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1.
Nat Commun ; 15(1): 7610, 2024 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-39218971

RESUMO

Single-cell transcriptomics has emerged as a powerful tool for understanding how different cells contribute to disease progression by identifying cell types that change across diseases or conditions. However, detecting changing cell types is challenging due to individual-to-individual and cohort-to-cohort variability and naive approaches based on current computational tools lead to false positive findings. To address this, we propose a computational tool, scDist, based on a mixed-effects model that provides a statistically rigorous and computationally efficient approach for detecting transcriptomic differences. By accurately recapitulating known immune cell relationships and mitigating false positives induced by individual and cohort variation, we demonstrate that scDist outperforms current methods in both simulated and real datasets, even with limited sample sizes. Through the analysis of COVID-19 and immunotherapy datasets, scDist uncovers transcriptomic perturbations in dendritic cells, plasmacytoid dendritic cells, and FCER1G+NK cells, that provide new insights into disease mechanisms and treatment responses. As single-cell datasets continue to expand, our faster and statistically rigorous method offers a robust and versatile tool for a wide range of research and clinical applications, enabling the investigation of cellular perturbations with implications for human health and disease.


Assuntos
COVID-19 , Células Dendríticas , RNA-Seq , SARS-CoV-2 , Análise de Célula Única , Transcriptoma , Análise de Célula Única/métodos , Humanos , COVID-19/virologia , COVID-19/genética , RNA-Seq/métodos , Células Dendríticas/metabolismo , SARS-CoV-2/genética , Biologia Computacional/métodos , Perfilação da Expressão Gênica/métodos , Células Matadoras Naturais/metabolismo , Imunoterapia/métodos , Análise de Sequência de RNA/métodos , Análise da Expressão Gênica de Célula Única
2.
Ageing Res Rev ; 100: 102411, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38986845

RESUMO

Alzheimer's Disease (AD) is a challenging neurodegenerative condition, with overwhelming implications for affected individuals and healthcare systems worldwide. Animal models have played a crucial role in studying AD pathogenesis and testing therapeutic interventions. Remarkably, studies on the genetic factors affecting AD risk, such as APOE and TREM2, have provided valuable insights into disease mechanisms. Early diagnosis has emerged as a crucial factor in effective AD management, as demonstrated by clinical studies emphasizing the benefits of initiating treatment at early stages. Novel diagnostic technologies, including RNA sequencing of microglia, offer promising avenues for early detection and monitoring of AD progression. Therapeutic strategies remain to evolve, with a focus on targeting amyloid beta (Aß) and tau pathology. Advances in animal models, such as APP-KI mice, and the advancement of anti-Aß drugs signify progress towards more effective treatments. Therapeutically, the focus has shifted towards intricate approaches targeting multiple pathological pathways simultaneously. Strategies aimed at reducing Aß plaque accumulation, inhibiting tau hyperphosphorylation, and modulating neuroinflammation are actively being explored, both in preclinical models and clinical trials. While challenges continue in developing validated animal models and translating preclinical findings to clinical success, the continuing efforts in understanding AD at molecular, cellular, and clinical levels offer hope for improved management and eventual prevention of this devastating disease.


Assuntos
Doença de Alzheimer , Modelos Animais de Doenças , Diagnóstico Precoce , Doença de Alzheimer/genética , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/metabolismo , Animais , Humanos , Peptídeos beta-Amiloides/metabolismo , Camundongos
3.
Cureus ; 16(3): e56443, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38638772

