Nevin Manimala

Cell Mol Neurobiol. 2024 Feb 16;44(1):22. doi: 10.1007/s10571-024-01456-7.

ABSTRACT

Calcitonin gene-related peptide (CGRP) is synthesized and secreted by trigeminal ganglion neurons, and is a key neuropeptide involved in pain and immune regulation. This study investigates the expression of CGRP in the trigeminal ganglion (TG) and its regulatory role in the polarization of macrophages in rats with temporomandibular arthritis. A rat model of temporomandibular arthritis was established using CFA. Pain behavior was then observed. Temporomandibular joint (TMJ) and the TG were collected, and immunohistochemistry, immunofluorescence (IF) staining, and RT-qPCR were used to examine the expression of CGRP and macrophage-related factors. To investigate the impact of CGRP on macrophage polarization, both CGRP and its antagonist, CGRP 8-37, were separately administered directly within the TG. Statistical analysis revealed that within 24 h of inducing temporomandibular arthritis using CFA, there was a significant surge in CD86 positive macrophages within the ganglion. These macrophages peaked on the 7th day before beginning their decline. In this context, it’s noteworthy that administering CGRP to the trigeminal ganglion can prompt these macrophages to adopt the M2 phenotype. Intriguingly, this study demonstrates that injecting the CGRP receptor antagonist (CGRP 8-37) to the ganglion counteracts this shift towards the M2 phenotype. Supporting these in vivo observations, we found that in vitro, CGRP indeed fosters the M2-type polarization of macrophages. CGRP can facilitate the conversion of macrophages into the M2 phenotype. The phenotypic alterations of macrophages within the TG could be instrumental in initiating and further driving the progression of TMJ disorders.

PMID:38363424 | DOI:10.1007/s10571-024-01456-7

Environ Monit Assess. 2024 Feb 16;196(3):272. doi: 10.1007/s10661-024-12408-5.

ABSTRACT

Magnetic proxy approaches proved to be efficient for potentially toxic elements (PTEs) pollution assessment when targeting forests or areas with a homogenous background where anthropogenic magnetic signals could be easily distinguished. Here, we present a multidisciplinary approach for magnetic susceptibility ([Formula: see text]) and HM assessment in a complex area in the Nile Delta, where geogenic input, land use, and various industries with different fly ash and surface water emissions interfere. Statistical analysis discriminates between the effects of lithologic elements and the concentrations of toxic anthropogenic elements. The studied elements are classified into lithogenic and anthropogenic-related (HMs, Au industry, and fertilizers industry) groups with maximum contamination levels of eight anthropogenic-related and highly toxic PTEs (Cu, Zn, Mo, Cd, Sb, Pb, Hg, and As) in the Akrasha industrial area (pollution load index = 15.84). Considering the whole data set, the numerical correlation of [Formula: see text] with most PTE concentrations and the pollution load index (PLI) is weak, while it is moderate to strong with lithogenic elements. However, a comparison of lithogenic elements and PTE concentrations along with x-values in two separate clusters supports the correspondence of lithology with elevated x-values in silt and clay-rich soil samples as well as HM concentration in industrial sandy soils. Correspondence between magnetic maps and chemistry data with land use reflects the potential of magnetic proxy methods for qualitative PTE pollution pre-delineation of the polluted spots, provided that lithological conditions are carefully considered.

PMID:38363423 | DOI:10.1007/s10661-024-12408-5

EJNMMI Res. 2024 Feb 16;14(1):19. doi: 10.1186/s13550-024-01078-6.

ABSTRACT

BACKGROUND: Mutations in the epidermal growth factor receptor (EGFR) kinase domain are common in non-small cell lung cancer. Conventional tyrosine kinase inhibitors target the mutation site in the ATP binding pocket, thereby inhibiting the receptor’s function. However, subsequent treatment resistance mutations in the ATP binding site are common. The EGFR allosteric inhibitor, EAI045, is proposed to have an alternative mechanism of action, disrupting receptor signaling independent of the ATP-binding site. The antibody cetuximab is hypothesized to increase the number of accessible allosteric pockets for EAI045, thus increasing the potency of the inhibitor. This work aimed to gain further knowledge on pharmacokinetics, the EGFR mutation-targeting potential, and the influence of cetuximab on the uptake by radiolabeling EAI045 with carbon-11 and tritium.

