RESUMEN
Persulfides (RSSH) are biologically important reactive sulfur species that are endogenously produced, protect key cysteine residues from irreversible oxidation, and are important intermediates during different enzymatic processes. Although persulfides are stronger nucleophiles than their thiol counterparts, persulfides can also act as electrophiles in their neutral, protonated form in specific environments. Moreover, persulfides are electrophilic at both sulfur atoms, and the reaction with a thiolate can lead to either H2S release with disulfide formation or alternatively result in transpersulfidation. Despite the broad acceptance of these reaction pathways, the specific properties that control whether persulfides react through the H2S-releasing or transpersulfidation pathway remain elusive. Herein, we use a combined computational and experimental approach to directly investigate the reactivity between persulfides and thiols to answer these questions. Using density functional theory (DFT) calculations, we demonstrate that increasing steric bulk or electron withdrawal near the persulfide can shunt persulfide reactivity through the transpersulfidation pathway. Building from these insights, we use a synthetic persulfide donor and an N-iodoacetyl l-tyrosine methyl ester (TME-IAM) trapping agent to experimentally monitor and measure transpersulfidation from a bulky penicillamine-based persulfide to a cysteine-based thiol, which, to the best of our knowledge, is the first direct observation of transpersulfidation between low-molecular-weight species. Taken together, these combined approaches highlight how the properties of persulfides are directly impacted by local environments, which has significant impacts in understanding the complex chemical biology of these reactive species.
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Teoría Funcional de la Densidad , Sulfuro de Hidrógeno , Sulfuros , Sulfuros/química , Sulfuro de Hidrógeno/química , Compuestos de Sulfhidrilo/química , Cisteína/químicaRESUMEN
BACKGROUND: Glycosylation is an enzyme-catalyzed post-translational modification that is distinct from glycation and is present on a majority of plasma proteins. N-glycosylation occurs on asparagine residues predominantly within canonical N-glycosylation motifs (Asn-X-Ser/Thr) although non-canonical N-glycosylation motifs Asn-X-Cys/Val have also been reported. Albumin is the most abundant protein in plasma whose glycation is well-studied in diabetes mellitus. However, albumin has long been considered a non-glycosylated protein due to absence of canonical motifs. Albumin contains two non-canonical N-glycosylation motifs, of which one was recently reported to be glycosylated. METHODS: We enriched abundant serum proteins to investigate their N-linked glycosylation followed by trypsin digestion and glycopeptide enrichment by size-exclusion or mixed-mode anion-exchange chromatography. Glycosylation at canonical as well as non-canonical sites was evaluated by liquid chromatography-tandem mass spectrometry (LC-MS/MS) of enriched glycopeptides. Deglycosylation analysis was performed to confirm N-linked glycosylation at non-canonical sites. Albumin-derived glycopeptides were fragmented by MS3 to confirm attached glycans. Parallel reaction monitoring was carried out on twenty additional samples to validate these findings. Bovine and rabbit albumin-derived glycopeptides were similarly analyzed by LC-MS/MS. RESULTS: Human albumin is N-glycosylated at two non-canonical sites, Asn68 and Asn123. N-glycopeptides were detected at both sites bearing four complex sialylated glycans and validated by MS3-based fragmentation and deglycosylation studies. Targeted mass spectrometry confirmed glycosylation in twenty additional donor samples. Finally, the highly conserved Asn123 in bovine and rabbit serum albumin was also found to be glycosylated. CONCLUSIONS: Albumin is a glycoprotein with conserved N-linked glycosylation sites that could have potential clinical applications.
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Albúminas , Glicoproteínas , Glicosilación , Animales , Bovinos , Humanos , Albúminas/metabolismo , Secuencia de Aminoácidos , Cromatografía Liquida , Glicopéptidos/metabolismo , Glicopéptidos/química , Glicoproteínas/metabolismo , Glicoproteínas/química , Datos de Secuencia Molecular , Espectrometría de Masas en TándemRESUMEN
BACKGROUND: Chest wall tumors are a heterogeneous group of tumors that are managed by surgeons from diverse specialties. Due to their rarity, there is no consensus on their diagnosis and management. MATERIALS: This retrospective, descriptive analysis includes patients with malignant chest wall tumors undergoing chest wall resection. Tumors were classified as primary, secondary, and metastatic tumors. The analysis includes clinicopathological characteristics, resection-reconstruction profile, and relapse patterns. RESULTS: A total of 181 patients underwent chest wall resection between 1999 and 2020. In primary tumors (69%), the majority were soft tissue tumors (59%). In secondary tumors, the majority were from the breast (45%) and lung (42%). Twenty-five percent of patients received neoadjuvant chemotherapy, and 98% of patients underwent R0 resection. Soft tissue, skeletal + soft tissue, and extended resections were performed in 45%, 70%, and 28% of patients, respectively. The majority of patients (60%) underwent rib resections, and a median of 3.5 ribs were resected. The mean defect size was 24 cm2. Soft tissue reconstruction was performed in 40% of patients, mostly with latissimus dorsi flaps. Rigid reconstruction was performed in 57% of patients, and 18% underwent mesh-bone cement sandwich technique reconstruction. Adjuvant radiotherapy and chemotherapy were given to 29% and 39% of patients, respectively. CONCLUSIONS: This is one of the largest single-institutional experiences on malignant chest wall tumors. The results highlight varied tumor spectra and multimodality approaches for optimal functional and survival outcomes. In limited resource setting, surgery, including reconstructive expertise, is very crucial.
