Direct analysis in real time mass spectrometry (DART-MS/MS) for rapid urine opioid detection in a clinical setting.

BACKGROUND AND AIMS: Current laboratory methods for opioid detection involve an initial screening with immunoassays which offers efficient but non-specific results and a subsequent liquid chromatography-tandem mass spectrometry (LC-MS/MS) confirmation which offers accurate results but requires extensive sample preparation and turnaround time. Direct Analysis in Real Time (DART) tandem mass spectrometry is evaluated as an alternative approach for accurate opioid detection with efficient sample preparation and turnaround time. MATERIALS AND METHODS: DART-MS/MS was optimized by testing the method with varying temperatures, operation modes, extraction methods, hydrolysis times, and vortex times. The method was evaluated for 12 opioids by testing the analytical measurement range, percent carryover, precision studies, stability, and method-to-method comparison with LC-MS/MS. RESULTS: DART-MS/MS shows high sensitivity and specificity for the detection of 6-acetylmorphine, codeine, hydromorphone, oxymorphone, hydrocodone, naloxone, buprenorphine, norfentanyl, and fentanyl in urine samples. However, its performance was suboptimal for norbuprenorphine, morphine and oxycodone. CONCLUSION: In this proof-of-concept study, DART-MS/MS is evaluated for its rapid quantitative definitive testing of opioids drugs in urine. Further research is needed to expand its application to other areas of drug testing.

The effect of genetic polymorphisms in STIM1 and ORAI1 on erythropoietin resistance in Egyptian patients with end-stage renal disease.

Chronic renal failure (CRF) is an incurable disease with unique challenges. Anemia is a frequent complication affecting dialysis patients. Erythropoietin (EPO) is used to treat anemia, but a poor response may result. We investigated genetic polymorphisms of store-operated calcium channel (SOC) signaling, an important erythropoietin-activated pathway that may induce EPO resistance in patients with renal failure. A total of 108 end stage renal disease (ESRD) patients were selected for this study. Patients were divided into two groups according to their erythropoietin resistance index (ERI): 39 patients with an ERI>10 and 69 patients with an ERI<10. We selected four tagging single nucleotide polymorphisms (tSNPs) in STIM1 and five in ORAI1 in our study. A polymerase chain reaction was performed, and genotyping against EPO resistance was correlated. Patients with the AG genotype of rs1561876 in STIM1, the TC genotype of rs6486795 in ORAI1, and the TG or GG genotypes of rs12320939 in ORAI1 were associated with an increased risk of erythropoietin resistance. Overall, we reported a moderately significant relationship between genetic polymorphisms of STIM1 and EPO resistance. We also reported a highly significant relationship between genetic polymorphisms of ORAI1 and EPO resistance. The (A-A-G) haplotype of STIM1 and the (G-T-G-T-A, G-C-G-C-G, or G-T-T-C-G) haplotypes of ORAI1 were significantly associated with EPO resistance.

Evaluating various properties of nanohydroxyapatite synthesized from eggshells and dual-doped with Si4+ and Zn2+: An in vitro study.

Background: This study aimed to evaluate morphological, chemical and biocompatible properties of nanohydroxyapatite (N-HA) synthesized from eggshells and dual-doped with Si4+ and Zn2+. Methods: In the current study, N-HA was synthesized from chicken eggshells using the wet chemical precipitation method and doped with Si4+ and Zn2+. The physical assessment was carried out using field emission scanning electron microscopy (FE-SEM), energy dispersive X-ray (EDX) analysis, and X-ray diffraction (XRD) analysis. Crystal size was calculated using the Scherrer equation. Cytotoxicity was studied in vitro using the MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide) cytotoxicity assay. The optical density (OD) of each well was obtained and recorded at 570 nm for 24 h (t1), 48 h (t2), 72 h (t3), and 5 days (t4) using a microplate reader. Results: The results of Si-Zn-doped HA showed a high specific surface area with an irregular nano-sized spherical particle structure. The atomic percentage provided the ratio of calcium to phosphate; for non-doped HA, the atomic Ca/P ratio was 1.6, but for Si-Zn-doped HA, where Zn+2 Ca and Si + replaced 4 substituted P, the atomic ratio (Ca + Zn)/(P + Si) was 1.76. The average crystal size of Si-Zn-doped HA was 46 nm, while for non-doped HA it was 61 nm. both samples were non-toxic and statistically significantly less viable than the control group After 5 days, the mean cell viability of Si-Zn-doped HA (79.17 ± 2.18) was higher than that of non-doped HA (76.26 ± 1.71) (P = 0.091). Conclusions: The MTT assay results showed that Si-Zn-doped HA is biocompatible. In addition, it showed characteristic physiochemical properties of a large surface area with interconnected porosity.

