Search

Automated preprocessing methods are critically needed to process the large publicly-available EEG databases, but the optimal approach remains unknown because we lack data quality metrics to compare them. Here, we designed a simple yet robust EEG data quality metric assessing the percentage of significant channels between two experimental conditions within a 100 ms post-stimulus time range. Because of volume conduction in EEG, given no noise, most brain-evoked related potentials (ERP) should be visible on every single channel. Using three publicly available collections of EEG data, we showed that, with the exceptions of high-pass filtering and bad channel interpolation, automated data corrections had no effect on or significantly decreased the percentage of significant channels. Referencing and advanced baseline removal methods were significantly detrimental to performance. Rejecting bad data segments or trials could not compensate for the loss in statistical power. Automated Independent Component Analysis rejection of eyes and muscles failed to increase performance reliably. We compared optimized pipelines for preprocessing EEG data maximizing ERP significance using the leading open-source EEG software: EEGLAB, FieldTrip, MNE, and Brainstorm. Only one pipeline performed significantly better than high-pass filtering the data.

Adverse reactions to tuberculosis treatment can impact patient adherence and prognosis. Hypothyroidism is a frequent adverse reaction caused using ethionamide, prothionamide, and para-aminosalicylic acid and is often underdiagnosed. We searched Scielo, Scopus, and EMBASE databases, including 67 articles. Antitubercular drug-induced hypothyroidism has a prevalence of 17%. It occurs after 2 to 3 months of treatment and resolves within 4 to 6 weeks after discontinuation. It is postulated to result from the inhibition of thyroperoxidase function, blocking thyroid hormone synthesis. Symptoms are nonspecific, necessitating individualized thyroid-stimulating hormone measurement for detection. Specific guidelines for management are lacking, but initiation of treatment with levothyroxine, as is customary for primary hypothyroidism, is recommended. Discontinuation of antitubercular drugs is discouraged, as it may lead to unfavorable consequences. Antitubercular drug-induced hypothyroidism is more common than previously thought, affecting one in six MDR-TB patients. Despite diagnostic and treatment recommendations, implementation is hindered in low-income countries due to the lack of certified laboratories. New drugs for tuberculosis treatment may affect thyroid function, requiring vigilant monitoring for complications, including hypothyroidism. [ABSTRACT FROM AUTHOR]

BackgroundTreatment of multidrug-resistant tuberculosis requires long-term therapy with a combination of multiple second-line drugs. These drugs are associated with numerous adverse events that can cause severe morbidity, such as deafness, and in some instances can lead to death. Our aim was to estimate the absolute and relative frequency of adverse events associated with different tuberculosis drugs to provide useful information for clinicians and tuberculosis programmes in selecting optimal treatment regimens.MethodsWe did a meta-analysis using individual-level patient data that were obtained from studies that reported adverse events that resulted in permanent discontinuation of anti-tuberculosis medications. We used a database created for our previous meta-analysis of multidrug-resistant tuberculosis treatment and outcomes, for which we did a systematic review of literature published between Jan 1, 2009, and Aug 31, 2015 (updated April 15, 2016), and requested individual patient-level information from authors. We also considered for this analysis studies contributing patient-level data in response to a public call made by WHO in 2018. Meta-analysis for proportions and arm-based network meta-analysis were done to estimate the incidence of adverse events for each tuberculosis drug.Findings58 studies were identified, including 50 studies from the updated individual patient data meta-analysis for multidrug-resistant tuberculosis treatment. 35 of these studies, with 9178 patients, were included in our analysis. Using meta-analysis of proportions, drugs with low risks of adverse event occurrence leading to permanent discontinuation included levofloxacin (1·3% [95% CI 0·3-5·0]), moxifloxacin (2·9% [1·6-5·0]), bedaquiline (1·7% [0·7-4·2]), and clofazimine (1·6% [0·5-5·3]). Relatively high incidence of adverse events leading to permanent discontinuation was seen with three second-line injectable drugs (amikacin: 10·2% [6·3-16·0]; kanamycin: 7·5% [4·6-11·9]; capreomycin: 8·2% [6·3-10·7]), aminosalicylic acid (11·6% [7·1-18·3]), and linezolid (14·1% [9·9-19·6]). Risk of bias in selection of studies was judged to be low because there were no important differences between included and excluded studies. Variability between studies was significant for most outcomes analysed.InterpretationFluoroquinolones, clofazimine, and bedaquiline had the lowest incidence of adverse events leading to permanent drug discontinuation, whereas second-line injectable drugs, aminosalicylic acid, and linezolid had the highest incidence. These results suggest that close monitoring of adverse events is important for patients being treated for multidrug-resistant tuberculosis. Our results also underscore the urgent need for safer and better-tolerated drugs to reduce morbidity from treatment itself for patients with multidrug-resistant tuberculosis.FundingCanadian Institutes of Health Research, Centers for Disease Control and Prevention (USA), American Thoracic Society, European Respiratory Society, and Infectious Diseases Society of America.

Current machine learning classifiers have successfully been applied to whole-genome sequencing data to identify genetic determinants of antimicrobial resistance (AMR), but they lack causal interpretation. Here we present a metabolic model-based machine learning classifier, named Metabolic Allele Classifier (MAC), that uses flux balance analysis to estimate the biochemical effects of alleles. We apply the MAC to a dataset of 1595 drug-tested Mycobacterium tuberculosis strains and show that MACs predict AMR phenotypes with accuracy on par with mechanism-agnostic machine learning models (isoniazid AUC = 0.93) while enabling a biochemical interpretation of the genotype-phenotype map. Interpretation of MACs for three antibiotics (pyrazinamide, para-aminosalicylic acid, and isoniazid) recapitulates known AMR mechanisms and suggest a biochemical basis for how the identified alleles cause AMR. Extending flux balance analysis to identify accurate sequence classifiers thus contributes mechanistic insights to GWAS, a field thus far dominated by mechanism-agnostic results.

Objectives5-aminosalicylates (5-ASA) are frequently continued in patients with moderate-severe ulcerative colitis (UC), even after escalation to biologic agents, without evaluation of the benefit of this approach. We conducted an individual participant data (IPD) pooled analysis of trials of infliximab and golimumab in UC, to evaluate whether concomitant use of 5-ASA modifies clinical outcomes among anti-tumor necrosis factor (TNF)-α-treated patients.MethodsWe included IPD from five trials of infliximab and golimumab in patients with moderate-severe UC (ACT-1 and -2, PURSUIT-SC, PURSUIT-M, NCT00336492). Patients treated with infliximab or golimumab were categorized as receiving concomitant 5-ASA or not at time of trial entry. Primary outcome was clinical remission (Mayo Clinic Score

Compound 5-{[(2E)-3-bromo-3-carboxyprop-2-enoyl]amino}-2-hydroxybenzoic acid (C1), a new 5-aminosalicylic acid (5-ASA) derivative, has proven to be an antioxidant in vitro and an anti-inflammatory agent in mice. The in vivo inhibition of myeloperoxidase was comparable to that of indomethacin. The aim of this study was to take another step in the preclinical evaluation of C1 by examining acute toxicity with the up-and-down OECD method and pharmacokinetic profiles by administration of the compound to Wistar rats through intravenous (i.v.), oral (p.o.), and intraperitoneal (i.p.) routes. According to the Globally Harmonized System, C1 belongs to categories 4 and 5 for the i.p. and p.o. routes, respectively. An RP-HPLC method for C1 quantification in plasma was successfully validated. Regarding the pharmacokinetic profile, the elimination half-life was approximately 0.9 h with a clearance of 24 mL/min after i.v. administration of C1 (50 mg/kg). After p.o. administration (50 mg/kg), the maximum plasma concentration was reached at 33 min, the oral bioavailability was about 77%, and the compound was amply distributed to all tissues evaluated. Therefore, C1 administered p.o. in rats is suitable for reaching the colon where it can exert its effect, suggesting an important advantage over 5-ASA and indomethacin in treating ulcerative colitis and Crohn’s disease.

