptores de Orexina/metabolismo , Pirimidinas/farmacologia , Quinazolinas/farmacologia , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Animais , Modelos Animais de Doenças , Cães , Relação Dose-Resposta a Droga , Humanos , Camundongos , Microssomos Hepáticos/efeitos dos fármacos , Modelos Moleculares , Estrutura Molecular , Antagonistas dos Receptores de Orexina/síntese química , Antagonistas dos Receptores de Orexina/química , Pirimidinas/síntese química , Pirimidinas/química , Quinazolinas/síntese química , Quinazolinas/química , Ratos , Relação Estrutura-AtividadeRESUMO
Recent clinical studies have demonstrated that dual orexin receptor antagonists (OX1R and OX2R antagonists or DORAs) represent a novel treatment option for insomnia patients. Previously we have disclosed several compounds in the diazepane amide DORA series with excellent potency and both preclinical and clinical sleep efficacy. Additional SAR studies in this series were enabled by the expansion of the acetonitrile-assisted, diphosgene-mediated 2,4-dichloropyrimidine synthesis to novel substrates providing an array of Western heterocycles. These heterocycles were utilized to synthesize analogs in short order with high levels of potency on orexin 1 and orexin 2 receptors as well as in vivo sleep efficacy in the rat.
Assuntos
Antagonistas dos Receptores de Orexina , Pirimidinas/química , Pirimidinas/farmacologia , Sono/efeitos dos fármacos , Animais , Descoberta de Drogas , Humanos , Pirimidinas/síntese química , Ratos , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológicoRESUMO
Orexin receptor antagonists have demonstrated clinical utility for the treatment of insomnia. The majority of clinical efforts to date have focused on the development of dual orexin receptor antagonists (DORAs), small molecules that antagonize both the orexin 1 and orexin 2 receptors. Our group has recently disclosed medicinal chemistry efforts to identify highly potent, orally bioavailable selective orexin 2 receptor antagonists (2-SORAs) that possess acceptable profiles for clinical development. Herein we report additional SAR studies within the 'triaryl' amide 2-SORA series focused on improvements in compound stability in acidic media and time-dependent inhibition of CYP3A4. These studies resulted in the discovery of 2,5-disubstituted isonicotinamide 2-SORAs such as compound 24 that demonstrated improved stability and TDI profiles as well as excellent sleep efficacy across species.
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Descoberta de Drogas , Antagonistas dos Receptores de Orexina , Piridinas/farmacologia , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Tiazóis/farmacologia , Animais , Cães , Relação Dose-Resposta a Droga , Humanos , Camundongos , Estrutura Molecular , Piridinas/síntese química , Piridinas/química , Ratos , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/químicaRESUMO
Biocatalyst mediated regio- and stereo-selective hydroxylation and epoxidation on (Z)-α-santalol were achieved for the first time, using a fungal strain Mucor piriformis. Four novel metabolites were characterized as 10,11-cis-ß-epoxy-α-santalol, 5α-hydroxy-(Z)-α-santalol, 10,11-dihydroxy-α-santalol and 5α-hydroxy-10,11-cis-ß-epoxy-α-santalol. Using Amano PS lipase from Burkholderia cepacia, α- and ß-isomers of 10,11-cis-epoxy-α-santalol were resolved efficiently.
