Fluid Levels Research Articles

Integrating 16S rRNA Sequencing, Microflora Metabolism, and Network Pharmacology to Investigate the Mechanism of SBL in Alleviating HDM-Induced Allergic Rhinitis.

Allergic rhinitis (AR) is a series of allergic reactions to allergens in the nasal mucosa and is one of the most common allergic diseases that affect both children and adults. Shi-Bi-Lin (SBL) is the modified formula of Cang Er Zi San (CEZS), a traditional Chinese herbal formula used for treating AR. Our study aims to elucidate the anti-inflammatory effects and mechanisms of SBL in house dust mite-induced AR by regulating gut microflora metabolism. In vivo studies showed that nasal allergies and the infiltration of inflammatory cells in the nasal epithelium were significantly suppressed by SBL. Moreover, SBL restored the impaired nasal epithelial barrier function with an increased tight junction protein expression and reduced the endothelial nitric oxide synthase (eNOS). Interestingly, SBL significantly reconstituted the abundance and composition of gut microbiota in AR mice; it increased the relative abundance of potentially beneficial genera and decreased the relative abundance of harmful genera. SBL also restored immune-related metabolisms, which were significantly increased and correlated with suppressing inflammatory cytokines. Furthermore, a network analysis and molecular docking indicated IL-6 was a possible target drug candidate for the SBL treatment. SBL dramatically reduced the IL-6 level in the nasal lavage fluid (NALF), suppressing the IL-6 downstream Erk1/2 and AKT/PI3K signaling pathways. In conclusion, our study integrates 16S rRNA sequencing, microflora metabolism, and network pharmacology to explain the immune mechanism of SBL in alleviating HDM-induced allergic rhinitis.

The association between rs6859 in NECTIN2 gene and Alzheimer's disease is partly mediated by pTau.

Emerging evidence suggests a connection between vulnerability to infections and Alzheimer's disease (AD). The nectin cell adhesion molecule 2 (NECTIN2) gene coding for a membrane component of adherens junctions is involved in response to infections, and its single nucleotide polymorphism (SNP) rs6859 was significantly associated with AD risk in several human cohorts. It is unclear, however, how exactly rs6859 influences the development of AD pathology. The aggregation of hyperphosphorylated tau protein (pTau) is a key pathological feature of neurodegeneration in AD, which may be induced by infections, among other factors, and potentially influenced by genes involved in both AD and vulnerability to infections, such as NECTIN2. We conducted a causal mediation analysis (CMA) on a sample of 708 participants in the Alzheimer's disease Neuroimaging Initiative (ADNI). The relationship between rs6859 and Alzheimer's disease (AD), with AD (yes/no) as the outcome and pTau-181 levels in the cerebrospinal fluid (CSF) acting as a mediator in this association, was assessed. Adjusted estimates from the probit and linear regression models were used in the CMA model, where an additive model considered an increase in dosage of the rs6859 A allele (AD risk factor). The increase in dose of allele A of the SNP rs6859 resulted in about 0.144 increase per standard deviation (SD) of pTau-181 (95% CI: 0.041, 0.248, p < 0.01). When included together in the probit model, the change in A allele dose and each standard deviation change in pTau-181 predicted 6.84% and 9.79% higher probabilities for AD, respectively. In the CMA, the proportion of the average mediated effect was 17.05% and was higher for the risk allele homozygotes (AA), at 19.40% (95% CI: 6.20%, 43.00%, p < 0.01). The sensitivity analysis confirmed the evidence of a robust mediation effect. This study reported a new potential causal relationship between pTau-181 and AD. We found that the association between rs6859 in the NECTIN2 gene and AD is partly mediated by pTau-181 levels in CSF. The rest of this association may be mediated by other factors. Our finding sheds light on the complex interplay between genetic susceptibility, protein aggregation, and neurodegeneration in AD. Further research, using other biomarkers, is needed to uncover the remaining mechanisms of the association between the NECTIN2 gene and AD.

