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The antioxidative effect of Monodora myristica seed acetone extract and its effect on chemical functional groups were investigated in sickled erythrocytes as well as molecular modeling of the antisickling potentials of its secondary metabolites. The extract was subjected to gas chromatography–mass spectrometry to identify the compounds present, which were then docked into the allosteric-binding site of deoxy-hemoglobin. The extract was incubated with sickled erythrocytes at 37°C for 6, 12, and 24 h and were subjected to antioxidative analysis for reduced glutathione (GSH), superoxide dismutase (SOD), catalase, and lipid peroxidation (LPO). Chemical functional group of the treated cells was analyzed via Fourier transform infrared spectroscopy (FTIR). The predominant compounds identified were 17-octadecynoic acid; oleic acid, androstan-3-one, 17-hydroxy-2-methyl- (2.beta.,5.beta.,17.beta.)-; estran-3-one, 17-(acetyloxy)-2-methyl-, (2.alpha., 5.alpha., 17.beta.), and (+)-3-carene, 10-(acetylmethyl)-. They all fitted well within the active site of Hb with good binding affinity, as evidenced by the negative CDocker interaction energies of their complexes ranging between −54.4 and −26.7 kcal/mol. Treatment with the extract exacerbated SOD and catalase activities as well as GSH level, while LPO was suppressed. This antioxidative activity was time and/or dose dependent, with 6 and 12 h incubation showing the optimum activity. FTIR analysis of the treated cells showed the presence of hydrophobic functional groups. The synergetic molecular interaction of the major compounds of the extract with the α-dimer of Hb depicts an antisickling effect of M. myristica acetone extract. This is accompanied by exacerbation of endogenous antioxidant enzymes activity and modification of the functional chemistry of the cells. [ABSTRACT FROM AUTHOR]

Michelia champaca leaf and stem extracts have been evaluated for phytochemical constituents, in vitro antimicrobial efficacy and TLC bioautography assay. Qualitative phytochemical analysis of various solvents and water extracts demonstrated the presence of tannins, glycosides, steroids, flavonoids, anthraquinones, coumarins and lactones, phlobatanins, and reducing sugars. Polysaccharides was not observed in both the extracts and saponins was absent in all the leaf extracts tested. The in vitro antimicrobial activity of various solvents and water extracts was further assessed against nine bacteria and two fungi respectively. Hexane and chloroform extracts were found to be more potent being capable of exerting significant inhibitory activities against majority of the isolates such as Pseudomonas sp., Salmonella sp., Staphylococcus aureus 1 and 2 and Aspergillus niger. The highest in vitro inhibitory activity was observed for S. aureus 1 with wide zone of inhibition diameter (31 mm) followed by Aspergillus niger (29 mm). Thin layer bioautography assay of hexane leaf extract demonstrated a single large welldefined growth inhibition zone against S. aureus 1 observed at Rf value of 0.67. [ABSTRACT FROM AUTHOR]

Introduction: The role for routine thymectomy in patients with secondary or tertiary hyperparathyroidism (SHPT, THPT) is unclear. We aim to compare rates of recurrence and complications in patients who underwent subtotal parathyroidectomy with and without thymectomy., Methods: Patients who underwent surgery for renal HPT at a tertiary endocrine surgery center between 2010 and 2022 were reviewed. Presence of parathyroid tissue in resected tissue was identified through pathology reports. A multivariate logistic regression was used to compare baseline characteristics, recurrence rates and complications between those who did and did not undergo thymectomy., Results: Of 107 patients who underwent subtotal parathyroidectomy, 29 (27.1 ​%) underwent concomitant thymectomy. Recurrence occurred in 15 patients (14 ​%). Thymectomy did not affect recurrence (OR: 0.33, 95%CI: 0.06-1.28, p ​= ​0.14), but was associated with permanent hypoparathyroidism (OR: 4.62, 95%CI: 1.67-13.18, p ​= ​0.003). Fewer parathyroid specimens increased the odds of thymectomy (p ​= ​0.04). Parathyroid glands were found in 6 thymectomy samples (20.7 ​%)., Conclusion: Thymectomy at the time of subtotal parathyroidectomy for renal HPT was not associated with disease recurrence, but increased likelihood of permanent hypoparathyroidism., (Crown Copyright © 2024. Published by Elsevier Inc. All rights reserved.)

A greener, safer, and more efficient methodology for the synthesis of (Z)-5-benzylidene-2-thioxothiazolidin-4-ones (3 a-u) and (Z)-5-benzylidenethiazolidine-2,4-diones (4 a-i) has been developed. The deep eutectic solvent (DES) ZnCl 2 /urea used as a greener solvent as well as a catalyst in this study accelerated the condensation of rhodanine and thiazolidine-2,4-dione with different aldehydes to afford the target scaffolds in excellent yields (88-98 %). The reaction methodology adopted offered significant advantages such as mild reaction conditions, functional group tolerance, quick reaction time, column-free isolation, catalytic recyclability, and applicability to gram-scale production. Moreover, density function theory calculations were carried out to investigate the global reactivity and stability profiles of these compounds. Finally, the green metrics analysis supported the greener nature of the present methodology., (© 2024 The Authors. ChemistryOpen published by Wiley-VCH GmbH.)