Assuntos
Lipase/metabolismo , Mucor/metabolismo , Sesquiterpenos/metabolismo , Biocatálise , Burkholderia cepacia/enzimologia , Hidroxilação , Conformação Molecular , Sesquiterpenos Policíclicos , EstereoisomerismoRESUMO
Aim: Pharmaceutical promotion is the principal aspect of the healthcare system. In this study, we aimed to portray the opinion of doctors and medical representatives (MRs) on conventional pharmaceutical ways (usage of promotional or educational paper materials and physician drug samples) for pharmaceutical promotion. Materials and Methods: In this cross-sectional observational study, data were collected from doctors and MRs across India using self-administered Google forms. Data were analyzed, and results were drawn. Results: A total of 314 doctors and 272 MRs participated in the study. As per 95.5% of doctors, continuing medical education (CME)/books/online information is the most common and convenient method to update medical knowledge, whereas 67.9% of MRs also think the same. Only 5.5% of doctors prefer paper material provided by pharmaceutical companies to update their knowledge. Most doctors say paper materials provided by pharmaceutical companies contribute less than 25% to product information, rather CME, books, and online information contribute significantly. MRs also think similarly. 66.2% of MRs agree that more than 25% of paper material gets wasted due to non-distribution. 73.2% of doctors and 75.4% of MRs agree that the use of paper materials for product promotion is not cost-effective, even if it contributes to deforestation. Only 51% of doctors use more than 50% of medical samples in patient care and only half of doctors and MRs think expired medical samples are disposed of correctly. 56.1% of doctors and 71.4% of MRs think a significant amount of medical samples are wasted and are hazardous to the environment. Conclusions: Both doctors and MRs are of the opinion that the conventional method of paper promotion, that is, paper material and drug samples, is not cost-effective and also not eco-friendly. Hence, need to rethink - is there a need to change with time?
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INTRODUCTION: Global mortality is significantly influenced by myocardial infarction. Scientists have examined the role of the copper-containing protein ceruloplasmin in heart attacks. It helps to regulate oxidative stress, iron metabolism, and inflammation. Vitamin C's antioxidative qualities lend credence to the idea that it could help prevent cardiovascular disease. Several studies have shown that elevated uric acid levels are related to a higher risk of myocardial infarction. With this background, we conducted this study to estimate levels of ceruloplasmin, vitamin C, and uric acid in patients with myocardial infarction. MATERIALS AND METHODS: A tertiary care hospital in central India carried out this comparative cross-sectional study. The study was conducted between December 2022 and April 2023. Patients of any gender with newly diagnosed myocardial infarction who received admission to the intensive care unit and had ST-segment elevation of at least 2 mm in two or more consecutive electrocardiogram leads were included in the patient group. The control group consisted of individuals who did not exhibit any changes associated with myocardial infarction. Based on sex, age, and body mass index, the 75 control and 75 patients were matched. Ceruloplasmin, vitamin C, and uric acid were analyzed and compared. RESULTS: The uric acid levels among the patient group were 10.34 ± 3.23 mg/dL, and among the controls, they were 3.45 ± 1.12 mg/dL (p<0.001). The ceruloplasmin levels among the patient group were 64.34 ± 4.21 mg/dL, and among the controls, they were 29.23 ± 3.82 mg/dL (p<0.001). The vitamin C levels among the patient group were 13.80 ± 0.94 µmol/L, and among the controls, they were 45.62 ± 4.34 µmol/L (p<0.001). CONCLUSION: The patients with myocardial infarction demonstrated significantly elevated levels of ceruloplasmin and uric acid, while their vitamin C levels were lower in comparison. It is crucial to comprehend the underlying mechanisms through which these parameters influence the development of myocardial infarction.
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Tagging of small bioactive molecules with a fluorophore is a highly sensitive method to trace their cellular activities through real-time visual information. Here we disclose a 7-nitrobenzo-2-oxa-1,3-diazole (NBD)-based, high-yielding, one-pot labeling protocol for hydroxylated molecules using Yamaguchi coupling as the key reaction. This methodology was successfully applied on several sensitive and complex hydroxylated bioactive compounds including 7-deacetylazadiradione, simvastatin, camptothecin, andrographolide, cinchonine, ß-dihydroartemisinin, and azadirachtin A. Further, utility of this protocol was illustrated on the cytotoxic activity of azadiradione derivatives against several cancer cell lines through cell imaging of two qualified fluorescent probes.