This article introduces a Combined .symmetrical and complementary Input Pairs (CIP) of a Differential Difference Amplifier (DDA), to boost the total Common-Mode Rejection Ratio (CMRR) for multi-channel neural signal recording. The proposed CIP-DDA employs three input pairs (transconductors). The dc-coupled input neural signal connection, via the gate terminal of the first transconductor, yields a high input impedance. The high-pass corner frequency and dc quiescent operation point are stabilized by the second transconductor. The calibration path of differential-mode gain and Common-Mode Feedback (CMFB) is provided by the proposed third transconductor. The parallel connection has no need for extra voltage headroom of input and output. The proposed CIP-DDA is targeted at integrated circuit realization and designed in a 0.18-μm CMOS technology. The proposed CIP-DDAs with system CMFB achieve an average CMRR of 103 dB, and each channel consumes circa 3.6 μW power consumption.

Background: The selective recognition of drugs and its metabolism or decomposition products is significant to drug development and drug resistance research. Fluorescence-based techniques provide satisfying sensitivity by target-triggered chemical reaction. However, the interference from the matrix or additives usually restricts the specific detection. It is highly desirable to explore specific chemical reactions for achieving selective perception of these species., Results: We report a specific m-aminophenol (MAP)-dopamine (DA) reaction, which generates highly fluorescent azamonardine-like products. Based on this reaction, fluorometric and indirect detection of p-aminosalicylic acid (typical antituberculosis drug, PAS) can be realized using the DA-based probe with high sensitivity. The acid induces the decarboxylation of PAS and produces MAP, which reacts with DA and generates fluorescent azamonardine-like products. The practical application of the proposed method is validated by the accurate PAS analysis in urine samples and Pasinazid tablets. Interestingly, none of additives in the Pasinazid tablets contribute comparable fluorescence variation., Significance: This work discovers a new MAP-DA reaction for the first time, it not only explores sensitive PAS drug detection probe, but also demonstrates the feasibility of the development of novel drug analysis platform by recognizing decomposition product with specific reaction. Thus, new avenues for the exploration of simple and rapid spectrophotometric probes toward various drug analytes with high specify and sensitivity based on this tactic might be possible in analytical and drug-related fields., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Objective: This study aims to further explore the role of angiogenic vs anti-angiogenic factors in placenta accreta spectrum (PAS)., Methods: This cohort study included all patients with placenta previa and placenta accreta spectrum (PAS) disorders undergoing surgery at Dr. Soetomo Hospital (Academic Hospital of Universitas Airlangga, Surabaya, Indonesia) from May to September 2021. Venous blood samples for PLGF and sFlt-1 were drawn immediately prior to surgery. Placental tissue samples were taken during surgery. The FIGO grading was diagnosed intraoperatively by an experienced surgeon and confirmed by the pathologist and followed by immunohistochemistry (IHC) staining. The sFlt-1 and PLGF serum were performed by an independent laboratory technician., Results: Sixty women were included in this study (20 women with placenta previa; 10 women with FIGO PAS grade 1; 8 women with FIGO PAS grade 2; 22 women with FIGO PAS grade 3). The median with 95% Confidence interval of PLGF serum values in placenta previa, FIGO grade I, grade II, and grade III were 233.68 (0.00-2434.00), 124.39 (10.42-663.68), 236.89 (18.83-418.99) and 237.31 (2.26-3101.00) ( p  = .736); the median values with 95% CI of serum sFlt-1 levels in placenta previa, FIGO grade I, grade II, and grade III were 2816.50 (418.00-12925.00), 2506.00 (227.50-16104.00), 2494.50 (888.52-20812.00), and 1601.00 (662.16-9574.00) ( p  = .037). Placental PLGF expression in placenta previa, FIGO grade 1, grade II, and grade III showed median values (with 95% CI) of 4.00 (1.00-9.00), 4.00 (2.00-9.00), 4.00 (4.00-9.00), and 6.00 (2.00-9.00) ( p  = .001); sFlt-1 expression median values (with 95% CI) were 6.00 (2.00-9.00), 6.00 (2.00-9.00), 4.00 (1.00-9.00), and 4.00 (1.00-9.00) ( p  = .004). Serum PLGF and sFlt-1 levels did not correlate with placental tissue expression ( p  = .228; p  = .586)., Conclusion: There are differences in PAS's angiogenic processes ​according to the severity of trophoblast cell invasion. But there is no overall correlation between serum levels and PLGF and sFlt-1 expression in the placenta, suggesting the imbalance between angiogenic and anti-angiogenic are local mechanisms in the placental and the uterine wall.

George P Christophi, Arvind Rengarajan, Matthew A Ciorba Division of Gastroenterology, Washington University School of Medicine, St. Louis, MO, USA Abstract: Ulcerative colitis (UC) is an immune-mediated disease of the colon that is characterized by diffuse and continuous inflammation contiguous from the rectum. Half of UC patients have inflammation limited to the distal colon (proctitis or proctosigmoiditis) that primarily causes symptoms of bloody diarrhea and urgency. Mild-to-moderate distal UC can be effectively treated with topical formulations (rectal suppositories, enemas, or foam) of mesalamine or steroids to reduce mucosal inflammation and alleviate symptoms. Enemas or foam formulations adequately reach up to the splenic flexure, have a minimal side-effect ­profile, and induce remission alone or in combination with systemic immunosuppressive therapy. Herein, we compare the efficacy, cost, patient tolerance, and side-effect profiles of steroid and mesalamine rectal formulations in distal UC. Patients with distal mild-to-moderate UC have a remission rate of approximately 75% (NNT =2) after treatment for 6 weeks with mesalamine enemas. Rectal budesonide foam induces remission in 41.2% of patients with mild-to-moderate active distal UC compared to 24% of patient treated with placebo (NNT =5). However, rectal budesonide has better patient tolerance profile compared to enema formulations. Despite its favorable efficacy, safety, and cost profiles, patients and physicians significantly underuse topical treatments for treating distal colitis. This necessitates improved patient education and physician familiarity regarding the indications, effectiveness, and potential financial and tolerability barriers in using rectal formulations. Keywords: inflammatory bowel disease, treatment cost effectiveness, Crohn’s disease, ulcerative colitis, colon mucosa, proctitis suppositories, topical immunosuppressive therapy