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Procedimientos de Cirugía Plástica , Neoplasias Torácicas , Pared Torácica , Humanos , Pared Torácica/patología , Pared Torácica/cirugía , Femenino , Estudios Retrospectivos , Masculino , Persona de Mediana Edad , Neoplasias Torácicas/patología , Neoplasias Torácicas/terapia , Neoplasias Torácicas/cirugía , Anciano , Adulto , Pronóstico , Estudios de Seguimiento , Neoplasias de los Tejidos Blandos/terapia , Neoplasias de los Tejidos Blandos/patología , Neoplasias de los Tejidos Blandos/cirugía , Adulto Joven , Tasa de Supervivencia , Anciano de 80 o más Años , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/cirugía , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/terapia , Recurrencia Local de Neoplasia/cirugía , Adolescente , Colgajos QuirúrgicosRESUMEN
KEY MESSAGE: Sr67 is a new stem rust resistance gene that represents a new resource for breeding stem rust resistant wheat cultivars Re-appearance of stem rust disease, caused by the fungal pathogen Puccinia graminis f. sp. tritici (Pgt), in different parts of Europe emphasized the need to develop wheat varieties with effective resistance to local Pgt populations and exotic threats. A Kyoto University wheat (Triticum aestivum L.) accession KU168-2 was reported to carry good resistance to leaf and stem rust. To identify the genomic region associated with the KU168-2 stem rust resistance, a genetic study was conducted using a doubled haploid (DH) population from the cross RL6071 × KU168-2. The DH population was phenotyped with three Pgt races (TTKSK, TPMKC, and QTHSF) and genotyped using the Illumina 90 K wheat SNP array. Linkage mapping showed the resistance to all three Pgt races was conferred by a single stem rust resistance (Sr) gene on chromosome arm 6AL, associated with Sr13. Presently, four Sr13 resistance alleles have been reported. Sr13 allele-specific KASP and STARP markers, and sequencing markers all showed null alleles in KU168-2. KU168-2 showed a unique combination of seedling infection types for five Pgt races (TTKSK, QTHSF, RCRSF, TMRTF, and TPMKC) compared to Sr13 alleles. The phenotypic uniqueness of the stem rust resistance gene in KU168-2 and null alleles for Sr13 allele-specific markers showed the resistance was conferred by a new gene, designated Sr67. Since Sr13 is less effective in hexaploid background, Sr67 will be a good source of stem rust resistance in bread wheat breeding programs.
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Basidiomycota , Puccinia , Triticum , Humanos , Fitomejoramiento , AlelosRESUMEN
Distal arthrogryposis type 5D (DA5D) is clinically characterized by knee extension contractures, distal joint contractures, clubfoot, micrognathia, ptosis, and scoliosis. We report nine affected individuals from eight unrelated Indian families with DA5D. Although the overall musculoskeletal phenotype is not very distinct from other distal arthrogryposis, the presence of fixed knee extension contractures with or without scoliosis could be an important early pointer to DA5D. We also report a possible founder variant in ECEL1 along with four novel variants and further expand the genotypic spectrum of DA5D.
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Artrogriposis , Efecto Fundador , Fenotipo , Humanos , Artrogriposis/genética , Artrogriposis/patología , Masculino , Femenino , India , Niño , Preescolar , Linaje , Adolescente , Mutación/genética , Lactante , Estudios de Asociación Genética , Estudios de Cohortes , Genotipo , Adulto , MetaloendopeptidasasRESUMEN
The Gewald reaction is a well-established one-pot method to access 2-aminothiophenes from carbonyl compounds, activated acetonitriles, and elemental sulfur. To elucidate the reaction's poorly understood mechanism, with regard to the decomposition of sulfur and polysulfide intermediates, we have performed a comprehensive computational study using density functional theory (DFT) calculations at the M06-2X (or ωB97X-D)/aug-cc-pV(T + d)Z/SMD(C2H5OH) level of theory. The results show that the reaction is initiated by a Knoevenagel-Cope condensation, followed by opening of the elemental sulfur, leading to polysulfide formation. The polysulfide intermediates can interconvert and decompose using various mechanisms including unimolecular cyclization, nucleophilic degradation, and scrambling. Protonation of the polysulfides changes their electrophilic behavior and provides a kinetically favorable pathway for their decomposition. This protonation-induced intermolecular degradation is feasible for polysulfides of all lengths, but unimolecular decomposition is kinetically favored for long polysulfides (≥6 sulfur atoms). None of the pathways provide any thermodynamic benefit due to the lack of resonance-stabilized leaving group, and a complex equilibrium of polysulfides of all lengths is expected in solution. Cyclization of the monosulfide with aromatization to the thiophene product is the only driving force behind the reaction, funneling all of the various intermediates into the observed product in a thermodynamically controlled process.