This proposed model explores the intricate Ca 2+ dynamics within the pancreatic acinar cells (PACs) by emphasizing the role of store-operated Ca 2+ entry (SOCE) and the mitochondrial-associated membranes (MAMs) in the secretory region (apical) of the PACs. Traditionally, Ca 2+ releases from the endoplasmic reticulum (ER) via calcium-induced calcium release (CICR). It has been shown to be important in regulating functions such as secretion of digestive enzymes in PACs. However, this model posits that upon the depletion of Ca 2+ in the ER, the signaling protein stromal interaction molecule (STIM1) is activated. Activated STIM1, then facilitates the opening of Orai channels, allowing Ca 2+ influx through the store-operated calcium channels (SOCCs). The model highlights the complexity of the Ca 2+ dynamics, and the importance of SOCE and MAMs in the PACs Ca 2+ homeostasis. The numerical and bifurcation analysis illustrate how changes in agonist concentrations can lead to the diverse Ca 2+ oscillation patterns, such as thin to broader oscillations, sinusoidal patterns, and baseline fluctuations, driven by the feedback mechanisms involving Ca 2+ and inositol 1,4,5 trisphosphate (IP 3 ). This understanding could have broader implications for cellular physiology and the development of therapies targeting Ca 2+ signaling pathways., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Use of permanent hair dyes causes unintended oxidative damage during the short time frame of the dyeing process that leads to perceivable changes in the feel, manageability and appearance of hair. Moreover, after hair has been dyed, regular exposure to the sun as a key environmental stressor continues to stimulate additional oxidative damage and to induce newly developed hair colours to fade prematurely or undergo changes in colour quality., Objective: To document the utility of acetyl zingerone methyl ether (MAZ) as a newly designed haircare ingredient to afford extra protection against oxidative damage and safeguard the integrity of hair colour., Results: We demonstrate that MAZ is compatible chemically with the high alkaline conditions required for the colouring process and from theoretical calculations preferentially binds Fe and Cu ions relative to Ca or Zn ions. In model Fenton reactions MAZ effectively chelated active redox metals (Fe and Cu ions) in the presence of excess Ca +2 ions to inhibit the production of hydroxyl radicals, and in separate studies, MAZ neutralized singlet oxygen with greater efficiency than α-tocopherol by a factor of 2.5. When mixed into permanent dyes prior to hair tress application, MAZ significantly reduced combing forces, and SEM images led to substantial reductions in visual signs of surface damage. In a 28-day clinical study, relative to controls, mixing MAZ into hair dyes prior to application interfered neither with colour development nor with ability to cover grey hair and led to significant improvements in perceived attributes associated with hair's condition immediately following the dyeing process. Over a 28-day maintenance phase, especially between Day 14 and Day 28, continued use of shampoo and conditioner containing MAZ significantly preserved gloss measurements and hair colour in terms of longevity and colour quality as remaining desired and fresh compared to use of control shampoo and conditioner., Conclusion: This work establishes MAZ as a next-generation hair care ingredient for use in permanent dyes to attenuate oxidative damage and in shampoos and conditioners to promote longevity of hair colour and to maintain overall health and appearance of hair on a daily basis., (© 2024 Society of Cosmetic Scientists and Societe Francaise de Cosmetologie.)

In the present study, we identified that two representative compounds (7c and 9f) of our newly synthesized coumarin-tagged bis-triazoles induced apoptosis in human pancreatic cells (PANC-1) by caspase 3/7mediated pathway. Both 7c and 9f (IC50 = 7.15 ± 1.19 and 6.09 ± 0.79 µM, respectively) were found to be ~100 times superior against PANC-1 as compared to the standard drug Gemcitabine (IC50 = >500 µM), without showing any toxicity to the normal pancreatic epithelial cells (H6C7). Molecular docking studies further endorsed them as potential pancreatic cancer therapeutics due to their strong hydrogen bonding interactions with the epidermal growth factor receptor (EGFR) enzyme, which is overexpressed in cancerous cells including pancreatic cancer. Additionally, these compounds also showed moderate inhibitory activity against a panel of microbial strains. Overall, our findings reveal that the coumarin hybrids 7c and 9f are viable chemotypes to be adopted as templates for the development of new anticancer drugs, particularly against pancreatic cancer., (© 2024 Wiley‐VCH GmbH.)