Background and Aim Prevalence of colonic diverticulosis is increasing worldwide with age, and up to 25% of patients who have colonic diverticulosis might experience diverticulitis. However, a definitive approach of preventing recurrent diverticulitis remains unknown. 5-aminosalicylic acid (5-ASA) agents are anti-inflammatory agents and have been used to prevent recurrent diverticulitis, and there have been some randomized clinical trials (RCTs). However, the efficacy results for secondary prevention in uncomplicated diverticulitis differed across studies. Our aim was to clarify the efficacy and safety of 5-ASA agents in the prevention of recurrent diverticulitis. Methods We searched MEDLINE, EMBASE, Web of Science, and the Cochrane library with no language restrictions. Two reviewers independently assessed and selected RCTs. The data were pooled using a random effect model and were presented in the pooled risk ratio (RR) and 95% confidence interval (CI). Cochrane's Q and I-squared statistics were used to assess heterogeneity. The protocol was registered at PROSPERO. Results Seven articles with eight RCTs from 329 potentially relevant articles were included. 5-ASA agents were not superior to controls in preventing recurrent diverticulitis (RR 0.86, 95% CI 0.63 to 1.17, I2 = 60%) and the incidence of adverse events was not different between 5-ASA agents and controls (RR 0.97, 95% CI 0.84 to 1.11, I2 = 45%). However, some included studies were few in number of participants and substantial risk of bias. Conclusions 5-aminosalicylic acid agents were not associated with prevention of recurrent diverticulitis. [ABSTRACT FROM AUTHOR]

The article presents a novel circular substrate-integrated waveguide (SIW) bandpass filter (BPF) with controllable bandwidth. The proposed BPF was configured using two microstrip feed lines, semi-circular SIW cavities, capacitive slots, and inductive vias. The circular cavity was divided into two halves, and the two copies were cascaded. The resulting bisected and cascaded structures were then connected back-to-back. Finally, by introducing two inductive vias to the circular center cavity, a transmission zero was generated. In order to examine the design concept, a coupling matrix was generated. To demonstrate the theory, a third-order BPF was realized, fabricated, and experimentally validated. The BPF prototype features a wide passband of 8.7%, a low insertion loss of 1.1 dB, and a stopband of 1.5 f0 with a rejection level better than 20 dB, which makes it a potential candidate for microwave sensing and communication industries.

In this study, new derivatives of the antitubercular and anti-inflammatory drug, 4-aminosaliclic acids (4-ASA) were synthesized, characterized, and evaluated for these activities. In vivo and in viro evaluation of anti-inflammatory activity revealed that compounds 10, 19 and 20 are the most active with potent cyclooxygenase-2 (COX-2) and 5-lipooxgenase (5-LOX) inhibition and without causing gasric lesions. The minimum inhibitory concentrations (MIC) of the newly synthesized compound were, also, measured against Mycobacterium tuberculosis H37RV. Among the tested compounds 17, 19 and 20 exhibited significant activities against the growth of M. tuberculosis. 20 is the most potent with (MIC 1.04 µM) 2.5 folds more potent than the parent drug 4-ASA. 20 displayed low cytotoxicity against normal cell providing a high therapeutic index. Important structure features were analyzed by docking and structure-activity relationship analysis to give better insights into the structural determinants for predicting the anti-inflammatory and anti-TB activities. Our results indicated that compounds 19 and 20 are potential lead compounds for the discovery of dual anti-inflammatory and anti-TB drug candidates., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The title compound, C11H10N2O4S, crystallized with two independent molecules (A and B) in the asymmetric unit. They differ primarily in the rotational orientation of the five-membered heterocyclic ring. In molecule A this ring is inclined to the benzene ring by 48.17 (8)°, while in molecule B the same dihedral angle is 23.07 (8)°. In each molecule there is an intramolecular O—H...O hydrogen bond involving the adjacent hydroxyl group and the ester carbonyl O atom. In the crystal, the A molecules are linked via pairs of N—H...N hydrogen bonds, forming inversion dimers. These dimers are linked to the B molecules via N—H.·O, C—H...O and C—H...S hydrogen bonds forming corrugated sheets lying parallel to (102).

A new method for the selective extraction of p-aminosalicylic acid from aqueous and urine samples has been developed using magnetic molecularly imprinted polymer nanoparticles before determination by high-performance liquid chromatography. The Fe3O4 nanoparticles were first prepared through the chemical coprecipitation of Fe2+ and Fe3+ and then coated with a vinyl shell. Subsequently, a layer of molecularly imprinted polymers was grafted onto the vinyl-modified magnetic nanoparticles by precipitation polymerization. FTIR spectroscopy, scanning electron microscopy, vibrating sample magnetometry, and thermogravimetric analysis were applied to characterize the sorbent properties. Moreover, the predominant parameters affecting the magnetic solid phase extraction such as sample pH, sorption and elution times, the amount of sorbent, and composition and volume of eluent were investigated thoroughly. The maximum sorption capacity of the imprinted polymer toward p-aminosalicylic acid was 70.9 mg/g, which is 4.5 times higher than that of the magnetic nonimprinted polymer. The magnetic molecularly imprinted polymer nanoparticles were applied for the selective extraction of p-aminosalicylic acid from aqueous and urine samples and satisfactory results were achieved. The results illustrate that magnetic molecularly imprinted polymer nanoparticles have a great potential in the extraction of p-aminosalicylic acid from environmental and biological matrices. [ABSTRACT FROM AUTHOR]

Objective:Although aminosalicylic acid (ASA) preparations have been used as first-line drugs for the treatment of ulcerative colitis (UC), no consistent view has been established regarding the ASA dose during the remission-maintenance phase of the disease. In this study, we examined whether the ASA dose should be reduced during the remission-maintenance phase. Materials and methods:This study included 203 patients in the remission-maintenance phase of UC. The Mayo endoscopic subscore (MES) was used to evaluate mucosa. Comparison and analysis were performed between patients whose ASA dose had been unchanged and whose dose had been reduced, between patients with endoscopic healing (EH) group and those without endoscopic healing (WEH) group, and between patients with an MES of 0 and 1. Results:Comparison between the unchanged-ASA and reduced-ASA groups revealed that the remission-maintenance rate was higher in the unchanged-ASA group (p < 0.001). Next, the remission-maintenance rate was higher in the EH/unchanged-ASA group than in the EH/reduced-ASA group (p = 0.042). Comparison between the MES 0 and 1 groups revealed that the remission-maintenance rate was higher in the MES 0 group (p = 0.007). In addition, no significant difference in remission-maintenance rates was observed between the MES 0/unchanged-ASA group and the MES 0/reduced-ASA group (p = 0.108). Conclusion:When the same ASA dose is maintained regardless of the presence or absence of EH, remission is more likely to be maintained. If the ASA dose must be reduced, dose reduction is more advantageous after an MES of 0 is achieved. [ABSTRACT FROM PUBLISHER]

Inflammatory bowel disease and its various treatments may affect the kidney in several ways. Recently, case reports have been published documenting the development of nephrotic syndrome after the treatment for inflammatory bowel disease with 5-aminosalicylic acid derivatives. We report a 50-year-old patient who was diagnosed with Crohn′s disease and was treated with mesalamine. The patient subsequently developed nephrotic syndrome and a renal biopsy showed minimal change disease. He was treated with losartan and rosuvastatin and showed improvement in his renal function and serum cholesterol level. This is the first reported case in Crohn′s disease although there have been six previous case reports of nephrotic syndrome following salicylic acid derivatives for ulcerative colitis.

