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Well conducted clinical trials are the mainstay for generating evidence on preferred treatments. In order to adequately protect the interests of the trial participants, the Central Licensing Authority of India has formulated guidelines to determine the quantum of compensation in cases of regulatory clinical trial related injury or death. However, these guidelines do not address the nuances of trials recruiting children aged under 16 years, within which, neonates are the most vulnerable population. Thus, there is a need for addressing this lacuna in the current guidelines. This article examines the challenges in determining the quantum of compensation in neonatal clinical trials using the current formula, which is a corollary to the challenges faced by the authors in procuring clinical trial insurance for the Probiotic supplementation for Prevention of Neonatal Sepsis (ProSPoNS) trial. Further, it suggests a template for a differential formula using birthweight of infants, which is one of the many important factors impacting neonatal mortality.
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Ensaios Clínicos como Assunto , Humanos , Recém-Nascido , Índia , Compensação e Reparação/legislação & jurisprudênciaRESUMO
The move toward early detection and treatment of cancer presents challenges for value assessment using traditional endpoints. Current cancer management rarely considers the full economic and societal benefits of therapies. Our study used a modified Delphi process to develop principles for defining and assessing value of cancer therapies that aligns with the current trajectory of oncology research and reflects broader notions of value. 24 experts participated in consensus-building activities across 5 months (16 took part in structured interactions, including a survey, plenary sessions, interviews, and off-line discussions, while 8 participated in interviews). Discussion focused on: 1) which oncology-relevant endpoints should be used for assessing treatments for early-stage cancer and access decisions for early-stage treatments, and 2) the importance of additional value components and how these can be integrated in value assessments. The expert group reached consensus on 4 principles in relation to the first area (consider oncology-relevant endpoints other than overall survival; build evidence for endpoints that provide earlier indication of efficacy; develop evidence for the next generation of predictive measures; use managed entry agreements supported by ongoing evidence collection to address decision-maker evidence needs) and 3 principles in relation to the second (routinely use patient reported outcomes in value assessments; assess broad economic impact of new medicines; consider other value aspects of relevance to patients and society).
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Immune checkpoint inhibitors (ICIs) ± chemotherapy is the standard treatment for driver mutation-negative non-small cell lung cancer (NSCLC). However, accessibility to ICIs in LMICs is limited due to high cost, and platinum-based chemotherapy remains the mainstay of treatment. Metformin has anticancer properties, and studies suggest synergism between metformin and pemetrexed. Based on preclinical evidence, this combination may be more beneficial for STK11-mutated NSCLC, a subgroup, inherently resistant to ICIs. In this Simon two-stage, single-arm phase 2 trial, we investigated metformin with pemetrexed-carboplatin (PC) in patients with treatment-naive stage IV non-squamous NSCLC. The primary outcome was 6-month progression-free survival (PFS) rate. Secondary outcomes were safety, overall survival (OS), overall response rate (ORR), proportion of STK11 mutation, and effect of STK11 mutation on 6-month PFS rate. The study was terminated for futility after interim analysis. The median follow-up was 34.1 months. The 6-month PFS rate was 28% (95% CI 12.4-0.46). The median PFS and OS were 4.5 (95% CI 2.2-6.1) and 7.4 months (95% CI 5.3-15.3), respectively. The ORR was 72%. Gastrointestinal toxicities were the most common. No grade 4/5 toxicities were reported. Targeted sequencing was possible in nine cases. Two patients had STK11 mutation and a poor outcome (PFS < 12 weeks). We could not demonstrate the benefit of metformin with CP in terms of improvement in 6-month PFS rate; however, the combination was safe (CTRI/2019/02/017815).