RESUMEN
The crystal structure of the metal-organic framework (MOF), {Mn2(1,4-bdc)2(DMF)2}n (1) (1,4-bdcH2, 1,4-benzenedicarboxylic acid; DMF, N,N-dimethylformamide), is known for a long time; however, its desolvated structure, {Mn2(1,4-bdc)2}n (1'), is not yet known. The first-principles-based computational simulation was used to unveil the structure of 1' that shows the expansion in the framework, leading to pore opening after the removal of coordinated DMF molecules. We have used 1' that contains open metal sites (OMSs) in the structure in cyanosilylation and CO2 cycloaddition reactions and recorded complete conversions in a solventless setup. The pore opening in 1' allows the facile diffusion of small aldehyde molecules into the channels, leading to complete conversion. The reactions with larger aldehydes, 2-naphthaldehyde and 9-anthracenecarboxaldehyde, also show 99.9% conversions, which are the highest reported until date in solventless conditions. The in silico simulations illustrate that larger aldehydes interact with Mn(II) OMSs on the surfaces, enabling a closer interaction and facilitating complete conversions. The catalyst shows high recyclability, exhibiting 99.9% conversions in the successive reaction cycles with negligible change in the structure. Our investigations illustrate that the catalyst 1' is economical, efficient, and robust and allows reactions in a solventless greener setup, and therefore the catalysis with 1' can be regarded as "green catalysis".
RESUMEN
BACKGROUND: Ten-eleven translocases (TETs) are enzymes responsible for demethylation processes, playing a crucial role in maintaining the body's methylation balance. Dysregulation of TET expression can lead to abnormal methylation levels. Isocitrate dehydrogenases (IDH) are upstream genes involved in Kreb cycle responsible for production of α-ketoglutarate (α-KG). α-KG and vitamin C are cofactors of TET3 enzyme. There is limited data on the relationship between TET3 and its cofactor Vitamin C in head and neck carcinoma (H&NC). METHODS AND RESULTS: In this study, we have investigated the expression of the TET3 gene along with IDH1/2 genes involved in the Krebs cycle in the peripheral blood of 32 H&NC patients compared to 32 healthy controls. We estimated serum levels of TET3 protein and vitamin C and 5-hydroxymethylcytosine (5-hmC) percentage in DNA isolated from EDTA blood samples. Our findings revealed that TET3 and IDH1/2 were downregulated in H&NC patients compared to healthy controls. Serum levels of TET3 and Vitamin C were low in H&NC patients compared to healthy controls. Diminished levels of percentage 5-hmC were detected in EDTA blood samples of H&NC patients compared to controls. Spearman correlation analysis revealed a significant positive correlation between TET3 levels, vitamin C levels and 5-hmC percentage. CONCLUSION: The low levels of Vitamin C are believed to contribute to decreased activity of the TET3 gene and less conversion of 5-methylcytosine (5-mC) to 5-hmC. Dietary supplementation of Vitamin C may increase TET3 activity.
