Synthesis, Antimicrobial Activities, and Molecular Modeling Studies of Agents for the Sortase A Enzyme.

Sortase A (SrtA) is an attractive target for developing new anti-infective drugs that aim to interfere with essential virulence mechanisms, such as adhesion to host cells and biofilm formation. Herein, twenty hydroxy, nitro, bromo, fluoro, and methoxy substituted chalcone compounds were synthesized, antimicrobial activities and molecular modeling strategies against the SrtA enzyme were investigated. The most active compounds were found to be T2, T4, and T19 against Streptococcus mutans (S. mutans) with MIC values of 1.93, 3.8, 3.94 µg/mL, and docking scores of -6.46, -6.63, -6.73 kcal/mol, respectively. Also, these three active compounds showed better activity than the chlorohexidine (CHX) (MIC value: 4.88 µg/mL, docking score: -6.29 kcal/mol) in both in vitro and in silico. Structural stability and binding free energy analysis of S.mutans SrtA with active compounds were measured by molecular dynamic (MD) simulations throughout 100 nanoseconds (ns) time. It was observed that the stability of the critical interactions between these compounds and the target enzyme was preserved. To prove further, in vivo biological evaluation studies could be conducted for the most promising precursor compounds T2, T4, and T19, and it might open new avenues to the discovery of more potent SrtA inhibitors.

Investigation of α-glucosidase and α-amylase inhibitory effects of phenoxy chalcones and molecular modeling studies.

Diabetes mellitus is one of the most critical health problems affecting the quality of life of people worldwide, especially in developing countries. According to the World Health Organization reports, the number of patients with diabetes is approximately 420 million, and this number is estimated to be 642 million in 2040. There are 2 main types of diabetes: Type 1 (T1DM), where the body cannot produce enough insulin, and Type 2 (T2DM), where the body cannot use insulin properly. Patients with T1DM are treated with insulin injections while oral glucose-lowering drugs are used for patients with T2DM. Oral antihyperglycemic drugs used in the treatment of type 2 diabetes mellitus have different mechanisms. Among these, α-Glucosidase and α-amylase inhibitors are one of the most important inhibitors. The antidiabetic effect of the chalcones, which show rich activity, draws attention. This research aims to synthesize chalcone derivatives that could show potential antidiabetic activity. In this study, the inhibitory activity of the chalcone compounds (4a-4g, 5a-5g) was tested against α-glucosidase and α-amylase enzymes. Besides, molecular modeling was utilized to predict potential interactions of the synthesized compounds that exhibit inhibitory effects. In both in vitro and in silico studies, the analyses revealed that compound 5e exhibits strong inhibitory effects against α-glucosidase enzymes (Binding energy: -7.75 kcal/mol, IC50 : 28.88 µM). Additionally, compound 4f demonstrates encouraging inhibitory effects against α-Amylase (Binding energy: -11.08 kcal/mol, IC50 : 46. 21 µM).

Urinary neopterin and biopterin indicate that inflammation has a role in autism spectrum disorder.

Inflammation is thought to be involved in the pathogenesis of autism spectrum disorder (ASD). Pteridine metabolites are biomarkers of inflammation that increase on immune system activation. In this study, we investigated the urinary pteridine metabolites in ASD patients as a possible biomarker for immune activation and inflammation. This observational, cross-sectional, prospective study collected urine samples from 212 patients with ASD and 68 age- and sex-matched healthy individuals. Urine neopterin (NE) and biopterin (BIO) levels were measured. Patients who had chronic disorders, active infection at the time of sampling, or high C-reactive protein levels were excluded. The urine NE and BIO concentrations were determined by high-performance liquid chromatography. The ratios of both NE and BIO to creatinine (CRE) were used to standardise the measurements. The NE/CRE and NE/BIO levels were significantly higher in ASD patients than controls. Univariate and multivariate models revealed a significant increase in NE/CRE and NE/BIO in ASD patients. There was a significant relationship between the NE/BIO [average area under the curve (AUC) = 0.717; range: 0.637-0.797] and NE/CRE (average AUC = 0.756; range: 0.684-0.828) ratios, which distinguished individuals with ASD from controls. The elevated NE/CRE and NE/BIO ratios suggest that inflammation and T cell-mediated immunity are involved in the pathophysiology of autism. NE/BIO could serve as a diagnostic inflammatory marker in the pathogenesis of ASD.