RESUMO

Introduction Pancreatic fluid collection (PFC) is one of the most frequent complications associated with acute pancreatitis. The route of drainage is guided by the size and site of collection. The present study aims to assess the clinical and technical success of transgastric percutaneous drainage (PCD) for managing retrogastric walled-off pancreatic necrosis (WOPN). Materials and methods A total of 44 patients with acute pancreatitis diagnosed with WOPN who underwent transgastric PCD with ultrasound or CT guidance as part of standard clinical management were included in the study. Patients were observed for improvement in clinical parameters, and treatment outcomes were noted in terms of technical success, clinical success, adverse events, need for additional procedures, hospital stay, and duration of placement of all drains. Data for the internalization of transgastric PCD was also observed in the study. Results Technical success during the drain placement was observed in 93% (n=41) of patients.Internalization of the transgastric drain was attempted in 12 patients and successful in 11 (91%). The median duration of hospital stay from the time of placement of the first PCD until discharge and the median duration of all PCDs placed were higher in patients where the transgastric drain was not internalized as compared to patients where the transgastric drain was internalized. Conclusion In WOPN, transgastric drain placement and successful internalization in any form help in the early resolution of peripancreatic and abdominal collections. It also reduces the time to percutaneous catheter removal, which in turn reduces the morbidity and decreases the need for additional interventions or surgery.

4.
Mycoses ; 67(1): e13681, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38214352

RESUMO

BACKGROUND: The present epidemic of dermatophytosis in India is marked by an increase in chronic, recurrent and disseminated cases. A combination of oral itraconazole and topical luliconazole is being increasingly utilised by dermatologists in India. The superiority of this combination is not supported by robust clinical trial data. OBJECTIVE: We conducted this randomised, open-label, two arms, parallel assignment intervention trial between November 2022 and May 2023 to determine the superiority of topical 1% Luliconazole over bland emollient as adjuvant to systemic Itraconazole therapy in the management of dermatophytosis. METHOD: In this study, 135 patients of either sex were randomised to two study cohorts. Major exclusions being concomitant medical illness, use of concomitant medication and substance abuse. Participants were randomly assigned to receive topical bland emollient, (Cohort I, n = 67) or topical luliconazole, (Cohort II, n = 68). Both cohorts received oral itraconazole 200 mg/day (100 mg BID) and levocetirizine 5 mg twice a day as a systemic regime. Clinical and mycological cure at the end of 6 weeks and clinical relapse among cure patients during 10-week follow-up were observed. RESULTS: The cure rates for Cohorts I and II at 6 weeks were 50 (74.62%) and 56 (82.35%), (p = .46), respectively. During the 4-week follow-up period, clinical relapses were observed in 16 (32%) of the 50 patients in Cohort I and 12 (21.43%) of the 56 patients in Cohort II (p = .18). Luliconazole cohort shows a significantly higher medical cost (p < .05). CONCLUSION: Our study shows a similar cure rate and relapse rate for patients receiving topical Luliconazole versus topical bland emollient as an adjuvant to the systemic itraconazole regime.


Assuntos
Imidazóis , Itraconazol , Tinha , Humanos , Itraconazol/uso terapêutico , Antifúngicos/uso terapêutico , Emolientes/uso terapêutico , Tinha/tratamento farmacológico , Recidiva
5.
Methods Mol Biol ; 2743: 223-237, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38147219

RESUMO

The modified cysteinyl-labeling assay enables the labeling, enrichment, and detection of all members of the protein tyrosine phosphatase (PTP) superfamily that become reversibly oxidized in cells to facilitate phosphorylation-dependent signaling. In this chapter, we describe the method in detail and highlight the pitfalls of avoiding post-lysis oxidation of PTPs to measure the dynamic and transient oxidation and reduction of PTPs in cell signaling.


Assuntos
Proteínas Tirosina Fosfatases , Transdução de Sinais , Bioensaio , Morte Celular , Oxirredução
6.
Cureus ; 15(4): e37911, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-37122975