Coffee arabica research (1932-2023): Performance, thematic evolution and mapping, global landscape, and emerging trends.

Background: Research on Coffea arabica focuses on various aspects, including genetics, breeding, climate change resilience, pest and disease management, agronomy, sensory analysis, and sustainability. This study aims to analyze the hotspots, conceptual map and dynamicity, global landscape, and emerging trends in Coffea arabica research (CA-R). Methods: A comprehensive dataset comprising data-driven articles (N = 3967) from 1932 to 2023 was extracted from Scopus using predefined search terms. VOSviewer and Bibliometrix applications were utilized to analyze the data. Thematic evolution was examined by identifying shifts in research focus over time. The global landscape was assessed by examining comparative productivity and collaborative dynamics. Highly-cited CA-R was identified to highlight key findings in specific research areas. Results: The analysis revealed a steady growth of CA-R (annual growth rate = 6.53 %), with strong international collaboration (international co-authorships = 29.35 %) and significant contributions from various countries. Brazil leads the way with 1601 publications, accounting for 28.55 % of the total. Recognizable CA-R focused on important areas such as pollination, shade management, nanotechnology applications, roasting effects, disease management, and environmental impacts. Thematic analysis identified five distinct clusters representing different CA-R themes: "coffee", "coffea," "fermentation," "Coffea arabica," and "climate change." Emerging themes such as "in vitro culture," "sustainable agriculture," "climate change," and "coffee berry borer" were also identified. Conclusion: The current findings enhance our understanding of CA-R and lay the groundwork for future studies in the coffee industry.

Shear-aligned graphene oxide nanosheets incorporated PVDF composite membranes for selective dye rejection with high water flux.

Membrane technology is crucial in addressing water pollution challenges, particularly in removing dyes from wastewater. This study presents a novel approach to fabricating shear-aligned graphene oxide (GO) nanosheets incorporated polyvinylidene fluoride (PVDF) membranes for achieving exceptional dye rejection efficiency while maintaining high water flux. The membranes were prepared by dispersing graphene oxide within a PVDF matrix and subsequent subjection to shear alignment techniques. Shear and flow-induced alignment were explored to achieve precise and controlled alignment of graphene oxide flakes within the PVDF matrix. The resulting membranes exhibited enhanced structural integrity and optimized molecular packing of PVDF and GO, enabling them to selectively reject dyes while allowing efficient water permeation. The fabricated membranes were extensively characterized using appropriate testing methods. The results demonstrated that the shear-aligned GO sheets infused PVDF composite membranes exhibited outstanding dye rejection (96-99%) performance, surpassing conventional membranes while maintaining high water flux. This innovative membrane fabrication approach holds significant promise for advanced water treatment applications, offering a sustainable solution for selective dye removal and efficient water purification.

Somatostatin Peptides Prevent Increased Human Colonic Epithelial Permeability Induced by Hypoxia.

Mesenteric ischemia increases gut permeability and bacterial translocation. In human colon, chemical hypoxia induced by 2,4-dinitrophenol (DNP) activates basolateral intermediate conductance K+ (IK) channels (designated KCa3.1 or KCNN4) and increases paracellular shunt conductance/permeability (GS), but whether this leads to increased macromolecule permeability is unclear. Somatostatin (SOM) inhibits IK channels and prevents hypoxia-induced increases in GS. Thus, we examined whether octreotide (OCT), a synthetic SOM analogue, prevents hypoxia-induced increases GS in human colon and hypoxia-induced increases in total epithelial conductance (GT) and permeability to FITC-dextran 4000 (FITC) in rat colon. The effects of serosal SOM and OCT on increases in GS induced by 100 µM DNP were compared in isolated human colon. The effects of OCT on DNP-induced increases in GT and transepithelial FITC movement were evaluated in isolated rat distal colon. GS in DNP-treated human colon was 52% greater than in controls (P = 0.003). GS was similar when 2 µM SOM was added after or before DNP treatment, in both cases being less (P <0.05) than with DNP alone. 0.2 µM OCT was equally effective preventing hypoxia-induced increases in GS, whether added after or before DNP treatment. In rat distal colon, DNP significantly increased GT by 18% (P = 0.016) and mucosa-to-serosa FITC movement by 43% (P = 0.01), and 0.2 µM OCT pre-treatment completely prevented these changes. We conclude that OCT prevents hypoxia-induced increases in paracellular/macromolecule permeability and speculate it may limit ischemia-induced gut hyperpermeability during abdominal surgery, thereby reducing bacterial/bacterial toxin translocation and sepsis.