Assessment of Maintenance Activities and Strategies for Tractor and Operator Care in Gurage Zone, Wolkite Town, Ethiopia

Data was collected from 53 tractor operators and stakeholders from the Wolkite. Many types of tractors were used and the common brands were Sonalika, Indo-farm, John Deer, Massey, Fergusson, and New Holland. Of these tractors, about 30.18%, 20.75%, and 18.86% were used for plowing, harrowing, transporting, threshing, planting, and spraying activities by Sonalika, Indo-farm, and John deer respectively. Regarding training to operate the machine, about 71.69% replied yes and about 28.31% replied don&amp;apos;t have the training to maintain the machine, but they develop their skills through different experiences. But for their maintenance activities, they replied as 22.64% for daily, 92.45% for weekly, and 100% for monthly. In the case of checking the fluid level of the tractors about 9.43% within 3 hours, 20.75% within 6 hours, and 84.9% within 10 hours with oil level, about 3.77% within 3 hours, 11.32% within 6 hours and 98.11 within 10 hours for checking the water level and lastly about 15.09% within 3 hours, 71.69% within 6 hours and 94.33% within 10 hours to check the level of fuels. Moreover the washing of the tractors after the operation was 1.88% washed their tractors after operation; about 5.66% didn&amp;apos;t wash their tractors, and about 92.46 washed without schedule. For lubricating different rotating parts of the tractors, about 56% of the respondents lubricate their tractor parts and about 92.45% of the respondents clean the battery cables and terminals frequently. About 3.77% and 16.98% use shelter for their tractors and record-keeping experience during their work.

Helicobacter pylori upregulates PAD4 expression via stabilising HIF-1α to exacerbate rheumatoid arthritis

ObjectiveHelicobacter pylori infection has been reported to aggravate rheumatoid arthritis (RA), but the relevant mechanism remains unclear. This study aimed to investigate the underlying pathogenic mechanism of H. pylori infection...

The ARDS microenvironment enhances MSC-induced repair via VEGF in experimental acute lung inflammation

Clinical trials investigating the potential of mesenchymal stromal cells (MSCs) for the treatment of inflammatory diseases, such as acute respiratory distress syndrome (ARDS), have been disappointing; with less than 50% of patients responding to treatment. Licensed MSCs show enhanced therapeutic efficacy in response to cytokine-mediated activation signals. There are two distinct sub-phenotypes of ARDS: hypo- and hyper-inflammatory. We hypothesised that pre-licensing MSCs in a hyper-inflammatory ARDS environment would enhance their therapeutic efficacy in acute lung inflammation (ALI). Serum samples from ARDS patients were segregated into hypo- and hyper-inflammatory categories based on IL-6 levels. MSCs were licensed with pooled serum from hypo- or hyper-inflammatory ARDS patients or healthy serum controls. Our findings show that hyper-inflammatory ARDS pre-licensed MSC conditioned medium (MSC-CMHyper) led to a significant enrichment in tight junction expression and enhanced barrier integrity in lung epithelial cells in vitro and in vivo; in a VEGF-dependent manner. Importantly, while both MSC-CMHypo and MSC-CMHyper significantly reduced IL-6 and TNFα levels in the bronchoalveolar lavage fluid (BALF) of LPS-induced ALI mice, only MSC-CMHyper significantly reduced lung permeability and overall clinical outcomes including weight loss and clinical score. Thus the hypo- and hyper-inflammatory ARDS environment may differentially influence MSC cytoprotective and immunomodulatory functions.

Evaluating the complement C1q levels in serum and cerebrospinal fluid in multiple sclerosis patients: Could it serve as a valuable marker in clinical practice?

Immunohistochemical studies have identified complement component C1q in MS lesions. We aimed to compare serum (sC1q) and CSF (csfC1q) levels in a large cohort of MS patients (pwMS) (n = 222) with those of healthy controls (HC, n = 52), individuals with other immune (IND, n = 14), and non-immune neurological disorders (nIND, n = 15), and to analyze their correlation with other biomarkers.pwMS were divided into three series based on their origin. CSF samples were unavailable for HC. All three pwMS cohorts had lower sC1q levels compared to HC and IND. csfC1q was higher in one pwMS cohort, with a trend in another, and correlated with IgG, Free Kappa Light Chains, GFAP, and Chitinase-3 Like Protein-1 in CSF. Our findings suggest a significant role for C1q in MS pathophysiology, potentially serving as a biomarker for disease identification.