RESUMO

Objective In this study, we aimed to optimize various grayscale, Doppler, and elastography parameters and evaluate their diagnostic performance in the preoperative diagnosis of biliary atresia (BA). Materials and methods A total of 158 infants aged <6 months with neonatal cholestasis (NC) were enrolled in the study and sonography was performed after four hours of fasting. For comparison of elastography, 31 exclusively age-matched controls, not suffering from liver disease, were included separately. Triangular cord and gallbladder (GB) parameters were considered as primary parameters, while right hepatic artery (RHA) caliber, RHA-to-right portal vein (RPV) ratio, hepatic subcapsular flow (HSF), and shear wave elastography (SWE) were considered as secondary parameters. Diagnosis of infants with BA was confirmed on histopathology. Data were presented as mean ±standard deviation (SD) and frequency. Differences between groups were compared using the Chi-square test and the unpaired student t-test. Receiver operating characteristic (ROC) curve analysis was done for individual ultrasound/Doppler/SWE parameters to calculate the optimal cutoff value. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy were calculated for each parameter and their combinations. Results Of the primary parameters, GB contractility index (CI) and length showed the highest sensitivity and specificity respectively. A cutoff of 14 kPA was derived for SWE for the diagnosis of BA. Among secondary parameters, SWE had the best diagnostic performance, better than even the individual primary parameters. A combination of primary parameters with SWE in series showed the highest accuracy. Conclusion Among secondary parameters, elastography can prove to be highly useful. The highest accuracy in diagnosing BA can be obtained by combining primary parameters with SWE.

7.
Am J Respir Crit Care Med ; 207(8): 1055-1069, 2023 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-36913491

RESUMO

Rationale: Genetic studies suggest that SOX17 (SRY-related HMG-box 17) deficiency increases pulmonary arterial hypertension (PAH) risk. Objectives: On the basis of pathological roles of estrogen and HIF2α (hypoxia-inducible factor 2α) signaling in pulmonary artery endothelial cells (PAECs), we hypothesized that SOX17 is a target of estrogen signaling that promotes mitochondrial function and attenuates PAH development via HIF2α inhibition. Methods: We used metabolic (Seahorse) and promoter luciferase assays in PAECs together with the chronic hypoxia murine model to test the hypothesis. Measurements and Main Results: Sox17 expression was reduced in PAH tissues (rodent models and from patients). Chronic hypoxic pulmonary hypertension was exacerbated by mice with conditional Tie2-Sox17 (Sox17EC-/-) deletion and attenuated by transgenic Tie2-Sox17 overexpression (Sox17Tg). On the basis of untargeted proteomics, metabolism was the top pathway altered by SOX17 deficiency in PAECs. Mechanistically, we found that HIF2α concentrations were increased in the lungs of Sox17EC-/- and reduced in those from Sox17Tg mice. Increased SOX17 promoted oxidative phosphorylation and mitochondrial function in PAECs, which were partly attenuated by HIF2α overexpression. Rat lungs in males displayed higher Sox17 expression versus females, suggesting repression by estrogen signaling. Supporting 16α-hydroxyestrone (16αOHE; a pathologic estrogen metabolite)-mediated repression of SOX17 promoter activity, Sox17Tg mice attenuated 16αOHE-mediated exacerbations of chronic hypoxic pulmonary hypertension. Finally, in adjusted analyses in patients with PAH, we report novel associations between a SOX17 risk variant, rs10103692, and reduced plasma citrate concentrations (n = 1,326). Conclusions: Cumulatively, SOX17 promotes mitochondrial bioenergetics and attenuates PAH, in part, via inhibition of HIF2α. 16αOHE mediates PAH development via downregulation of SOX17, linking sexual dimorphism and SOX17 genetics in PAH.


Assuntos
Hipertensão Pulmonar , Hipertensão Arterial Pulmonar , Masculino , Ratos , Feminino , Camundongos , Animais , Hipertensão Pulmonar/metabolismo , Células Endoteliais/metabolismo , Pulmão , Artéria Pulmonar , Hipóxia/complicações , Estrogênios , Hipertensão Arterial Pulmonar/metabolismo , Hipertensão Pulmonar Primária Familiar/complicações , Proteínas HMGB/metabolismo , Fatores de Transcrição SOXF/genética
8.
Cureus ; 14(9): e29002, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36112972

RESUMO

Sinistral portal hypertension in the setting of acute pancreatitis is a known complication owing to splenic vein thrombosis. It can lead to upper gastrointestinal bleeding due to the development of fundal gastric varices due to the shunting of blood via short gastric veins. However, in the setting of acute pancreatitis, surgical procedures can have high post-operative morbidity. Emergent management of cases with absent gastro-renal shunt can be done by partial splenic arterial embolization, as it is minimally invasive and can provide similar results. Herein, we report a case series of two cases of acute pancreatitis complicated with splenic vein thrombosis and gastric varices, which were managed by partial splenic artery embolization.