Safety of COVID-19 vaccines in children with inborn errors of metabolism in terms of developing metabolic decompensation.

AIM: There are no recommended guidelines or clinical studies on safety of COVID-19 vaccines in patients with inborn errors of metabolism (IEMs). Here, we aimed to examine the relationship between COVID-19 vaccination and metabolic outcome in paediatric IEM patients. METHODS: Patients with IEM between the ages of 12 and 18 were enrolled. Term metabolic decompensation was defined as acute disruption in metabolic homeostasis due to vaccination. Clinical and biochemical markers were compared between pre- and post-vaccination periods. RESULTS: Data from a total of 36 vaccination episodes in 18 patients were included. Thirteen patients had intoxication-type metabolic disorders including organic acidemia (OA), urea cycle disorders (UCDs), maple syrup urine disease (MSUD) and phenylketonuria (PKU); 4 patients had energy metabolism disorders including fatty acid metabolism disorders and LIPIN 1 deficiency; and 1 patient had glycogen storage disorder (GSD) type 5. Seventeen patients received BNT162b2, and 1 received CoronaVac because of an underlying long QT syndrome. Fatty acid metabolism disorders, LIPIN 1 deficiency and GSD type 5 were included in the same group named 'metabolic myopathies'. In two PKU patients, plasma phenylalanine level increased significantly within 24 h following the second dose of vaccination. None of the OA, UCD, MSUD and metabolic myopathy patients experienced acute metabolic attack and had emergency department admission due to metabolic decompensation within 1 month after vaccination. CONCLUSIONS: COVID-19 vaccines did not cause acute metabolic decompensation in a cohort of 18 children with IEM.

Design, in Silico Studies and Biological Evaluation of New Chiral Thiourea and 1,3-Thiazolidine-4,5-dione Derivatives.

In this study, new chiral thiourea and 1,3-thiazolidine-4,5-dione derivatives were synthesized, it was aimed to evaluate the various biological activities and molecular docking of these compounds. Firstly, the new thioureas (1-16) were obtained by reacting 1-naphthylisothiocyanate with different chiral amines. Then, the chiral thioureas were cyclized with oxalyl chloride to obtain 1,3-thiazolidine-4,5-dione derivatives (17-32). All compounds were evaluated with several in vitro antioxidant and enzyme inhibition activities. Compound 30 was the most active compound against AChE, with a value of IC50 =8.09±0.58 µM. On the other hand, all compounds were tested in silico absorption, distribution, metabolism, and excretion (ADME) assays to better understand their bioavailability. These physicochemical properties, pharmacokinetics, and drug-likeness of all compounds were calculated using SwissADME. Furthermore, according to molecular docking analyses compound 30 exhibited significant binding affinities for all enzymes. Based on our overall observations, compound 30 could be recommended as a potential lead for the therapuetic of Alzheimer's.

Nocturnal Blood Pressure Estimation from Sleep Plethysmography Using Machine Learning.

BACKGROUND: Elevated nocturnal blood pressure (BP) is a risk factor for cardiovascular disease (CVD) and mortality. Cuffless BP assessment aided by machine learning could be a desirable alternative to traditional cuff-based methods for monitoring BP during sleep. We describe a machine-learning-based algorithm for predicting nocturnal BP using single-channel fingertip plethysmography (PPG) in healthy adults. METHODS: Sixty-eight healthy adults with no apparent sleep or CVD (53% male), with a median (IQR) age of 29 (23-46 years), underwent overnight polysomnography (PSG) with fingertip PPG and ambulatory blood pressure monitoring (ABPM). Features based on pulse morphology were extracted from the PPG waveforms. Random forest models were used to predict night-time systolic blood pressure (SBP) and diastolic blood pressure (DBP). RESULTS: Our model achieved the highest out-of-sample performance with a window length of 7 s across window lengths explored (60 s, 30 s, 15 s, 7 s, and 3 s). The mean absolute error (MAE ± STD) was 5.72 ± 4.51 mmHg for SBP and 4.52 ± 3.60 mmHg for DBP. Similarly, the root mean square error (RMSE ± STD) was 6.47 ± 1.88 mmHg for SBP and 4.62 ± 1.17 mmHg for DBP. The mean correlation coefficient between measured and predicted values was 0.87 for SBP and 0.86 for DBP. Based on Shapley additive explanation (SHAP) values, the most important PPG waveform feature was the stiffness index, a marker that reflects the change in arterial stiffness. CONCLUSION: Our results highlight the potential of machine learning-based nocturnal BP prediction using single-channel fingertip PPG in healthy adults. The accuracy of the predictions demonstrated that our cuffless method was able to capture the dynamic and complex relationship between PPG waveform characteristics and BP during sleep, which may provide a scalable, convenient, economical, and non-invasive means to continuously monitor blood pressure.