Opportunities for Microphysiological Systems in Toxicity Testing of New Drug Modalities.

New drug modalities offer life-saving benefits for patients through access to previously undruggable targets. Yet these modalities pose a challenge for the pharmaceutical industry, as side effects are complex, unpredictable, and often uniquely human. With animal studies having limited predictive value due to translatability challenges, the pharmaceutical industry seeks out new approach methodologies. Microphysiological systems (MPS) offer important features that enable complex toxicological processes to be modeled in vitro such as (a) an adjustable complexity of cellular components, including immune components; (b) a modifiable tissue architecture; (c) integration and monitoring of dynamic mechanisms; and (d) a multiorgan connection. Here we review MPS studies in the context of four clinical adverse events triggered by new drug modalities: peripheral neuropathy, thrombocytopenia, immune-mediated hepatotoxicity, and cytokine release syndrome. We conclude that while the use of MPS for testing new drug modality-induced toxicities is still in its infancy, we see strong potential going forward.

Valproic acid-induced teratogenicity is driven by senescence and prevented by Rapamycin in human spinal cord and animal models.

Valproic acid (VPA) is an effective and widely used anti-seizure medication but is teratogenic when used during pregnancy, affecting brain and spinal cord development for reasons that remain largely unclear. Here we designed a genetic recombinase-based SOX10 reporter system in human pluripotent stem cells that enables tracking and lineage tracing of Neural Crest cells (NCCs) in a human organoid model of the developing neural tube. We found that VPA induces extensive cellular senescence and promotes mesenchymal differentiation of human NCCs. We next show that the clinically approved drug Rapamycin inhibits senescence and restores aberrant NCC differentiation trajectory after VPA exposure in human organoids and in developing zebrafish, highlighting the therapeutic promise of this approach. Finally, we identify the pioneer factor AP1 as a key element of this process. Collectively our data reveal cellular senescence as a central driver of VPA-associated neurodevelopmental teratogenicity and identifies a new pharmacological strategy for prevention. These results exemplify the power of genetically modified human stem cell-derived organoid models for drug discovery.

Impact of COVID-19 on Sleep, Anxiety, and Depression Among Medical Call Center Staff: Insights from a January 2021 Study.

BACKGROUND The COVID-19 outbreak emerged as a dual threat, effecting both the physical and mental well-being of healthcare staff. This study aimed to evaluate sleep quality using the Pittsburgh Sleep Quality Index (PSQI), levels of anxiety and depression using the Hospital Anxiety Depression Scale (HADS), and the significant influencing factors during COVID-19 pandemic in 284 workers in a medical call center in January 2021. MATERIAL AND METHODS Out of 443 pre-hospital care providers, 284 consented to participate. Data collection was done using an introductory information form, the PSQI for sleep quality, and the HADS for anxiety (HADS-A) and depression (HADS-D). Surveys were hosted on an online survey website and distributed via WhatsApp, with completed forms retrieved from the website. RESULTS Male sex (P=0.0001) and extended working hours in current workplace (P=0.017) were associated with higher HADS-A scores. Health problems, increased need for mental support, and poor job satisfaction correlated with lower HADS-D scores (P=0.025, P=0.005, P=0.0001, respectively) and higher PSQI scores (P=0.008, P=0.009, P=0.008, respectively). A moderately significant positive correlation was found between overall sleep quality and HADS-A (P=0.001, r=0.538) and HADS-D scores (P=0.001, r=0.493). CONCLUSIONS The pandemic significantly impacted the mental health and sleep quality of frontline healthcare personnel, necessitating the identification and mitigation of adverse psychosocial factors. Implementing and evaluating psychoeducational programs and establishing multidisciplinary mental health teams can provide for essential support and counseling, promoting the well-being of healthcare staff and ensuring effective emergency care.