9.
Sci Signal ; 15(730): eabn6875, 2022 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-35439023

RESUMO

Increased production of reactive oxygen species plays an essential role in the pathogenesis of several diseases, including cardiac hypertrophy. In our search to identify redox-sensitive targets that contribute to redox signaling, we found that protein tyrosine phosphatase 1B (PTP1B) was reversibly oxidized and inactivated in hearts undergoing hypertrophy. Cardiomyocyte-specific deletion of PTP1B in mice (PTP1B cKO mice) caused a hypertrophic phenotype that was exacerbated by pressure overload. Furthermore, we showed that argonaute 2 (AGO2), a key component of the RNA-induced silencing complex, was a substrate of PTP1B in cardiomyocytes and in the heart. Our results revealed that phosphorylation at Tyr393 and inactivation of AGO2 in PTP1B cKO mice prevented miR-208b-mediated repression of thyroid hormone receptor-associated protein 1 (THRAP1; also known as MED13) and contributed to thyroid hormone-mediated cardiac hypertrophy. In support of this conclusion, inhibiting the synthesis of triiodothyronine (T3) with propylthiouracil rescued pressure overload-induced hypertrophy and improved myocardial contractility and systolic function in PTP1B cKO mice. Together, our data illustrate that PTP1B activity is cardioprotective and that redox signaling is linked to thyroid hormone responsiveness and microRNA-mediated gene silencing in pathological hypertrophy.


Assuntos
MicroRNAs , Proteína Tirosina Fosfatase não Receptora Tipo 1 , Animais , Cardiomegalia/metabolismo , Complexo Mediador , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 1/genética , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo
10.
Antibiotics (Basel) ; 11(1)2022 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-35052956

RESUMO

Thymoquinone (2-methyl-5-propan-2-ylcyclohexa-2,5-diene-1,4-dione; TQ), a principal bioactive phytoconstituent of Nigella sativa essential oil, has been reported to have high antimicrobial potential. Thus, the current study evaluated TQ's antimicrobial potential against a range of selected human pathogens using in vitro assays, including time-kill kinetics and anti-biofilm activity. In silico molecular docking of TQ against several antimicrobial target proteins and a detailed intermolecular interaction analysis was performed, including binding energies and docking feasibility. Of the tested bacteria and fungi, S. epidermidis ATCC 12228 and Candida albicans ATCC 10231 were the most susceptible to TQ, with 50.3 ± 0.3 mm and 21.1 ± 0.1 mm zones of inhibition, respectively. Minimum inhibitory concentration (MIC) values of TQ are in the range of 12.5-50 µg/mL, while minimum biocidal concentration (MBC) values are in the range of 25-100 µg/mL against the tested organisms. Time-kill kinetics of TQ revealed that the killing time for the tested bacteria is in the range of 1-6 h with the MBC of TQ. Anti-biofilm activity results demonstrate that the minimum biofilm inhibitory concentration (MBIC) values of TQ are in the range of 25-50 µg/mL, while the minimum biofilm eradication concentration (MBEC) values are in the range of 25-100 µg/mL, for the tested bacteria. In silico molecular docking studies revealed four preferred antibacterial and antifungal target proteins for TQ: D-alanyl-D-alanine synthetase (Ddl) from Thermus thermophilus, transcriptional regulator qacR from Staphylococcus aureus, N-myristoyltransferase from Candida albicans, and NADPH-dependent D-xylose reductase from Candida tenuis. In contrast, the nitroreductase family protein from Bacillus cereus and spore coat polysaccharide biosynthesis protein from Bacillus subtilis and UDP-N-acetylglucosamine pyrophosphorylase from Aspergillus fumigatus are the least preferred antibacterial and antifungal target proteins for TQ, respectively. Molecular dynamics (MD) simulations revealed that TQ could bind to all four target proteins, with Ddl and NADPH-dependent D-xylose reductase being the most efficient. Our findings corroborate TQ's high antimicrobial potential, suggesting it may be a promising drug candidate for multi-drug resistant (MDR) pathogens, notably Gram-positive bacteria and Candida albicans.