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5-Metilcitosina , Ácido Ascórbico , Metilación de ADN , Dioxigenasas , Epigénesis Genética , Neoplasias de Cabeza y Cuello , Isocitrato Deshidrogenasa , Humanos , 5-Metilcitosina/análogos & derivados , 5-Metilcitosina/metabolismo , Dioxigenasas/genética , Dioxigenasas/metabolismo , Masculino , Epigénesis Genética/genética , Femenino , Isocitrato Deshidrogenasa/genética , Isocitrato Deshidrogenasa/metabolismo , Persona de Mediana Edad , Neoplasias de Cabeza y Cuello/genética , Neoplasias de Cabeza y Cuello/sangre , Metilación de ADN/genética , Ácido Ascórbico/metabolismo , Ácido Ascórbico/sangre , Adulto , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/metabolismo , Regulación Neoplásica de la Expresión Génica , Regulación hacia Abajo/genética , Anciano , Estudios de Casos y ControlesRESUMEN
Gaucher disease type 3 is a chronic neuronopathic disorder with wide-ranging effects, including hepatosplenomegaly, anaemia, thrombocytopenia, skeletal disease and diverse neurological manifestations. Biallelic mutations in GBA1 reduce lysosomal acid ß-glucosidase activity, and its substrates, glucosylceramide and glucosylsphingosine, accumulate. Enzyme replacement therapy and substrate reduction therapy ameliorate systemic features of Gaucher disease, but no therapies are approved for neurological manifestations. Venglustat is an investigational, brain-penetrant, glucosylceramide synthase inhibitor with potential to improve the disease by rebalancing influx of glucosylceramide with impaired lysosomal recycling. The Phase 2, open-label LEAP trial (NCT02843035) evaluated orally administered venglustat 15 mg once-daily in combination with maintenance dose of imiglucerase enzyme replacement therapy during 1 year of treatment in 11 adults with Gaucher disease type 3. Primary endpoints were venglustat safety and tolerability and change in concentration of glucosylceramide and glucosylsphingosine in CSF from baseline to Weeks 26 and 52. Secondary endpoints included change in plasma concentrations of glucosylceramide and glucosylsphingosine, venglustat pharmacokinetics in plasma and CSF, neurologic function, infiltrative lung disease and systemic disease parameters. Exploratory endpoints included changes in brain volume assessed with volumetric MRI using tensor-based morphometry, and resting functional MRI analysis of regional brain activity and connectivity between resting state networks. Mean (SD) plasma venglustat AUC0-24 on Day 1 was 851 (282) ngâ¢h/ml; Cmax of 58.1 (26.4) ng/ml was achieved at a median tmax 2.00 h. After once-daily venglustat, plasma concentrations (4 h post-dose) were higher compared with Day 1, indicating â¼2-fold accumulation. One participant (Patient 9) had low-to-undetectable venglustat exposure at Weeks 26 and 52. Based on mean plasma and CSF venglustat concentrations (excluding Patient 9), steady state appeared to be reached on or before Week 4. Mean (SD) venglustat concentration at Week 52 was 114 (65.8) ng/ml in plasma and 6.14 (3.44) ng/ml in CSF. After 1 year of treatment, median (inter-quartile range) glucosylceramide decreased 78% (72, 84) in plasma and 81% (77, 83) in CSF; median (inter-quartile range) glucosylsphingosine decreased 56% (41, 60) in plasma and 70% (46, 76) in CSF. Ataxia improved slightly in nine patients: mean (SD, range) total modified Scale for Assessment and Rating of Ataxia score decreased from 2.68 [1.54 (0.0 to 5.5)] at baseline to 1.55 [1.88 (0.0 to 5.0)] at Week 52 [mean change: -1.14 (95% CI: -2.06 to -0.21)]. Whole brain volume increased slightly in patients with venglustat exposure and biomarker reduction in CSF (306.7 ± 4253.3 mm3) and declined markedly in Patient 9 (-13894.8 mm3). Functional MRI indicated stronger connectivity at Weeks 26 and 52 relative to baseline between a broadly distributed set of brain regions in patients with venglustat exposure and biomarker reduction but not Patient 9, although neurocognition, assessed by Vineland II, deteriorated in all domains over time, which illustrates disease progression despite the intervention. There were no deaths, serious adverse events or discontinuations. In adults with Gaucher disease type 3 receiving imiglucerase, addition of once-daily venglustat showed acceptable safety and tolerability and preliminary evidence of clinical stability with intriguing but intrinsically inconsistent signals in selected biomarkers, which need to be validated and confirmed in future research.
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Enfermedad de Gaucher , Enfermedades del Sistema Nervioso , Humanos , Adulto , Glucosilceramidasa/uso terapéutico , Glucosilceramidasa/genética , Enfermedad de Gaucher/tratamiento farmacológico , Enfermedad de Gaucher/genética , Glucosilceramidas/uso terapéutico , Enfermedad Crónica , Biomarcadores , Enfermedades del Sistema Nervioso/tratamiento farmacológico , AtaxiaRESUMEN
Four novel antimony (III) and bismuth(III) complexes of the kind Cl-Sb-O-C(OR)-CH(CH3 )C-NH-(CH2 )2 -NH-C(CH3 )CH:C(OR)-O [where R = -CH3 , M = Sb (1a); R = -C2 H5 , M = Sb (1b); R = -CH3, M = Bi (1c); R = -C2 H5 , M = Bi (1d)] were successfully prepared by reacting antimony(III)chloride and bismuth(III)chloride with sodium salt of ß-enamino esters in 1:1 stoichiometry, which were further structurally characterized by physicochemical and IR, 1 H, 13 C NMR spectral and mass spectrometry. Structural analysis revealed that all four derivatives of both antimony and bismuth display octahedarl geometry which has been optimized through computational studies. These derivatives along with their parent ligands were subsequently assayed in vitro for antibacterial (Bacillus subtilis, Pseudomonas aeruginosa) and antifungal (Aspergillus niger and Candida albicans) activities. Synthesized complexes were more efficacious in terms of biological activities as compared to parent ligands Further synthesized compounds were evaluated for their in vitro cytotoxic activity against lung cancer cell line A549 using MTT method. IC50 value for all four complexes was determined and all of them are found active. Computational studies of the representative complexes have been done using B3LYP/631-G* basis sets to provide optimized geometry.
