Nevin Manimala

eNeuro. 2024 Aug 15:ENEURO.0291-24.2024. doi: 10.1523/ENEURO.0291-24.2024. Online ahead of print.

ABSTRACT

Volatile anesthetics are currently believed to cause unconsciousness by acting on one or more molecular targets including neural ion channels, receptors, mitochondria, synaptic proteins, and cytoskeletal proteins. Anesthetic gases including isoflurane bind to cytoskeletal microtubules (MTs) and dampen their quantum optical effects, potentially contributing to causing unconsciousness. This possibility is supported by the finding that taxane chemotherapy consisting of microtubule-stabilizing drugs reduces the effectiveness of anesthesia during surgery in human cancer patients. In order to experimentally assess the contribution of MTs as functionally relevant targets of volatile anesthetics, we measured latencies to loss of righting reflex (LORR) under 4% isoflurane in male rats injected subcutaneously with vehicle or 0.75 mg/kg of the brain-penetrant microtubule-stabilizing drug epothilone B (epoB). EpoB-treated rats took an average of 69 seconds longer to become unconscious as measured by latency to LORR. This was a statistically significant difference corresponding to a standardized mean difference (Cohen’s d) of 1.9, indicating a “large” normalized effect size. The effect could not be accounted for by tolerance from repeated exposure to isoflurane. Our results suggest that binding of the anesthetic gas isoflurane to microtubules causes unconsciousness and loss of purposeful behavior in rats (and presumably humans and other animals). This finding is predicted by models that posit consciousness as a property of a quantum physical state of neural microtubules.Significance statement Our study establishes that action on intracellular microtubules is the mechanism, or one of the mechanisms, by which the inhalational anesthetic gas isoflurane induces unconsciousness in rats. This finding has potential clinical implications for understanding how taxane chemotherapy interferes with anesthesia in humans, and more broadly for avoiding anesthesia failures during surgery. Our results are also theoretically important because they provide support for microtubule-based theories of anesthetic action and consciousness.

PMID:39147581 | DOI:10.1523/ENEURO.0291-24.2024

Zhongguo Ying Yong Sheng Li Xue Za Zhi. 2024 Aug 16;40:e20240021. doi: 10.62958/j.cjap.2024.021.

ABSTRACT

BACKGROUND AND OBJECTIVES: Nanosponges are one of the most innovative ways to use the newest developments in nanodrugs delivery. Nanosponges can catch drugs that dissolve in water or ones that don’t. This work uses statistical design to find the best nanosponges for drugs that don’t dissolve easily and make them.

MATERIAL AND METHODS: It was looked into how to statistically make the most of the effects of independent factors. The ethyl cellulose ratio and stirring rate were chosen based on how they affected the dependent variables, such as particle size and how well they were trapped. FTIR, SEM, zeta potential, entrapment efficiency, and particle size data were used to test the nanosponges that were made. Using carbopol, the best lot of nanosponges was added to the gel.

RESULTS: Using ethyl cellulose and polyvinyl alcohol as stabilizers in the emulsion liquid diffusion method, it was possible to make drug-loaded nanosponges. It was possible to make the nanosponges composition work better by using Central Composite Design. It has been seen that making drug-filled nanosponges improves stability.

CONCLUSION: The study showcased the enhanced capacity of a formulation with decreased particle size and high entrapment efficiency to disseminate effectively.

PMID:39147577 | DOI:10.62958/j.cjap.2024.021

Occup Environ Med. 2024 Aug 15:oemed-2023-109192. doi: 10.1136/oemed-2023-109192. Online ahead of print.

ABSTRACT

OBJECTIVE: This follow-up study of uranium processing workers at the Fernald Feed Materials Production Center examines the relationship between radiation exposure and cancer and non-cancer mortality among 6403 workers employed for at least 30 days between 1951 and 1985.