11.
J Exp Psychol Hum Percept Perform ; 48(3): 232-245, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35084931

RESUMO

For vision and audition to accurately inform judgments about an object's location, the brain must reconcile the variable anatomical correspondence of the eyes and ears, and the different frames of reference in which stimuli are initially encoded. To do so, it has been suggested that multisensory cues are eventually represented within a common frame of reference. If this is the case, then they should be similarly susceptible to distortion of this reference frame. Following this reasoning, we asked participants to locate visual and auditory probes in a crossmodal variant of the induced Roelofs effect, a visual illusion in which a large, off-center visual frame biases the observer's perceived straight-ahead. Auditory probes were mislocalized in the same direction and with a similar magnitude as visual probes due to the off-center visual frame. However, an off-center auditory frame did not elicit a significant mislocalization of visual probes, indicating that auditory context does not elicit an induced Roelofs effect. These results suggest that the locations of auditory and visual stimuli are represented within a common frame of reference, but that the brain does not rely on stationary auditory context, as it does visual, to maintain this reference frame. (PsycInfo Database Record (c) 2022 APA, all rights reserved).


Assuntos
Ilusões , Estimulação Acústica , Percepção Auditiva , Sinais (Psicologia) , Humanos , Estimulação Luminosa/métodos , Percepção Espacial , Percepção Visual
12.
Int J Pharm ; 613: 121414, 2022 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-34952149

RESUMO

Drug-eluting contact lens can substitute the multiple eye drop therapy. However, loading hydrophobic drug like cyclosporine in the contact lens is very challenging, due to low drug uptake (via soaking method); and alteration in the swelling and optical properties which restricts its clinical application. To address the above issues, graphene oxide (GO, large surface area with oxygen containing functional groups) was incorporated in the contact lenses during fabrication. These GO-laden contact lenses (SM-GO-Cys) as well as blank contact lenses (SM-Cys) were soaked in the solution of cyclosporine. Alternatively, cyclosporine-laden contact lenses (DL-Cys-20) and cyclosporine-GO-laden contact lenses (DL-Cys-20-GO) were fabricated by adding drug and drug-GO (at various level of GO) during fabrication, respectively. Contact angle and swelling data showed increase in water holding capacity of GO laden contact lenses. Optical property was significantly improved due to molecular dispersion of drug on the surface of GO sheets. The drug uptake and in vitro release profile was improved with GO-laden contact lenses by soaking method (SM-GO-Cys-400n) due to hydrophobic interactions between GO and drug. Adding cyclosporine-GO (DL-Cys-20-GO-800n) during fabrication significantly improved drug release kinetics with higher drug leaching (during extraction and sterilization) due to increased swelling, improved dissolution and molecular dispersion of drug on GO sheets. Ocular irritation and histopathological studies demonstrated the safety of GO-contact lens. The in vivo drug release studies in the rabbit eye showed significant improvement in mean residence time (MRT) and area under the curve (AUC) using DL-Cys-20-GO-800n contact lens compared to eye drop solution with reduction in protein adherence value. The study demonstrated that the incorporation of GO into the contact lens can control the release of cyclosporine as well as improved the lens swelling and transmittance properties.


Assuntos
Lentes de Contato , Grafite , Animais , Ciclosporina , Hidrogéis , Coelhos
13.
Antibiotics (Basel) ; 10(8)2021 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-34438937