Anti-nuclear antibody testing in children: How much is really necessary?

BACKGROUND: Anti-nuclear antibody (ANA) testing is most commonly ordered by general pediatricians to evaluate children with musculoskeletal system complaints. Given the limited utility of the test, we aimed to estimate the effectiveness of ordering ANA testing in childhood. METHODS: Children referred to our department to be examined due to positive ANA findings between 2008 and 2020 were included in the study. Those with less than one-year follow-up period, those with previously known rheumatic or autoimmune disease, and those diagnosed as an autoimmune and/or rheumatic disease at the first visit were excluded. Data were obtained from their medical records, retrospectively. The parents of all of the patients were called via phone, data were verified, and missing information was collected. RESULTS: Three hundred and fifty-eight patients (230 females) were eligible for the study. The median age of positive ANA findings was 9.31 (1.3-17.86) years and the median follow-up duration was 4.85 (1-11.91) years. Most of the patients had no underlying disease (n = 337, 94.1%). The most common reason for ordering ANA testing was to evaluate musculoskeletal system symptoms (n = 225, 62.8%). None of our patients referred to us due to positive ANA findings developed any autoimmune conditions or ANA associated rheumatic disease. Hypermobility syndrome is the most common final diagnosis among our ANA-positive patients. CONCLUSION: We suggest that instead of using it as a screening tool, ANA testing should be performed only if there is a strong suspicion of autoimmune diseases or certain rheumatic conditions, such as systemic lupus erythematosus.

Dietary Fat and Sugar Differentially Affect ß-Adrenergic Stimulation of Cardiac ERK and AKT Pathways in C57BL/6 Male Mice Subjected to High-Calorie Feeding.

BACKGROUND: High dietary fat and sugar promote cardiac hypertrophy independently from an increase in blood pressure. The respective contribution that each macronutrient exerts on cardiac growth signaling pathways remains unclear. OBJECTIVE: The goal of this study was to investigate the mechanisms by which high amounts of dietary fat and sugar affect cardiac growth regulatory pathways. METHODS: Male C57BL/6 mice (9 wk old; n = 20/group) were fed a standard rodent diet (STD; kcal% protein-fat-carbohydrate, 29-17-54), a high-fat diet (HFD; 20-60-20), a high-fat and high-sugar Western diet (WD; 20-45-35), a high-sugar diet with mixed carbohydrates (HCD; 20-10-70), or a high-sucrose diet (HSD; 20-10-70). Body composition was assessed weekly by EchoMRI. Whole-body glucose utilization was assessed with an intraperitoneal glucose tolerance test. After 6 wk on diets, mice were treated with saline or 20 mg/kg isoproterenol (ISO), and the activity of cardiac growth regulatory pathways was analyzed by immunoblotting. Data were analyzed by ANOVA with data from the STD group included for references only. RESULTS: Compared with HCD and HSD, WD and HFD increased body fat mass 2.7- to 3.8-fold (P < 0.001), induced glucose intolerance (P < 0.001), and increased insulin concentrations >1.5-fold (P < 0.05), thereby enhancing basal and ISO-stimulated AKT phosphorylation at both threonine 308 and serine 473 residues (+25-63%; P < 0.05). Compared with HFD, the high-sugar diets potentiated ISO-mediated stimulation of the glucose-sensitive kinases PYK2 (>47%; P < 0.05 for HCD and HSD) and ERK (>34%; P < 0.05 for WD, HCD, and HSD), thereby leading to increased phosphorylation of protein synthesis regulator S6K1 at threonine 389 residue (>64%; P < 0.05 for WD, HCD, and HSD). CONCLUSIONS: Dietary fat and sugar affect cardiac growth signaling pathways in C57BL/6 mice through distinct and additive mechanisms. The findings may provide new insights into the role of overnutrition in pathological cardiac remodeling.

EEG-like signals can be synthesized from surface representations of single motor units of facial muscles.

