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Stroke is a devastating neurological event with limited treatment opportunities. Recent advances in understanding the underlying pathogenesis of cerebral ischemia support the involvement of multiple biochemical pathways in the development of the ischemic damage. Fenamates are classical non-steroidal anti-inflammatory drugs but they are also highly subunit-selective modulators of GABAA receptors, activators of IKS potassium channels and antagonists of non-selective cation channels and the NLRP3 inflammosome. In the present study we investigated the effect of mefenamic acid (MFA) in a rodent model of ischemic stroke and then addressed the underlying pharmacological mechanisms in vitro for its actions in vivo. The efficacy of MFA in reducing ischemic damage was evaluated in adult male Wistar rats subjected to a 2-h middle cerebral artery occlusion. Intracerebroventricular (ICV) infusion of MFA (0.5 or 1 mg/kg) for 24 h, significantly reduced the infarct volume and the total ischemic brain damage. In vitro, the fenamates, MFA, meclofenamic acid, niflumic acid, and flufenamic acid each reduced glutamate-evoked excitotoxicity in cultured embryonic rat hippocampal neurons supporting the idea that this is a drug class action. In contrast the non-fenamate NSAIDs, ibuprofen and indomethacin did not reduce excitotoxicity in vitro indicating that neuroprotection by MFA was not dependent upon anti-inflammatory actions. Co-application of MFA (100 μM) with either of the GABAA antagonists picrotoxin (100 μM) or bicuculline (10 μM) or the potassium channel blocker tetraethylammonium (30 mM) did not prevent neuroprotection with MFA, suggesting that the actions of MFA also do not depend on GABAA receptor modulation or potassium channel activation. These new findings indicate that fenamates may be valuable in the adjunctive treatment of ischemic stroke.

Injuries to the heart and great vessels should always be considered after blunt chest trauma. Valvular damage rarely occurs after blunt trauma, but symptoms may be delayed. A 58-year-old woman was referred to our hospital with exertional dyspnea (functional class III) and palpitations for elective transesophageal echocardiography. Her symptoms had exacerbated in the preceding 2 or 3 months. Physical examination showed holosystolic murmurs (IV/VI) at the lower sternal border with extension to the apex. Transesophageal echocardiography revealed avulsion of the base of the posterior mitral valve leaflet (P3) from the annulus. In the past medical history, there was a history of a motor vehicle accident 9 months earlier. The patient was recommended for mitral valve surgery. Mitral valve replacement was performed, and the diagnosis was confirmed by surgery. The patient was discharged without any complications.

Background/Aims. The anthracycline and taxane-based chemotherapy regimens are the standard adjuvant treatment of node-positive breast cancer patients. Although it was believed that docetaxel and paclitaxel are similarly effective as adjuvant treatment in node-positive breast cancer, recent studies report that weekly paclitaxel is superior to weekly and triweekly docetaxel schedules in terms of overall survival (OS) and disease-free survival (DFS). However, to the best of our knowledge, no study has compared weekly paclitaxel with a dose-dense regimen of docetaxel. The current study is aimed at evaluating the outcome of women with node-positive breast cancer who had received weekly paclitaxel compared with those treated with dose-dense docetaxel. Methods. This study included patients from two prospective studies conducted in our institute from April 2007 to March 2009. Ninety-one women with axillary lymph node-positive breast cancer who had received four cycles of dose-dense epirubicin and cyclophosphamide were treated with either weekly paclitaxel (80 mg/m2) for 12 doses or biweekly docetaxel (75 mg/m2) for four cycles. Results. After a median follow-up of 88 and 109 months, 11 (23.4%) and 10 (22.7%) patients had experienced disease recurrence (p=0.16), while 10 (21.3%) and 5 (11.4%) patients had died in the paclitaxel and docetaxel arm, respectively (p=0.56). No significant difference could be seen in 5-year DFS or OS among groups (HR: 0.58; 95% CI: 0.19–1.81, p=0.35; HR: 0.58; 95% CI: 0.19–1.81, p=0.35, respectively). Conclusion. In conclusion, both evaluated adjuvant chemotherapy regimens have comparable effectiveness regarding DFS and OS.

Background. Adding taxanes to anthracycline-based adjuvant chemotherapy has shown significant improvement particularly in node-positive patients, but optimal dose and schedule remain undetermined. Objectives. This study aimed to assess the feasibility of dose-dense epirubicin and cyclophosphamide followed by docetaxel in node-positive breast cancer. Methods. All Patients first received 4 cycles of epirubicin (100 mg/m2) and cyclophosphamide (600 mg/m2) at 2-week interval then followed by docetaxel (100 mg/m2) at 2-week interval for 4 cycles, with daily Pegfilgrastim (G-CSF) that was administered in all patients on days 3–10 after each cycle of epirubicin and cyclophosphamide infusion. Results. Fifty-eight patients with axillary lymph node-positive breast cancer were enrolled in the study, of whom 42 (72.4%) completed the regimen. There were two toxicity-related deaths, one patient due to grade 4 febrile neutropenia and the other due to congestive heart failure. Grade 3/4 neutropenia and febrile neutropenia were 13.8% and 5.1%. The most common grade 3/4 nonhematological complications were as follows: skin-nail disorders (48.3%), hand-foot syndrome (34.4%), paresthesia (38%), arthralgia (27.5%), and paresis (24.1%). Conclusions. Dose-dense epirubicin and cyclophosphamide followed by docetaxel with G-CSF support are not feasible, and it is not recommended for further investigation.