RESULTS: 2-(5-fluoro-2-hydroxyphenyl)-2-((2-iodobenzyl)amino)-N-(thiazol-2-yl)acetamide and 2-(5-fluoro-2-hydroxyphenyl)-N-(5-iodothiazol-2-yl)-2-(1-oxoisoindolin-2-yl)acetamide were synthesized as precursors for the carbon-11 and tritium labeling of EAI045, respectively. [¹¹C]EAI045 was synthesized using [¹¹C]CO in a palladium-catalyzed ring closure in a 10 ± 1% radiochemical yield (decay corrected to end of [¹¹C]CO₂ production), > 97% radiochemical purity and 26 ± 1 GBq/µmol molar activity (determined at end of synthesis) in 51 min. [³H]EAI045 was synthesized by a tritium-halogen exchange in a 0.2% radiochemical yield, 98% radiochemical purity, and 763 kBq/nmol molar activity. The ability of [¹¹C]EAI045 to differentiate between L858R/T790M mutated EGFR expressing H1975 xenografts and wild-type EGFR expressing A549 xenografts was evaluated in female nu/nu mice. The uptake was statistically significantly higher in H1975 xenografts compared to A549 xenografts (0.45 ± 0.07%ID/g vs. 0.31 ± 0.10%ID/g, P = 0.0166). The synergy in inhibition between EAI045 and cetuximab was evaluated in vivo and in vitro. While there was some indication that cetuximab influenced the uptake of [³H]EAI045 in vitro, this could not be confirmed in vivo when tumor-bearing mice were administered cetuximab (0.5 mg), 24 h prior to injection of [¹¹C]EAI045.

CONCLUSIONS: EAI045 was successfully labeled with tritium and carbon-11, and the in vivo results indicated [¹¹C]EAI045 may be able to distinguish between mutated and non-mutated EGFR in non-small cell lung cancer mouse models. Cetuximab was hypothesized to increase EAI045 uptake; however, no significant effect was observed on the uptake of [¹¹C]EAI045 in vivo or [³H]EAI045 in vitro in H1975 xenografts and cells.

PMID:38363422 | DOI:10.1186/s13550-024-01078-6

Skeletal Radiol. 2024 Feb 16. doi: 10.1007/s00256-024-04609-3. Online ahead of print.

ABSTRACT

OBJECTIVE: To investigate the CT features of incidental rib enhancement (RE) and to summarize the CT characteristics for distinguishing the RE from sclerotic metastasis (SM) in patients with malignancies.

MATERIAL AND METHODS: This retrospective observational study enrolled 79 patients with RE (involved 133 ribs) during October 2014 and December 2021. Another 53 patients with SM (160 SM) in the same period were selected randomly for comparison. The location, enhancement patterns of RE were reviewed. The CT values of RE regions and SM were measured and statistically analyzed.

RESULTS: Most REs (70 patients, 88.6%) were in the 1st to 6th ribs. 50 patients had solitary RE and 29 with multiple REs in a regional distribution. All the REs were closely connected to the intercostal venous plexus (ICVP) ipsilateral to the injection site. No visible abnormalities on unenhanced scans were detected in all REs. One hundred and twenty REs (90.2%) had nodular/patchy enhancement. The CT value of RE regions in the venous phase was lower than that in the arterial phase (589.8 ± 344.2 HU versus 1188.5 ± 325.3 HU, p < 0.001). During the venous phase, most REs (125, 94.0%) shrank or disappeared. SM appeared similar on both contrast-enhanced and unenhanced scans in terms of shape and CT values.

CONCLUSION: The RE demonstrated characteristic CT features. The manifestations of nodular/patchy enhancement in the arterial phase, decreased density and shrinkage or disappearance during the venous phase, and no abnormality on unenhanced scans, as well as a close connection with the ICVP, may help differentiate RE from SM.

PMID:38363418 | DOI:10.1007/s00256-024-04609-3

Arch Gynecol Obstet. 2024 Feb 16. doi: 10.1007/s00404-024-07376-7. Online ahead of print.

ABSTRACT

BACKGROUND: Critical aortic stenosis (AS) in fetuses may progress to hypoplastic left heart syndrome (HLHS) with need for postnatal single ventricular (SV) palliation. Fetal aortic valvuloplasty (FAV) is performed to achieve postnatal biventricular (BV) circulation. However, the impact of FAV on fetal myocardial function is difficult to measure. Prediction of postnatal circulatory status and, therefore, counseling is challenging.

METHODS: Retrospective study of fetuses with critical AS who underwent FAV. Global Longitudinal Peak Systolic Strain (GLPSS) of the left ventricle (LV) and right ventricle (RV) were retrospectively analyzed before and after intervention. Fisher’s Exact Test and Mann-Whitney-U Test were used for univariant statistical analysis.

RESULTS: 23 fetuses with critical AS were included. After intervention fetuses demonstrated more negative LV-GLPSS mean values post- vs. pre-intervention (- 5.36% vs. – 1.57%; p < 0.05). RV-GLPSS was decreased in all fetuses, there was no peri-interventional change. 20 fetuses were born alive. Postnatally, 10 had BV and 10 SV circulation. Improved post-interventional LV-GLPSS strain values correlated with BV outcome (p < 0.05). Pre-interventional continuous LV-GLPSS values correlated with postnatal SV vs. BV outcome (p < 0.05).