A series of triclosan azo-adducts were synthesized to investigate their structure-activity relationship against Mycobacterium tuberculosis and non-tuberculous mycobacteria. The series' most potent compound was four and sixteen times more active than triclosan and rifabutin against drug-resistant Mycobacterium abscessus , respectively, while being less cytotoxic to human macrophages than triclosan on day one. Additionally, one of the azo-adducts was twice as efficient against M. tuberculosis as triclosan and twice as effective against Mycobacterium marinum as isoniazid. Furthermore, the synthesized azo-adducts were equally effective against M. abscessus strains overexpressing InhA, suggesting that these compounds work through a distinct mechanism., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Shekhar reports financial support was provided by University Grants Commission, India. Vipan Kumar reports financial support was provided by 10.13039/501100001332Council for Scientific and Industrial Research, India. Mattheo Alcaraz reports financial support was provided by 10.13039/501100001665French National Research Agency, France. Associate Editor, Heliyon (Pharmaceutical Sciences Section) Vipan Kumar If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

In our work, a novel series of europium (III) (Eu 3+ ) (5, 10 and 15 wt %) doped cobalt tetroxide@cupric oxide (Co 3 O 4 @CuO) nanomaterials (NMs) were synthesized by facile coprecipitation method. The synthesized NMs were characterized by XRD (X-ray diffraction), FT-IR (Fourier transform infrared), UV (ultraviolet)-visible absorption spectra, XPS (X-ray photoelectron), BET (Brunauer-Emmett-Teller) analytical methods. Crystal structure studies revealed the formation of polycrystalline nature with monoclinic and cubic phase. The morphology studies of Eu 3+ x :Co 3 O 4 @CuO (x = 5, 10 and 15 wt %) showed petal shape nanoparticles (NPs) with agglomeration. Redshift in optical absorption spectra appeared with a significant impact on the optical band gap as Eu 3+ concentration increases on Co 3 O 4 @CuO bimetallic oxide NMs. The chemical composition and valence state of the elements confirmed from XPS studies detected the presence of Eu, Cu, Co, O and C elements. An increase in the pore size and surface area resulted as the Eu 3+ concentration increased on Co 3 O 4 @CuO NMs. However, room temperature photoluminescence (RTPL) spectra of Co 3 O 4 @CuO bimetallic oxide NMs at two different excitations (λ excitation  = 280 nm, 320 nm) showed sharp, strong emission intensities located at near ultraviolet (NUV) region and weak emissions detected at far ultraviolet (FUV) regions of the RTPL spectrum. Further, visible range emission intensities were displayed by Eu 3+ :Co 3 O 4 @CuO (5, 10 and 15 wt %) NMs when exited at 280 nm. The characteristic white light emission peaks in the visible range of the RTPL spectra showed intense blue, green and orange colours. Emission intensity increases with an increase in Eu 3+ concentration on Co 3 O 4 @CuO bimetallic oxide NMs. The fluorescence (FL) decay spectra of Eu 3+ 10wt% and 15 wt% : Co 3 O 4 @CuO NMs showed a decay lifetime of 2.54 and 2.31 ns (ns) attributed to the dynamic, ultrafast excitation energy transfer between Eu 3+ (dopant) and Co 3 O 4 @CuO (host) NMs. It is proposed that enhanced RTPL emission intensity and FL decay behavior of Eu 3+ x :Co 3 O 4 @CuO NMs closely related to the change in the optical band gap, variation in the crystallite size, formation of more number of oxygen vacancies in the crystal structure of hybrid nanomaterials., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Compared to younger age, older age (≥ 65 yr) is associated with worse outcomes after severe traumatic brain injury (TBI). We sought to describe the association of older age with in-hospital death and aggressiveness of intervention., Methods: We conducted a retrospective cohort study of adult (age ≥ 16 yr) patients with severe TBI admitted to a single academic tertiary care neurotrauma centre between January 2014 and December 2015. We collected data through chart review as well as from our institutional administrative database. We provided descriptive statistics and used multivariable logistic regression to evaluate the independent association of age with the primary outcome, in-hospital death. The secondary outcome was early withdrawal of life-sustaining therapy., Results: There were 126 adult patients (median age 67 yr [Q1-Q3, 33-80 yr]) with severe TBI during the study period who met our eligibility criteria. The most common mechanism was high-velocity blunt injury (55 patients [43.6%]). The median Marshall score was 4 (Q1-Q3, 2-6), and the median Injury Severity Score was 26 (Q1-Q3, 25-35). After controlling for confounders including clinical frailty, pre-existing comorbidity, injury severity, Marshall score and neurologic examination at admission, we observed that older patients were more likely than younger patients to die in hospital (odds ratio 5.10, 95% confidence interval 1.65-15.78). Older patients were also more likely to experience early withdrawal of life-sustaining therapy and less likely to receive invasive interventions., Conclusion: After controlling for confounding factors relevant to older patients, we observed that age was an important and independent predictor of in-hospital death and early withdrawal of life-sustaining therapy. The mechanism by which age influences clinical decision-making independent of global and neurologic injury severity, clinical frailty and comorbidities remains unclear., Competing Interests: Competing interests: At the time of acceptance, Victoria Saigle was affiliated with the CMAJ Group; however, she was not involved in any tasks related to the Canadian Journal of Surgery. Michael Chassé reports payment for expert testimony. No other competing interests were declared., (© 2023 CMA Impact Inc. or its licensors.)