Background: Patients on immunosuppressive drugs have been excluded from COVID-19 vaccines trials, creating concerns regarding their efficacy., Aims: To explore the humoral response to COVID-19 vaccines in patients with inflammatory bowel disease (IBD) METHODS: Effectiveness and Safety of COVID-19 Vaccine in Patients with Inflammatory Bowel Disease (IBD) Treated with Immunomodulatory or Biological Drugs (ESCAPE-IBD) is a prospective, multicentre study promoted by the Italian Group for the study of Inflammatory Bowel Disease. We present data on serological response eight weeks after the second dose of COVID-19 vaccination in IBD patients and healthy controls (HCs)., Results: 1076 patients with IBD and 1126 HCs were analyzed. Seropositivity for anti-SARS-CoV-2 IgG was reported for most IBD patients, even if with a lesser rate compared with HCs (92.1% vs. 97.9%; p<0.001). HCs had higher antibody concentrations (median OD 8.72 [IQR 5.2-14-2]) compared to the whole cohort of IBD patients (median OD 1.54 [IQR 0.8-3.6]; p<0.001) and the subgroup of IBD patients (n=280) without any treatment or on aminosalicylates only (median OD 1.72 [IQR 1.0-4.1]; p<0.001)., Conclusions: Although most IBD patients showed seropositivity after COVID-19 vaccines, the magnitude of the humoral response was significantly lower than in HCs. Differently from other studies, these findings seem to be mostly unrelated to the use of immune-modifying treatments (ClinicalTrials.govID:NCT04769258)., Competing Interests: Conflict of interest FSM served as an advisory board member and/or received lecture grants from AbbVie, Biogen, Galapagos, Janssen, MSD, Pfizer, Samsung Bioepis, Takeda Pharmaceuticals. MP served as an advisory board member and/or received lecture grants from MSD, Takeda, Janssen, Pfizer, Abbvie. SS received lecture fees from or served as a consultant and advisory board member for AbbVie, Arena, Gilead, Janssen Pharmaceuticals and Takeda. CB received lecture fees from Takeda, MSD, AbbVie and Janssen. FC received lecture fees from or served as a consultant or advisory board member for Abbvie, Janssen, Pfizer, Takeda Pharmaceuticals. OMN received lecture fees from Ferring, Fresenius Kabi, and Janssen. MCF received consultancy fees from Roche, Takeda, Jannsen-Cilag, Pfizer, Sandoz, Biogen, Galapagos and research economic support from Abbvie. GF served as a consultant and advisory board member for Janssen, Takeda, Pfizer, Amgen, Celltrion, Sandoz, Samsung Bioepis, Ferring, Vifor, Galapagos. FC served as consultant to Abbvie, MSD, Takeda, Janssen, Roche, Celgene, Bristol Myers Squibb, Galapagos, Gilead, Pfizer, Mundipharma, Galapagos, Biogen, received lecture fees from Abbvie, Ferring, Takeda, Allergy Therapeutics, Janssen, Pfizer, Biogen, and unrestricted research grants from Giuliani, Sofar, MSD, Takeda, Abbvie .AO served as an advisory board member for AbbVie, Galapagos, MSD, Janssen, Pfizer, Takeda Pharmaceuticals, and received lecture grants from AbbVie, MSD, Sofar, Chiesi, Janssen, Pfizer, and Takeda Pharmaceuticals. All other authors: nothing to disclose., (Copyright © 2022. Published by Elsevier Ltd.)

Lead (Pb) is considered to be a major environmental pollutant and occupational health hazard worldwide which may lead to neuroinflammation. However, an effective treatment for Pb-induced neuroinflammation remains elusive. The aim of this study was to investigate the mechanisms of Pb-induced neuroinflammation, and the therapeutic effect of sodium para-aminosalicylic acid (PAS-Na, a non-steroidal anti-inflammatory drug) in rat cerebral cortex. The results indicated that Pb exposure induced pathological damage in cerebral cortex, accompanied by increased levels of inflammatory factors tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β). Moreover, Pb decreased the expression of silencing information regulator 2 related enzyme 1 (SIRT1) and brain-derived neurotrophic factor (BDNF), and increased the levels of high mobile group box 1 (HMGB1) expression and p65 nuclear factor-κB (NF-κB) phosphorylation. PAS-Na treatment ameliorated Pb-induced histopathological changes in rat cerebral cortex. Moreover, PAS-Na reduced the Pb-induced increase of TNF-α and IL-1β levels concomitant with a significant increase in SIRT1 and BDNF levels, and a decrease in HMGB1 and the phosphorylation of p65 NF-κB expression. Thus, PAS-Na may exert anti-inflammatory effects by mediating the SIRT1/HMGB1/NF-κB pathway and BDNF expression. In conclusion, in this novel study PAS-Na was shown to possess an anti-inflammatory effect on cortical neuroinflammation, establishing its efficacy as a potential treatment for Pb exposures., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objectives: This study investigated the prevalence and significant clinical outcomes of pre-extensively drug-resistant plus additional drug-resistant tuberculosis (pre-XDR-plus) in Henan Provincial Chest Hospital between 2017 and 2021., Methods: We analysed and summarized the drug sensitivity test (DST) results of clinical Mycobacterium tuberculosis (MTB) strains in TB patients seeking care in the Tuberculosis Clinical Medical Research Centre of Henan Province between 2017 and 2021. Medical records of pre-extensively drug-resistant plus additional drug-resistant TB patients were statistically analysed, including demographic characteristics, regimens, and outcomes., Results: Of the 3689 Mycobacterium tuberculosis strains, 639 (17.32%), 353 (9.56%), and 109 (2.95%), multidrug-resistant tuberculosis (MDR-TB), pre-extensively drug-resistant tuberculosis (pre-XDR), and pre-XDR-plus, respectively. The proportion of MDR decreased from 19.1% in 2017 to 17.5% in 2021 (χ 2  = 0.686, P = 0.407), the proportion of pre-XDR from 11.4% in 2017 to 9.0% in 2021 (χ 2  = 2.39, P = 0.122), and pre-XDR-plus from 4.7% in 2017 to 1.8% in 2020, with the declining trend was significant (χ 2  = 9.348, P = 0.002). The most commonly used anti-TB drugs were pyrazinamide (PZA, 37/46, 80.43%) and cycloserine (CS, 32/46, 69.57%), followed by linezolid (LZD, 25/46, 54.35%), protionamide (TH, 25/46, 54.35%), and para-aminosalicylic acid (PAS, 23/46, 50.00%). Patients receiving the LZD regimen were 5 times more likely to have a favourable outcome than those not receiving LZD (OR = 6.421, 95% CI 2.101-19.625, P = 0.001). Patients receiving a regimen containing CS were 4 times more likely to have a favourable outcome compared to those not taking CS (OR = 5.444, 95% CI 1.650-17.926, P = 0.005)., Conclusions: Our data suggest that the population of pre-XDR-plus had significantly decreased over the past five years in the Henan Provincial Chest Hospital. The COVID-19 and flood disaster affect TB patients' selection of medical services. In addition, the pre-XDR-plus patients whose regimens contain LZD or CS were more likely to have favourable outcomes., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

This paper presents a high-order low-pass filter for the equivalent-input-disturbance (EID) approach to improving the disturbance-rejection performance. The configuration characteristic of the presented filter clearly explains the reason why the disturbance-rejection performance is improved and provides a guideline to design it. Using the presented filter to replace the conventional filter derives a high-order EID (HEID) approach. It is easy to apply the small-gain theorem in deriving stability conditions of the HEID-based control system. Moreover, the presented filter is proved to be better than the conventional one. Finally, a comparison shows the validity and superiority of the presented method. And a simulation result shows that the HEID approach is easily extended in a multiple-input, multiple-output system even with effects of a white noise and parameter uncertainties., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 ISA. Published by Elsevier Ltd. All rights reserved.)