RESUMO

Leishmaniasis, a Neglected Tropical Parasitic Disease (NTPD), is induced by several Leishmania species and is disseminated through sandfly (Lutzomyia longipalpis) bites. The parasite has developed resistance to currently prescribed antileishmanial drugs, and it has become pertinent to the search for new antileishmanial agents. The current study aimed to investigate the in vitro and in silico antileishmanial activity of two newly sourced actinomycins, X2 and D, produced by the novel Streptomyces smyrnaeus strain UKAQ_23. The antileishmanial activity conducted on promastigotes and amastigotes of Leishmania major showed actinomycin X2 having half-maximal effective concentrations (EC50), at 2.10 ± 0.10 µg/mL and 0.10 ± 0.0 µg/mL, and selectivity index (SI) values of 0.048 and 1, respectively, while the actinomycin D exhibited EC50 at 1.90 ± 0.10 µg/mL and 0.10 ± 0.0 µg/mL, and SI values of 0.052 and 1. The molecular docking studies demonstrated squalene synthase as the most favorable antileishmanial target protein for both the actinomycins X2 and D, while the xanthine phosphoribosyltransferase was the least favorable target protein. The molecular dynamics simulations confirmed that both the actinomycins remained stable in the binding pocket during the simulations. Furthermore, the MMPBSA (Molecular Mechanics Poisson-Boltzmann Surface Area) binding energy calculations established that the actinomycin X2 is a better binder than the actinomycin D. In conclusion, both actinomycins X2 and D from Streptomyces smyrnaeus strain UKAQ_23 are promising antileishmanial drug candidates and have strong potential to be used for treating the currently drug-resistant leishmaniasis.

14.
Sci Rep ; 11(1): 14539, 2021 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-34267232

RESUMO

Streptomyces smyrnaeus UKAQ_23, isolated from the mangrove-sediment, collected from Jubail,Saudi Arabia, exhibited substantial antimicrobial activity against methicillin-resistant Staphylococcus aureus (MRSA), including non-MRSA Gram-positive test bacteria. The novel isolate, under laboratory-scale conditions, produced the highest yield (561.3 ± 0.3 mg/kg fermented agar) of antimicrobial compounds in modified ISP-4 agar at pH 6.5, temperature 35 °C, inoculum 5% v/w, agar 1.5% w/v, and an incubation period of 7 days. The two major compounds, K1 and K2, were isolated from fermented medium and identified as Actinomycin X2 and Actinomycin D, respectively, based on their structural analysis. The antimicrobial screening showed that Actinomycin X2 had the highest antimicrobial activity compared to Actinomycin D, and the actinomycins-mixture (X2:D, 1:1, w/w) against MRSA and non-MRSA Gram-positive test bacteria, at 5 µg/disc concentrations. The MIC of Actinomycin X2 ranged from 1.56-12.5 µg/ml for non-MRSA and 3.125-12.5 µg/ml for MRSA test bacteria. An in-silico molecular docking demonstrated isoleucyl tRNA synthetase as the most-favored antimicrobial protein target for both actinomycins, X2 and D, while the penicillin-binding protein-1a, was the least-favorable target-protein. In conclusion, Streptomyces smyrnaeus UKAQ_23 emerged as a promising source of Actinomycin X2 with the potential to be scaled up for industrial production, which could benefit the pharmaceutical industry.


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Dactinomicina/farmacologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Streptomyces/metabolismo , Antibacterianos/isolamento & purificação , Antibacterianos/metabolismo , Simulação por Computador , Meios de Cultura/química , Dactinomicina/isolamento & purificação , Dactinomicina/metabolismo , Avaliação Pré-Clínica de Medicamentos/métodos , Fermentação , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Simulação de Acoplamento Molecular , Estrutura Molecular , Filogenia , Streptomyces/genética
15.
Oral Oncol ; 117: 105199, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33568326

RESUMO

BACKGROUND: Paraganglioma is a rare type of neuroendocrine tumor with the ability to secrete neuropeptide and catecholamines in excess. Sympathetic hyperactivity, severe persistent headache and hypertension is the most common clinical presentation of paraganglioma similar to pheocromocytoma. Case report We reported a case of 19 year old girl with severe headache and hypertension, from past 6 month. On further imaging evaluation for the headache, the computed tomography of the abdomen plus pelvis was suggestive of left pre para aortic paraganglioma measuring of 3.4 cm in diameter. Surgical excision of mass was done. Histopathological examination of surgical specimen was consistent with the diagnosis of paraganglioma. Patient is on regular follow up without any subjective or objective evidence of the disease. CONCLUSION: Retroperitoneal paraganglioma may be one of the causes for commonly occurring symptomatic headache, which is benign in nature, but possibility of transformation of malignant paraganglioma can occur. The surgical excision of mass is the treatment of choice.