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Antiinfecciosos , Antineoplásicos , Antimonio/farmacología , Bismuto/farmacología , Bismuto/química , Teoría Funcional de la Densidad , Cloruros , Antiinfecciosos/farmacología , Antiinfecciosos/química , Pruebas de Sensibilidad MicrobianaRESUMEN
We present updated, evidence-based clinical practice guidelines from the Indian Society of Pediatric Nephrology (ISPN) for the management of urinary tract infection (UTI) and primary vesicoureteric reflux (VUR) in children. These guidelines conform to international standards; Institute of Medicine and AGREE checklists were used to ensure transparency, rigor, and thoroughness in the guideline development. In view of the robust methodology, these guidelines are applicable globally for the management of UTI and VUR. Seventeen recommendations and 18 clinical practice points have been formulated. Some of the key recommendations and practice points are as follows. Urine culture with > 104 colony forming units/mL is considered significant for the diagnosis of UTI in an infant if the clinical suspicion is strong. Urine leukocyte esterase and nitrite can be used as an alternative screening test to urine microscopy in a child with suspected UTI. Acute pyelonephritis can be treated with oral antibiotics in a non-toxic infant for 7-10 days. An acute-phase DMSA scan is not recommended in the evaluation of UTI. Micturating cystourethrography (MCU) is indicated in children with recurrent UTI, abnormal kidney ultrasound, and in patients below 2 years of age with non-E. coli UTI. Dimercaptosuccinic acid scan (DMSA scan) is indicated only in children with recurrent UTI and high-grade (3-5) VUR. Antibiotic prophylaxis is not indicated in children with a normal urinary tract after UTI. Prophylaxis is recommended to prevent UTI in children with bladder bowel dysfunction (BBD) and those with high-grade VUR. In children with VUR, prophylaxis should be stopped if the child is toilet trained, free of BBD, and has not had a UTI in the last 1 year. Surgical intervention in high-grade VUR can be considered for parental preference over antibiotic prophylaxis or in children developing recurrent breakthrough febrile UTIs on antibiotic prophylaxis.
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Infecciones Urinarias , Reflujo Vesicoureteral , Niño , Humanos , Lactante , Microscopía , Succímero , Urinálisis , Infecciones Urinarias/diagnóstico , Infecciones Urinarias/tratamiento farmacológico , Infecciones Urinarias/etiología , Reflujo Vesicoureteral/complicaciones , Reflujo Vesicoureteral/diagnóstico , Reflujo Vesicoureteral/terapiaRESUMEN
BACKGROUND: Eighty-five percent of infants with congenital nephrotic syndrome (CNS) and 66% with infantile NS (INS) are likely to have a monogenic etiology. There exists a significant genetic variability between different regions and ethnic groups. This study aimed to determine the genetic defects in children with CNS and INS by establishing a registry in western India. METHODS: In this cross-sectional study, pediatric nephrologists from 13 private and government institutions shared relevant clinical data and details of the genetic evaluation of children presenting with NS within the first year of life. RESULTS: The median age at presentation was 9 months (range 1-23, IQR 3-13 months), history of consanguinity between parents existed in 14 patients (34%), family history of similar illness in 6 (15%), and extra-renal manifestations in 17 (41%). Twenty-five (61%) were confirmed to have a monogenic etiology. NPHS1 gene was the most implicated (9/25) followed by PLCE1 (5/25). There were 12 variants of uncertain significance (VUS) involving 10 genes (10/25, 40%), and no definite genetic abnormality was found in 4 (25%). A re-analysis of these VUS attempted 2-3 years later facilitated reclassification of 7/12 (58%); increasing the diagnostic yield from 61 to 68.2%. CONCLUSIONS: Consistent with worldwide data, variants in NPHS1 gene were the most common cause of NS in infancy; however, PLCE1 was implicated more frequently in our cohort. NUP93 and COL4A3 were reported in early onset NS for the first time. Reclassification of VUS should be attempted, if feasible, since it may lead to a useful revision of diagnosis.