To compare the effects of aminosalicylic acid, glucocorticoids and immunosuppressants on the expression levels of multidrug resistance genes in patients with ulcerative colitis (UC), with the aim of providing a theoretical and therapeutic basis for the diagnosis, treatment, and prevention of UC. Fresh colonic mucosal tissues or postoperative pathological biopsies from 148 UC patients were collected, and the distribution sites and morphology of P-glycoprotein (P-gp) were detected using immunohistochemical staining. RT-PCR was used to quantify the expression levels of multidrug resistance gene (MDR1) mRNA before and after the corresponding treatment, and the effects of aminosalicylic acid, glucocorticoids and immunosuppressive drugs on P-gp were compared. In addition, the effects of the three drugs on MDR1 mRNA were analyzed. Administration of 5-aminosalicylic acid (5-ASA) drugs did not correlate with MDR1 expression in UC, whereas administration of glucocorticoids and immunosuppressive drugs was positively correlated with MDR1 expression profile. The expression levels of MDR1 mRNA and its product P-gp were significantly upregulated in patients who did not respond to glucocorticoids and immunosuppressive drugs. 5-ASA had no effect on the expression levels of MDR1 and its product P-gp in patients with a confirmed diagnosis of UC. However, the use of glucocorticoids and immunosuppressants can increase the expression level of MDR1., (© 2022. The Author(s).)

In this paper, a novel form of the Gaussian filter, the Mittag-Leffler filter is presented. This new filter uses the Mittag-Leffler function in the probability-density function. Such Mittag-Leffler distribution is used in the convolution kernel of the filter. The filter has three parameters that may adjust the curve shape due to the filter-forgetting factor. Illustrative examples present the main advantages of the proposed filter compared to classical Gaussian filtering techniques, as well as real ECG-signal denoising. Some implementation notes, along with the Matlab function, are also presented.

In this study, the effect of non-covalent interactions on the para-aminosalicylic acid complex is explored using density functional theory (DFT) in the gas phase and the solution. Our findings exhibit that the achieved binding energies considerably change on going from the gas phase to the solution. Based on the obtained results, the absolute value of the binding energy of the complex in the polar solvents is lower than the non-polar ones while in the gas phase it is higher than the solution. The atoms in molecules (AIM) and the natural bond orbital (NBO) analyses are applied to estimate the topological properties and the charge transfer during complexation, respectively. The results indicate that the presence of the cation-π interaction increases the strength of the intramolecular hydrogen bond in the studied complex. Finally, the various electronic descriptors such as energy gap, hardness, softness, and electronic chemical potential are investigated to gain further insight into these interactions. According to the achieved results, the high energy gap of the complex in the water solvent indicates high chemical stability and low reactivity compared to the others. On the other hand, the most reactive as well as the softest complex belongs to the gas phase., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Process impurities found in the drug substance 5-aminosalicylic acid were determined by micellar electrokinetic capillary chromatography (MECC). In order to enhance the detection of trace impurities, the parent drug was dissolved to an unusually high concentration of 5 mg/mL. To reduce the dispersive processes of electromigration dispersion and anti-stacking, both of which occur at high solute concentration, the electrolyte pH was adjusted to be close to the apparent isoelectric point (pI) of the zwitterionic drug. In this fashion, the net charge on the solute should approach zero thereby minimizing the aforementioned sources of band-broadening. Two additional developments are reported. Short sodium hydroxide washes were used to optimize the MECC reproducibility. The elimination of anti-stacking permitted the use of peak heights to quantitate low level impurities with improved precision. The method was compared to the high-performance liquid chromatographic (HPLC) method found in the United States Pharmacopoeia (USP). Both the MECC and HPLC methods were found to be similar with regard to migration-retention time reproducibility, peak area-height reproducibility, linearity and limit of quantitation. The MECC separation is 2× faster than HPLC. Both methods meet the system suitability requirements described in the USP. [Copyright &y& Elsevier]

An array of pharmaceutical compounds and impurities were used to investigate the applicability of atmospheric pressure ionization mass spectrometry (MS) to routinely detect coeluting impurities in HPLC (i.e. peak purity). Four drugs were individually tested against their related impurity set using a straightforward HPLC–MS peak purity strategy. For the investigated set, which represents 24 unique drug-impurity permutations, 75% of the coeluting impurities were detected at levels <1.0%, including one-third at 0.1% (%, w/w). Factors that affect the applicability of this peak purity approach are also discussed. [ABSTRACT FROM AUTHOR]

Our objective was to evaluate the performance of whole-genome sequencing (WGS) from early positive liquid cultures for predicting Mycobacterium tuberculosis complex (MTBC) drug resistance. Clinical isolates were obtained from tuberculosis patients at Shanghai Pulmonary Hospital (SPH). Antimicrobial susceptibility testing (AST) was performed, and WGS from early Bactec mycobacterial growth indicator tube (MGIT) 960-positive liquid cultures was performed to predict the drug resistance using the TB-Profiler informatics platform. A total of 182 clinical isolates were enrolled in this study. Using phenotypic AST as the gold standard, the overall sensitivity and specificity for WGS were, respectively, 97.1% (89.8 to 99.6%) and 90.4% (83.4 to 95.1%) for rifampin, 91.0% (82.4 to 96.3%) and 95.2% (89.1 to 98.4%) for isoniazid, 100.0% (89.4 to 100.0%) and 87.3% (80.8 to 92.1%) for ethambutol, 96.6% (88.3 to 99.6%) and 61.8% (52.6 to 70.4%) for streptomycin, 86.8% (71.9 to 95.6%) and 95.8% (91.2 to 98.5%) for moxifloxacin, 86.5% (71.2 to 91.5%) and 95.2% (90.3 to 98.0%) for ofloxacin, 100.0% (54.1 to 100.0%) and 67.6% (60.2 to 74.5%) for amikacin, 100.0% (63.1 to 100.0%) and 67.2% (59.7 to 74.2%) for kanamycin, 62.5% (24.5 to 91.5%) and 88.5% (82.8 to 92.8%) for ethionamide, 33.3% (4.3 to 77.7%) and 98.3% (95.1 to 99.7%) for para-aminosalicylic acid, and 0.0% (0.0 to 12.3%) and 100.0% (97.6 to 100.0%) for cycloserine. The concordances of WGS-based AST and phenotypic AST were as follows: rifampin (92.9%), isoniazid (93.4%), ethambutol (89.6%), streptomycin (73.1%), moxifloxacin (94.0%), ofloxacin (93.4%), amikacin (68.7%), kanamycin (68.7%), ethionamide (87.4%), para-aminosalicylic acid (96.2%) and cycloserine (84.6%). We conclude that WGS could be a promising approach to predict MTBC resistance from early positive liquid cultures. IMPORTANCE In this study, we used whole-genome sequencing (WGS) from early positive liquid (MGIT) cultures instead of solid cultures to predict drug resistance of 182 Mycobacterium tuberculosis complex (MTBC) clinical isolates to predict drug resistance using the TB-Profiler informatics platform. Our study indicates that WGS may be a promising method for predicting MTBC resistance using early positive liquid cultures.