Background: Obstructive sleep apnea (OSA) is the most common sleep-related breathing disorder associated with multisystem organ involvement. The STOP-BANG questionnaire is a short and valid questionnaire used to screen OSA. This study aimed to investigate the ability of the STOP-BANG questionnaire to predict postoperative OSA- related respiratory complications in patients undergoing bariatric surgery., Materials and Methods: In this cross-sectional study, all the eligible patients were evaluated in preoperative visits using a predetermined checklist including demographic and clinical information related to OSA and the STOP-BANG questionnaire. After bariatric surgery, patients were assessed for postoperative OSA-related complications. The receiver operating characteristic (ROC) curve was used to determine the cut-off point of the STOP-BANG checklist score based on the patient's postoperative outcomes., Results: In total, 115 subjects were included in the study. There were significant associations in terms of gender, age, body mass index (BMI), patient's neck circumference, diabetes, heart diseases, and the mask ventilation grade variables between the two groups of patients with high risk and low risk according to the STOP-BANG questionnaire (P < 0.05 for all comparisons). In addition, ai rway obstruction and hypoxia (mild and moderate) were more prevalent in the high-risk group than in the low-risk one (P < 0.05 for all comparisons). A significant difference was reported with a cut-off score of 2 in the STOP-BANG questionnaire for those with and without airway obstruction. Moreover, the cut-off point of 4 in the STOP-BANG questionnaire was determined as a predictor for both airway obstruction and mild-to-moderate hypoxia., Conclusion: STOP- BANG scores may be used as a preoperative risk stratification tool to predict the risk of intraoperative adverse events and postoperative complications in bariatric surgery., (Copyright© 2024 National Research Institute of Tuberculosis and Lung Disease.)

[This corrects the article DOI: 10.1371/journal.pone.0192697.].

Rubisco (Ribulose-1, 5-biphosphate carboxylase/oxygenase) is the most important enzyme on earth, catalyzing the first step of photosynthetic CO2 fixation. So, without it, there would be no storing of the sun's energy in plants. Molecular adaptation of Rubisco to C4 photosynthetic pathway has attracted a lot of attention. C4 plants, which comprise less than 5% of land plants, have evolved more efficient photosynthesis compared to C3 plants. Interestingly, a large number of independent transitions from C3 to C4 phenotype have occurred. Each time, the Rubisco enzyme has been subject to similar changes in selective pressure, thus providing an excellent model for convergent evolution at the molecular level. Molecular adaptation is often identified with positive selection and is typically characterized by an elevated ratio of non-synonymous to synonymous substitution rate (dN/dS). However, convergent adaptation is expected to leave a different molecular signature, taking the form of repeated transitions toward identical or similar amino acids. Here, we used a previously introduced codon-based differential-selection model to detect and quantify consistent patterns of convergent adaptation in Rubisco in eudicots. We further contrasted our results with those obtained by classical codon models based on the estimation of dN/dS. We found that the two classes of models tend to select distinct, although overlapping, sets of positions. This discrepancy in the results illustrates the conceptual difference between these models while emphasizing the need to better discriminate between qualitatively different selective regimes, by using a broader class of codon models than those currently considered in molecular evolutionary studies.

Background: Phylogenetic codon models are often used to characterize the selective regimes acting on protein-coding sequences. Recent methodological developments have led to models explicitly accounting for the interplay between mutation and selection, by modeling the amino acid fitness landscape along the sequence. However, thus far, most of these models have assumed that the fitness landscape is constant over time. Fluctuations of the fitness landscape may often be random or depend on complex and unknown factors. However, some organisms may be subject to systematic changes in selective pressure, resulting in reproducible molecular adaptations across independent lineages subject to similar conditions., Results: Here, we introduce a codon-based differential selection model, which aims to detect and quantify the fine-grained consistent patterns of adaptation at the protein-coding level, as a function of external conditions experienced by the organism under investigation. The model parameterizes the global mutational pressure, as well as the site- and condition-specific amino acid selective preferences. This phylogenetic model is implemented in a Bayesian MCMC framework. After validation with simulations, we applied our method to a dataset of HIV sequences from patients with known HLA genetic background. Our differential selection model detects and characterizes differentially selected coding positions specifically associated with two different HLA alleles., Conclusion: Our differential selection model is able to identify consistent molecular adaptations as a function of repeated changes in the environment of the organism. These models can be applied to many other problems, ranging from viral adaptation to evolution of life-history strategies in plants or animals.

We have used a statistical approach for protein secondary structure prediction based on information theory and simultaneously taking into consideration pairwise residue types and conformational states. Since the prediction of residue secondary structure by one residue window sliding make ambiguity in state prediction, we used a dynamic programming algorithm to find the path with maximum score. A score system for residue pairs in particular conformations is derived for adjacent neighbors up to ten residue apart in sequence. The three state overall per-residue accuracy, Q3, of this method in a jackknife test with dataset created from PDBSELECT is more than 70%.