Background: We aimed to investigate the association of preoperative calcium and parathyroid hormone (PTH) levels with sensitivity and accuracy of dual energy computed tomography (DECT), single-photon emission CT with 99m Tc-sestamibi (CT-MIBI), and ultrasound (US) for pre-operative localization primary hyperparathyroid (PHP) patients., Methods: Patients undergoing parathyroidectomy for PHP at a tertiary care facility who underwent DECT, CT-MIBI and US between 2012 and 2021 were stratified by preoperative calcium and PTH levels., Results: Of 278 patients, those with high calcium and PTH levels had a higher sensitivity and accuracy with DECT (87.7%, 85.2%) compared to CT-MIBI (82.3%, 79.0%), and US (61.7%, 53.1%). DECT was more sensitive and accurate than other preoperative localization techniques in subgroups with normal PTH (DECT sensitivity 60.9%, accuracy 52.1%) and normal calcium levels (41.7%, 33.3%)., Conclusion: Preoperative calcium and PTH were associated with sensitivity and accuracy of pre-operative localization in PHP. DECT was sensitive and accurate for preoperative localization compared to other first-line imaging techniques., Competing Interests: Declaration of competing interest The authors do not report any conflicts of interest., (Crown Copyright © 2023. Published by Elsevier Inc. All rights reserved.)

Introduction: Vaccination is an effective strategy for preventing SARS-CoV-2 infection and associated mortality. Renal Transplant Recipients (RTRs) are vulnerable to acquiring infection and high mortality due to their immunocompromised state. Varying responses to the different vaccines, depending on types of vaccines and population, have been reported. Vaccines supply is also limited. The current study evaluated the seroconversion rate after SARS-CoV-2 infection and 2 doses of either COVAXIN™ or COVISHIELD™ vaccination in RTR., Methods: The serum anti-SARS-CoV-2 spike protein neutralizing antibody titer was measured in 370 RTRs who acquired SARS-CoV-2 infection (n=172), yet not vaccinated; and those vaccinated with COVAXIN™ (n=78), and COVISHIELD™ (n=120) by chemiluminescence microparticle immunoassay methods from serum., Result: Overall, the seroconversion rate either after vaccination or infection was 85.13% (315/370). The vaccine-associated seroconversion was 80.30% (159/198). SARS-CoV-2 infection-associated seroconversion was 90.69% (156/172), COVISHIELD™ associated seroconversion was 79.2% (95/120), and COVAXIN™ associated seroconversion was 82.05% (64/78). The median IgG titer in the SARS-CoV-2 infection group was 646.50 AU/ml (IQR: 232.52-1717.42), in the COVAXIN™ group was 1449.75 AU/ml (IQR: 400.0-3068.55), and the COVISHIELD™ vaccination group was 1500.51 AU/ml (IQR: 379.47-4938.50). The seroconversion rate and antibody titers were similar irrespective of the place of sampling. Patient's age-associated seroconversion in <45 years was 88.01% (213/242), 45.1-60 years was 83.18% (94/113), and > 60 years was 58.3% (7/12)., Conclusions: Both infection and vaccination induce robust antibody formation in RTRs. The seroconversion rate after SARS-CoV-2 infection was higher but with a lower antibody titer than vaccines. The vaccines, COVAXIN™ and COVISHIELD™, induce more elevated antibody titers than natural infection. The seroconversion rate and antibody titer in Indian RTRs appears to be better than in the western population, irrespective of their vaccination status., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Prasad, Bansal, Yadav, Manhas, Yadav, Gautam, Kushwaha, Singh, Bhadauria, Yachha, Behera and Kaul.)

Background: Adverse effects on the health and well-being changes may also express as a decreased sleep quality in COVID-19 patients. This study aimed to assess sleep quality among confirmed COVID-19 patients and the non-COVID-19 Pakistani population., Methods: An online cross-sectional survey was conducted between April and September 2020 in Punjab province, Pakistan. Information about demographic characteristics, COVID-19 diseased status, prior knowledge about COVID-19, and sleep quality using the Pittsburgh Sleep Quality Index (PSQI) was collected., Results: A total of 597 participants were included in this study, 296 (49.6%) COVID-19 patients and 301(50.4%) non-COVID-19 population. The PQSI was used to measure seven distinct sleep components; subjective quality, latency, duration, efficiency, disturbances, medication, and daytime dysfunction. Where mean ± standard deviation (SD) were 0.96 ± 0.743, 1.47 ± 1.032, 0.97 ± 1.006, 0.61 ± 0.995, 1.13 ± 0.649, 0.23 ± 0.651, 1.02 ± 0.861 respectively in total population (N = 597). Sleep latency, sleep duration, and sleep efficiency did not show a significant difference in the T-Test. While sleep quality, sleep disturbances, sleep medication, and daytime dysfunction showed a significant difference between both populations., Conclusion: In conclusion, we highlighted the poor sleep quality in COVID-19 patients as compared to the non-COVID-19 population ., (© 2022 The Author(s).)