METHODS: We estimated cumulative, individual, annualised doses to 15 organs/tissues from external, internal and radon exposures. Vital status and cause of death were ascertained in 2017. The analysis employed standardised mortality ratios, Cox proportional hazards and Poisson regression models. Competing risk analysis was conducted for cardiovascular disease (CVD) mortality risk given several assumptions about risk independent of competing outcomes. Emphysema was examined to assess the potential for confounding by smoking.

RESULTS: Vital status was confirmed for 98.1% of workers, with 65.1% deceased. All-cause mortality was less than expected in salaried but not hourly workers when compared with the US population. A statistically significant dose response was observed between external (but not total or internal) lung dose and lung cancer mortality (HR at 100 mGy adjusted for internal dose=1.45; 95% CI=1.05 to 2.01). Significantly increased HRs at 100 mGy dose to heart were observed for CVD (1.27; 95% CI=1.07 to 1.50) and ischaemic heart disease (1.30; 95% CI=1.07 to 1.58). CVD risk remained elevated regardless of competing risk assumptions. Both external and internal radiation were associated with emphysema.

CONCLUSIONS: Lung cancer was associated with external dose, though positive dose responses for emphysema imply residual confounding by smoking. Novel use of competing risk analysis for CVD demonstrates leveraging retrospective data for future risk prediction.

PMID:39147576 | DOI:10.1136/oemed-2023-109192

Food Res Int. 2024 Sep;192:114838. doi: 10.1016/j.foodres.2024.114838. Epub 2024 Jul 27.

ABSTRACT

In this study, for the very first time, aqueous extracts obtained from flowers of spontaneously grown or cultivated Onopordum platylepis (Murb.) Murb. thistles were used as coagulating agents for the pilot-scale manufacture of Caciofiore, a traditional Italian raw ewe’s milk cheese. Cheese prototypes were compared to control cheeses curdled with a commercial thistle rennet obtained from flowers of Cynara cardunculus L. After 45 days of ripening under controlled conditions, both the experimental and control cheese prototypes were analyzed for: cheese yield, physico-chemical (pH, titratable acidity, a_w, proximate composition), morpho-textural (color and texture), and microbiological parameters (viable cell counts and species composition assessed by Illumina sequencing), as well as volatile profile by SPME-GC-MS. Slight variations in titratable acidity, color, and texture were observed among samples. Based on the results overall collected, neither the yield nor the proximate composition was apparently affected by the type of thistle coagulant. However, the experimental cheese prototypes curdled with extracts from flowers of both spontaneous or cultivated thistles showed 10 % higher values of water-soluble nitrogen compared to the control prototypes. On the other hand, these latter showed slightly higher loads of presumptive lactococci, thermophilic cocci, coliforms, and eumycetes, but lower counts of Escherichia coli. No statistically significant differences were revealed by the metataxonomic analysis of the bacterial and fungal biota. Though most volatile organic compounds (VOCs) were consistent among the prototypes, significant variability was observed in the abundance of some key aroma compounds, such as butanoic, hexanoic, and octanoic acids, ethanol, propan-2-ol, isobutyl acetate, 2-methyl butanoic acid, and 3-methyl butanal. However, further investigations are required to attribute these differences to either the type of coagulant or the metabolic activity of the microorganisms occurring in the analyzed cheese samples. The results overall collected support the potential exploitation of O. platylepis as a novel source of thistle coagulant to produce ewe’s milk cheeses.

PMID:39147526 | DOI:10.1016/j.foodres.2024.114838

Food Res Int. 2024 Sep;192:114816. doi: 10.1016/j.foodres.2024.114816. Epub 2024 Jul 24.