CONCLUSION: In some fetuses, LV myocardial function assessed by speckle tracking echocardiography (STE) improves after FAV. Improved post-interventional LV-GLPSS correlates with biventricular postnatal outcome. Furthermore, pre-interventional LV- and RV-GLPSS correlate with postnatal outcome. Further studies are needed to asses, if pre-interventional STE parameters might predict which fetuses will benefit from FAV with postnatal BV circulation.

PMID:38363396 | DOI:10.1007/s00404-024-07376-7

Eur J Pediatr. 2024 Feb 16. doi: 10.1007/s00431-024-05464-z. Online ahead of print.

ABSTRACT

Recent research links early weight changes (EWC) with bronchopulmonary dysplasia (BPD) in preterm neonates, while lung ultrasound score (LUS) has shown promise in predicting BPD. We aimed to explore the correlation between LUS and EWC as markers of extravascular lung edema and to investigate the correlation between LUS and EWC in preterm infants with respiratory distress syndrome regarding future BPD development. This secondary analysis of a prospective study involved infants ≤ 28 weeks gestation. Enrolled infants underwent lung ultrasound assessment on postnatal days 3, 7 and 14, measuring LUS. EWC was computed on the same time points. Infants were classified as either having BPD or not. Descriptive statistics, correlation coefficient, and area under the receiver operating characteristic (AUROC) curve analysis were utilized. Of 132 infants, 70 (53%) had BPD. Univariate analysis revealed statistically significant differences in LUS and EWC at days 3, 7, and 14 between BPD and no-BPD groups (p < 0.001). A statistically significant but weak positive correlation existed between LUS and EWC (r0.37, r0.29, r0.24, and p < 0.01) at postnatal days 3, 7, and 14, respectively. AUROC analysis indicated LUS having superior predictive capacity for the need for invasive mechanical ventilation at day 14 as well as the later BPD development compared to EWC (p < 0.0001).

CONCLUSION: In a cohort of extreme preterm infants, our study revealed a positive yet weak correlation between LUS and EWC, suggesting that EWC was not the major contributing to the evolving chronic lung disease.

WHAT IS KNOWN: • Recent evidence links Early Weight-Changes with bronchopulmonary dysplasia in preterm neonates. • Lung ultrasound score has shown promise in early prediction of the subsequent development of bronchopulmonary dysplasia in preterm infants. No studies have examined the correlation between Early Weight-Changes and Lung ultrasound score in preterm infants during first 2 weeks after birth.

WHAT IS NEW: • Our study demonstrated a positive and statistically significant correlation between early LUS and EWC, indicating their potential role as early predictors for the subsequent development of BPD in extreme preterm infants. • The weak correlation between the two parameters may stem from the possible restricted influence of EWC, given that it may not be the primary factor contributing to the evolving chronic lung disease.

PMID:38363393 | DOI:10.1007/s00431-024-05464-z

Bull Math Biol. 2024 Feb 16;86(3):32. doi: 10.1007/s11538-024-01257-5.

ABSTRACT

In some patients with myeloproliferative neoplasms (MPN), two genetic mutations are often found: JAK2 V617F and one in the TET2 gene. Whether one mutation is present influences how the other subsequent mutation will affect the regulation of gene expression. In other words, when a patient carries both mutations, the order of when they first arose has been shown to influence disease progression and prognosis. We propose a nonlinear ordinary differential equation, the Moran process, and Markov chain models to explain the non-additive and non-commutative mutation effects on recent clinical observations of gene expression patterns, proportions of cells with different mutations, and ages at diagnosis of MPN. Combined, these observations are used to shape our modeling framework. Our key proposal is that bistability in gene expression provides a natural explanation for many observed order-of-mutation effects. We also propose potential experimental measurements that can be used to confirm or refute predictions of our models.

PMID:38363386 | DOI:10.1007/s11538-024-01257-5

Pediatr Pulmonol. 2024 Feb 16. doi: 10.1002/ppul.26915. Online ahead of print.

ABSTRACT

BACKGROUND: Can physiotherapy with a positive expiratory pressure (PEP) mask improve peripheral ventilation inhomogeneity, a typical feature of children with cystic fibrosis (cwCF)? To answer this question, we used the nitrogen multiple-breath washout (N₂ MBW) test to measure diffusion-convection-dependent inhomogeneity arising within the intracinar compartment (S_acin *VT).

METHODS: For this randomized, sham-controlled crossover trial, two N₂ MBW tests were performed near the hospital discharge date: one before and the other after PEP mask therapy (1 min of breathing through a flow-dependent PEP device attached to a face mask, followed by three huffs and one cough repeated 10 times) by either a standard (10-15 cmH₂ 0) or a sham (<5 cmH₂ 0) procedure on two consecutive mornings. Deception entailed misinforming the subjects about the nature of the study; also the N₂ MBW operators were blinded to treatment allocation. Study outcomes were assessed with mixed-effect models.