Efficacy and safety of first-line anti-tuberculosis drugs combined with Linezolid for the treatment of pediatric tuberculous meningitis in real-word practice

Objective: To evaluate the efficacy and safety of first-line anti-tuberculosis (TB) drugs combined with linezolid in treatment of children with tuberculous meningitis (TBM). Methods: A retrospective cohort study design was performed. Eight-nine Children diagnosed as TBM during January 1st 2016 and December 31st 2023 in Department of Infectious Disease, Children's Hospital of Chongqing Medical University were enrolled in the study. According to different treatment regimens, children were divided into a group of first-line anti-tuberculous drugs (isoniazid, rifampicin, pyrazinamide, ethambutol (HRZE)) and a group of HRZE and linezolid combination (HRZEL). The efficacy and safety of the 2 regimens were compared and the relationship between linezolid drug concentration and adverse reactions were analyzed. Comparisons between groups were performed using χ2 test and Mann-Whitney U test. Results: The 89 children with TBM included 53 males and 36 females with an onset age of 4.6 (1.4, 9.6) years. There were 27 cases in the HZREL group and 62 cases in the HRZE group. Before treatment, positive rate of interferon-gamma release assays (IGRA) in HRZEL group was lower than that in HRZE group (64% (16/25) vs.92% (55/60), χ2=9.82, P<0.05), but protein level of cerebrospinal fluid (CSF) was higher than that in HRZE group (1.2 (1.0, 2.0) vs.0.8 (0.4,1.4) g/L, Z=0.32, P<0.05). By the end of the intensive phase, there were no significant differences of rates of CSF improvement and etiology negativity between HRZEL group and HRZE group (both P>0.05).The 44 TBM children with high CSF protein (>1 g/L) included 25 males and 19 females with an onset age of 6.7 (3.0, 11.8) years. There were 21 cases in the HZREL group and 23 cases in the HRZE group accordingly. Before treatment, there were no significant differences of positive rate of IGRA test and CSF protein level between the 2 groups (62% (13/21) vs. 87% (20/23), 1.7 (1.1, 2.2) vs. 1.5 (1.2, 1.9) g/L, χ2=3.67, Z=0.23, both P>0.05). There were no significant differences in CSF indicators, etiology negativity or imaging remission between the two groups by the end of intensive phase (all P>0.05). Higher frequencies of granulocytopenia, gastrointestinal symptoms as well as withdrawal or change of drugs were found in HRZEL group when compared to those in HRZE group (44% (12/27) vs. 19% (12/62), 7% (2/27) vs. 0, 33% (9/27) vs. 3% (2/62), χ2=6.01, 4.70, 15.74, all P<0.05). Conclusions: The efficacy of HRZEL regimen is similar to conventional HRZE regimen in children with TBM, but with higher adverse effect. Prudentially evaluating the pros and cons of linezolid in the usage of drug-susceptible TB and carefully monitoring of linezolid associated adverse effects is suggested.

Next-Generation Contraceptive Intravaginal Ring: Comparison of Etonogestrel and Ethinyl Estradiol In Vitro and In Vivo Release from 3D-Printed Intravaginal Ring and NuvaRing.

Intravaginal rings (IVRs) represent a well-established, woman-controlled and sustained vaginal drug delivery system suitable for a wide range of applications. Here, we sought to investigate the differences in etonogestrel (ENG) and ethinyl estradiol (EE) release from a 3D-printed IVR utilizing continuous liquid interface production (CLIP™) (referred to as CLIPLOW for low drug loading and CLIPHIGH IVRs for high drug loading) and NuvaRing, a commercially available injection molded IVR. We conducted in vitro release studies in simulated vaginal fluid to compare the release of ENG and EE from CLIPLOW IVRs and NuvaRing. CLIPLOW IVRs had a similar hormone dose to NuvaRing and exhibited slightly slower ENG release and greater EE release in vitro compared to NuvaRing. When administered to female sheep, NuvaRing demonstrated greater ENG/EE levels in plasma, vaginal tissue and vaginal fluids compared to CLIPLOW IVR despite similar drug loadings. Leveraging observed hormones levels in sheep from NuvaRing as an effective contraceptive benchmark, we developed a long-acting CLIPHIGH IVR with increased ENG and EE doses that demonstrated systemic and local hormone levels greater than the NuvaRing for 90 days in sheep. No signs of toxicity were noted regarding general health, colposcopy, or histological analysis in sheep after CLIPHIGH IVR administration. Our results provided (1) a comparison of ENG and EE release between a 3D-printed IVR and NuvaRing in vitro and in vivo, (2) a preclinical pharmacokinetic benchmark for vaginally delivered ENG and EE and (3) the generation of a 90-day CLIP IVR that will be utilized in future work to support the development of a long-acting ENG/EE IVR combined with an antiretroviral for the prevention of HIV and unplanned pregnancy.