ABSTRACT

Lipids are the key matrix for the presence of odorants in meat products. The formation mechanism of odorants of air-fried (AF) pork at 230 °C was elucidated from the perspectives of lipids and heat transfer using physicochemical analyses and multidimensional statistics. Twenty-nine key aroma compounds were identified, with pyrazines predominantly contributing to the roasty aroma of air-fried roasted pork. Untargeted lipidomics revealed 1184 lipids in pork during roasting, with phosphatidylcholine (PC), phosphatidylethanolamine (PE), and triglyceride (TG) being the major lipids accounting for about 60 % of the total lipids. TG with C₁₈ acyl groups, such as TG 16:1_18:1_18:2 and TG 18:0_18:0_20:3, were particularly significant in forming the aroma of AF pork. The OPLS-DA model identified seven potential biomarkers that differentiate five roasting times, including PC 16:0_18:3 and 2-ethyl-3,5-dimethylpyrazine. Notably, a lower specific heat capacity and water activity accelerated heat transfer, promoting the formation and retention of odorants in AF pork.

PMID:39147509 | DOI:10.1016/j.foodres.2024.114816

Food Res Int. 2024 Sep;192:114771. doi: 10.1016/j.foodres.2024.114771. Epub 2024 Jul 15.

ABSTRACT

This comprehensive study explores the phytoconstituents of different parts of pumpkin (Cucurbita pepo) including flesh, peel, seeds, pumpkin juice, and pumpkin seed oil. Utilizing advanced analytical techniques including UPLC-QqQ-MS and GC-TSQ-MS combined with multivariate statistical analysis, 94 distinct chromatographic peaks from various chemical classes were annotated. Predominant classes included phenolic acids, flavonoids, cucurbitacins, amino acids, triterpenoids, fatty acids, sterols, carotenoids, and other compounds. For more comprehensive chemical profiling of the tested samples, fractionation of the different parts of the fruit was attempted through successive solvent extraction. The unsaponifiable part of the oils, analyzed by GC, showed that the phytosterols, namely ß-sitosterol, and stigmasterol are in the majority. All pumpkin extracts showed significant inhibition of carbohydrase enzymes and glucose uptake promotion by cells. Pumpkin flesh butanol fraction exhibited potent α-glucosidase inhibition, while pumpkin defatted seed methylene chloride fraction showed strong α-amylase inhibition. Additionally, pumpkin seed oil and defatted seed petroleum ether fraction demonstrated high glucose uptake activity. Bioactive metabolites including vaccenic acid, sinapic acid, kuguacin G, luteolin hexoside, delta-7-avenasterol, cucurbitosides and others were unveiled through OPLS multivariate models elucidating the anti-diabetic potential of pumpkin. These findings support the use of pumpkin as a functional food, offering insights into its mechanisms of action in diabetes management.

PMID:39147478 | DOI:10.1016/j.foodres.2024.114771

Lancet Psychiatry. 2024 Sep;11(9):720-730. doi: 10.1016/S2215-0366(24)00224-4.

ABSTRACT

BACKGROUND: Cognitive deficits might contribute to the elevated risk of life-course psychopathology observed in maltreated children. Leading theories about the links between childhood maltreatment and cognitive deficits focus on documented exposures (objective experience), but empirical research has largely relied on retrospective self-reports of these experiences (subjective experience), and the two measures identify largely non-overlapping groups. We aimed to test the associations of objective and subjective measures of maltreatment with cognitive abilities within the same individuals.

METHODS: We studied a cohort of individuals from the US Midwest with both objective, court-documented evidence of childhood maltreatment and subjective self-reports of individuals’ histories at age 29 years. Between the ages of 29 years and 41 years, participants were assessed with a comprehensive set of cognitive tests, including tests of general verbal intelligence (Quick Test and Wide Range Achievement Test-Revised [WRAT]), non-verbal intelligence (Matrix Reasoning Test [MRT]), executive function (Stroop Test and Trail Making Test Part B [TMT-B]), and processing speed (Trail Making Test Part A [TMT-A]). Participants were also assessed for psychopathology (Center for Epidemiologic Studies Depression Scale and Beck Anxiety Inventory). We tested the associations between objective or subjective measures of childhood maltreatment with cognitive functions using ordinary least squares regression. To test whether cognitive deficits could explain previously described associations between different measures of maltreatment and subsequent psychopathology, we re-ran the analyses accounting for group differences in the Quick Test. People with lived experience were not involved in the research or writing process.