The effect of vitamin D3 and omega-3 combination, taken orally, on triglycerides, lining of intestine and the biodiversity of gut.

AIMS: The gut microbiota plays a key role in host health. An intake of omega-3 and vitamin D3 in a separate manner is vital for maintaining good health of gut microbiota and controlling some illness manifestations. The aim of this study is to investigate the potential change in biodiversity of the gut microbiome in healthy rats supplemented with vitamin D3, omega-3 alone and their combination and to reflect onto the triglyceride levels in serum and fecal samples. METHODS: Using the 16S rRNA gene Miseq Illumina NGS, and monitoring triglyceride levels in serum and fecal samples coupled with several clinical parameters, we examined the effect of orally taken combination of omega-3 and vitamin D3 alongside the separate intake of supplements on gut microbiota in 24 healthy white Wistar rats for six weeks. RESULTS: The study findings showed that combination treatment encouraged the growth of opportunistic Clostridia class during day 21 and 42 of treatment by 7.7 and 7.4 folds, respectively, exhibited incomplete absorption levels for both supplements when used concomitantly, demonstrated a damaging effect on the gut intestinal lining wall thickness (126um) when compared to control group (158um), increasing lumen diameter (400um) and showed higher triglyceride level in fecal samples. CONCLUSION: These findings indicate that omega-3 and vitamin D3 supplements as combination intake reveal unfavorable effects, thus, it is advised to conduct further in-depth studies to clarify the presence or absence of any chemical interaction between both supplements' molecules and to investigate based on human model to attain a superior perspective.

Robotic parastomal hernia repair: A single-center cohort study.

Parastomal hernia is a common occurrence following stoma construction, necessitating surgical intervention in symptomatic cases. This study presents a comprehensive analysis of Robotic-Assisted Parastomal Hernia Repair (r-PSHR), utilizing the Da Vinci Xi™ Surgical System. Retrospective analysis was conducted on patients undergoing r-PSHR at a high-volume center. Surgical variables, complications, and recurrence rates were assessed. The primary technique involved a modified Sugarbaker intraperitoneal onlay mesh. Eighty-six patients underwent r-PSHR, predominantly females (59.3%), with mean age 60.8 years. Mean BMI was 31.0. Most patients were classified as ASA 2 (31.4%) or ASA 3 (65.1), with 64.6% having no prior PSH repair. Index procedures primarily involved laparoscopic colonic resections (27.8%) and open abdominoperineal resections (27.8%). Parastomal hernias were mainly associated with end ileostomy (50%) and end colostomy (47.7%). A hybrid modification was required in 22.1% of cases, with only one conversion to open repair. Mean operative time was 257 min. Thirty-day morbidity was 40.7% and includes ileus (24.4%), deep surgical-site infections (7.0%), acute kidney injury (5.8%), and sepsis (5.8%). Grade IIIB complications occurred in 5.8% of cases. Thirty-day readmissions were observed in 19.8% of cases. There were five cases (5.8%) of recurrence within 15 months post-surgery. This study highlights the effectiveness of r-PSHR in managing parastomal hernia. R-PSHR shows promising outcomes with an acceptable post-operative occurrence profile and a favorable recurrence rate.

Prevalence, trends, and outcomes of cerebral infarction in patients with aneurysmal subarachnoid hemorrhage in the USA.