Assuntos
Cefaleia , Hipertensão , Paraganglioma , Neoplasias Retroperitoneais , Adulto , Feminino , Cefaleia/etiologia , Humanos , Hipertensão/etiologia , Paraganglioma/complicações , Paraganglioma/diagnóstico por imagem , Paraganglioma/cirurgia , Neoplasias Retroperitoneais/complicações , Neoplasias Retroperitoneais/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Adulto Jovem
16.
NPJ Syst Biol Appl ; 7(1): 2, 2021 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-33420045

RESUMO

Metabolic reprogramming and its molecular underpinnings are critical to unravel the duality of cancer cell function and chemo-resistance. Here, we use a constraints-based integrated approach to delineate the interplay between metabolism and epigenetics, hardwired in the genome, to shape temozolomide (TMZ) resistance. Differential metabolism was identified in response to TMZ at varying concentrations in both the resistant neurospheroidal (NSP) and the susceptible (U87MG) glioblastoma cell-lines. The genetic basis of this metabolic adaptation was characterized by whole exome sequencing that identified mutations in signaling pathway regulators of growth and energy metabolism. Remarkably, our integrated approach identified rewiring in glycolysis, TCA cycle, malate aspartate shunt, and oxidative phosphorylation pathways. The differential killing of TMZ resistant NSP by Rotenone at low concentrations with an IC50 value of 5 nM, three orders of magnitude lower than for U87MG that exhibited an IC50 value of 1.8 mM was thus identified using our integrated systems-based approach.


Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , Glioblastoma/genética , Temozolomida/farmacologia , Antineoplásicos Alquilantes/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/fisiologia , Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Técnicas Genéticas , Genética , Glioblastoma/tratamento farmacológico , Glioblastoma/metabolismo , Humanos , Metabolômica/métodos , Transdução de Sinais/efeitos dos fármacos , Biologia de Sistemas/métodos
17.
Int J Biol Macromol ; 171: 514-526, 2021 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-33428954

RESUMO

The Alginate-Neusilin US2 micro-composite (MC) beads were fabricated and optimized for oral delivery of hesperidin (HES). A 32 full factorial design encompassing independent variables (factors) such as the concentration of sodium alginate (X1), and Neusilin US2 (X2) and dependant variables (response) such as particle size (Y1), entrapment efficiency (Y2), and swelling degree (Y3). Nine batches were prepared by formulation design employing statistical software JMP 13.2.1. The multiple regression analysis (MLRA) was carried to explore the influence of factor over responses. Further, a prediction profiler was used to trace the optimum concentration of factors based on desirable responses. The optimized beads (OF) were characterized for their morphology and size by motic microscopy and scanning electron microscopy. In vitro release, kinetic studies were performed in simulated gastric and intestinal fluids. In vivo pharmacokinetic studies revealed better absorption of HES from optimized beads (OF) compared to HES suspension which could be due to the prevention of acidic degradation of HES in the stomach. The estimated shelf life of OF formulation was found to be 3.86 years suggested better stability after fabrication. In a nutshell, the developed micro-composite beads of HES could be a better alternative for promising oral sustained delivery of HES.


Assuntos
Alginatos/química , Compostos de Alumínio/química , Portadores de Fármacos/química , Suco Gástrico/metabolismo , Hesperidina/administração & dosagem , Compostos de Magnésio/química , Silicatos/química , Administração Oral , Alginatos/administração & dosagem , Alginatos/farmacocinética , Compostos de Alumínio/administração & dosagem , Compostos de Alumínio/farmacocinética , Animais , Líquidos Corporais/metabolismo , Técnicas de Química Analítica , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/farmacocinética , Composição de Medicamentos , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Hesperidina/farmacocinética , Intestinos , Cinética , Compostos de Magnésio/administração & dosagem , Compostos de Magnésio/farmacocinética , Masculino , Microscopia Eletrônica de Varredura , Microesferas , Tamanho da Partícula , Ratos Wistar , Silicatos/administração & dosagem , Silicatos/farmacocinética
18.
BJR Case Rep ; 6(4): 20200080, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-33299597

RESUMO

We are reporting a case of a 47-year-old male with primary synovial sarcoma of the right parotid gland with tumor thrombus extension in the right internal jugular vein and right atrium. The rarity of this occurrence as documented in the review of the literature provides for uncertainty about proper management. Our case represents a rare occurrence with the unique radiological finding that has implications for management.