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Síndrome Nefrótico , Sistema de Registros , Humanos , Síndrome Nefrótico/genética , Síndrome Nefrótico/epidemiología , Síndrome Nefrótico/congénito , Síndrome Nefrótico/diagnóstico , India/epidemiología , Sistema de Registros/estadística & datos numéricos , Masculino , Femenino , Lactante , Estudios Transversales , Pruebas Genéticas/métodos , Proteínas de la Membrana/genética , Edad de Inicio , Predisposición Genética a la EnfermedadRESUMEN
OBJECTIVE: The objective of this study is to investigate the effect of a reduction in the prescribed post-operative ibuprofen dosage on frequency of post-tonsillectomy bleeding. METHODS: A quality improvement study was conducted at a single tertiary care pediatric hospital with patients weighing >40 kg undergoing tonsillectomy. The intervention was limiting the post-operative ibuprofen dosage to a maximum of 400 mg per dose. Data was collected on all patients returning to the hospital with bleeding after tonsillectomy. The primary outcome was the rate of post-tonsillectomy bleeding. Statistical analysis was conducted using nonparametric comparisons and a run chart. RESULTS: A total of 199 tonsillectomy patients >40 kg were included in the study. There were 119 (59.8 %) females and 80 (40.2 %) males total. The pre-intervention group had a total of 56 patients while the post-intervention group had a total of 143 patients. There was no statistical difference in age, weight, or sex between the pre- and post-intervention groups (p > .05). The post-tonsillectomy hemorrhage rate was 11/56 (19.6 %) before the intervention, and 11/143 (7.7 %) after the intervention (p = .016). Children who experienced a bleeding event were significantly older (mean 15.9 years, 95 % CI 14.5-17.3) than those who did not (13.5 years, 95 % CI 12.9-14.1; p = .011). The run chart revealed that the intervention resulted in a nonrandom decrease in rate of post-tonsillectomy bleeding. CONCLUSIONS: Post-tonsillectomy bleeding rate decreased with a ceiling post-operative ibuprofen dose of 400 mg/dose in this quality improvement study. Further research is warranted.
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Ibuprofeno , Tonsilectomía , Masculino , Femenino , Niño , Humanos , Tonsilectomía/efectos adversos , Tonsilectomía/métodos , Mejoramiento de la Calidad , Hemorragia Posoperatoria/epidemiología , Hemorragia Posoperatoria/etiología , Hemorragia Posoperatoria/prevención & control , Hospitales , Dolor Postoperatorio , Estudios RetrospectivosRESUMEN
The present study evaluates and compares the performance of different rainfall products, namely, Climate Hazards Group InfraRed Precipitation with Station (CHIRPS), India Meteorological Department (IMD) gridded, Prediction of Worldwide Energy Resource (POWER), and Precipitation Estimation from Remotely Sensed Information using Artificial Neural Network-Climate Data Record (PERSIANN-CDR) with gauge-based measurements over Narmada River basin, India. The ground-based daily rainfall data (1981-2020) of 11 gauging stations have been collected from the Water Resources Department, Madhya Pradesh and the evaluation of rainfall product has been accomplished on a point-to-grid basis (nearest neighbor method) at annual and seasonal scales with the help of continuous and categorical statistical metrics. The results reveal a strong positive correlation (> 0.75) between rainfall estimates of different products and gauge-based measurements at annual scale demonstrating higher similarity in rainfall estimates and observed data, whereas seasonal estimates have exhibited comparatively weaker relationship. Likewise, percent bias (PBIAS) demonstrates least bias in annual and monsoon rainfall estimates and high in other seasons. These findings reveal that rainfall estimates tend to improve with increasing time scale (season to annual). However, majority of the rainfall products have overestimated the low rainfall (western region) and underestimated the high rainfall (eastern and southeastern regions). Further, the values of critical success index (CSI) indicate IMD gridded product outperforms in detecting rainfall events accurately followed by POWER, PERSIANN-CDR, and CHIRPS. These results suggest that IMD gridded estimates provide the best alternate to ground-based rain measurements. However, rainfall estimates from POWER, PERSIANN-CDR and CHIRPS can also be used in various hydrometeorological investigations over Narmada River basin.