BACKGROUND AND PURPOSE: Cerebral infarction remains an important cause of death or disability in patients with aneurysmal subarachnoid hemorrhage (SAH). The prevalence, trends, and outcomes of cerebral infarction in patients with aneurysmal SAH at a national level are not known. METHODS: We identified the proportion of patients who develop cerebral infarction (ascertained using validated methodology) among patients with aneurysmal SAH and annual trends using the Nationwide Inpatient Sample (NIS) from 2016 to 2021. We analyzed the effect of cerebral infarction on in-hospital mortality, routine discharge without palliative care (based on discharge disposition), poor outcome defined by the NIS SAH outcome measure, and length and costs of hospitalization after adjusting for potential confounders. RESULTS: A total of 35,305 (53.6%) patients developed cerebral infarction among 65,840 patients with aneurysmal SAH over a 6-year period. There was a trend toward an increase in the proportion of patients who developed cerebral infarction from 51.5% in 2016 to 56.1% in 2021 (p trend p<.001). Routine discharge was significantly lower (30.5% vs. 37.8%, odds ratio [OR] 0.82, 95% confidence interval [CI] 0.75-0.89, p<.001), and poor outcome defined by NIS-SAH outcome measure was significantly higher among patients with cerebral infarction compared with those without cerebral infarction (67.4% vs. 59.3%, OR 1.29, 95% CI 1.18-1.40, p<.001). There was no difference in in-hospital mortality (13.0% vs. 13.6%, OR 0.94, 95% CI 0.85-1.05, p = .30). The length of stay (median 18 days [interquartile range [IQR] 13-25] vs. 14 days [IQR 9-20]), coefficient 3.04, 95% CI 2.44-3.52 and hospitalization cost (median $96,823 vs. $71,311, coefficient 22,320, 95% CI 20,053-24,587) were significantly higher among patients who developed cerebral infarction compared with those who did not develop cerebral infarction. CONCLUSIONS: Cerebral infarction was seen in 54% of the patients with a trend toward an increase in the affected proportion of patients with aneurysmal SAH. Patients with cerebral infarction had higher rates of adverse outcomes and required higher resources during hospitalization.

Analysis of Anticancer Taxanes in Turkish Hazelnut (Corylus avellana L.) Genotypes Using High-Performance Liquid Chromatography.

Objectives: This study aimed to investigate the anticancer taxane profiles of edible and non-edible parts of seven Turkish hazelnut (Corylus avellana L.) genotypes. Hazelnut is one of the healthy foods rich in nutrients and antioxidants. Its regular consumption is associated with a reduced risk of coronary heart disease and cancer. Hazelnut has been described as a plant source that produces taxanes which are widely used in many cancers. Türkiye is a homeland of hazelnut culture and has its own cultivars. Investigation of anticancer taxane profiles in different parts of Turkish hazelnut genotypes is important to show the potential and value of this plant from the perspective of the pharmaceutical and food industries. Materials and Methods: In this study, green leafy covers (GLCs) and hard shells (HSs) (non-edible parts), skinless kernels (SKs), brown-skins (BSs), and brown-skinned kernels (BSKs) (edible parts) of Çakildak, Sivri, Tombul, Palaz, and Kalinkara as standard and Ham and Sivri Yagli as local genotypes were used. The five parts of each genotype were ground to powder and eliminated to a size of less than 80 mesh. Each part was extracted using hexane and methanol for 10-deacetylbaccatin III (10-DAB III), baccatin III (BAC III), cephalomannine, and paclitaxel analyses in three replicates. Samples and standards were analyzed by acetonitrile: water gradient method on NOVA Spher 100 Phenyl-Hexyl C18 column inhigh-performance liquid chromatography reverse phase system with 228 nm ultraviolet detector and 1.0 mL/min flow rate. Microsoft Office Excel, 2016, and analysis of variance Jamovi Version 2.3 were used for statistical and data analysis, consecutively. Results: Hazelnut parts differed to a very high degree from each other in terms of the highest amount of 10- DAB III (Ham HSs, 9,15 µg/g), BAC III (Kalinkara BSs, 7.24 µg/g), cephalomannine (Sivri Yagli BSs, 6.37 µg/g), and paclitaxel (Ham BSKs, 4.36 µg/g) they contained. While HSs, BSKs, and BSs were rich in taxanes in all of the analyzed genotypes, SKs, and GLCs remain limited for anticancer taxanes. Conclusion: This is the first report that revealed the differences in taxane contents of Turkish hazelnuts including previously untested standard and local genotypes and their parts. Significant differences between genotype and hazelnut parts are expected to highlight the health benefits of consuming raw Turkish hazelnut with BSs and their possible use as a functional food. These results add more information to elucidate the bioactive potential of Turkish hazelnuts and their by-products and provide a promising resource for the food and pharmaceutical industry with an anticancer perspective.

Rapamycin's lifespan effect is modulated by mito-nuclear epistasis in Drosophila.