RESULTS: The study sample was 19 cwCF (ten girls), aged 11.4 (2.7) years. The adjusted S_acin *VT mean difference between the standard and the sham procedure was -0.015 (90% confidence interval [CI]: -∞ to 0.025) L^-1 . There was no statistically significant difference in S_cond *VT and lung clearance index between the two procedures: -0.005 (95% CI: -0.019 to 0.01) L^-1 and 0.49 (95% CI: -0.05 to 1.03) turnovers, respectively.

CONCLUSION: Our findings do not support evidence for an immediate effect of PEP mask physiotherapy on S_acin *VT with pressure range 10-15 cmH₂ 0. Measurement with the N₂ MBW and the crossover design were found to be time-consuming and unsuitable for a short-term study of airway clearance techniques.

PMID:38362833 | DOI:10.1002/ppul.26915

Clin Transl Sci. 2024 Feb;17(2):e13687. doi: 10.1111/cts.13687.

ABSTRACT

Co-administration of clesacostat (acetyl-CoA carboxylase inhibitor, PF-05221304) and ervogastat (diacylglycerol O-acyltransferase inhibitor, PF-06865571) in laboratory models improved non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) end points and mitigated clesacostat-induced elevations in circulating triglycerides. Clesacostat is cleared via organic anion-transporting polypeptide-mediated hepatic uptake and cytochrome P450 family 3A (CYP3A); in vitro clesacostat is identified as a potential CYP3A time-dependent inactivator. In vitro ervogastat is identified as a substrate and potential inducer of CYP3A. Prior to longer-term efficacy trials in participants with NAFLD, safety and pharmacokinetics (PK) were evaluated in a phase I, non-randomized, open-label, fixed-sequence trial in healthy participants. In Cohort 1, participants (n = 7) received clesacostat 15 mg twice daily (b.i.d.) alone (Days 1-7) and co-administered with ervogastat 300 mg b.i.d. (Days 8-14). Mean systemic clesacostat exposures, when co-administered with ervogastat, decreased by 12% and 19%, based on maximum plasma drug concentration and area under the plasma drug concentration-time curve during the dosing interval, respectively. In Cohort 2, participants (n = 9) received ervogastat 300 mg b.i.d. alone (Days 1-7) and co-administered with clesacostat 15 mg b.i.d. (Days 8-14). There were no meaningful differences in systemic ervogastat exposures when administered alone or with clesacostat. Clesacostat 15 mg b.i.d. and ervogastat 300 mg b.i.d. co-administration was overall safe and well tolerated in healthy participants. Cumulative safety and no clinically meaningful PK drug interactions observed in this study supported co-administration of these two novel agents in additional studies exploring efficacy and safety in the management of NAFLD.

PMID:38362827 | DOI:10.1111/cts.13687

Riv Psichiatr. 2024 Jan-Feb;59(1):28-34. doi: 10.1708/4205.41946.

ABSTRACT

AIMS: This study aims to present an overview of the clinical experience of the counseling service “Sportello Studenti”. The service offers free diagnostic and therapeutic psychological assistance to all Tor Vergata University of Rome students.

METHODS: Preliminary findings on the prevalence of anxious, depressive, and prodromal symptoms in a subset of participants recruited during the initial three-year period of the service’s operation (2019-2022) are presented. Beck’s Depression Inventory II (BDI-II), Symptom Checklist-90-Revised (SCL-90-R), Prodromal Questionnaire 16 (PQ-16) and Aberrant Salience Inventory (ASI) have been used to investigate principle psychopathological dimensions.

RESULTS: 261 students aged 18 to 35 completed the assessment (180 female – 69%). Mild widespread depressive symptoms (35.5%) and mild to severe suicide ideation (5.1%) were highlighted. Ninety students (37.2%) result at a higher risk condition for psychosis. A significant statistical correlation between negative psychopathological indicators, such as suicidal thoughts and age, suggests that younger students exhibit higher susceptibility and vulnerability to mental health issues.

DISCUSSION AND CONCLUSIONS: The increasing prevalence of distress among young individuals represents an urgent public health concern that necessitates immediate intervention. It is crucial for countries to adopt a comprehensive approach to promoting psychological and mental health. University counseling services serve as an effective initial intervention to address the negative impact of mental illness on academic performance, social interactions, and emotional well-being in young individuals. They also play a pivotal role in the early identification of individuals at risk of developing severe psychiatric disorders. Sportello Studenti has proven to be a valuable initiative addressing the mental health needs of University of Tor Vergata students, underscoring the significance of promoting psychological well-being.

PMID:38362786 | DOI:10.1708/4205.41946