A series of quinazolin-4-one Schiff bases were synthesized and tested in vitro for their cytotoxicity against two cancerous cell lines (MCF-7, Caco-2) and a human embryonic cell line (HEK-293) including their antibacterial evaluation against two Gram-positive and four Gram-negative bacterial strains. Most of the quinazoline-Schiff bases exhibited potent cytotoxicity against Caco-2. 3-[(Z)-({4-[(But-2-yn-1-yl)oxy]phenyl}methylidene)amino]-2-methylquinazolin-4(3H)-one (6f) with the O-butyne functional group displayed three-fold higher cytotoxic activity (IC 50 =376.8 μM) as compared to 5-fluorouracil (5-FU; IC 50 =1086.1 μM). However, all compounds were found to be toxic to HEK-293, except for 3-[(Z)-({4-[(2,4-difluorophenyl)methoxy]phenyl}methylidene)amino]-2-methylquinazolin-4(3H)-one (6h) that showed ∼three-fold lower toxicity and higher selectivity index than 5-FU. Structure-activity relationship (SAR) analysis revealed that O-alkylation generally increased the anticancer activity and selectivity of quinazoline-4-one Schiff bases toward Caco-2 cells. The fluorinated Schiff-base generally exhibited even more significant cytotoxic activity compared to their chlorine analogs. Surprisingly, none of the quinazoline-4-one Schiff bases displayed encouraging antibacterial activity against the bacterial strains investigated. Most of the compounds were predicted to show compliance with the Lipinski parameters and ADMET profiles, indicating their drug-like properties., (© 2021 Wiley-VHCA AG, Zurich, Switzerland.)

Succinate dehydrogenase (SDH) is an inner mitochondrial membrane protein complex that links the Krebs cycle to the electron transport system. It can produce significant amounts of superoxide ([Formula: see text]) and hydrogen peroxide (H 2 O 2 ); however, the precise mechanisms are unknown. This fact hinders the development of next-generation antioxidant therapies targeting mitochondria. To help address this problem, we developed a computational model to analyze and identify the kinetic mechanism of [Formula: see text] and H 2 O 2 production by SDH. Our model includes the major redox centers in the complex, namely FAD, three iron-sulfur clusters, and a transiently bound semiquinone. Oxidation state transitions involve a one- or two-electron redox reaction, each being thermodynamically constrained. Model parameters were simultaneously fit to many data sets using a variety of succinate oxidation and free radical production data. In the absence of respiratory chain inhibitors, model analysis revealed the 3Fe-4S iron-sulfur cluster as the primary [Formula: see text] source. However, when the quinone reductase site is inhibited or the quinone pool is highly reduced, [Formula: see text] is generated primarily by the FAD. In addition, H 2 O 2 production is only significant when the enzyme is fully reduced, and fumarate is absent. Our simulations also reveal that the redox state of the quinone pool is the primary determinant of free radical production by SDH. In this study, we showed the importance of analyzing enzyme kinetics and associated side reactions in a consistent, quantitative, and biophysically detailed manner using a diverse set of experimental data to interpret and explain experimental observations from a unified perspective., Competing Interests: Conflict of interest—The authors declare that they have no conflicts of interest with the contents of this article., (© 2020 Manhas et al.)

Despite the outstanding clinical results of immune checkpoint blockade (ICB) in melanoma and other cancers, clinical trials in breast cancer have reported low responses to these therapies. Current efforts are now focused on improving the treatment efficacy of ICB in breast cancer using new combination designs such as molecularly targeted agents, including histone deacetylase inhibitors (HDACi). These epigenetic drugs have been widely described as potent cytotoxic agents for cancer cells. In this work, we report new noncanonical regulatory properties of ultra-selective HDAC6i over the expression and function of epithelial-mesenchymal transition pathways and the invasiveness potential of breast cancer. These unexplored roles position HDAC6i as attractive options to potentiate ongoing immunotherapeutic approaches. These new functional activities of HDAC6i involved regulation of the E-cadherin/STAT3 axis. Pretreatment of tumors with HDAC6i induced critical changes in the tumor microenvironment, resulting in improved effectiveness of ICB and preventing dissemination of cancer cells to secondary niches. Our results demonstrate for the first time that HDAC6i can both improve ICB antitumor immune responses and diminish the invasiveness of breast cancer with minimal cytotoxic effects, thus departing from the cytotoxicity-centric paradigm previously assigned to HDACi. SIGNIFICANCE: Ultraselective HDAC6 inhibitors can reduce tumor growth and invasiveness of breast cancer by noncanonical mechanisms unrelated to the previously cytotoxic properties attributed to HDAC inhibitors., (©2020 American Association for Cancer Research.)