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Metformina , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Pemetrexede , Carboplatina , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Metformina/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
BACKGROUND: Mammalian lungs comprise a complex microbial ecosystem that interacts with host physiology. Previous research demonstrates that the environment significantly contributes to bacterial community structure in the upper and lower respiratory tract. However, the influence of host genetics on the makeup of lung microbiota remains ambiguous, largely due to technical difficulties related to sampling, as well as challenges inherent to investigating low biomass communities. Thus, innovative approaches are warranted to clarify host-microbe interactions in the mammalian lung. RESULTS: Here, we aimed to characterize host genomic regions associated with lung bacterial traits in an advanced intercross mouse line (AIL). By performing quantitative microbial profiling (QMP) using the highly precise method of droplet digital PCR (ddPCR), we refined 16S rRNA gene amplicon-based traits to identify and map candidate lung-resident taxa using a QTL mapping approach. In addition, the two abundant core taxa Lactobacillus and Pelomonas were chosen for independent microbial phenotyping using genus-specific primers. In total, this revealed seven significant loci involving eight bacterial traits. The narrow confidence intervals afforded by the AIL population allowed us to identify several promising candidate genes related to immune and inflammatory responses, cell apoptosis, DNA repair, and lung functioning and disease susceptibility. Interestingly, one genomic region associated with Lactobacillus abundance contains the well-known anti-inflammatory cytokine Il10, which we confirmed through the analysis of Il10 knockout mice. CONCLUSIONS: Our study provides the first evidence for a role of host genetic variation contributing to variation in the lung microbiota. This was in large part made possible through the careful curation of 16S rRNA gene amplicon data and the incorporation of a QMP-based methods. This approach to evaluating the low biomass lung environment opens new avenues for advancing lung microbiome research using animal models.
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OBJECTIVE: To evaluate the effect of surgical intervention on serum insulin-like growth factor 1 levels in patients with obstructive sleep apnoea. METHODS: A prospective study was conducted in a tertiary care hospital of adult patients with obstructive sleep apnoea for whom continuous positive airway pressure therapy failed or was refused. All patients underwent polysomnography and serum insulin-like growth factor 1 evaluation pre-operatively and at three months post-operatively. The site of surgery was determined using Müller's manoeuvre and ApneaGraph AG 200. RESULTS: Fifteen patients were included with a mean age of 38 years: 11 males and 4 females. The mean pre-operative Apnoea-Hypopnoea Index using polysomnography was 53.7 events per hour, and the mean post-operative Apnoea-Hypopnoea Index at three months was 15.3 events per hour (p = 0.0001). The mean pre-operative serum insulin-like growth factor 1 was 160.2 µg/l, while the mean post-operative value was 236.98 µg/l (p = 0.005). CONCLUSION: In adult patients with obstructive sleep apnoea for whom continuous positive airway pressure therapy fails, site-specific surgical intervention to treat the obstruction leads to an increase in serum insulin-like growth factor 1 levels.
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Fator de Crescimento Insulin-Like I , Apneia Obstrutiva do Sono , Adulto , Feminino , Masculino , Humanos , Estudos Prospectivos , Apneia Obstrutiva do Sono/cirurgia , Pressão Positiva Contínua nas Vias Aéreas , PolissonografiaRESUMO
A multi-frame, X-ray diffraction (XRD) detector system has been developed for use in time-resolved XRD measurements during single-event experiments at the Dynamic Compression Sector (DCS) at the Advanced Photon Source (APS). The system is capable of collecting four sequential XRD patterns separated by 153â ns, the period of the APS storage ring in the 24-bunch mode. This capability allows an examination of the temporal evolution of material dynamics in single-event experiments, such as plate impact experiments, explosive detonations, and split-Hopkinson pressure bar experiments. This system is available for all user experiments at the DCS. Here, the system description and measured performance parameters (detective quantum efficiency, spatial and temporal resolution, and dynamic range) are presented along with procedures for synchronization and image post-processing.