Aromadendrin Inhibits Lipopolysaccharide-Induced Inflammation in BEAS-2B Cells and Lungs of Mice.

Aromadendrin is a phenolic compound with various biological effects such as anti-inflammatory properties. However, its protective effects against acute lung injury (ALI) remain unclear. Therefore, this study aimed to explore the ameliorative effects of aromadendrin in an experimental model of lipopolysaccharide (LPS)-induced ALI. In vitro analysis revealed a notable increase in the levels of cytokine/chemokine formation, nuclear factor kappa B (NF-κB) activation, and myeloid differentiation primary response 88 (MyD88)/toll-like receptor (TLR4) expression in LPS-stimulated BEAS-2B lung epithelial cell lines that was ameliorated by aromadendrin pretreatment. In LPS-induced ALI mice, the remarkable upregulation of immune cells (ICs) and IL-1β/IL-6/TNF-α levels in the bronchoalveolar lavage fluid (BALF) and inducible nitric oxide synthase (iNOS)/cyclooxygenase-2 (COX-2)/CD68 expression in lung was decreased by the oral administration of aromadendrin. Histological analysis revealed the presence of cells in the lungs of acute lung injury (ALI) mice, which was alleviated by aromadendrin. In addition, aromadendrin ameliorated lung edema. This in vivo effect of aromadendrin was accompanied by its inhibitory effect on LPS-induced NF-κB activation, MyD88/TLR4 expression, and signal transducer and activator of transcription 3 (STAT3) activation. Furthermore, aromadendrin increased the expression of heme oxygenase-1 (HO-1)/ NAD(P)H quinone dehydrogenase 1 (NQO1) in the lungs of ALI mice. In summary, the in vitro and in vivo studies demonstrated that aromadendrin ameliorated endotoxin-induced pulmonary inflammation by suppressing cytokine formation and NF-κB activation, suggesting that aromadendrin could be a useful adjuvant in the treatment of ALI.

Elevated cerebrospinal fluid galectin-3 and associated cytokines after severe traumatic brain injury in patients.

This study aimed to investigate the galectin-3 and associated cytokines levels in the cerebrospinal fluid (CSF) of severe traumatic brain injury (sTBI) patients. Temporal CSF expression of galectin-3 and associated cytokines levels in sTBI patients within 1-week post-injury were studied using the multiplex bead array. STBI patient group was stratified using the Modified Rankin Score (mRS) into 3 groups: mRS 6 (died), mRS 5 (severely disabled) and mRS 1-4 (mild-to-moderately disabled) group. Analysis for bead array data using Kruskal-Wallis test with post hoc Dunn's multiple comparisons test, and temporal changes and correlation analysis using Spearman's correlation were carried out. At day 1 post-injury, CSF galectin-3 and interleukin-6 (IL-6), interleukin-10 (IL-10), cysteine-cysteine motif chemokine ligand-2 (CCL-2), and cysteine-cysteine motif chemokine ligand-20 (CCL-20), but not interleukin-1β (IL-1β) and tumor necrosis factor (TNF-α) levels were significantly elevated in mRS 5 group compared to non-TBI controls. Temporal correlation analysis at 1-7 days showed decreased IL-10 level in the mRS 6 group, decreased IL-10 and CCL-2 levels in mRS 5 group, and decreased IL-6, CCL-2, and CCL-20 levels in the mRS 1-4 group. Receiver operating characteristic curve analyses revealed a significant area under the curve for comparison between mRS 6 and mRS 5 groups for galectin-3 and IL-6. No significant differences in sex, age, Glasgow Coma Scale score, C-reactive protein levels and types of TBI-induced hemorrhages were observed between the groups. CSF galectin-3 and associated cytokines, especially IL-6, CCL-2 and CCL-20 levels were different within sub-groups of sTBI patients, suggesting their potential use in sTBI prognostics.