Electrodes for recording electroencephalogram (EEG) are placed on or around cranial muscles; hence, their electrical activity may contaminate the EEG signal even at rest conditions. Due to its role in maintaining mandibular posture, tonic activity of temporalis muscle interferes with the EEG signal particularly at fronto-temporal locations at single motor unit (SMU) level. By obtaining surface representation of a motor unit, we can evaluate its interference in EEG and if we could sum surface representations of several tonically active motor units, we could estimate the overall myogenic contamination in EEG. Therefore, in this study, we followed re-composition (RC) approach and generated EEG-like artefact model using surface representations of single motor units (RC). Furthermore, we compared signal characteristics of RC signals with simultaneously recorded EEG signal at different locations in terms of power spectral density and coherence. First, we found that RC signal represented the power spectral distribution of an EMG signal. Second, RC signal reflected the discharge rate of a SMU giving the greatest surface representation amplitude and strongest interference appeared as distinguishable frequency peak on RC power spectra. Moreover, for strong interferences, RC also contaminated the EEG at F7 and other EEG electrodes. These findings are important to illustrate the susceptibility of EEG signal to myogenic artefacts even at rest and the research using EEG coherence comparisons should consider muscle activity while drawing conclusions about neuronal interactions and oscillations.

Reevaluation of reflex responses of the human masseter muscle to electrical lip stimulation.

We examined the reflex response of the human masseter muscle to electrical stimulation of the lip using both single motor unit and surface electromyogram based methods. Using the classical analysis methods, reflex response to mild electrical stimuli generated two distinct short-lasting inhibitions. This pattern may reflect the development of combinations of short- and long-latency inhibitory postsynaptic potentials as a result of the mildly painful electrical lip stimulation. However, this pattern appearing in the classical analysis methods may have developed as a consequence of earlier responses and may not be genuine. This study examined the genuineness of these responses using both the classical analysis methods and the discharge rate method to uncover the realistic postsynaptic potentials in human trigeminal motor nucleus. Using the discharge rate method, we found that the electrical lip stimulation only generated a long-lasting single or compound inhibitory response that is followed by late, long-lasting excitation. These findings have important implications on the redrawing of the neuronal pathways of the trigeminal nerve that are frequently used to judge neuromuscular disorders of the trigeminal region.NEW & NOTEWORTHY We examined the human masseter reflex response to electrical stimulation of lower lip to uncover realistic postsynaptic potentials in the trigeminal motor nucleus. We found that the stimulation generates a long-lasting single or compound inhibitory response that is followed by a late, long-lasting excitation. These findings have important implications on the redrawing of the neuronal pathways of the trigeminal nerve that are frequently used to judge neuromuscular disorders of the trigeminal region.

Vibration parameters affecting vibration-induced reflex muscle activity.

PURPOSE: To determine vibration parameters affecting the amplitude of the reflex activity of soleus muscle during low-amplitude whole-body vibration (WBV). MATERIALS AND METHODS: This study was conducted on 19 participants. Vibration frequencies of 25, 30, 35, 40, 45, and 50 Hz were used. Surface electromyography, collision force between vibration platform and participant's heel measured using a force sensor, and acceleration measured using an accelerometer fixed to the vibration platform were simultaneously recorded. RESULTS: The collision force was the main independent predictor of electromyographic amplitude. CONCLUSION: The essential parameter of vibration affecting the amplitude of the reflex muscle activity is the collision force.

Whole-body vibration-induced muscular reflex: Is it a stretch-induced reflex?

[Purpose] Whole-body vibration (WBV) can induce reflex responses in muscles. A number of studies have reported that the physiological mechanisms underlying this type of reflex activity can be explained by reference to a stretch-induced reflex. Thus, the primary objective of this study was to test whether the WBV-induced muscular reflex (WBV-IMR) can be explained as a stretch-induced reflex. [Subjects and Methods] The present study assessed 20 healthy males using surface electrodes placed on their right soleus muscle. The latency of the tendon reflex (T-reflex) as a stretch-induced reflex was compared with the reflex latency of the WBV-IMR. In addition, simulations were performed at 25, 30, 35, 40, 45, and 50 Hz to determine the stretch frequency of the muscle during WBV. [Results] WBV-IMR latency (40.5 ± 0.8 ms; 95% confidence interval [CI]: 39.0-41.9 ms) was significantly longer than T-reflex latency (34.6 ± 0.5 ms; 95% CI: 33.6-35.5 ms) and the mean difference was 6.2 ms (95% CI of the difference: 4.7-7.7 ms). The simulations performed in the present study demonstrated that the frequency of the stretch signal would be twice the frequency of the vibration. [Conclusion] These findings do not support the notion that WBV-IMR can be explained by reference to a stretch-induced reflex.