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Alzheimer's disease (AD) is a multifactorial neurological disorder associated with neuropathological and neurobehavioral changes, like cognition and memory loss. Pathological hallmarks of AD comprise oxidative stress, formation of insoluble ß-amyloid (Aß) plaques, intracellular neurofibrillary tangles constituted by hyperphosphorylated tau protein (P-tau), neurotransmitters dysbalanced (DA, NE, 5-HT, GABA and Glutamate) and metal deposition. Chronic exposure to metals like aluminium and copper causes accumulation of Aß plaques, promotes oxidative stress, neuro-inflammation, and degeneration of cholinergic neurons results in AD-like symptoms. In the present study, rats were administered with aluminium chloride (200 mg/kg p.o) and copper sulfate (0.5 mg/kg p.o) alone and in combination for 28 days. Allicin (10 and 20 mg/kg i.p) was administered from day 7 to day 28. Spatial and recognition memory impairment analysis was performed using Morris water maze, Probe trial, and Novel Object Recognition test. Animals were sacrificed on day 29, brain tissue was isolated, and its homogenate was used for biochemical (lipid peroxidation, nitrite, and glutathione), neuro-inflammatory (IL-1ß, IL-6 and TNF- α), neurotransmitters (DA, NE, 5-HT, GABA and Glutamate), Aß(1-42) level, Al concentration estimation, and Na+/K+-ATPase activity. In the present study, aluminium chloride and copper sulfate administration increased oxidative stress, inflammatory cytokines release, imbalanced neurotransmitters' concentration, and promoted ß-amyloid accumulation and Na+/K+-ATPase activity. Treatment with allicin dose-dependently attenuated these pathological events via restoration of antioxidants, neurotransmitters concentration, and inhibiting cytokine release and ß-amyloid accumulation. Moreover, allicin exhibited the neuroprotective effect through antioxidant, anti-inflammatory, neurotransmitters restoration, attenuation of neuro-inflammation and ß-amyloid-induced neurotoxicity.
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Cloreto de Alumínio/toxicidade , Disfunção Cognitiva/induzido quimicamente , Sulfato de Cobre/toxicidade , Dissulfetos/farmacologia , Inflamação/tratamento farmacológico , Neurotransmissores/metabolismo , Ácidos Sulfínicos/farmacologia , Peptídeos beta-Amiloides/genética , Peptídeos beta-Amiloides/metabolismo , Animais , Disfunção Cognitiva/tratamento farmacológico , Dissulfetos/química , Glutationa , Aprendizagem/efeitos dos fármacos , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Estrutura Molecular , Nitritos , Ratos , Ratos Wistar , Ácidos Sulfínicos/químicaRESUMO
Introduction: Neonatal jaundice results from combined effects of both increased production of bilirubin and decreased hepatic excretory capacity in neonates. Since its discovery, phototherapy is the most widespread treatment used in neonatal jaundice. In this work, we try to search for a relationship between exposure to phototherapy and decrease in serum bilirubin (linearity vs proportionality). Methods:The present research was non-randomized prospective study conducted in the Neonatal Intensive Care Unit (NICU), Department of Paediatrics, AIIMS, New Delhi, and the Department of Pharmacology, AIIMS, New Delhi, India. Subjects were recruited from neonates admitted in NICU AIIMS, which meets our selection criteria. Infants were given a low dose of either phototherapy continuously or phototherapy for the first six hours and a double dose of phototherapy for the next six hours. Samples were collected before the beginning of the study (0 hours) and then at six and 12 hours. Bilirubin concentration was measured using HPLC and (LC-MS/MS). Results and conclusion:The percentage of reduction during the 6-12-hour interval was compared with that during the 0-6-hour interval if all experimental conditions were kept unchanged. A relationship curve between percentage of reduction and irradiance was created based on the percentage of reduction in serum bilirubin during the 0-6-hour and 0-12-hour intervals. The present study suggests that the relationship between efficacy, as measured by percentage of reduction in serum bilirubin, and irradiance is unlikely to be linear. Collected data are insufficient to clearly distinguish between proportionality and saturation point, considering that the results may be possible with both of these hypotheses.