Prof Analysis of CXCL12 and S100A12 levels in peripheral blood and synovial fluid and their correlation with severity in patients with knee osteoarthritis

Abstract: To investigate the expression of CXCL12 and S100A12 in peripheral blood (PB) and synovial fluid (SF) of patients with knee osteoarthritis (OS) and to analyze the correlation between them and the severity of knee OS. 60 patients with kneeOS treated in our hospital from January 2020 to December 2022 were selected as the experimental group, and 60 healthy knee joints with similar age were selected as the control group. The fasting venous blood of 120 subjects was drawn in the early morning, and the SF was extracted during joint operation or sodium hyaluronate injection. Put the collected PB and SF in the refrigerator at-80℃. The levels of CXCL12 and S100A12 in PB and SF were detected by enzyme linked immunosorbent assay (Elisa). The correlation between the levels of CXCL12 and S100A12 in PB and SF and Kmurl L grade and WOMAC score. The levels of CXCL12 and S100A12 in PB and SF in the observation group were raised than those in the control group. There were significant differences in the levels of CXCL12 and S100A12 in PB and SF in the experimental group. The higher the Kmurl grade of knee OS, the higher the concentration of CXCL12 and S100A12 in PB and SF. The levels of CXCL12 and S100A12 in PB of knee OS were positively correlated with WOMAC score (r = 0.767, 0.521 respectively, P &lt; 0.05), see figure 1. The levels of CXCL12 and S100A12 in SF of knee OS were positively correlated with WOMAC score (r = 0.663, 0.357 respectively, P &lt; 0.05). The levels of CXCL12 and S100A12 in PB and SF are positively correlated with the severity of knee OS. The levels of CXCL12 and S100A12 in PB and SF can provide basis for the evaluation and prognosis of knee OS.

Technical Feasibility and Outcome of Cryoablation of Aneurysmal Bone Cysts in Pediatric Patients

PurposeTo evaluate the clinical and imaging outcome of aneurysmal bone cysts (ABCs) in children using percutaneous cryoablation as the sole treatment. Materials and MethodsThis retrospective study included 7 children with a mean age of 8.7 years (range, 3.0–11.9 years) who underwent at least 1 cryoablation for ABC. Cryoablation needles were placed and guided by computed tomography (CT). Imaging follow-up and clinical examination were performed by radiography 1 and 6 months after the procedure and magnetic resonance (MR) imaging was performed 3 and 12 months after the procedure. Additional cryoablation was performed in case of MR imaging–detected recurrence. Data were analyzed by anatomical location, measurement of lesion volume, numbers of intralesional cysts, grade of mineralization (5-point Likert scale), pain (0 [none] to 4 [severe]), and grade of fluid-fluid levels (FFLs; 4-point Likert scale). ResultsFourteen cryoablations were performed. Patients showed volume reduction, with 1 showing a complete response and 6 showing partial response. Following treatment, there was a substantial reduction in lesion volume compared with baseline, leading to a mean volume decrease of 81.9% (range, 66.8%–100%). The grade of mineralization (3.2 [SD ± 1.2] after therapy vs 1.1 [SD ± 0.3] at baseline), grade of FFL (1.6 [SD ± 0.5] after therapy vs 3.4 [SD ± 1.1] at baseline), and pain (0.29 [SD ± 0.4] after therapy vs 1.86 [SD ± 0.7] at baseline) significantly improved after therapy (all P < .05). One severe adverse event occurred. ConclusionsCryoablation is an effective treatment option for ABC in children. Further research is needed to compare it with other techniques.

Positive Effect of 25-Hydroxyvitamin D (25(OH)D) Levels in Follicular Fluid on Embryonic Developmental Potential in Diminished Ovarian Reserve (DOR) Patients Undergoing Microstimulation.