Compound 5-{[(2E)-3-bromo-3-carboxyprop-2-enoyl]amino}-2-hydroxybenzoic acid (C1), a new 5-aminosalicylic acid (5-ASA) derivative, has proven to be an antioxidant in vitro and an anti-inflammatory agent in mice. The in vivo inhibition of myeloperoxidase was comparable to that of indomethacin. The aim of this study was to take another step in the preclinical evaluation of C1 by examining acute toxicity with the up-and-down OECD method and pharmacokinetic profiles by administration of the compound to Wistar rats through intravenous (i.v.), oral (p.o.), and intraperitoneal (i.p.) routes. According to the Globally Harmonized System, C1 belongs to categories 4 and 5 for the i.p. and p.o. routes, respectively. An RP-HPLC method for C1 quantification in plasma was successfully validated. Regarding the pharmacokinetic profile, the elimination half-life was approximately 0.9 h with a clearance of 24 mL/min after i.v. administration of C1 (50 mg/kg). After p.o. administration (50 mg/kg), the maximum plasma concentration was reached at 33 min, the oral bioavailability was about 77%, and the compound was amply distributed to all tissues evaluated. Therefore, C1 administered p.o. in rats is suitable for reaching the colon where it can exert its effect, suggesting an important advantage over 5-ASA and indomethacin in treating ulcerative colitis and Crohn's disease. [ABSTRACT FROM AUTHOR]

• Application of NC 3 carbon-like nanotube as a drug delivery system for 5-aminosalicylic acid anticancer drug is studied. • The solvation energy reveals the solubility of the studied drug in the aqueous medium. • Drug-carrier interaction is weakened in the acidic medium of cancerous tissues. One of the widespread applications of nano-materials which is currently investigated is in drug delivery vehicles for various anticancer drugs for reducing their serious side effects which is usually done through their transportation into targeted tumor cells. In this study, the performance of a pristine NC 3 carbon-like nanotube (NC 3 NT) was scrutinized as a vehicle to deliver 5-aminosalicylic acid (5-ASA) through density functional theory (DFT) at B3LYP-D3 theory level with 6-31G (d, p) basis set. The adsorption energies (E ads) for the ASA@NC 3 NT complexes were approximately −18.62 in the gas phase whereas they were approximately 29.73 kcal mol−1 in the water phase. The more negative E ad values in the solvent phase show that the NC 3 NT has the ability to enhance the solubility of 5-ASA and change the interaction between them in the aqueous phase. Based on fractional and NBO charge transfer analyses, the charge transport from the 5-ASA molecules to the surface of the NC 3 NT is significant. Moreover, the electronic spectra related to the ASA/NC 3 NT complexes have a blue shift towards shorter wavelengths of approximately 19 nm based on the ultraviolet–visible analysis. We can conclude, based on our calculations, that the above-mentioned nanotube could be employed as a vehicle for delivering 5-ASA. [ABSTRACT FROM AUTHOR]

Bile acids are believed to be involved in the formation of colonic cancer, and 5-aminosalicylic acid and other salicylates may have a protective role. The precise mechanisms of both actions are not known, but modifications (stimulation or inhibition) of basal or oxygen-radical induced DNA base hydroxylation as potential early events in tumor formation by these compounds may be involved in such actions. We, therefore, investigated whether: (1) bile acids in concentrations as they occur systemically or intraluminally are able to enhance basal or OH*-radical-stimulated base hydroxylation in DNA from calf thymus; (2) 5-aminosalicylic acid, its main intestinal metabolite N-acetyl-aminosalicylic acid and salicylate, the main aspirin metabolite, are able to inhibit this hydroxylation; and (3) DNA from calf thymus can be used as a model by comparing its base composition and hydroxylation with DNA from normal human colonic mucosa. We found an enhancement of the OH*-radical-induced DNA hydroxylation especially 8-OH adenine with 214.0%. On the other hand 5-ASA, N-acetyl-ASA, and salicylate showed a concentration-dependent inhibition of OH*-stimulated hydroxylation with IC50 between 0.04 +/- 0.01 mM (X +/- SD) and 1.3 +/- 0.1 mM. No effects were observed on basal hydroxylation. Electron spin resonance spectroscopy studies showed reduction of the corresponding base signals pointing to a scavenger mechanism. In DNA isolated from normal human colonic mucosa (N = 7) a similar base distribution was found as in calf thymus; hydroxylation was < or = 1.0% in both systems. From our results we conclude that DNA from calf thymus may serve as a model for human colonic mucosal DNA and that one of the carcinogenic actions of bile acids may be enhancement of oxygen-radical-induced DNA base hydroxylation, especially 8-OH adenine. The absence of effects under unstimulated conditions supports their role as cocarcinogens. The concentration-dependent inhibition of OH*-stimulated DNA hydroxylation by 5-ASA, salicylate, and N-acetyl-ASA may be a possible mechanism of chemoprevention. [ABSTRACT FROM AUTHOR]

There is a growing body of experimental data to suggest that the chronically inflamed intestine and/or colon may be subjected to considerable oxidative stress. The most probable sources of these oxidants are the phagocytic leukocytes since these cells are known to be present in large numbers in the inflamed mucosa and are known to produce significant amounts of reactive oxygen species in response to certain inflammatory stimuli. Because the colonic mucosa contains relatively small amounts of antioxidant enzymes (e.g. SOD, catalase, GSH peroxidase) it is possible that the gut mucosa may be overwhelmed during times of active inflammation which could result in intestinal injury. If reactive oxygen species play an important role in mediating mucosal injury in IBD then it should be possible to attenuate this injury by the use of antioxidants. One such drug is the sulfasalazine metabolite 5-ASA. It may not be coincidence that this potent antiinflammatory metabolite is a potent antioxidant that possesses multiple mechanisms of action including nitrogen, carbon and oxygen-centered free radical scavenging properties as well as the ability to decompose HOCl and scavenge hemoprotein-associated oxidants. In addition 5-ASA has the additional property of being able to chelate iron and render it poorly redox active. The reason that 5-ASA is so effective in vivo may be due to this multitude of antioxidant properties. This would also suggest that other, more potent antioxidants may prove beneficial in the treatment of IBD. [ABSTRACT FROM AUTHOR]