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Bacopa monnieri (L.) Wettst. (BM) has been traditionally used in Ayurveda for improving memory and cognitive deficits which is also evidenced through experimental and clinical studies. The neuropharmacological properties of BM are attributed to "bacosides", a complex mixture of saponin compounds. BM extracts enriched with bacosides offers commercial advantage due to perceived higher efficacy. However, there is no scientific data to support the same. In the present study, methanolic extract of BM (BME) was compared with bacosides enriched (BME-EF) vis a vis bacosides free fraction (BME-FF). Potential antioxidant and cholinesterase inhibitory activity has been evaluated using in vitro and in vivo methods. BME showed not only the highest anti-amnesic efficacy but also antioxidant and cholinesterase inhibitory activity, followed by either BME-FF or BME-EF. Interestingly, no significant differences were found in between the groups. These findings dispel the notion that bacosides enrichment enhances anti-amnesic efficacy and also suggests the contribution of other components.
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Bacopa , Saponinas , Triterpenos , Ayurveda , Extratos Vegetais/farmacologia , Saponinas/farmacologia , Triterpenos/farmacologiaRESUMO
Despite extensive shock wave and static compression experiments and corresponding theoretical work, consensus on the crystal structure and the melt boundary of Fe at Earth's core conditions is lacking. We present in situ x-ray diffraction measurements in laser-shock compressed Fe that establish the stability of the hexagonal-close-packed (hcp) structure along the Hugoniot through shock melting, which occurs between â¼242 to â¼247 GPa. Using previously reported hcp Fe Hugoniot temperatures, the melt temperature is estimated to be 5560(360) K at 242 GPa, consistent with several reported Fe melt curves. Extrapolation of this value suggests â¼6400 K melt temperature at Earth's inner core boundary pressure.
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High pressure structural transformations are typically characterized by the thermodynamic state (pressure-volume-temperature) of the material. We present in situ x-ray diffraction measurements on laser-shock compressed silver and platinum to determine the role of deformation-induced lattice defects on high pressure phase transformations in noble metals. Results for shocked Ag show a copious increase in stacking faults (SFs) before transformation to the body-centered-cubic (bcc) structure at 144-158 GPa. In contrast, shock compressed Pt remains largely free of SFs and retains the fcc structure to over 380 GPa. These findings, along with recent results for shock compressed gold, show that SF formation promotes high pressure structural transformations in shocked noble metals that are not observed under static compression. Potential SF-related mechanisms for fcc-bcc transformations are discussed.
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AIM: To evaluate the burden and association of cardiometabolic risk factors in the spouses of women with and without hyperglycaemia in pregnancy. METHODS: Women with (n = 204) and without (n = 197) hyperglycaemia in pregnancy, along with their spouses, participated in this cross-sectional study. The hyperglycaemia in pregnancy group included women with gestational diabetes and diabetes in pregnancy. A detailed questionnaire was completed for all participants (men and women), documenting relevant personal and medical history, along with biochemical investigations (men). RESULTS: A total of 401 couples were evaluated at the time point during the pregnancy of 24.7 ± 5.2 gestational weeks (mean ± sd). Dysglycaemia (prediabetes or diabetes), overweight/obesity (BMI ≥25 kg/m2 ) and metabolic syndrome were detected in 120 (58.9%), 123 (60.3%) and 98 spouses (48.3%) of women with hyperglycaemia in pregnancy, respectively. In the fully adjusted model, an increased risk of dysglycaemia [odds ratio 1.43 (95% CI 0.95-2.17); P = 0.088], overweight/obesity [odds ratio 1.49 (95% CI 0.98-2.27); P = 0.064] and metabolic syndrome [odds ratio 2.00 (95% CI 1.30-3.07); P = 0.001] was seen in the spouses of women with hyperglycaemia in pregnancy. The prevalence of these metabolic conditions was higher in spouses of women with diabetes in pregnancy compared to spouses of women with gestational diabetes mellitus. CONCLUSIONS: A high burden of cardiometabolic risk factors was observed in the spouses of women with hyperglycaemia in pregnancy. The opportunity provided by pregnancy could be used by the healthcare system not only to improve the health of the woman and her offspring, but also her spouse.