This study aimed to explore the effect of 25-hydroxyvitamin D (25(OH)D) levels in follicular fluid (FF) on the embryo outcome with diminished ovarian reserve (DOR) patients undergoing in vitro fertilization (IVF) by microstimulation protocol. A prospective cohort study of 79 patients with DOR who underwent IVF using the microstimulation protocol was conducted. Based on the level of 25(OH)D in follicular fluid (25(OH)D-FF), the patients were divided into a high-value group (25(OH)D-FF>11.1, n = 50) and a low-value group (25(OH)D-FF>11.1, n = 29). Correlation analysis was conducted between the level of 25(OH)D-FF and the rate of high-quality embryos on day 3 (D3). Logistic regression analysis of factors affecting the presence or absence of D3-available embryos in patients with DOR was conducted. The number of oocytes retrieved, mature oocytes (MII), normal fertilization rate, number of available embryos on D3, and high-quality embryo rate were lower in the low-value group than in the high-value group (p = 0.000, p = 0.000, p = 0.009, p = 0.000, p = 0.001). The clinical pregnancy rate of frozen embryo transfer (FET) between the two groups was no statistically significant difference (p > 0.05); correlation analysis between the 25(OH)D-FF level and the rate of high-quality embryos was performed using Spearman's rank-sum test, and there was a positive correlation (R = 0.271, P<0.01). Logistic analysis showed that 25(OH)D-FF level was a protective factor for embryonic outcome (odds ratio (OR) > 1, P<0.01). The 25(OH)D level in FF has a positive effect on embryonic outcomes in DOR patients with IVF using the microstimulation protocol. Vitamin D (VD) supplementation can be used to increase the number of available embryos and improve the quality of embryos for patients with DOR who are undergoing microstimulation of IVF.

PKCδ serves as a potential biomarker and therapeutic target for microglia-mediated neuroinflammation in Alzheimer's disease.

To investigate the role of a novel type of protein kinase C delta (PKCδ) in the neuroinflammation of Alzheimer's disease (AD). We analyzed PKCδ and inflammatory cytokines levels in cerebrospinal fluid (CSF) of AD and normal controls, as well as their correlations. The cellular expression pattern of PKCδ and the effects of PKCδ modulation on microglia-mediated neuroinflammation were evaluated by quantitative real-time polymerase chain reaction (qRT-PCR), western blot, RNA sequencing (RNA-seq), and immunofluorescence staining. PKCδ levels were increased dramatically in the CSF of AD patients and positively correlated with cytokines. PKCδ is expressed mainly in microglia in the brain. Amyloid beta (Aβ) stimulation increased PKCδ expression and secretion, which led to upregulation of the nuclear factor kappa B (NF-κB) pathway and overproduction of proinflammatory cytokines. Downregulation or inhibition of PKCδ attenuated Aβ-induced microglial responses and improved cognitive function in an AD mouse model. Our study identifies PKCδ as a potential biomarker and therapeutic target for microglia-mediated neuroinflammation in AD. Protein kinase C delta (PKCδ) levels increase in cerebrospinal fluid (CSF) of patients with Alzheimer's disease (AD), and positively correlate with elevated inflammatory cytokines in human subjects. PKCδ is expressed mainly in microglia in vivo, whereas amyloid beta (Aβ) stimulation increases PKCδ expression and secretion, causing upregulation of the nuclear factor kappa B (NF-κB) pathway and production of inflammatory cytokines. Downregulation or inhibition of PKCδ attenuates Aβ-enhanced NF-κB signaling and cytokine production in microglia and improves cognitive function in AD mice. PKCδ serves as a potential biomarker and therapeutic target for microglia-mediated neuroinflammation in AD.

Associations between neonicotinoid insecticide levels in follicular fluid and serum and reproductive outcomes among women undergoing assisted reproductive technology: An observational study

Neonicotinoid insecticides (NEOs) are a widely used type of insecticide found globally, leading to broad human exposure. However, there is limited research on how internal exposure levels of NEOs and their metabolites impact in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) outcomes. A study was conducted at the Sixth Affiliated Hospital of Sun Yat-sen University between 2017 and 2020 involving 436 women undergoing IVF/ICSI treatment. Data on demographics and clinical history were collected from medical records. The concentrations of 11 NEOs and 4 NEO metabolites in follicular fluid and serum were measured using a salting-out assisted liquid–liquid extraction method and liquid chromatography–tandem mass spectrometry. Our findings indicated that NEOs were prevalent in women with infertility. One NEO metabolite, N-dm-ACE, was detected in all samples with median concentrations of 0.221 ng/mL in follicular fluid and 0.228 ng/mL in serum. The study showed a decrease in the number of retrieved oocytes, mature oocytes, 2 PN zygotes, and high-quality embryos as the number of exposed NEOs in follicular fluid increased. Women in the highest tertile of N-dm-ACE exposure had fewer mature oocytes, 2 PN zygotes, and lower oocyte maturity rates compared to those in the lowest tertile. The findings suggest that exposure to NEOs may negatively impact reproductive outcomes in IVF/ICSI pregnancies, particularly affecting oocyte retrieval and embryo quality. This study highlights the potential adverse effects of environmental NEO exposure on IVF/ICSI outcomes, emphasizing the importance of considering such exposures in preconception care.