The macrolide drug rapamycin is a benchmark anti-ageing drug, which robustly extends lifespan of diverse organisms. For any health intervention, it is paramount to establish whether benefits are distributed equitably among individuals and populations, and ideally to match intervention to recipients' needs. However, how responses to rapamycin vary is surprisingly understudied. Here we investigate how among-population variation in both mitochondrial and nuclear genetics shapes rapamycin's effects on lifespan. We show that epistatic "mito-nuclear" interactions, between mitochondria and nuclei, modulate the response to rapamycin treatment. Differences manifest as differential demographic effects of rapamycin, with altered age-specific mortality rate. However, a fitness cost of rapamycin early in life does not show a correlated response, suggesting that mito-nuclear epistasis can decouple costs and benefits of treatment. These findings suggest that a deeper understanding of how variation in mitochondrial and nuclear genomes shapes physiology may facilitate tailoring of anti-ageing therapy to individual need.

Incretin hormone agonists: Current and emerging pharmacotherapy for obesity management.

Obesity continues to be a significant global health challenge, affecting over 800 million individuals worldwide. Traditional management strategies, including dietary, exercise, and behavioral interventions, often result in insufficient and unsustainable weight loss. Lifestyle modification remains the cornerstone of obesity management, providing the foundation for other strategies. While options such as bariatric surgery remain an effective intervention for severe obesity, it is associated with its own set of risks and is typically reserved for patients who have not achieved the desired results with pharmacotherapy and lifestyle interventions. Incretin hormone agonists represent a significant advancement in the pharmacotherapy of obesity, offering substantial weight reduction and cardiometabolic benefits. Agents like liraglutide, semaglutide, and tirzepatide supported by key clinical trials such as Satiety and Clinical Adipose Liraglutide Evidence (SCALE), Semaglutide Treatment Effect in People with Obesity (STEP) program trials, and Tirzepatide Once Weekly for the Treatment of Obesity (SURMOUNT-1) have demonstrated remarkable efficacy in promoting weight loss and improving metabolic outcomes. Additionally, novel therapies, including dual and triple incretin agonists, are under investigation and hold the potential for further advancements in obesity treatment. These novel therapies can be categorized by their mechanisms of action and route of administration into oral glucagon-like peptide-1 (GLP-1) receptor agonists, triple agonists (targeting GLP-1, glucose-dependent insulinotropic polypeptide [GIP], and glucagon receptors), and glucagon receptor-GLP-1 receptor co-agonists. Other innovative approaches include oral GIP-GLP-1 receptor co-agonists, and the combination of long-acting amylin receptor agonists with GLP-1 receptor agonists. The ongoing development of incretin-based therapies and the expanding availability of currently available agents are expected to enhance clinical outcomes further and reduce the burden of obesity-related health complications. This review aims to discuss the mechanisms and efficacy of current and emerging incretin hormone agonists for obesity management.

A prospective longitudinal study assessing the impact of rhinovirus and bacterial infections in acute exacerbations of chronic rhinosinusitis.

BACKGROUND: Acute exacerbations of chronic rhinosinusitis (AECRS) are thought to arise from common viral infections progressing to secondary bacterial infections. However, the pathophysiology of AECRS remains poorly understood due to a lack of prospective longitudinal studies. METHODS: We conducted a one-year prospective longitudinal study involving chronic rhinosinusitis (CRS) adults. At baseline, we assessed subjective symptom scores using a validated upper respiratory infection questionnaire (WURSS), sinonasal outcome testing scores (SNOT-22), and endoscopic scores (modified Lund-Kennedy score). Every 2 weeks, we contacted subjects to collect WURSS and SNOT-22 scores. If WURSS scores were ≥1 and SNOT-22 scores were ≥ 8.9 compared with baseline, subjects underwent an AECRS assessment. We identified rhinovirus (RV) incidence through viral nasal brushings at each visit and bacterial infection through bacterial swabs if mucus scores were ≥1. RESULTS: Thiry-five of 80 CRS subjects reported at least one AECRS episode during the year, predominantly occurring in the fall and winter seasons. RV infections were detected in 8 of 35 cases, bacterial infections in 17 of 35, and co-occurring infections in 7 of 35. All subjects with AECRS visits exhibited significantly higher endoscopic scores compared with baseline. Subjects with co-occurring RV and bacterial infections demonstrated higher disease severity compared with those with either RV or bacterial infection, or no infection. CONCLUSIONS: In a one-year prospective longitudinal study involving CRS adults, we identified significant risk factors for AECRS including seasonality and the presence of RV and bacterial infections. These data suggest a standard definition of AECRS and the need to target RV and bacterial infections if we are to help reduce disease severity.