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Diabetes Mellitus/epidemiologia , Diabetes Gestacional/epidemiologia , Síndrome Metabólica/epidemiologia , Obesidade/epidemiologia , Gravidez em Diabéticas/epidemiologia , Cônjuges/estatística & dados numéricos , Adulto , Fatores de Risco Cardiometabólico , Estudos Transversais , Feminino , Humanos , Índia/epidemiologia , Sobrepeso/epidemiologia , Estado Pré-Diabético/epidemiologia , GravidezRESUMO
Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder characterized by restrictive behaviour, deficit in social skills and interaction. The multifactorial etiology, complex pathophysiology and different combination of symptoms (unusual speech patterns, frequent repetition of phrases) make it difficult to treat. Thus, present study aimed to find the protective effects of oxiracetam alone and in combination with zinc on brain behavioral, biochemical, pro-inflammatory cytokines and neurotransmitters level. Rats were administered with propionic acid (250 mg/kg p.o.) for 3 days and immediately on next day treatment were given with oxiracetam (25, 50 mg/kg i.p), zinc (4 mg/kg) as well as oxiracetam (25 mg/kg i.p) in combination with zinc (4 mg/kg p.o). Behavioral parameters were performed from 22th to 28th day. On 29th day, all the animals were sacrificed by cervical dislocation and the brain was preserved for biochemical (LPO, GSH, nitrite, mitochondrial complex I, IV and cAMP), neuroinflammatory (TNF-α, IL-1ß, IL-6) and neurotransmitters (5-HT, GABA, glutamate and acetylcholine) analysis. The propionic acid administration showed memory impairment, restrictive behavior, increased proinflammatory cytokines level, biochemical and neurotransmitters alteration. However, treatment with oxiracetam alone and in combination with zinc significantly attenuated behavioral, biochemical, inflammatory cytokines and restored neurotransmitters level. The finding of present study demonstrated that oxiracetam alone and in combination with zinc afforded superior anti-autistic effect through antioxidant, anti-inflammatory and anti-excitotoxic mechanisms and could serve as attractive strategy in managing autism.
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Transtorno do Espectro Autista/induzido quimicamente , Transtorno do Espectro Autista/tratamento farmacológico , Locomoção/efeitos dos fármacos , Propionatos/toxicidade , Pirrolidinas/uso terapêutico , Zinco/uso terapêutico , Animais , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Transtorno do Espectro Autista/psicologia , Locomoção/fisiologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Psicotrópicos/farmacologia , Psicotrópicos/uso terapêutico , Pirrolidinas/farmacologia , Ratos , Ratos Wistar , Interação Social/efeitos dos fármacos , Zinco/farmacologiaRESUMO
In this work, we present the results of 1 yr of upgraded Giant Metrewave Radio Telescope timing measurements of PSR J0514-4002A, a 4.99-ms pulsar in a 18.8-d eccentric ([Formula: see text]) orbit with a massive companion located in the globular cluster NGC 1851. Combining these data with earlier Green Bank Telescope data, we greatly improve the precision of the rate of advance of periastron, [Formula: see text] which, assuming the validity of general relativity, results in a much refined measurement of the total mass of the binary, [Formula: see text]. Additionally, we measure the Einstein delay parameter, γ, something that has never been done for any binary system with an orbital period larger than [Formula: see text]10 h. The measured value, [Formula: see text], is by far the largest for any binary pulsar. Furthermore, we measure the proper motion of the system ([Formula: see text] and [Formula: see text]), which is not only important for analysing its motion in the cluster, but is also essential for a proper interpretation of γ, given the latter parameter's correlation with the variation of the projected semimajor axis. The measurements of γ and the proper motion enable a separation of the system component masses: we obtain a pulsar mass of [Formula: see text] and a companion mass of [Formula: see text]. This raises the possibility that the companion is also a neutron star. Searches for radio pulsations from the companion have thus far been unsuccessful; hence, we cannot confirm the latter hypothesis. The low mass of this millisecond pulsar - one of the lowest ever measured for such objects - clearly indicates that the recycling process can be achieved with a relatively small amount of mass transfer.