Assessing blood-brain barrier dysfunction and its association with Alzheimer’s pathology, cognitive impairment and neuroinflammation

BackgroundBlood-brain barrier (BBB) alterations may contribute to AD pathology through various mechanisms, including impaired amyloid-β (Aβ) clearance and neuroinflammation. Soluble platelet-derived growth factor receptor beta (sPDGFRβ) has emerged as a potential biomarker for BBB integrity. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) offers a direct assessment of BBB permeability. However, the relationship between BBB dysfunction, cognitive impairment, and AD pathology remains unclear, with inconsistent findings in the literature.MethodsWe conducted a cross-sectional study using data from the DELCODE and DESCRIBE cohorts to investigate BBB dysfunction in participants with normal cognition (NC), mild cognitive impairment (MCI), and AD dementia. BBB function was assessed using DCE-MRI and sPDGFRβ levels in cerebrospinal fluid and AD biomarkers Aβ and tau were measured. In a subset of patients, the CSF/plasma-ratio of albumin (QAlb) as a standard marker of BBB integrity and markers of neuroinflammation were analyzed.Results91 participants (NC: 44, MCI: 21, AD: 26) were included in the analysis. The average age was 74.4 years, 42% were female. Increased hippocampal BBB disruption was observed in the AD-group (Ktrans: 0.55 × 10− 3 min− 1 ± 0.74 × 10− 3 min− 1) but not the MCI-group (Ktrans: 0.177 × 10− 3 min− 1 ± 0.22 × 10− 3 min− 1), compared to the NC group (Ktrans: 0.19 × 10− 3 min− 1 ± 0.37 × 10− 3 min− 1, p < .01). sPDGFRβ was not significantly different between the cognitive groups. However, sPDGFRβ levels were significantly associated with age (r = .33, p < .01), independent of vascular risk factors. Further, sPDGFRβ showed significant positive associations with soluble Aβ levels (Aβ40: r = .57, p < .01; Aβ42: r = .39, p < .01) and YKL-40 (r = .53, p < .01), a marker of neuroinflammation. sPDGFRβ/DCE-MRI was not associated with overall AD biomarker positivity or APOE-status.ConclusionIn dementia, but not MCI, hippocampal BBB disruption was observed. sPDGFRβ increased with age and was associated with neuroinflammation independent of cognitive impairment. The association between Aβ and sPDGFRβ may indicate a bidirectional relationship reflecting pericytes’ clearance of soluble Aβ and/or vasculotoxic properties of Aβ.

Tribocorrosion behaviour of CoCrMo in simulated body fluid under anaerobic conditions

CoCrMo has been used as an implant material for a long time due to its excellent combination of strength, corrosion resistance and biocompatibility. The formation of a thin passive oxide film on the surface of the material plays a crucial role in its performance. This passive film can be ruptured during contact between two surfaces, but usually reforms in short timescales. However, the reformation of the film depends on the availability of oxygen in the surrounding fluid. The oxygen level in human tissue, cartilage and synovial fluid, around which the implant is situated, is much lower than that in laboratory testing under open-air conditions. Moreover, the local oxygen concentration and pH values in the body vary from patient to patient, depending on the patient's health condition and other factors, which leads to variation in the corrosion resistance of metallic implants. Therefore, an implant that performs well at one time may still experience an undesirable level of corrosion at another. Thus, evaluation of the tribocorrosion of implant materials carried out in open-air conditions does not reflect the actual process the implants undergo once in the body, particularly if there is irritation due to injury or surgery. In this study, we investigate the tribocorrosion behaviour of CoCrMo in bioactive solutions under fully aerobic to anaerobic conditions with varying loads/contact pressures. The anaerobic condition leads to a reduction in wear rate and a reduction in the extent of tribofilm formation but does not have an appreciable effect on friction. The mechanisms are discussed in detail.