Background: Gender disparities in faculty rank have yet to be studied among Canadian physicians. The purpose of this study was to determine whether differences in region, training, research productivity and years in practice explain gender differences in academic promotion among Canadian general surgeons., Methods: We developed a cross-sectional database of faculty-appointed general surgeons practising in the hospitals affiliated with the 17 universities within the Association of Faculties of Medicine of Canada in 2017 using publicly available directories, university and hospital websites, and direct communication. The data were collected between October and December 2018 and included gender, residency completion year, graduate education, fellowships, number of publications and Scopus h-index; faculty lists and professorship status were verified by program administrators or division heads of their respective divisions. The dependent variable was binary: full professor or not. A combined outcome of associate or full professor was also analyzed. We analyzed all variables in a multivariable logistic regression model., Results: Of the 17 institutions contacted, all but 1 confirmed the faculty lists and professorship status. A total of 405 surgeons were included, of whom 111 (27.4%) were women. Sixty-eight women (61.3%) and 120 men (40.8%) were assistant professors, and 9 women (8.1%) and 75 men (25.5%) were full professors. Although on average women had completed residency more recently than men (15.2 yr v. 19.2 yr, p < 0.001), there was no difference between men and women in the mean number of publications as residents (2.98 v. 2.74, p = 0.7) or per year of practice (3.12 v. 2.09, p = 0.2), number of fellowships pursued ( p = 0.7) or graduate education ( p = 0.2). In the multivariable model (C-statistic = 0.88), gender remained significantly associated with full professorship (odds ratio 2.79, 95% confidence interval 1.13 to 6.92), along with years in practice (odds ratio 1.61, 95% confidence interval 1.13 to 2.30)., Interpretation: After controlling for years in practice, training and research productivity measures, we found that female surgeons with faculty appointments in Canada were less likely than their male counterparts to receive promotion to full professor. Pervasive inequities in systems of promotion must be addressed., Competing Interests: Competing interests: None declared., (Copyright 2020, Joule Inc. or its licensors.)

The immunomodulatory potentials of the crude methanolic extract and fractions [n-hexane (Hex), n-dichloromethane (DCM), ethyl acetate (EtOAc) and n-butanol (BuOH)] of Clerodendrum volubile flowers were investigated on whole blood phagocytic oxidative burst using luminol-amplified chemiluminescence technique. They were also investigated for their free radicals scavenging activities. The DCM fraction showed significant (p<0.05) anti-oxidative burst and free radical scavenging activities indicating high immunomodulatory and antioxidant potencies respectively. Cytotoxicity assay of the DCM fraction revealed a cytotoxic effect on CC-1 normal cell line. GCMS analysis revealed the presence of triacetin; 3,6-dimethyl-3-octanol; 2R - Acetoxymethyl-1,3,3-trimethtyl - 4t - (3-methyl-2-buten-1-yl) - 1c - cyclohexanol and Stigmastan - 3,5-diene in DCM fraction. These compounds were docked with the active sites of cyclooxygenase-2 (COX-2). Triacetin, 3,6-dimethyl-3-Octanol, and 2R-Acetoxymethyl-1,3,3-trimethtyl-4t-(3-methyl-2-buten-1-yl)-1c-cyclohexanol docked comfortably with COX-2 with good scoring function (-CDocker energy) indicating their inhibitory potency against COX-2. 3,6-dimethyl-3-Octanol, displayed the lowest predicted free energy of binding (-21.4kcalmol -1 ) suggesting its stronger interaction with COX-2, this was followed by 2R - Acetoxymethyl-1, 3, 3-trimethtyl-4t-(3-methyl-2-buten-1-yl)-1c-cyclhexanol (BE=-20.5kcalmol -1 ), and triacetin (BE=-10.9kcalmol -1 ). Stigmastan - 3,5-diene failed to dock with COX-2. The observed suppressive effect of the DCM fraction of C. volubile flower methanolic extract on phagocytic oxidative burst indicates an immunomodulatory potential. This is further reflected in its free scavenging activities and synergetic modulation of COX-2 activities by its identified compounds in silico., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

We present a simple model for calcium oscillations in the pancreatic acinar cells. This model is based on the calcium release from two receptors, inositol trisphosphate receptors (IPR) and ryanodine receptors (RyR) through the process of calcium induced calcium release (CICR). In pancreatic acinar cells, when the Ca²⁺ concentration increases, the mitochondria uptake it very fast to restrict Ca(2+) response in the cell. Afterwards, a much slower release of Ca²⁺ from the mitochondria serves as a calcium supply in the cytosol which causes calcium oscillations. In this paper we discuss a possible mechanism for calcium oscillations based on the interplay among the three calcium stores in the cell: the endoplasmic reticulum (ER), mitochondria and cytosol. Our model predicts that calcium shuttling between ER and mitochondria is a pacemaker role in the generation of Ca²⁺ oscillations. We also consider the calcium dependent production and degradation of (1,4,5) inositol-trisphosphate (IP3), which is a key source of intracellular calcium oscillations in pancreatic acinar cells. In this study we are able to predict the different patterns of calcium oscillations in the cell from sinusoidal to raised-baseline, high frequency and low-frequency baseline spiking.