Discovery of New Dual-Target Agents Against PPAR-γ and α-Glucosidase Enzymes with Molecular Modeling Methods: Molecular Docking, Molecular Dynamic Simulations, and MM/PBSA Analysis.

Type 2 diabetes mellitus (T2DM) has become a serious public health problem both in our country and worldwide, being the most prevalent type of diabetes. The combined use of drugs in the treatment of T2DM leads to serious side effects, including gastrointestinal problems, liver toxicity, hypoglycemia, and treatment costs. Hence, there has been a growing emphasis on drugs that demonstrate dual interactions. Several studies have suggested that dual-target agents for peroxisome proliferator-activated receptor-γ (PPAR-γ) and alpha-glucosidase (α-glucosidase) could be a potent approach for treating patients with diabetes. We aim to develop new antidiabetic agents that target PPAR-γ and α-glucosidase enzymes using molecular modeling techniques. These compounds show dual interactions, are more effective, and have fewer side effects. The molecular docking method was employed to investigate the enzyme-ligand interaction mechanisms of 159 newly designed compounds with target enzymes. Additionally, we evaluated the ADME properties and pharmacokinetic suitability of these compounds based on Lipinski and Veber's rules. Compound 70, which exhibited favorable ADME properties, demonstrated more effective binding energy with both PPAR-γ and α-glucosidase enzymes (-12,16 kcal/mol, -10.07 kcal/mol) compared to the reference compounds of Acetohexamide (-9.31 kcal/mol, -7.48 kcal/mol) and Glibenclamide (-11.12 kcal/mol, -8.66 kcal/mol). Further, analyses of MM/PBSA binding free energy and molecular dynamics (MD) simulations were conducted for target enzymes with compound 70, which exhibited the most favorable binding affinities with both enzymes. Based on this information, our study aims to contribute to the development of new dual-target antidiabetic agents with improved efficacy, reduced side effects, and enhanced reliability for diabetes treatment.

Insights into vascular physiology from sleep photoplethysmography.

STUDY OBJECTIVES: Photoplethysmography (PPG) in consumer sleep trackers is now widely available and used to assess heart rate variability (HRV) for sleep staging. However, PPG waveform changes during sleep can also inform about vascular elasticity in healthy persons who constitute a majority of users. To assess its potential value, we traced the evolution of PPG pulse waveform during sleep alongside measurements of HRV and blood pressure (BP). METHODS: Seventy-eight healthy adults (50% male, median [IQR range] age: 29.5 [23.0, 43.8]) underwent overnight polysomnography (PSG) with fingertip PPG, ambulatory blood pressure monitoring, and electrocardiography (ECG). Selected PPG features that reflect arterial stiffness: systolic to diastolic distance (∆T_norm), normalized rising slope (Rslope) and normalized reflection index (RI) were derived using a custom-built algorithm. Pulse arrival time (PAT) was calculated using ECG and PPG signals. The effect of sleep stage on these measures of arterial elasticity and how this pattern of sleep stage evolution differed with participant age were investigated. RESULTS: BP, heart rate (HR) and PAT were reduced with deeper non-REM sleep but these changes were unaffected by the age range tested. After adjusting for lowered HR, ∆T_norm, Rslope, and RI showed significant effects of sleep stage, whereby deeper sleep was associated with lower arterial stiffness. Age was significantly correlated with the amount of sleep-related change in ∆T_norm, Rslope, and RI, and remained a significant predictor of RI after adjustment for sex, body mass index, office BP, and sleep efficiency. CONCLUSIONS: The current findings indicate that the magnitude of sleep-related change in PPG waveform can provide useful information about vascular elasticity and age effects on this in healthy adults.

Exosomes released from cisplatin-resistant ovarian cancer cells modulate the reprogramming of cells in tumor microenvironments toward the cancerous cells.