FINDINGS: The cohort included 1196 individuals (582 [48·7%] female, 614 [51·3%] male; 752 [62·9%] White, 417 [34·9%] Black, 36 [3·8%] Hispanic) who were assessed between 1989 and 2005. Of the 1179 participants with available data, 173 had objective-only measures of childhood maltreatment, 492 had objective and subjective measures, 252 had subjective-only measures, and 262 had no measures of childhood maltreatment. Participants with objective measures of childhood maltreatment showed pervasive cognitive deficits compared with those without objective measures (Quick Test: β=-7·97 [95% CI -9·63 to -6·30]; WRAT: β=-7·41 [-9·09 to -5·74]; MRT: β=-3·86 [-5·86 to -1·87]; Stroop Test: β=-1·69 [-3·57 to 0·20]; TMT-B: β=3·66 [1·67 to 5·66]; TMT-A: β=2·92 [0·86 to 4·98]). The associations with cognitive deficits were specific to objective measures of neglect. In contrast, participants with subjective measures of childhood maltreatment did not differ from those without subjective measures (Quick Test: β=1·73 [95% CI -0·05 to 3·50]; WRAT: β=1·62 [-0·17 to 3·40]; MRT: β=0·19 [-1·87 to 2·24]; Stroop Test: β=-1·41 [-3·35 to 0·52]; TMT-B: β=-0·57 [-2·69 to 1·55]; TMT-A: β=-0·36 [-2·38 to 1·67]). Furthermore, cognitive deficits did not explain associations between different measures of maltreatment and subsequent psychopathology.

INTERPRETATION: Previous studies based on retrospective reports of childhood maltreatment have probably grossly underestimated the extent of cognitive deficits in individuals with documented experiences of childhood maltreatment, particularly neglect. Psychopathology associated with maltreatment is unlikely to emerge because of cognitive deficits, but might instead be driven by individual appraisals, autobiographical memories, and associated schemas.

FUNDING: National Institute of Justice, National Institute of Mental Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institute on Aging, Doris Duke Charitable Foundation, and National Institute for Health and Care Research.

PMID:39147460 | DOI:10.1016/S2215-0366(24)00224-4

Mutat Res Genet Toxicol Environ Mutagen. 2024 Aug-Sep;898:503806. doi: 10.1016/j.mrgentox.2024.503806. Epub 2024 Jul 25.

ABSTRACT

Stainless steel welders are exposed to heavy filler metals. We evaluated the concentration of these metals in whole blood and urine, and the relevant biochemical parameters in relation to the total chromosomal aberrations (CAs), chromatid-type (CTA-type, CTAs) and chromosome-type (CSA-type, CSAs), in 117 welders and control individuals. Statistically higher concentrations of the total Cr, Ni and Mn were observed in whole blood and urine of welders, and the concentrations were higher in welders who smoked. On the contrary, concentrations of urinary heavy metals Cr and Mn adjusted for creatinine were significantly higher in the control groups. A statistically higher frequency of total CAs was observed in the whole group of welders, and also in the non-smoking welders, as compared to controls. The frequency of total CAs significantly correlated with the concentration of Cr, Ni and Mn in whole blood (R=0.61, P˂0.0001, R=0.33, P˂0.0001 and R=0.66, P˂0.0001, respectively), with urinary concentrations of Ni and Mn (R=0.27, P=0.003 and R=0.28, P=0.003, respectively) and with urinary concentrations of Cr, Ni and Mn adjusted for creatinine (R=0.22, P=0.029, R=0.26, P=0.005 and R=0.20, P=0.030, respectively). Likewise, the frequency of CTA-types significantly correlated with the concentration of Cr and Mn in whole blood (R=0.31, P=0.0007 and R=0.34, P=0.0002). The frequency of CSA-types significantly correlated with concentrations of Cr, Ni and Mn in whole blood (R=0.43, P˂0.0001, R=0.38, P˂0.0001 and R=0.46, P˂0.0001, respectively). The statistically higher values of serum creatinine and total bilirubin were detected in all welders, as well as in smokers when compared to the corresponding controls. The exposure to heavy metals in welders increased the frequencies of CAs and altered the balance between urinary excretion of heavy metals and their possible accumulation.

