Tag: nevin manimala

J Pharmacol Exp Ther. 2023 Oct 12:JPET-PI-2023-001663. doi: 10.1124/jpet.123.001663. Online ahead of print.

ABSTRACT

The chemical warfare agent sulfur mustard and its structural analog nitrogen mustard (NM) cause severe vesicating skin injuries. The pathologic mechanisms for the skin injury following mustard exposure are poorly understood, therefore, no effective countermeasure is available. Previous reports demonstrated the protective activity of carvedilol, an FDA-approved β-blocker, against ultraviolet radiation-induced skin damage. Thus, the current study evaluated the effects of carvedilol on NM-induced skin injuries in vitro and in vivo. In the murine epidermal cell line JB6 Cl 41-5a, β-blockers with different receptor subtype selectivity were examined. Carvedilol and both of its enantiomers R- and S-carvedilol were the only tested ligands statistically reducing NM-induced cytotoxicity. Carvedilol also reduced NM-induced apoptosis and p53 expression. In SKH-1 mice, NM increased epidermal thickness, damaged skin architecture, and induced NF-kB related pro-inflammatory genes as assessed by RT² Profiler{trade mark, serif} PCR Arrays. To model chemical warfare scenario, 30 minutes after exposure to NM, 10 µM carvedilol was applied topically. Twenty-four hours after NM exposure, carvedilol attenuated NM-induced epidermal thickening, which in such a short time is due to an anti-inflammatory activity; Ki-67 expression, a marker of cellular proliferation, and multiple pro-inflammatory genes. Supporting the in vitro data, the non-β-blocking R-enantiomer of carvedilol had similar effects as racemic carvedilol, and there was no difference between carvedilol and R-carvedilol in the RT² Profiler{trade mark, serif} PCR Array data suggesting that the skin protective effects are independent of the β-adrenergic receptors. These data suggest that the β-blocker carvedilol and its enantiomers can be repurposed as countermeasures against mustard-induced skin injuries. Significance Statement The chemical warfare agent sulfur mustard and its structural analog nitrogen mustard cause severe vesicating skin injuries for which no effective countermeasure is available. This study evaluated the effects of an FDA-approved b-blocker carvedilol on nitrogen mustard-induced skin injuries, to repurpose this cardiovascular drug as a medical countermeasure.

PMID:37827703 | DOI:10.1124/jpet.123.001663

Anal Chim Acta. 2023 Oct 23;1279:341762. doi: 10.1016/j.aca.2023.341762. Epub 2023 Sep 5.

ABSTRACT

Data sets derived from practical experiments often pose challenges for (robust) statistical methods. In high-dimensional data sets, more variables than observations are recorded and often, there are also data present that do not follow the structure of the data majority. In order to handle such data with outlying observations, a variety of robust regression and classification methods have been developed for low-dimensional data. The high-dimensional case, however, is more challenging, and the variety of robust methods is much more limited. The choice of the method depends on the specific data structure, and numerical problems are more likely to occur. We give an overview of selected robust methods as well as implementations and demonstrate the application with two high-dimensional data sets from tribology. We show that robust statistical methods combined with appropriate pre-processing and sampling strategies yield increased prediction performance and insight into data differing from the majority.

PMID:37827663 | DOI:10.1016/j.aca.2023.341762

Anal Chim Acta. 2023 Oct 23;1279:341822. doi: 10.1016/j.aca.2023.341822. Epub 2023 Sep 15.

ABSTRACT

BACKGROUND: Accurate methods to assess DNA integrity are needed for many biomolecular methods. A multiplex digital PCR (dPCR) method designed for interspaced target sequences can be used to assess sequence integrity of large DNA strands. The ratio of single positive partitions versus double positive partitions is then used to calculate the sheared DNA strands. However, this simple calculation is only valid with low DNA concentration. We here describe a method based on probability calculations which enables DNA quality analysis in a large dynamic range of DNA concentrations.

RESULTS: Known DNA integrity percentages were mimicked using artificial double stranded DNA in low, intermediate and high DNA concentration scenarios, respectively 600, 12500 and 30000 copies of DNA per reaction. At low concentrations both methods were similar. However, at the intermediate concentration (12500 copies per reaction) the ratio based method started producing a larger error than the proposed probability calculation method with a mean relative error of 20.7 and 16.7 for the Bruner and the proposed method respectively. At the high concentration (30000 copies per reaction) only the proposed method provided accurate measurements with a mean relative error of 60.9 and 9.3 for the ratio based and the proposed method respectively. Furthermore, while both methods have a bias, it is constant for the proposed method, while it decreases with the integrity of the DNA for the ratio based method. The probability calculation equation was extended to 4 dimensions and a proof of concept experiment was performed, the data suggested that the 4 dimensional equation is valid.

SIGNIFICANCE AND NOVELTY: We here validate a method of estimating DNA integrity with dPCR using multiple probe combinations, allowing fast and flexible DNA integrity analysis. Additionally, we extend the method from 2 to 4 plex for more accurate DNA integrity measurements.