19.
BMJ Open ; 10(10): e037012, 2020 10 23.
Artigo em Inglês | MEDLINE | ID: mdl-33099493

RESUMO

OBJECTIVES: To estimate population sodium and potassium intakes and explore knowledge, attitudes and behaviour (KAB) towards the use of salt in adults in the Sultanate of Oman. DESIGN: National cross-sectional population-based survey. SETTING: Proportional random samples, representative of Omani adults (18 years or older), were obtained from all governorates of the Sultanate of Oman. PARTICIPANTS: Five hundred and sixty-nine (193 men, 376 women; 18 years or older) were included in the analysis (response rate 57%). Mean age was 39.4 years (SD 13.1). Participants attended a screening including demographic, anthropometric and physical measurements. PRIMARY AND SECONDARY OUTCOME MEASURES: We assessed dietary sodium, potassium and creatinine by 24-hour urinary sodium (UNa), potassium (UK) and creatinine (UCr) excretions. We collected KAB by a questionnaire on an electronic tablet. RESULTS: Mean UNa was 144.3 (78.8) mmol/day, equivalent to 9.0 g of salt/day and potassium excretion 52.6 (32.6) mmol/day, equivalent to 2.36 g/day, after adjusting for non-urinary losses. Men ate significantly more sodium and potassium than women. Only 22% of the sample had a salt intake below the WHO recommended target of 5 g/day and less than 10% met WHO targets for potassium excretion (>90 mmol/day). While 89.1% of those interviewed knew that consuming too much salt could cause serious health problems and only 6.9% felt they were using too much added salt, one in two participants used always or often salt, salty seasonings or salty sauces in cooking or when preparing food at home. CONCLUSIONS: In the Sultanate of Oman, salt consumption is higher and potassium consumption lower than recommended by WHO, both in men and in women. The present data provide, for the first time, evidence to support a national programme of population salt reduction to prevent the increasing burden of cardiovascular disease in the area.


Assuntos
Sódio na Dieta , Sódio , Adulto , Estudos Transversais , Feminino , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Masculino , Omã , Potássio , Cloreto de Sódio na Dieta
20.
Bioorg Chem ; 103: 104129, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32745757

RESUMO

A set of new Schiff bases of N-aryl 3- and 4-substituted maleimides has been prepared via condensation of N-aryl 3- and 4- substituted maleimides with p-toluene sulfonyl hydrazide in acidic medium at room temperature. The structures of synthesized compounds were characterized by IR, 1H NMR, 13C NMR, MS spectral data, and further confirmed by single-crystal x-ray crystallography for 5c. The computational study was carried out using Gaussian 09 software by using the B3LYP/6-311+G(d,p) basis set. Single-crystal study results showed much closeness with computational study results. These novel compounds were screened for their antimicrobial activity against two pathogenic bacteria such as Escherichia coli (ATCC 8739) and Staphylococcus aureus (ATCC25923) and two pathogenic fungi such as Aspergillus niger (MCIM10231) and Candida albicans (MTCC6275). The investigation of antimicrobial screening data showed that the most of tested compounds are moderate to good microbial inhibitors.


Assuntos
Antibacterianos/farmacologia , Antifúngicos/farmacologia , Teoria da Densidade Funcional , Maleimidas/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Antifúngicos/síntese química , Antifúngicos/química , Aspergillus niger/efeitos dos fármacos , Candida albicans/efeitos dos fármacos , Relação Dose-Resposta a Droga , Escherichia coli/efeitos dos fármacos , Maleimidas/síntese química , Maleimidas/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Bases de Schiff/síntese química , Bases de Schiff/química , Bases de Schiff/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Relação Estrutura-Atividade
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