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Monitoreo del Ambiente , Ríos , Benchmarking , Clima , IndiaRESUMEN
Among legumes, lentil serves as an imperative source of dietary proteins and are considered an important pillar of global food and nutritional security. The crop is majorly cultivated in arid and semi-arid regions and exposed to different abiotic stresses. Drought stress is a polygenic stress that poses a major threat to the crop productivity of lentils. It negatively influenced the seed emergence, water relations traits, photosynthetic machinery, metabolites, seed development, quality, and yield in lentil. Plants develop several complex physiological and molecular protective mechanisms for tolerance against drought stress. These complicated networks are enabled to enhance the cellular potential to survive under extreme water-scarce conditions. As a result, proper drought stress-mitigating novel and modern approaches are required to improve lentil productivity. The currently existing biotechnological techniques such as transcriptomics, genomics, proteomics, metabolomics, CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/cas9), and detection of QTLs (quantitative trait loci), proteins, and genes responsible for drought tolerance have gained appreciation among plant breeders for developing climate-resilient lentil varieties. In this review, we critically elaborate the impact of drought on lentil, mechanisms employed by plants to tolerate drought, and the contribution of omics approaches in lentils for dealing with drought, providing deep insights to enhance lentil productivity and improve resistance against abiotic stresses. We hope this updated review will directly help the lentil breeders to develop resistance against drought stress.
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Background and Aims: The present study was conducted to determine the optimal dose of cisatracurium for intubating conditions and onset and offset of neuromuscular blockade. Data in Indian population are scarce, and hence, the present study was planned to evaluate different doses of cisatracurium. Material and Methods: The prospective randomized double-blind study was conducted on 180 patients of either sex in the age group of 20-60 yrs., having physical status class I to III, scheduled for surgery under general anesthesia. After exclusion 154 patients were randomly divided into three groups comprising 52, 51, and 51, respectively, in Group A, Group B, and group C. They received 0.1 mgkg-1, 0.2 mgkg-1, and 0.3 mgkg-1 of cisatracurium, respectively, to facilitate endotracheal intubation. Time of onset, intubating conditions, hemodynamic parameters, signs of histamine release, and recovery time were noted. Results: Mean time to onset was maximum in group A (4.37 ± 0.48 minutes) and minimum in group C (2.33 ± 0.43 minutes). Intubating conditions were found excellent in 88% patients in group. Change in HR was found to be non-significant at all time periods, but decrease in MAP was found between 2 and 10 minutes in group C. Duration of action was longest in group C. Conclusion: We conclude that cisatracurium in dose of 0.2 mgkg-1 and 0.3 mgkg-1 provides good-to-excellent intubating conditions within less than 3 minutes.
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Venglustat inhibits the enzymatic conversion of ceramide to glucosylceramide, reducing available substrate for the synthesis of more complex glycosphingolipids. It offers a potential new approach to the treatment of patients with Fabry disease (α-Gal A deficiency), in whom progressive accumulation of such glycosphingolipids, including globotriaosylceramide (GL-3), in the lysosomes of a wide range of cell types often leads to vital organ complications in adulthood. An international, open-label, single-arm, Phase 2a uncontrolled 26-week clinical study (NCT02228460) and a 130-week extension study (NCT02489344) were conducted to assess the safety, pharmacodynamics, pharmacokinetics, and exploratory efficacy of 15 mg once daily oral venglustat in treatment-naïve adult male patients with classic Fabry disease. Of 11 patients (18-37 years old) who initially enrolled, nine completed the 26-week study and seven completed the extension study. A total of 169 treatment-emergent adverse events (TEAEs) were reported by nine patients, the majority being mild (73%) and unrelated to the study drug (70%). Nine serious TEAEs (serious adverse events) and 11 severe TEAEs, including a self-harm event, were reported. No deaths or treatment-related life-threatening adverse events were reported. Skin GL-3 scores in superficial skin capillary endothelium (SSCE), estimated by light microscopy, were unchanged from baseline at Week 26 in five patients, decreased in three patients, and increased in one patient. There was no significant change in GL-3 scores or significant shift in grouped GL-3 scores. Five of six patients had reductions from baseline in GL-3 score at the end of the extension study. At Weeks 26 and 156 the mean (standard deviation) changes from baseline in the fraction of the volume of SSCE cytoplasm occupied by GL-3 inclusions, measured by electron microscopy unbiased stereology, were - 0.06 (0.03) (p = 0.0010) and - 0.12 (0.04) (p = 0.0008), respectively. Venglustat treatment reduced markers in the synthetic and degradative pathway of major glycosphingolipids; proximal markers reduced rapidly and more distal markers (plasma GL-3 and globotriaosylsphingosine) reduced progressively. There were no biochemical or histological indications of progression of Fabry disease over 3 years of follow-up. These findings confirm target engagement and the pharmacodynamic effects of venglustat in adult males with classic Fabry disease. However, further clinical evaluation in larger studies is needed to determine efficacy and safety.