Exosomes released from cancer cells are involved in the reorganization of the tumor microenvironment which is the essential aspect of cancer pathogenesis. The intercommunications between cancer cells and diverse cell types in the microenvironment are accomplished by exosomes in ovarian cancer. Internalization pathway, intracellular fate, and biological functions in recipient cells mediated by exosomes released from cisplatin-resistant A2780cis have been studied. Also, histopathological evaluation of tumor, ovary, liver tissues and lymph nodes in vivo studies have been performed. The recipient cells internalized the exosomes via active uptake mechanisms, as shown by confocal microscopy. However, inhibitor studies and flow cytometry analysis showed that each recipient cell line used different uptake pathways. Also, confocal microscopy imaging indicated that the internalized exosomes trapped in the endosomes or phagosomes were distributed to the different cellular compartments including ER, Golgi, and lysosome. The transfer of exosomal oncogenic cargo into the cells modified the intracellular signaling of recipient cells including invasion and metastasis by Boyden-Chamber assay, proliferation by ATP analysis, epithelial-mesenchymal transition (EMT) markers at protein and mRNA levels by western blotting and real-time PCR, and protein kinases in the phospho-kinase array. This remodeling contributed to the initiation of carcinogenesis in ovarian epithelial and peritoneal mesothelial cells, and the progression of carcinogenesis in ovarian cancer cells. In addition, intraperitoneal tumor model studies show that exosomes released from cisplatin-resistant A2780cis cells may play role in the enlargement of lymph nodes, and tumor formations integrated with the liver, attached to the stomach and in the ovarian tissues.

Design, synthesis, and enzyme inhibition evaluation of some novel Mono- and Di-O-ß-D-Glycopyranosyl Chalcone analogues with molecular docking studies.

In this study, some novel mono- and di-O-ß-D-glycopyranosyl chalcone analogs were designed, synthesized, and characterized. The chalcone derivatives were synthesized with good yields by base-catalyzed Claisen-Schmidt condensation in EtOH solution. Then these chalcones were reacted with TAGBr (2,3,4,6-tetra-O-acetyl-α-D-glucopyranosylbromide) in dry acetone under the anhydrous condition at 0-5 °C. Deacylated was carried out by the Zemplen's method with NaOCH3 in dry methanol results in substituted chalcone-O-glycosides (mono- and di-O-ß-D-glycopyranosyl chalcone analogs). The chemical structures of all synthesized compounds were elucidated based on IR, NMR spectral data, and mass spectrometry. Further, the compounds (7a-c, 8a-c, 12a-c, 16a-c, and 17a-c) were tested for their enzyme inhibition activity against α-glycosidase, tyrosinase, and AChE with in vitro and in silico analysis. Amongst them, compounds 12a-c, 16a-c, and 17a-c displayed moderate or less enzyme inhibition activity against α-glycosidase while other compounds 7a-c and 8a-c) were not active. Remarkably interesting enzyme inhibition effects, with IC50 values below 30.59 ± 0.30 µM were recorded with 7c (IC50=11.07 ± 0.55 µM) against tyrosinase.

Synthesis and evaluation of the antioxidant and anti-tyrosinase activities of thiazolyl hydrazone derivatives and their application in the anti-browning of fresh-cut potato.

Tyrosinase is a key enzyme in the biosynthesis of melanin, which is responsible for the browning of foods as well as many skin disorders. In order to develop new anti-browning agents with dual antioxidant and anti-tyrosinase capacities, a series of 30 thiazolyl hydrazone derivatives were synthesized. Among the molecules prepared, 6 and 30 were found to be the most potent tyrosinase inhibitors with IC50 values ​​comparable to that of kojic acid. Interestingly, 6 also has the highest radical scavenging activity among the prepared molecules. The inhibition kinetics study indicated that 6 is a non-competitive inhibitor while 30 inhibits tyrosinase competitively. The anti-browning assay of fresh-cut potato slices revealed that 6 and 30 are potent anti-browning agents with a capacity as high as kojic acid. The mechanisms of free radical scavenging and tyrosinase inhibition have been fully investigated in silico using computational kinetics, molecular docking, and molecular dynamics simulations.

A Rare Case of Laryngeal Osteosarcoma Causing Diagnostic Challenges.

Laryngeal osteosarcomas are extremely rare. They cause diagnostic difficulty for the otolaryngologist and pathologist. Differentiation from sarcomatoid carcinoma is challenging but important, as clinical features and treatment strategies are different. Total laryngectomy is generally the preferred surgical approach for laryngeal osteosarcomas. Since lymph node metastasis is not expected, neck dissection is not needed. In this report, we present a case diagnosed with laryngeal osteosarcoma post the examination of the total laryngectomy specimen of a laryngeal tumor that could not be histopathologically differentiated by punch biopsy.