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This research work deployed free radical polymerization for the development of pH-responsive hybrid nanocomposite hydrogels (NCHs) with the formation of improved interpenetrating networks (IPN). The crosslinked biopolymeric system was composed of (chitosan (CH)/guar gum (GG)/polyol) and a nanofiller (Cloisite 30B). The study was aimed to investigate the role of Cloisite 30B as a nanofiller and linseed oil-derived polyol to induce stable interpenetrating networks in chitosanâguar gum-based hydrogels. FT-IR analysis confirmed the formation of crosslinked networks with the formation of hydrogen bonds in the synthesized NCHs. Thermogravimetric analysis and differential scanning calorimetry revealed high thermal stability of the NCHs. The hydrolytic and soil burial degradation tests confirmed the biodegradability of the synthesized NCHs. An extraordinarily high swelling capacity in a buffer solution of pH 4.0 and 7.4 demonstrated their pH-responsive behavior. It has been demonstrated that even the minimal addition of polyol to the guar gum-based hydrogels has influenced the stability and characteristic features such as high swelling capacity owing to the formation of interpenetrating networks and the biodegradability of the hydrogels.
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Gold is believed to retain its ambient crystal structure at very high pressures under static and shock compression, enabling its wide use as a pressure marker. Our in situ x-ray diffraction measurements on shock-compressed gold show that it transforms to the body-centered-cubic (bcc) phase, with an onset pressure between 150 and 176 GPa. A liquid-bcc coexistence was observed between 220 and 302 GPa and complete melting occurs by 355 GPa. Our observation of the lower coordination bcc structure in shocked gold is in marked contrast to theoretical predictions and the reported observation of the hexagonal-close-packed structure under static compression.
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OBJECTIVE: Bauhinia purpurea (BP) Linn. (Caesalpiniaceae) is a plant of great medicinal importance and has been used since ancient times for treating many inflammatory conditions including arthritis. This study investigates the anti-arthritic potential of the hydroalcoholic extract from the stem bark of BP. MATERIALS AND METHODS: The anti-inflammatory and anti-arthritic activity of BP at various doses was used to evaluate its anti-inflammatory activity and anti-arthritic activity. Serum of arthritic rats was collected at day 21 for detecting serum cytokines level and to evaluate the effect of BP on its serum level. Furthermore, the safety of BP was evaluated in acute (5 days) and subacute (28 days) toxicity study in rats. RESULTS: There was a significant inhibition (P < 0.01) in paw edema at a different time scale with different doses of BP (50, 100, and 200 mg/kg). BP also demonstrated dose-dependent anti-arthritic activity on all observation days (3, 7, 14, and 21). In addition, there was also a significant decrease (P < 0.01) in oxidative stress markers, circulating pro-inflammatory cytokine (tumor necrosis factor alpha from 45.91 to 37.44, interleukin-1 (IL-1) ß from 18.24 to 16.06, and IL-6 from 69.77 to 58.44) and an increase in anti-inflammatory cytokine (IL-10 from 8.07 to 12.07) levels. BP was found to be safe with an oral LD50 value of >2 g/kg in acute toxicity study and also no toxicological effect was observed in the oral subacute toxicity study. CONCLUSION: This study demonstrates that BP bark possesses anti-arthritic activity potential and confirm its folklore use in the treatment of inflammatory conditions.