Clinical and preclinical insights into high-dose ambroxol therapy for Gaucher disease type 2 and 3: A comprehensive systematic review

RationaleGaucher disease (GD), an autosomal recessive lysosomal storage disease, results from GBA1 variants causing glucocerebrosidase (GCase) deficiency. While enzyme replacement therapy (ERT) helps with systemic symptoms, neurological complications in GD2 and GD3 persist due to the blood-brain-barrier (BBB) limiting ERT efficacy. Ambroxol, a BBB-permeable chaperone, enhances GCase activity. Our review explores high-dose ambroxol's therapeutic potential, both preclinical and clinical, in GD2 and GD3. MethodsPubMed was searched for studies published before March 2023, including clinical, animal, and in vitro studies focusing on the effect of high-dose ambroxol in GD2 and GD3. A narrative synthesis was performed. ResultsNine in vitro, three animal, and eight clinical studies were included, demonstrating varied responses to ambroxol across diverse outcome measures. In vitro and animal studies demonstrated reduced endoplasmatic reticulum stress due to the relocation of GCase from the ER to the lysosomes. In vitro cell lines exhibited varying degrees of increased GCase activity. Clinical trials observed reduced lyso-GL1 levels in plasma (41–89%) and cerebrospinal fluid (CSF) (26–97%), alongside increased GCase activity in GD3 patients. Ambroxol exhibited varying effects on neurological outcomes and development. No severe adverse events were reported. ConclusionHigh-dose ambroxol shows promise in managing neurological manifestations in GD3, albeit with uncertainties resulting from genetic heterogeneity and variable response. Further clinical trials, are essential for elucidating dosage-response relationships and refining treatment outcomes and strategies for neuronopathic GD.

Soluble E-Cadherin Contributes to Airway Inflammation in Severe Asthma.

Impaired airway epithelial barrier and decreased expression of E-cadherin are key features of severe asthma. As a gatekeeper of the mucosa, E-cadherin can be cleaved from the cell surface and released into the apical lumen as a soluble form (sE-cadherin).This study was aimed to investigate the role of sE-cadherin in severe asthma.Induced sputum was obtained from healthy subjects and patients with asthma. Two murine models of severe asthma were established using either TDI (toluene diisocyanate) or OVA (ovalbumin)/CFA (complete Freund's adjuvants). The role of sE-cadherin in severe asthma was evaluated by intraperitoneal injection of DECMA-1, a neutralizing antibody against sE-cadherin. Mice or THP-1-derived macrophages were treated with recombinant sE-cadherin to explore the pro-inflammatory mechanism of sE-cadherin.Severe asthma patients had a significantly higher sputum sE-cadherin level than the health subjects with mild to moderate asthma, which were positively correlated with sputum HMGB1 level and glucocorticoid dosage required for daily control. Allergen exposure markedly increased sE-cadherin level in the bronchoalveolar lavage fluid in mice. Treatment of DECMA-1 significantly attenuated allergen-induced airway inflammation and hyperresponsivenes in both models of severe asthma. While exposure to recombinant sE-cadherin dramatically up-regulated VEGF expression in THP-1-derived macrophages, and increased neutophlil and eosinophil infiltration into the airway as well as the release of VEGF and IL-6 in mice, both of which can be suppressed by pharmacological inhibition of ERK signaling.Taken together, our data indicated that sE-cadherin contributed to the airway inflammation of severe asthma in an ERK-depedent pathway.

Development of an extended action fostemsavir lipid nanoparticle

An extended action fostemsavir (FTR) lipid nanoparticle (LNP) formulation prevents human immunodeficiency virus type one (HIV-1) infection. This FTR formulation establishes a drug depot in monocyte-derived macrophages that extend the drug’s plasma residence time. The LNP’s physicochemical properties improve FTR’s antiretroviral activities, which are linked to the drug’s ability to withstand fluid flow forces and levels of drug cellular internalization. Each is, in measure, dependent on PEGylated lipid composition and flow rate ratios affecting the size, polydispersity, shape, zeta potential, stability, biodistribution, and antiretroviral efficacy. The FTR LNP physicochemical properties enable the drug-particle’s extended actions.