PMID:37827643 | DOI:10.1016/j.aca.2023.341822

Anal Chim Acta. 2023 Oct 23;1279:341781. doi: 10.1016/j.aca.2023.341781. Epub 2023 Sep 6.

ABSTRACT

A water-soluble negative sulfonic propyl ether β-CD polymer (SPE-β-CDP) to be used as chiral selector in capillary electrophoresis (CE) was polymerized. The sulfonic substitution degree of each β-CD in SPE-β-CDP was statistically homogenized. The only one negative peak in electrophoretogram with indirect ultraviolate method proved its uniformity of electrophoretic behavior. There were 7.12 sulfonic substitution in β-CD unit and 164 μmole β-CD units in each gram of SPE-β-CDP, which corresponded a molecular weight of 7000 or more. Compared with monomer, SPE-β-CDP was lower effect on electrical current of CE, indicating a high concentration of SPE-β-CDP could be added. Its separation ability was verified by 12 chiral drugs. SPE-β-CDP also showed advantages of good water solubility, easy preparation and recovery to reduce the overall cost. However, five of 12 chiral drugs were hardly to be fully separated which was normal for any kind of chiral selector. A newly adjustable gravity mediated capillary electrophoresis (AGM-CE) technology was proposed and combined with SPE-β-CDP to enhance the chiral separation efficiencies of propranolol, salbutamol, omeprazole, ofloxacin and phenoxybenzamine which were markedly improved to 3.02, 1.17, 7.63, 4.14, and 2.81, respectively. Furthermore, its gradient mode (AGMg-CE) was also used to improve resolution through utilizing the zero mobility point, at which the effective apparent mobility of one racemate was zero. Resolutions of five chiral drugs were significantly improved, especially resolution of carvedilol changed from 0.43 to 1.0. These indicated SPE-β-CDP as chiral selector, AGM-CE and AGMg-CE as new CE technologies had a great potential in chiral separation.

PMID:37827633 | DOI:10.1016/j.aca.2023.341781

Anal Chim Acta. 2023 Oct 23;1279:341809. doi: 10.1016/j.aca.2023.341809. Epub 2023 Sep 8.

ABSTRACT

Intracellular metabolic profiling reveals real-time metabolic information useful for the study of underlying mechanisms of cells in particular conditions such as drug resistance. However, mass spectrometry (MS), one of the leading metabolomics technologies, usually requires a large number of cells and complex pretreatments. Surface enhanced Raman scattering (SERS) has an ultrahigh detection sensitivity and specificity, favorable for metabolomics analysis. However, some targeted SERS methods focus on very limited metabolite without global bioprofiling, and some label-free approaches try to fingerprint the metabolic response based on whole SERS spectral classification, but comprehensive interpretation of biological mechanisms was lacking. (95) RESULTS: We proposed a label-free SERS technique for intracellular metabolic profiling in complex cellular lysates within 3 min. We first compared three kinds of cellular lysis methods and sonication lysis shows the highest extraction efficiency of metabolites. To obtain comprehensive metabolic information, we collected a spectral set for each sample and further qualified them by the Pearson correlation coefficient (PCC) to calculate how many spectra should be acquired at least to gain the adequate information from a statistical and global view. In addition, according to our measurements with 10 pure metabolites, we can understand the spectra acquired from complex cellular lysates of different cell lines more precisely. Finally, we further disclosed the variations of 22 SERS bands in enzalutamide-resistant prostate cancer cells and some are associated with the androgen receptor signaling activity and the methionine salvage pathway in the drug resistance process, which shows the same metabolic trends as MS. (149) SIGNIFICANCE: Our technique has the capability to capture the intracellular metabolic fingerprinting with the optimized lysis approach and spectral set collection, showing high potential in rapid, sensitive and global metabolic profiling in complex biosamples and clinical liquid biopsy. This gives a new perspective to the study of SERS in insightful understanding of relevant biological mechanisms. (54).

PMID:37827617 | DOI:10.1016/j.aca.2023.341809

J Card Fail. 2023 Oct;29(10):1343-1344. doi: 10.1016/j.cardfail.2023.10.002.

NO ABSTRACT

PMID:37827599 | DOI:10.1016/j.cardfail.2023.10.002

Clin Radiol. 2023 Nov;78(11):832-838. doi: 10.1016/j.crad.2023.05.001. Epub 2023 Aug 14.

ABSTRACT

AIM: To investigate the reliability of post-mortem computed tomography (PMCT) in a case series of homicides involving blunt-force, sharp-force, and ballistic trauma.

MATERIALS AND METHODS: The study investigates 16 homicide cases that underwent PMCT before autopsy. Two radiologists assessed the PMCT examinations and the data were compared to the forensic pathology findings. Data were organised in broad categories: foreign bodies, external injuries, soft-tissue and organ injuries, fractures, air in cavities, fluid collections, random pathology, and wound track. Findings were organised by systems: head and neck, thorax, abdomen and pelvis, extremities. Cohen’s kappa statistics were used to assess observer agreement.