A six-week placebo-controlled trial of the efficacy and safety of 6 g per day of 4-aminosalicylic acid (4-ASA) was conducted in 30 subjects with mild to moderately severe ulcerative colitis. Subjects were stratified into groups having distal (< 60 cm) or more extensive (> 60 cm) disease. Diarrhea, bleeding, sigmoidoscopic and biopsy appearance, and physician global assessment were scored to judge efficacy. Safety was evaluated by monitoring untoward symptoms and laboratory values. Median percent improvement was significantly greater (P < 0.05) in the 4-ASA > 60-cm group (42.7%) than in the placebo > 60-cm group (21.2%), but 4-ASA was not better than placebo for the < 60-cm group or the total study group. Severe dyspepsia (one subject), abnormal AST (transient in five, persistent in one) and elevated lipase without pancreatitis (six subjects) were noted. Thus 6 g 4-ASA for six weeks was more effective than placebo in mild to moderate ulcerative colitis extending more than 60 cm above the anus, but not in distal disease, and the drug was generally well tolerated. [ABSTRACT FROM AUTHOR]

Introduction: Mycobacterium tuberculosis infections are associated with severe local inflammatory reactions, which may be life-threatening and lead to tuberculosis pathogenesis and associated complications. Inorganic nanolayers have been vastly exploited for biomedical applications (especially in drug delivery) because of their biocompatible and biodegradable nature with the ability to release a drug in a sustained manner. Herein, we report a new nanodelivery system of inorganic nanolayers based on magnesium layered hydroxides (MgLH) and a successfully intercalated anti-tuberculosis drug para-aminosalicylic acid (PAS)., Methods: The designed anti-tuberculosis nanodelivery composite, MgLH-PAS, was prepared by a novel co-precipitation method using MgNO 3 as well MgO as starting materials., Results: The designed nano-formulation, PAS-MgLH, showed good antimycobacterial and antimicrobial activities with significant synergistic anti-inflammatory effects on the suppression of lipopolysaccharide (LPS) stimulated inflammatory mediators in RAW 264.7 macrophages. The designed nano-formulation was also found to be biocompatible with human normal lung cells (MRC-5) and 3T3 fibroblast cells. Furthermore, the in vitro release of PAS from PAS-MgLH was found to be sustained in human body simulated phosphate buffer saline (PBS) solutions of pH 7.4 and pH 4.8., Discussion: The results of the present study are highly encouraging for further in vivo studies. This new nanodelivery system, MgLH, can be exploited in the delivery of other drugs and in numerous other biomedical applications as well., Competing Interests: The authors report no conflicts of interest for this work., (© 2021 Saifullah et al.)

Background: Sodium p-aminosalicylic acid (PAS-Na) was reported to exhibit anti-inflammatory effect in the nervous system. However, the mechanism by which PAS-Na exhibits anti-inflammatory effects on manganese (Mn)-stimulated BV2 microglia cells remains unclear. Thus, this study investigated the role of PAS-Na in Mn-stimulated BV2 microglial cells., Methods: Microglia-like BV2 were treated with MnCl 2 with or without the non-steroidal anti-inflammatory drug PAS-Na for 12 or 24 h to examine cell viability using MTT; for 24 or 48 h to examine levels of NLRP3, CASP1, IL-1β, and IL-18 mRNA using Real-Time quantitative PCR; for 48 h to examine levels of NLRP3 and CASP1 inflammasomes, measured by western blot analysis; and for 48 h to examine levels of inflammatory cytokines, measured by enzyme-linked immunosorbent assay., Results: The MTT assay showed that PAS-Na produced significant neuroprotective effect by preventing Mn-induced inflammation in BV2 microglial cells. PAS-Na significantly concentration and time dependently inhibited Mn-induced production of NLRP3, CASP1, IL-1β, and IL-18., Conclusion: Taken together, our results suggest that PAS-Na exerts anti-inflammatory effects in Mn-stimulated BV2 microglial cells via downregulation of NLRP3, CASP1, IL-1β, and I L-18. Furthermore, a high concentration and prolonged PAS-Na treatment appear necessary for its therapeutic efficacy. Taken together, we conclude that PAS-Na affords therapeutic efficacy in mitigating neurological conditions associated with neuroinflammation.

The crystal structure prediction of the possible stable packings of pharmaceutical drug 4-amino-2-hydroxybenzoic acid was initiated through ab initio methods. The lattice energy values of the hypothetical conformers of the molecule generated for the global search were minimized, employing the associated distributed multipolar electron density. The crystal packing with minimum global energy corresponds to the experimental crystal. The conformer generated from the valid minimization was subjected to Quantum Theory of Atoms In Molecules (QTAIM) analysis in order to improve insight on the chemical properties of the crystal on which the pharmaceutical activity depends. The electron density and the Laplacian of the electron density were analyzed in detail for the non-covalent interactions in the crystal. While the dimer formed by the COOH/COOH homo-synthon has the strongest energy and is mostly electrostatic, other dimers formed in the crystal are mostly stabilized by dispersive forces. The complementarity of the inner and exterior electrostatic potential on the Hirshfeld was analyzed in the different crystal packings generated. • 31 Crystal packings of aminosalicylic acid were predicted. • Predicted structure with lowest energy is close to real structure. • Electrostatic properties and molecular interactions were compared. [ABSTRACT FROM AUTHOR]

A new copper(II) complex derived from the ligand ethylene [O,O'-bis{5-{(1E)-(2 hydroxyphenyl)methylene]amino} - 2-hydroxybenzoic acid] was designed, synthesized and characterized by spectroscopic (IR, UV-Vis, ESI-MS, X-ray diffraction, EPR and elemental analytical methods . In vitro interaction studies were carried out with CT DNA, HSA and SOD targets by employing various biophysical methods viz ., UV-Vis, fluorescence, FTIR (in case of HSA only), circular dichroism and gel electrophoresis. Notably, the copper(II) complex exhibited a high propensity for DNA binding via electrostatic mode; The results of fluorescence titration revealed that the copper(II) complex strongly quench the intrinsic fluorescence of HSA through a static quenching procedure. Copper(II) complex cleaves pBR322 DNA via hydrolytic mechanism and strongly binds to the DNA minor groove. Furthermore, Copper(II) complex cleaves pBR322 DNA via hydrolytic pathway. Our results showed that copper(II) complex is capable of inhibiting the growth of MCF7, A2780 and K562 tumor cell lines revealed remarkable cytotoxicity of Cu(II) complex with GI 50 values <10 μg mL -1 for most of the cell lines tested, which accompanied by systemic toxicity as was evident from the slightly significant histopathologic alterations in liver of mice. In addition, Cu(II) complex exhibit excellent superoxide dismutase (SOD) mimetic activity with an IC 50 of 0.109 μM. Molecular docking studies of the Cu(II) complex were carried out with DNA, HSA and SOD targets to ascertain the specific binding mode thereby substantiated the spectroscopic results. Communicated by Ramaswamy H. Sarma.

Despite polymorphism of crystalline active pharmaceutical ingredients (APIs) being a common phenomenon, reports on polymorphic co-crystals are limited. As polymorphism can vastly affect API properties, controlling polymorph generation is crucial. Control of the polymorph nucleation through the use of different solvents during solution crystallization has been used to obtain a desirable crystal polymorph. There have been two reported polymorphic forms of the 4-aminosalicylic acid-sulfamethazine co-crystals. These forms were found to have different thermodynamic stabilities. However, the control of co-crystal polymorph generation using preparation parameter manipulation has never been reported. The aim of this study was to establish the effect of different solvent parameters on the formation of different co-crystal polymorphic forms. Selection of the solvents was based on Hansen Solubility Parameters (HSPs) as solvents with different solubility parameters are likely to interact differently with APIs, ultimately affecting co-crystallization. Eight solvents with different HSPs were used to prepare co-crystals by solvent evaporation at two different temperatures. Through characterization of the co-crystals, a new polymorph has been obtained. The hydrogen bond acceptability seemed to affect the co-crystal form obtained more than the hydrogen bond donation ability. Furthermore, the use of HSPs can be utilized as an easy calculation method in screening and design of co-crystals., (Copyright © 2020. Published by Elsevier B.V.)