Asunto(s)
Enfermedad de Fabry , Humanos , Masculino , Adulto , Adolescente , Adulto Joven , Enfermedad de Fabry/patología , alfa-Galactosidasa/uso terapéutico , GlucosiltransferasasRESUMEN
Raised dermal scars including hypertrophic, and keloid scars as well as scalp-associated fibrosing Folliculitis Keloidalis Nuchae (FKN) are a group of fibrotic raised dermal lesions that mostly occur following cutaneous injury. They are characterized by increased extracellular matrix (ECM) deposition, primarily excessive collagen type 1 production by hyperproliferative fibroblasts. The extent of ECM deposition is thought to be proportional to the severity of local skin inflammation leading to excessive fibrosis of the dermis. Due to a lack of suitable study models, therapy for raised dermal scars remains ill-defined. Immune cells and their associated markers have been strongly associated with dermal fibrosis. Therefore, modulation of the immune system and use of anti-inflammatory cytokines are of potential interest in the management of dermal fibrosis. In this review, we will discuss the importance of immune factors in the pathogenesis of raised dermal scarring. The aim here is to provide an up-to-date comprehensive review of the literature, from PubMed, Scopus, and other relevant search engines in order to describe the known immunological factors associated with raised dermal scarring. The importance of immune cells including mast cells, macrophages, lymphocytes, and relevant molecules such as cytokines, chemokines, and growth factors, antibodies, transcription factors, and other immune-associated molecules as well as tissue lymphoid aggregates identified within raised dermal scars will be presented. A growing body of evidence points to a shift from proinflammatory Th1 response to regulatory/anti-inflammatory Th2 response being associated with the development of fibrogenesis in raised dermal scarring. In summary, a better understanding of immune cells and associated molecular markers in dermal fibrosis will likely enable future development of potential immune-modulated therapeutic, diagnostic, and theranostic targets in raised dermal scarring.
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Cicatriz Hipertrófica , Queloide , Humanos , Cicatriz Hipertrófica/metabolismo , Queloide/metabolismo , Matriz Extracelular/metabolismo , Fibroblastos/metabolismo , Fibrosis , CitocinasRESUMEN
The reactions of elemental sulfur (S8 ) and polysulfides with nucleophiles are relevant to organic synthesis, materials science and biochemistry, but the mechanisms by which they operate are still unknown due to the inherent thermodynamic and kinetic instability of polysulfide intermediates. Using Density Functional Theory (DFT) calculations at the ωB97X-D/aug-cc-pV(T+d)Z/SMD(MeCN) // ωB97X-D/aug-cc-pVDZ/SMD(MeCN) level of theory, we studied the mechanisms behind the reaction of elemental sulfur and polysulfides with cyanide and phosphines, which quantitatively generate the monosulfide products thiocyanate and phosphine sulfides, respectively. All plausible pathways including nucleophilic decomposition, unimolecular decomposition, scrambling reactions, and attack on thiosulfoxides, have been considered to provide the first comprehensive mechanistic picture for this class of reactions. Overall, intramolecular cyclization is identified as the most favorable decomposition pathway for long polysulfides. For short polysulfides, a mixture of unimolecular decomposition, nucleophilic attack, and scrambling pathways can be expected.
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Cianuros , Fosfinas , Fosfinas/química , Sulfuros/química , AzufreRESUMEN
BACKGROUND: Thrombotic microangiopathy (TMA) is usually caused due to dysregulation of the alternative complement pathway. Rarely, thrombotic microangiopathy is caused by non-complement mediated mutations in diacylglycerol kinase epsilon (DGKE); information about therapy and outcome of these patients is limited. METHODS: Medical records of patients, younger than 18 years, diagnosed with TMA and variants in DGKE were reviewed to include 12 patients from seven centers. Genetic studies included targeted exome sequencing and multiplex-ligation dependent probe amplification of CFH-CFHR5. RESULTS: Patients presented at a median age of 11 (7.5, 12.3) months; all were younger than 2 years. All patients had an infectious prodrome; enteroinvasive, enteropathogenic, and enterotoxigenic Escherichia coli were detected in two patients with diarrhea. Chief features included those of microangiopathic hemolysis (n = 11), microscopic hematuria (n = 10), nephrotic range proteinuria (n = 10), hypoalbuminemia (n = 6), elevated total cholesterol (n = 6), and hypocomplementemia (n = 4). Histopathology showed thrombotic microangiopathy (n = 4), overlapping with membranoproliferative pattern of injury (n = 1). At median 3.3 years of follow-up, significant hypertension and/or proteinuria (40%), relapses (66.7%), and death or progression to CKD (60%) were common. Genetic sequencing showed 13 homozygous and compound heterozygous variants (7 pathogenic, 3 likely pathogenic) located throughout DGKE; 11 variants were novel. CONCLUSIONS: This case series highlights the need to suspect DGKE nephropathy in young patients with TMA, especially those with severe proteinuria. Medium-term outcomes are unsatisfactory with risk of relapses, progressive kidney failure, and death. A higher resolution version of the Graphical abstract is available as Supplementary information.