The assessment of pharmacokinetics and neuroprotective effect of berberine hydrochloride-embedded albumin nanoparticles via various administration routes: comparative in-vivo studies in rats.

The current study aimed to evaluate the pharmacokinetics and neuroprotective effect of well-characterised berberine-bovine serum albumin (BBR-BSA) nanoparticles. BBR-BSA nanoparticles were generated by desolvation method. Entrapment efficiency, loading capacity, particle size, polydispersity index, surface morphology, thermal stability, and in-vitro release were estimated. In-vitro pharmacokinetic and tissue distribution were conducted. Their neuroprotection was evaluated against lipopolysaccharides-induced neurodegeneration. BBR-BSA nanoparticles showed satisfactory particle size (202.60 ± 1.20 nm) and entrapment efficiency (57.00 ± 1.56%). Results confirmed the formation of spheroid-thermal stable nanoparticles with a sustained drug release over 48 h. Sublingual and intranasal routes had higher pharmacokinetic plasma profiles than other routes, with Cmax values at 0.75 h (444 ± 77.79 and 259 ± 42.41 ng/mL, respectively). BBR and its metabolite distribution in the liver and kidney were higher than in plasma. Intranasal and sublingual treatment improves antioxidants, proinflammatory, amyloidogenic biomarkers, and brain architecture, protecting the brain. In conclusion, neuroinflammation and neurodegeneration may be prevented by intranasal and sublingual BBR-BSA nanoparticles.

Nano-cubosomes of the phyto-active principle in Withania somnifera: LC-MS-NMR, anti-microbial, and insights of the anti-neuropathic and anti-inflammatory mechanism.

Withania somnifera (W. somnifera) has a long history of safety in the amelioration of neuro-active ailments. The current study aims to explore Withania somnifera phyto-active principle anti-microbial, ant-neuropathic, and anti-inflammatory activities, and to modify these activities utilizing nano-cubosomes exploiting their mechanisms of action. Bio-guided fractionation technique was utilized, to identify the most phyto-active compound, using LC-MS-NMR online technique and biological models of diabetes, neuropathy, and inflammation. In-vitro antibacterial activity was also monitored. The HbA1c, in-vivo antioxidant (serum-catalase, TBARS, and GSH), serum insulin, and pro-inflammatory serum cytokines (TNF alpha, IL-six, and IL-ten) levels have been assessed to establish the anti-neuropathic and anti-inflammatory mechanisms. The nano-cubosomal formulations (CUB 1-3) were utilized to improve the W. somnifera most active compound efficacy. W. somnifera has shown ten major peaks; coagulin Q (10.2 %), dihydrowithanolide A (2.4 %), dihydrowithaferin D (1.8 %), physagulin D (7.6 %), withanoside V (2.3 %), withanolide A (WDA, 10.3 %), withafrin A (4.9 %), withaferin D (7.7 %), withanone 9 (9.9 %), withanolide D (4.8 %). The bio-guided fractionation technique utilizing LC-MS-NMR technique has proved that withanolide A (WDA) is the most phyto-active compound in W. somnifera. The latter has shown better results than WDA, which might be due to other effective compounds in Ws. However, CUB 3 (WDA nano-cubosomes dispersion) has shown more prominent anti-diabetic, anti-neuropathic, anti-inflammatory, and anti-bacterial potentials than Ws and WDA. Thus, CUB 3 modified WDA activity, and improved its efficacy. The normalization of HbA1c levels, increased insulin secretagogue potential, and the amelioration of the oxidative-stress may be the underlying Ws, WDA, and CUB 3 antidiabetic neuropathy mechanism. Moreover, the Ws, WDA, and CUB 1-3 anti-inflammatory mechanism might be due to the amelioration of the pro-inflammatory serum cytokines (decreasing TNF alpha and IL-six levels and increasing IL-ten). Thus, CUB 3 might be a powerful tool in augmenting Withania somnifera activity as an oral drug-delivery system and improving its efficacy against neuropathy and inflammation.