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Produtos Biológicos/química , Corantes Fluorescentes/química , Limoninas/química , Limoninas/farmacologia , Nitrobenzenos/química , Oxidiazóis/química , Concentração de Íons de Hidrogênio , Espectrometria de Fluorescência/métodosRESUMO
The orexin (or hypocretin) system has been identified as a novel target for the treatment of insomnia due to the wealth of biological and genetic data discovered over the past decade. Recently, clinical proof-of-concept was achieved for the treatment of primary insomnia using dual (OX1R/OX2R) orexin receptor antagonists. However, elucidation of the pharmacology associated with selective orexin-2 receptor antagonists (2-SORAs) has been hampered by the lack of orally bioavailable, highly selective small molecule probes. Herein, the discovery and optimization of a novel series of 2,5-diarylnicotinamides as potent and orally bioavailable orexin-2 receptor selective antagonists is described. A compound from this series demonstrated potent sleep promotion when dosed orally to EEG telemetrized rats.
Assuntos
Ácidos Nicotínicos/química , Ácidos Nicotínicos/farmacologia , Antagonistas dos Receptores de Orexina , Animais , Cães , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Humanos , Ácidos Nicotínicos/síntese química , Ácidos Nicotínicos/farmacocinética , Receptores de Orexina/metabolismo , Ligação Proteica/efeitos dos fármacos , Ratos , Relação Estrutura-AtividadeRESUMO
Phytochemical investigation of the acetone extract of the aerial parts of Leucas stelligera afforded four new compounds (1-4) belonging to the labdane diterpene series as well as two known flavones, velutin (5) and chrysoeriol (6). Structure elucidation of the new compounds was carried out using 1D and 2D NMR spectroscopic data and single-crystal X-ray crystallography of compound 1. Compounds 1-4 exhibited selective antimycobacterial activity against Mycobacterium tuberculosis with IC50 values in the range 5.02-9.80 µg/mL.
Assuntos
Antituberculosos/isolamento & purificação , Antituberculosos/farmacologia , Diterpenos/isolamento & purificação , Diterpenos/farmacologia , Lamiaceae/química , Mycobacterium tuberculosis/efeitos dos fármacos , Antituberculosos/química , Cristalografia por Raios X , Diterpenos/química , Ensaios de Seleção de Medicamentos Antitumorais , Flavonas/química , Flavonas/isolamento & purificação , Células Hep G2 , Humanos , Índia , Concentração Inibidora 50 , Testes de Sensibilidade Microbiana , Conformação Molecular , Estrutura Molecular , Ressonância Magnética Nuclear BiomolecularRESUMO
BACKGROUND & OBJECTIVES: Mother-to-child transmission (MTCT) is the most significant route of HIV transmission in children below the age of 15 yr. In India, perinatal HIV transmission, even after treatment, accounts for 5.4 per cent of HIV cases. The present study was conducted to evaluate the efficacy of anti-retro viral therapy (ART) or prophylactic treatment (PT) to control maternal viral load in HIV positive women, and its effect on vertical HIV transmission to their infants. METHODS: A total of 58 HIV positive women were enrolled at the time of delivery and their plasma samples were obtained within 24 h of delivery for estimation of viral load. Viral load analysis was completed in 38 women. Infants received single dose nevirapine within 2 h of birth and zidovudine for 6 wk. At the end of 18 month follow up, HIV positive or negative status was available in 28 infants. RESULTS: Results revealed undetectable levels of viral load in 58.3 per cent of women with ART compared to 30.7 per cent of women with PT. No women on ART had viral load more than 10,000 copies/ml, whereas seven (26.9%, P=0.07) women receiving PT had this viral load. Median CD4 count of women on PT (483 cells/µl) was high compared to the women on ART (289 cells/ µl). At the end of 18 months follow up, only two children were HIV positive, whose mothers were on PT. One had in utero transmission; infection detected within 48 h of delivery, while the other child was infected post partum as HIV was detected at six months follow up. INTERPRETATION & CONCLUSIONS: Women who received a single dose of nevirapine during delivery had higher levels of viral load than women on ART. Combination drug therapy for pregnant women is now a standard of care in most of the western countries; use of nevirapine monotherapy at the time of delivery in our settings is not effective in controlling viral load. This highlights initiation of ART in pregnant women to control their viral load and thus to inhibit mother to child HIV transmission.