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Anti-Inflamatórios/uso terapêutico , Artrite Experimental/tratamento farmacológico , Bauhinia , Extratos Vegetais/uso terapêutico , Animais , Anti-Inflamatórios/farmacologia , Artrite Experimental/sangue , Citocinas/sangue , Edema/sangue , Edema/tratamento farmacológico , Masculino , Extratos Vegetais/farmacologia , Ratos Wistar , Testes de Toxicidade SubagudaRESUMO
Post stroke recanalization has been associated with increased risk of oxidative stress. Stimulating endogenous antioxidant pathway by activation of nuclear factor erythroid-2-related factor-2 (Nrf2) plays a key role in neuronal defense against inflammation and oxidative stress in penumbra. Here, we explored whether monomethyl fumarate (MMF) could produce neuro-protection after ischemia/reperfusion (I/R) injury via Nrf2/HO1 activation. In male SD rats, middle cerebral artery was occluded for 90â¯min and confirmed using Laser Doppler flowmeter. MMF (10, 20 and 40â¯mg/kg) was administered in two divided doses at 30â¯min post ischemia and 5-10â¯min after reperfusion. After 24â¯h, effect on neurobehavioral parameters, infarct damage by TTC staining and MRI, oxidative stress and inflammatory cytokines were assessed. Expression studies of nuclear Nrf2 and cytoplasmic HO1 were performed in peri-infarct cortex and striatum; followed by dual immunofluorescence study to check the specific cell type. I/R induced neurobehavioral deficits and infarct damage were significantly (pâ¯<â¯0.05) attenuated by MMF (20 and 40â¯mg/kg). MMF, 20â¯mg/kg, significantly normalized I/R induced altered redox status and increased levels of TNF-α, IL-1ß in the ipsilateral cortex. MRI data showed significantly reduced infarct in cortex but not in striatum after MMF treatment. Expression of nuclear Nrf2 and cytoplasmic HO1 were significantly (pâ¯<â¯0.05) increased in peri-infarct cortex after treatment with MMF. Additionally, dual immunofluorescence showed increased Nrf2 expression in neurons and HO1 expression in neurons as well as astrocytes in peri-infarct cortex after MMF treatment. Our results show the neuro-protective potential of MMF probably by restricting the progression of damage from striatum to cortex through activation of Nrf2/HO1 pathway in peri-infarct cortex.
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Fumaratos/uso terapêutico , Heme Oxigenase (Desciclizante)/biossíntese , Infarto da Artéria Cerebral Média/metabolismo , Maleatos/uso terapêutico , Fator 2 Relacionado a NF-E2/biossíntese , Fármacos Neuroprotetores/uso terapêutico , Traumatismo por Reperfusão/metabolismo , Animais , Fumaratos/farmacologia , Infarto da Artéria Cerebral Média/tratamento farmacológico , Infarto da Artéria Cerebral Média/patologia , Masculino , Maleatos/farmacologia , Fator 2 Relacionado a NF-E2/agonistas , Fármacos Neuroprotetores/farmacologia , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/patologia , Traumatismo por Reperfusão/prevenção & controle , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologiaRESUMO
AIM: This study aims to determine whether a resource- and culturally appropriate lifestyle intervention programme in South Asian countries, provided to women with gestational diabetes (GDM) after childbirth, will reduce the incidence of worsening of glycaemic status in a manner that is affordable, acceptable and scalable. METHODS: Women with GDM (diagnosed by oral glucose tolerance test using the International Association of the Diabetes and Pregnancy Study Groups criteria) will be recruited from 16 hospitals in India, Sri Lanka and Bangladesh. Participants will undergo a repeat oral glucose tolerance test at 6 ± 3 months postpartum and those without Type 2 diabetes, a total sample size of 1414, will be randomly allocated to the intervention or usual care. The intervention will consist of four group sessions, 84 SMS or voice messages and review phone calls over the first year. Participants requiring intensification of the intervention will receive two additional individual sessions over the latter half of the first year. Median follow-up will be 2 years. The primary outcome is the proportion of women with a change in glycaemic category, using the American Diabetes Association criteria: (i) normal glucose tolerance to impaired fasting glucose, or impaired glucose tolerance, or Type 2 diabetes; or (ii) impaired fasting glucose or impaired glucose tolerance to Type 2 diabetes. Process evaluation will explore barriers and facilitators of implementation of the intervention in each local context, while trial-based and modelled economic evaluations will assess cost-effectiveness. DISCUSSION: The study will generate important new evidence about a potential strategy to address the long-term sequelae of GDM, a major and growing problem among women in South Asia. (Clinical Trials Registry of India No: CTRI/2017/06/008744; Sri Lanka Clinical Trials Registry No: SLCTR/2017/001; and ClinicalTrials.gov Identifier No: NCT03305939).