A mathematical model is proposed which systematically investigates complex calcium oscillations in pancreatic acinar cells. This model is based on calcium-induced calcium release via inositol trisphosphate receptors (IPR) and ryanodine receptors (RyR) and includes calcium modulation of inositol (1,4,5) trisphosphate (IP3) levels through feedback regulation of degradation and production. In our model, the apical and the basal regions are separated by a region containing mitochondria, which is capable of restricting Ca2+ responses to the apical region. We were able to reproduce the observed oscillatory patterns, from baseline spikes to sinusoidal oscillations. The model predicts that calcium-dependent production and degradation of IP3 is a key mechanism for complex calcium oscillations in pancreatic acinar cells. A partial bifurcation analysis is performed which explores the dynamic behaviour of the model in both apical and basal regions.

We used magnetic resonance imaging (MRI) to assess the efficacy of Na+/H+ exchanger isoform 1 (NHE-1) inhibition following cerebral ischemia. Transient focal cerebral ischemia was induced in wild-type controls (NHE-1(+/+)), NHE-1 genetic knockdown mice (NHE-1(+/-)), and NHE-1(+/+) mice treated with the selective NHE-1 inhibitor HOE642. Diffusion weighted imaging (DWI) revealed a brain lesion as early as 1 hour following reperfusion and illustrated significant protection in NHE-1(+/-) mice (16.2 +/- 7.9 mm3 in NHE-1(+/-) mice vs. 47.5 +/- 16.6 mm3 in NHE-1(+/+) mice). Knockdown of NHE-1 showed significantly smaller infarct at 72 hours on T2 imaging (21.2 +/- 12.6 mm3 in NHE-1(+/-) mice vs. 64.6 +/- 2.5 mm3 in NHE-1(+/+) mice). Administration of HOE642 prior to reperfusion or during early reperfusion reduced ischemic damage. Thus, high resolution T2 images can be used for consistent and precise calculation of lesion volumes, while changes of DWI are a sensitive early marker of ischemic injury. The results of this study demonstrate the therapeutic potential for inhibition of NHE-1 in treating cerebral ischemia.

Excessive activation of Na+/H+ exchanger isoform 1 (NHE-1) plays a role in cerebral ischemic injury. The current study investigated whether NHE-1 protein in ischemic brains is regulated by extracellular signal-regulated kinase (ERK)/90-kDa ribosomal S6 kinase (p90(RSK)) signaling pathways. A transient focal ischemia in mice was induced by a 60-min-occlusion of the middle cerebral artery followed by reperfusion for 3, 10, or 60 min (Rp). Expression of phosphorylated ERK 1/2 was significantly elevated in the ipsilateral hemispheres at 3-10 min Rp and reduced by 60 min Rp. An increase in phosphorylation of p90(RSK), a known NHE-1 kinase, was also detected at 3-10 min Rp, which was accompanied with a transient elevation of NHE-1 phosphorylation (p-NHE-1). Stimulation of p90(RSK) in ischemic neurons was downstream of ERK activation because inhibition of MEK1 (MAP kinase/ERK kinase) with its inhibitor U0126 blocked phosphorylation of p90(RSK). Moreover, direct inhibition of p90(RSK) by its selective inhibitor fluoromethyl ketone not only reduced p-NHE-1 expression but also ischemic infarct volume. Taken together, our study revealed that reperfusion triggers a transient stimulation of the ERK/p90(RSK) pathway. p90(RSK) activation contributes to cerebral ischemic damage in part via activation of NHE-1 protein.