Four forms of a salt combining two antitubercular drugs, clofazimine and 4-aminosalicylic acid, are reported and the crystal structure of two of these forms are described. TG/DSC analysis of all four forms demonstrate an increase in the temperature at which degradation (upon decarboxylation) occurs in comparison to pure 4-aminosalicylic acid. Water solubility evaluation indicates a significant increase of the amount of clofazimine detected in water (10.26 ± 0.52 μg/mL for form I, 12.27 ± 0.32 μg/mL for form II, 7.15 ± 0.43 μg/mL for form III and 8.50 ± 1.24 μg/mL for form IV) in comparison to pure clofazimine (0.20 ± 0.03 μg/mL)., (Copyright © 2020 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Mutations in the lipid transport protein ABCA12 cause the life-threatening skin condition harlequin ichthyosis (HI), which is characterized by the loss of skin barrier function, inflammation, and dehydration. Inflammatory responses in HI increase disease severity by impairing keratinocyte differentiation, suggesting amelioration of this phenotype as a possible therapy for the condition. Existing treatments for HI are based around the use of retinoids, but their value in treating patients during the neonatal period has been questioned relative to other improved management regimens, and their long-term use is associated with side effects. We have developed a conditional mouse model to demonstrate that topical application of the aminosalicylic acid derivatives 5ASA or 4ASA considerably improves HI keratinocyte differentiation without the undesirable side effects of the retinoid acitretin and salicylic acid (aspirin). Analysis of changes in gene expression shows that 4ASA in particular elicits compensatory upregulation of a large family of barrier function-related genes, many of which are associated with other ichthyoses, identifying this compound as a lead candidate for developing topical treatments for HI., Competing Interests: D.L.C., G.M.A.U., and I.M.S. are inventors on patent applications WO 2016/145488 A1, PCT/AU2016/050185, US 15/557405, India 201727036282, Europe 16764064.8, Australia 2016232987, Canada 2984949, Japan 2017-549008, and China 201680028353.X, related to ASA treatment of ichthyosis skin diseases and received funding from Factor Therapeutics under a research collaboration and option agreement., (© 2020 The Authors.)

The mechanism of action of para-aminosalicylic acid (PAS), a drug used to treat drug-resistant tuberculosis (TB), has been confirmed through the first synthesis and biochemical characterization of its active metabolite 7. The synthesis features the coupling of N 2 -acetyl-6-formylpterin obtained from the degradation of folic acid and appropriately functionalized arylamines to form Schiff bases. The sequential chemoselective reduction of the imine and pterin ring led to the formation of dihydrofolate analogue 7 and two other dihydropteroate species.

Literature dealing with antituberculosis chemotherapy of tuberculous meningitis (TBM) in adults and children is reviewed and recommendations made for the chemotherapy of TBM. Publications relating to the chemotherapy of TBM were reviewed which contribute to understanding the efficacy of different drugs and regimens in TBM treatment. The established classification of disease severity into stages I (no neurological signs and fully conscious), II (patients conscious but with neurological signs) and III (comatose or stuporous or with severe pareses) was used to compare regimens of isoniazid (INH), para-amino salicylic acid and streptomycin (INH regimens) used up to approximately 1970 with those using INH and rifampicin (RMP), supported by pyrazinamide and ethambutol or streptomycin (RMP regimens). Mortality in studies at all disease stages in adults or adults and children, with the children not distinguished, following INH regimens (12.4%, 25.2% and 55% at stages I, II and III respectively) did not differ significantly from that following introduction of RMP regimens (9.7%, 22.2% and 56% at stages I, II and III respectively), In studies of children only, mortality fell significantly following the introduction of RMP to 0%, 5.9% and 28.2% in children at stage I, II and III having been 10.2%, 22.3% and 49.4% respectively with INH regimens (P = 0.006). Following RMP regimens of 6 months duration, only 2 (1%) relapses occurred amongst 197 patients, after RMP regimens of 9-24 months only 1 (0.16%) relapse was recorded amongst 632 patients. Where INH resistance rates are <4% a directly observed INH, RMP, pyrazinamide and ethambutol for 2-months followed by INH and RMP for 4 months is recommended. If directly observed therapy cannot be practiced treatment duration should be extended to at least 9 months; if the risk of INH resistance or multidrug resistance is higher, the use of ethionamide and a fluoroquinolone and possibly cycloserine is recommended and pyrazinamide should be continued for full treatment duration. The penetration of RMP, ethambutol and streptomycin into cerebrospinal fluid is poor; higher dosages of RMP should be considered., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

The Tokyo metropolitan hospital society of chief medical technologist has carried out a staining survey once a year since 1992. This staining survey is performed to plan improvements of the staining technology at each hospital and reduction of differences among hospitals. This report describes the examination results for PAS stain, Papanicolaou stain, and PAM stain.

In this study, we proposed a testis-mediated germline chimera production system based on the transplantation of testicular cells directly into heterologous testes. The testicular cells of juvenile (4-wk-old) or adult (24-wk-old) Korean Ogol chickens with a recessive pigmentation inhibitory gene, with or without prior culture, were injected (2 x 10(7) cells/head) into the seminiferous tubules of juvenile or adult recipients with White Leghorn with a dominant pigmentation inhibitory gene in a 2 x 2 factorial arrangement. The localization of transplanted cells into the inner space of the seminiferous tubules was confirmed within 24 h after injection. Subsequent testcross analyses showed that 7.8% (5/64) of the recipients had chimeric status in their testes. The periods of time from transfer to hatching of the first progeny with black feathers were 38 and 45 days for adult cells transplanted into an adult recipient, 188 days for adult cells into a juvenile recipient, and 137 days for juvenile cells into a juvenile recipient. Culture of the testicular cells derived both colony-forming and monolayer-forming cells. The colony-forming cells were stained positively for periodic acid Schiff solution, and further reacted with anti-SSEA-1, anti-SSEA-3, and anti-SSEA-4 antibodies both before and after culture for 15 days. In conclusion, it may be possible to develop the testis-mediated germline chimera production technique, which extends the feasibility of genetic manipulations in avian species.

This study presents the morphology of the ovary, as well as the process of the vitellogenesis in oocytes of the tick Rhipicephalus sanguineus. The ovary of these individuals is of the panoistic type; therefore, it lacks nurse cells. This organ consists of a single tubular structure, continuous, and composed of a wall formed by small epithelial cells with rounded nuclei which delimit the lumen. The oocytes in the different developmental stages in this tick species were classified into five stages (I-V). They remain attached to the ovary during vitellogenesis by a cellular pedicel and afterwards the mature oocytes (stage V) are released into the ovary lumen.