RESULTS: Six gunshot-related homicides (37.5%), seven sharp-force-related homicides (43.75%), two blunt-force-related deaths (12.5%), and one homicide due to mechanical asphyxia (1.25%) were analysed. A total of 64 fractures were reported by the pathologists, 67 by radiologist 1 and 68 by radiologist 2. Agreement was deemed substantial in all cases. Pathologists failed to report gas in cavities while radiologists underreported superficial injuries.

CONCLUSION: An overall observation was that less accurate findings were produced by the blinded radiologist in comparison to the non-blinded one. The extremeness of homicides obscured the interpretation of PMCT leading to the observed discrepancies. The combination of PMCT and autopsies is deemed optimal when investigating homicidal events.

PMID:37827593 | DOI:10.1016/j.crad.2023.05.001

Transfus Med Rev. 2023 Jul;37(3):150747. doi: 10.1016/j.tmrv.2023.150747. Epub 2023 Jun 16.

ABSTRACT

Secondary transmission of variant Creutzfeldt-Jakob disease (vCJD) can occur through blood transfusion or receipt of plasma-derived products. However, published reviews on this topic are outdated, focused on a single country or product type, or did not comprehensively review modeling studies on the risk of transfusion-transmission. We reviewed existing data on observed and modeled risks of transfusion-transmission of vCJD. To date, five patients are suspected to have acquired clinical vCJD or a vCJD infection after receiving a blood or plasma-derived product from a donor who later developed clinical vCJD. All of these cases received a nonleukodepleted blood-derived product in the United Kingdom between 1994 and 1999. Thus, all transfusion-associated cases occurred before the adoption of universal leukodepletion in 1999, which supports the preferential tropism of vCJD for leukocytes. In descriptive cohort studies, no cases of clinical vCJD were observed over ∼13 years of follow-up. In modeling studies, the risk of collecting a contaminated donation was generally <23 per million donations, that of infection was generally <10 per million transfusions or doses, and that of clinical vCJD was generally <2 per million transfusions or doses. These low risk estimates and the two-decade long absence of new cases of transfusion-associated vCJD suggest vCJD poses minimal risks to the safety of the blood supply. Furthermore, despite concerns of a second wave driven by individuals harboring a non-MM genotype at codon 129 of PRNP, there has been only 1 autopsy-confirmed case of clinical vCJD in an MV individual in 2016. The current trend to reassess or (in some countries) fully withdraw the blood donation criteria related to vCJD therefore seems justified, safe, and may significantly expand the donor base.

PMID:37827587 | DOI:10.1016/j.tmrv.2023.150747

Eur Respir J. 2023 Oct 12:2201454. doi: 10.1183/13993003.01454-2022. Online ahead of print.

NO ABSTRACT

PMID:37827573 | DOI:10.1183/13993003.01454-2022

Heart. 2023 Oct 12:heartjnl-2023-323059. doi: 10.1136/heartjnl-2023-323059. Online ahead of print.

ABSTRACT

OBJECTIVE: The heterogeneous pathophysiology of the diverse heart failure with preserved ejection fraction (HFpEF) phenotypes needs to be examined. We aim to assess differences in the biomarkers among the phenotypes of HFpEF and investigate its multifactorial pathophysiology.

METHODS: This study is a retrospective analysis of the PURSUIT-HFpEF Study (N=1231), an ongoing, prospective, multicentre observational study of acute decompensated HFpEF. In this registry, there is a predefined subcohort in which we perform multibiomarker tests (N=212). We applied the previously established machine learning-based clustering model to the subcohort with biomarker measurements to classify them into four phenotypes: phenotype 1 (n=69), phenotype 2 (n=49), phenotype 3 (n=41) and phenotype 4 (n=53). Biomarker characteristics in each phenotype were evaluated.

RESULTS: Phenotype 1 presented the lowest value of N-terminal pro-brain natriuretic peptide (NT-proBNP), high-sensitive C reactive protein, tumour necrosis factor-α, growth differentiation factor (GDF)-15, troponin T and cystatin C, whereas phenotype 2, which is characterised by hypertension and cardiac hypertrophy, showed the highest value of these markers. Phenotype 3 showed the second highest value of GDF-15 and cystatin C. Phenotype 4 presented a low NT-proBNP value and a relatively high GDF-15.

CONCLUSIONS: Distinctive characteristics of biomarkers in HFpEF phenotypes would indicate differential underlying mechanisms to be elucidated. The contribution of inflammation to the pathogenesis varied considerably among different HFpEF phenotypes. Systemic inflammation substantially contributes to the pathophysiology of the classic HFpEF phenotype with cardiac hypertrophy.

TRIAL REGISTRATION NUMBER: UMIN-CTR ID: UMIN000021831.

PMID:37827559 | DOI:10.1136/heartjnl-2023-323059