Long-term neurodevelopmental effects of exclusively high cord lactate levels in term newborn.

INTRODUCTION: Cord arterial blood gas analysis (ABGA) results are used as diagnostic criteria for hypoxic-ischemic encephalopathy in newborns with suspected perinatal asphyxia. This study evaluated the effect of cord ABGA lactate level on the long-term neurodevelopment of newborns without any clinical signs of perinatal asphyxia. METHODS: This clinical observation study was designed among term babies born between 2018 and 2019 in our unit. Cases with a 5-min Apgar score <7 and signs of fetal distress in their antenatal follow-up were excluded. The cases (n = 1438) were divided into two groups those with high cord lactate levels (above 5 mmol/L, n = 92) and those with low lactate levels (below 2 mmol/L, n = 255). An Ages and Stages Questionnaire, Third Edition (ASQ-3) developmental screening questionnaire was sent to all parents. Patients with a chronological age between 24 and 42 months and for whom the parents fulfilled the questionnaire (low lactate group, n = 29, and high lactate group, n = 45) were evaluated. RESULTS: No difference was observed between the two groups in terms of demographic characteristics such as age (p = .1669), male gender (p = .906), mother's working situation (p = .948), mother's education level (p = .828), father's education level (p = .507), and family's total income (p = .642). Mean ACQ-3 developmental screening test scores were significantly lower in the high lactate group compared to the low lactate group concerning; fine motor (40 vs. 60, p = .001), problem-solving (50 vs. 60, p = .002), and personal social development (45 vs. 60, p = .003). No difference was observed in terms of communication and gross motor total scores. DISCUSSION: In general practice, routine cord ABGA is not generally recommended for patients with normal Apgar scores and no suspected hypoxia. However, in this study, we observed that cases with a normal 5-min Apgar score, no suspected perinatal asphyxia, and a cord lactate value of ≥5 fell behind their peers when evaluated with the ACQ-3 developmental screening questionnaire.

Design, Synthesis, Pharmacological Activities, Structure-Activity Relationship, and In Silico Studies of Novel 5-Substituted-2-(morpholinoimino)-thiazolidin-4-ones.

This study is aimed to synthesize morpholine- and thiazolidine-based novel 5-(substituted)benzylidene)-2-(morpholinoimino)-3-phenylthiazolidin-4-ones (3-26) and characterized by molecular spectroscopy. The synthesized compounds were subjected to antioxidant activity with anticholinesterase, tyrosinase, and urease inhibition activities and evaluated the structure-activity relationship (SAR) of enzyme inhibition activities. Compound 11 was found to be the most active antioxidant. In anticholinesterase inhibition, compound 12 (IC50: 17.41 ± 0.22 µM) was the most active against AChE, while compounds 3-26 ( except 3, 8, and 17) showed notable activity against BChE. Compounds 17 (IC50: 3.22 ± 0.70 mM), 15 (IC50: 5.19 ± 0.03 mM), 24 (IC50: 7.21 ± 0.27 mM), 23 (IC50: 8.05 ± 0.11 mM), 14 (IC50: 8.10 ± 0.22 mM), 25 (IC50: 8.40 ± 0.64 mM), 26 (IC50: 8.76 ± 0.90 mM), and 22 (IC50: 9.13 ± 0.55 mM) produced higher tyrosinase inhibition activity. In urease inhibition activity, compounds 20 (IC50: 16.79 ± 0.19 µM), 19 (IC50: 18.25 ± 0.50 µM), 18 (IC50: 20.24 ± 0.77 µM), 26 (IC50: 21.51 ± 0.44 µM), 25 (IC50: 21.70 ± 0.06 µM), and 24 (IC50: 22.49 ± 0.11 µM) demonstrated excellent activities. Besides, the molecular docking study was applied to better understand the inhibitory mechanism between (1-26) compounds and enzymes at the molecular level. According to the results of this study, the synthesized compounds exhibited a better binding affinity toward these enzymes compared to the positive control. Further, molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) binding free energy and molecular dynamics (MD) simulation analyses were performed for AChE with compound 26, which showed high inhibitory activity in silico and in vitro studies. In conclusion, novel morpholine and thiazolidine-based derivative compounds may be pharmacologically effective agents for AChE, BChE, tyrosinase, and urease enzymes.