PMID:39147451 | DOI:10.1016/j.mrgentox.2024.503806

Mutat Res Genet Toxicol Environ Mutagen. 2024 Aug-Sep;898:503791. doi: 10.1016/j.mrgentox.2024.503791. Epub 2024 Jun 29.

ABSTRACT

Bis(2-ethylhexyl) phthalate is the most abundant phthalate used as plasticizer to soften plastics and polymers included in medical devices. Human and environmental exposure may occur because DEHP is not chemically bound to plastics and can easily leach out of the materials. This phthalate is classified as reproductive toxicant and possible carcinogen to humans. The genotoxic potential has still to be clarified, but there are indications suggesting that DEHP may have aneugenic effects. To further investigate DEHP genotoxicity, the cytochalasin-block micronucleus assay was applied and combined with the CREST staining to characterise micronucleus content and gain insights on its genotoxic mode of action. Chromosomal damage was also analysed in metaphase and ana-telophase cells and the morphology of the mitotic spindle was investigated to evaluate the possible involvement of this cellular apparatus as a target of DEHP. Our findings indicated that DEHP induced a statistically significant increase in the frequency of micronuclei as well as in the frequency of CREST-positive micronuclei. Consistently, disturbance of chromosome segregation and induction of numerical chromosome changes were observed together with changes in spindle morphology, formation of multipolar spindles and alteration of the microtubule network. Experiments performed without metabolic activation demonstrated a direct action of DEHP on chromosome segregation not mediated by its metabolites. In conclusion, there is consistent evidence for an aneugenic activity of DEHP. A thresholded genotoxic activity was identified for DEHP, disclosing possible implications for risk assessment.

PMID:39147443 | DOI:10.1016/j.mrgentox.2024.503791

Eur Respir J. 2024 Aug 15:2400560. doi: 10.1183/13993003.00560-2024. Online ahead of print.

ABSTRACT

BACKGROUND: The real-world consequences of a Philips/Respironics recall for positive airway pressure (PAP) devices distributed between 2009 and 2021 are unknown.

METHODS: We conducted a retrospective population-based study using health administrative databases (Ontario, Canada) on all new adult PAP users identified through the provincial funding system, free of cancer at baseline, who initiated (claimed) PAP treatment between 2012 and 2018. Everyone was followed from the PAP claim date to the earliest of incident cancer diagnosis, death, or the end of the follow-up (March 2022). We used inverse probability of treatment weighting to balance baseline characteristics between individuals on recalled devices and those on devices from other manufacturers. Weighted hazard ratios of incident cancer were compared between groups.

RESULTS: Of 231 692 individuals identified, 58 204 (25.1%) claimed recalled devices, and 173 488 (74.9%) from other manufacturers. A meaningful baseline difference between groups (standardised difference≥0.10) was noted only by location-relevant covariates; other variables were mostly equally distributed (standardised differences≤0.06). Over a median follow-up of 6.3 years (IQR: 4.9-8.0), 11 166 (4.8%) developed cancer: unadjusted rates per 10 000 Person-Year (95 CI%) of 78.8 (76.0-81.7) in the recall group versus74.0 (72.4-75.6) in others (p=0.0034). Propensity score weighting achieved excellent balance in baseline characteristics between groups (standardised differences≤0.07). On a weighted sample, there was no statistical difference in the hazard of incident cancer between groups: cause-specific hazard ratio (recalled versus others) of 0.97, 95% CI: 0.89-1.06.

CONCLUSION: In our real-world population study, compared to other manufacturers and adjusting for confounders, recalled devices do not appear to be independently associated with developing cancer.

PMID:39147408 | DOI:10.1183/13993003.00560-2024