Background/aims: The molecular basis of hepatic dysfunction in thyrotoxicosis is not fully understood. Here, we investigated the effect of altered thyroidal status on death receptor pathways including p75 neurotrophin receptor (p75NTR), a member of tumor necrosis factor (TNF) receptor superfamily, in rat liver., Methods: Hyperthyroidism was induced in Sprague-Dawley rats by daily injections of triiodothyronine in a dose of 12.5 microg/100 g body weight for 10 days., Results: Terminal deoxynucleotide-transferase-mediated dUTP nick end labeling assay and caspase-3 activation data confirmed apoptosis in hyperthyroid rat liver. We observed the elevated levels of death ligands, TNF-alpha, Fas ligand and their cognate receptors, TNF-receptor-1 and Fas, and 8-fold increase in caspase-8 activation in hyperthyroid rat liver (p<0.001). We demonstrated for the first time that hyperthyroidism elevates p75NTR levels and its ligands, pro-nerve growth factor and pro-brain-derived neurotrophic factor, in rat liver. Further we showed that most of the apoptotic cells in hyperthyroid liver express p75NTR. We also demonstrated that triiodothyronine administration to rats causes NF-kappaB activation, but persistent exposure (10 days) to triiodothyronine deactivates NF-kappaB leading to sustained c-Jun N-terminal kinase (JNK) activation., Conclusions: This study showed that hyperthyroidism-induced apoptosis in rat liver involves the activation of death receptor-mediated pathways, including p75NTR.

Cerebral ischemia (stroke) triggers a complex series of biochemical and molecular mechanisms that impairs the neurologic functions through breakdown of cellular integrity mediated by excitotoxic glutamatergic signalling, ionic imbalance, free-radical reactions, etc. These intricate processes lead to activation of signalling mechanisms involving calcium/calmodulin-dependent kinases (CaMKs) and mitogen-activated protein kinases (MAPKs) such as extracellular signal-regulated kinase (ERK), p38, and c-Jun N-terminal kinase (JNK). The distribution of these transducers bring them in contact with appropriate molecular targets leading to altered gene expression, e.g. ERK and JNK mediated early gene induction, responsible for activation of cell survival/damaging mechanisms. Moreover, inflammatory reactions initiated at the neurovascular interface and alterations in the dynamic communication between the endothelial cells, astrocytes and neurons are thought to substantially contribute to the pathogenesis of the disease. The damaging mechanisms may proceed through rapid nonspecific cell lysis (necrosis) or by active form of cell demise (apoptosis or necroptosis), depending upon the severity and duration of the ischemic insult. A systematic understanding of these molecular mechanisms with prospect of modulating the chain of events leading to cellular survival/damage may help to generate the potential strategies for neuroprotection. This review briefly covers the current status on the molecular mechanisms of stroke pathophysiology with an endeavour to identify potential molecular targets such as targeting postsynaptic density-95 (PSD-95)/N-methyl-d-aspartate (NMDA) receptor interaction, certain key proteins involved in oxidative stress, CaMKs and MAPKs (ERK, p38 and JNK) signalling, inflammation (cytokines, adhesion molecules, etc.) and cell death pathways (caspases, Bcl-2 family proteins, poly (ADP-ribose) polymerase-1 (PARP-1), apoptosis-inducing factor (AIF), inhibitors of apoptosis proteins (IAPs), heat shock protein 70 (HSP70), receptor interacting protein (RIP), etc., besides targeting directly the genes itself. However, selecting promising targets from various signalling cascades, for drug discovery and development is very challenging, nevertheless such novel approaches may lead to the emergence of new avenues for therapeutic intervention in cerebral ischemia.

Cutaneous cells primarily depend upon carbohydrate metabolism for their energy requirement during healing process. But, it may be greatly hampered during various pathological and altered physiological conditions. The present study was therefore undertaken to investigate the intermediate steps of energy metabolism by measuring enzyme activities in the granulation tissues of immunocompromised and aged rats following excision-type of cutaneous injury. The activities of key regulatory enzymes hexokinase (HK), phosphofructokinase (PFK), lactate dehydrogenase (LDH), citrate synthase (CS) and glucose-6 phosphate dehydrogenase (G6PD) have been monitored in the wound tissues of immunocompromised and aged rats at different time intervals (2, 7, 14 and 21 days) of postwounding. The activities of HK and CS were found significantly decreased both in immunocompromised and aged rats as compared to control subjects. However G6PD exhibited an elevated activity at early stage followed by a decreased activity at later phase of healing both in immunocompromised and aged rats. The PFK and LDH demonstrated an upward trend in immunocompromised rats but a decreasing trend in aged rats. Thus, the results suggest that significant alterations in the activities of energy metabolizing enzymes in the granulation tissues in both immunocompromised as well as in aged rats may overall affect the energy availability for cellular activity needed for repair process. Hence, this may perhaps be one of the factor responsible for impaired healing in these subjects.

Foreign bodies in the laryngopharynx can occur without discrimination of age or sex. Their occurrence is influenced by mode of living, customs, habits and environment. T.M. Paramciwaran(1977) reported 56 cases of foreign bodies of tracheobronchial tree in the span of 5 years. A.S.A. Abdel-Salam and Alan G. Gibb (1980) mentioned that the vast majority of cases occur in young children. They have reported that undiagnosed foreign bodies cause mechanical effects, chemical reactions and may present as chronic pulmonary infection, allergic asthma, bronchiectasis, lung collapse or lung abscess. They present as emergencies and require skilful management.